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Vorinostat demonstrates antitumor activity in FL
Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.
In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).
However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.
Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.
Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.
The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).
The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.
At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).
The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.
None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.
That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.
Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).
At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.
There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).
Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).
However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.
Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed. 
Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.
In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).
However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.
Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.
Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.
The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).
The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.
At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).
The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.
None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.
That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.
Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).
At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.
There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).
Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).
However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.
Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.
Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.
In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).
However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.
Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.
Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.
The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).
The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.
At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).
The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.
None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.
That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.
Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).
At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.
There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).
Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).
However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.
Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.
Anticancer drugs might promote lymphoma
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Idelalisib more effective in CLL, iNHL than MCL
Credit: FDA
Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.
The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).
The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.
“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.
Solid survival rates in CLL
The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).
They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.
In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.
Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.
Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).
The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.
The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.
Longer response duration in iNHL
The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).
Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).
The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.
The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.
Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).
The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.
Short response, survival duration in MCL
The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.
Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.
The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.
Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).
The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.
Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.
“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”
Credit: FDA
Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.
The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).
The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.
“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.
Solid survival rates in CLL
The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).
They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.
In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.
Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.
Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).
The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.
The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.
Longer response duration in iNHL
The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).
Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).
The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.
The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.
Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).
The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.
Short response, survival duration in MCL
The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.
Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.
The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.
Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).
The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.
Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.
“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”
Credit: FDA
Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.
The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).
The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.
“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.
Solid survival rates in CLL
The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).
They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.
In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.
Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.
Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).
The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.
The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.
Longer response duration in iNHL
The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).
Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).
The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.
The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.
Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).
The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.
Short response, survival duration in MCL
The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.
Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.
The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.
Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).
The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.
Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.
“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”
RIT can improve transplant outcomes in NHL, CLL
GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.
Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).
But outcomes for patients with persistent disease are “underdescribed.”
So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.
Treatment details
The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).
The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m2 on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.
Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m2 of rituximab before an imaging dose of 111In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m2 of rituximab and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan.
Patient characteristics
In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.
“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”
There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.
Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).
RIT improves PFS, OS
The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).
When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.
“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.
Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).
The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).
The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).
“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”
In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.
Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.
Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.
GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.
Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).
But outcomes for patients with persistent disease are “underdescribed.”
So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.
Treatment details
The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).
The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m2 on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.
Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m2 of rituximab before an imaging dose of 111In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m2 of rituximab and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan.
Patient characteristics
In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.
“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”
There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.
Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).
RIT improves PFS, OS
The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).
When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.
“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.
Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).
The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).
The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).
“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”
In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.
Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.
Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.
GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.
Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).
But outcomes for patients with persistent disease are “underdescribed.”
So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.
Treatment details
The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).
The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m2 on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.
Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m2 of rituximab before an imaging dose of 111In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m2 of rituximab and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan.
Patient characteristics
In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.
“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”
There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.
Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).
RIT improves PFS, OS
The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).
When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.
“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.
Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).
The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).
The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).
“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”
In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.
Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.
Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.
Team identifies mutations that may drive FL
Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.
Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.
The team also identified mutations that seemed to drive FL toward a more aggressive form.
They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.
“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.
“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”
Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.
Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).
Patterns of evolution
The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.
Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.
These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.
Mutation prevalence, timing
The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).
More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).
Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.
The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).
They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).
And 17% of cases had mutations in genes important for B-cell development, including Ebf1.
Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.
On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.
“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.
“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”
Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.
Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.
The team also identified mutations that seemed to drive FL toward a more aggressive form.
They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.
“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.
“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”
Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.
Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).
Patterns of evolution
The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.
Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.
These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.
Mutation prevalence, timing
The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).
More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).
Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.
The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).
They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).
And 17% of cases had mutations in genes important for B-cell development, including Ebf1.
Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.
On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.
“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.
“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”
Genetic profiling has provided a clearer picture of follicular lymphoma (FL) development and progression, according to research published in Nature Genetics.
Investigators performed whole-genome and whole-exome sequencing of samples from FL patients and found a number of mutations that appeared to be responsible for disease onset.
The team also identified mutations that seemed to drive FL toward a more aggressive form.
They said these findings provide a number of new therapeutic targets that may stop FL from becoming aggressive or developing resistance to treatment.
“Resistance to treatment is a major problem for follicular lymphoma patients, as they often respond well to treatment and later relapse,” said study author Jude Fitzgibbon, PhD, of Barts Cancer Institute in London, England.
“[This] gives the cancer multiple opportunities to evolve into a more aggressive and more difficult-to-treat form of the disease. We’ve been able to chronicle the chain of genetic events that leads to aggressive forms of the disease. If we can develop treatments to prevent some of these changes from taking place, we should be able to stop the cancer in its tracks.”
Dr Fitzgibbon and his colleagues performed whole-genome or whole-exome sequencing of sequential FL and transformed FL pairs and matched germline samples from 10 FL cases with deep-targeted sequencing of 28 genes in an extension cohort.
Among the 10 cases, the researchers identified 1560 protein-altering variants affecting 908 genes, including missense changes (84.8%), short indels (8.9%), and nonsense mutations (6.3%).
Patterns of evolution
The investigators constructed phylogenetic trees for the 10 FL cases and discovered a common progenitor clone (CPC), as well as 2 patterns of evolution.
Eight of the cases exhibited evolution through a “rich” ancestral CPC, showing high clonal semblance between the FL and transformed-FL tumors. The other 2 cases showed evolution through a “sparse” CPC, with only 4 nonsynonymous mutations shared by the FL and transformed-FL samples.
These 2 patterns of evolution shared mutations in 3 genes—KMT2D, TNFRSF14, and CREBBP. According to the researchers, this suggests tumor dependency on these alterations during lymphomagenesis and progression.
Mutation prevalence, timing
The investigators then set out to determine the prevalence of the mutations they identified in the 10 cases. They performed deep-targeted resequencing of 28 candidate genes in an extension cohort of 100 independent FL biopsies and 32 paired FL-transformed FL cases (including the 10 index cases).
More than 70% of cases had concurrent mutations in at least 2 of the histone-modifying enzymes screened (CREBBP, EZH2, MEF2B, and KMT2D).
Twenty-eight percent of cases had mutations affecting at least one histone H1 gene. HIST1H1C and HIST1H1E were the most frequently mutated.
The researchers also saw frequent mutations in components of the JAK-STAT signaling pathway, including STAT6 (12%) and SOCS1 (8%).
They found mutually exclusive mutations in the NF-κB signaling pathway in a third of FLs, including CARD11 (11%) and TNFAIP3 (11%).
And 17% of cases had mutations in genes important for B-cell development, including Ebf1.
Finally, the investigators set out to differentiate early genetic events from late ones. They found that mutations in histone-modifying genes—KMT2D, CREBBP, and EZH2—as well as mutations in STAT6 and TNFRSF14 were predominantly clonal events.
On the other hand, mutations in EBF1 and regulators of NF-κB signaling—MYD88 and TNFAIP3—were gained at transformation.
“This study has uncovered some of the key molecular changes taking place [in FL] and offers new targets for treating the disease,” said Nell Barrie, of Cancer Research UK, the organization that funded this study.
“Research into the genetics that underpin cancer is helping us to better know the enemy and find new ways in which we might beat it.”
Immune microenvironment linked to prognosis of follicular lymphoma
Tumor-induced genetic changes in the immune cells of lymph nodes predict outcomes in patients with follicular lymphoma, according to a study published in the Journal of Clinical Oncology.
Investigators performed gene expression profiling of tumor-infiltrating T cells (TILs) from lymph node biopsies at diagnosis in 172 treatment-naive patients with follicular lymphoma and of T cells from reactive tonsils and peripheral blood of 12 healthy donors.
Compared with the T cells from healthy donors, the TILs had marked upregulation of several genes and downregulation of others, as well as impaired motility. Moreover, similar changes could be induced in healthy T cells by exposing them to lymphoma cells, said Dr. Shahryar Kiaii of the Institute of Cancer and Barts and the London School of Medicine and Dentistry and his associates.
The numbers and locations within the lymph nodes of the TILs showing altered gene expression predicted both overall survival and the time to transformation to B-cell lymphoma – sometimes dramatically. Certain combinations were associated with 70%-80% reductions in the risks of these outcomes.
"These results contribute to our understanding of the complex interactions of lymphoma cells, TILs, and macrophages in their microenvironment and help us generate hypotheses. But until we have a better understanding of these interactions, it does not yet seem feasible to incorporate [immunohistochemistry] analysis of TILs in [follicular lymphoma] for prognosis," the investigators wrote.
"However, because nonmalignant infiltrating immune cells play a crucial role in outcomes in [follicular lymphoma], understanding the nature and impact of the abnormalities induced in TILs in these patients is vital before any immunotherapeutic strategies can be implemented to alter the immune microenvironment in [follicular lymphoma]," they added.
In the study, the investigators constructed tissue microarrays and used mRNA expression profiles, real-time polymerase chain reaction assays, and immunohistochemistry to assess gene expression in highly purified CD4 and CD8 T cells.
Results showed that the TILs had an abnormal gene expression profile when compared with the healthy T cells, Dr. Kiaii and his associates said (J. Clin. Oncol. 2013;31:2654-61).
The genes showing the greatest upregulation were those for pro-melanin–concentrating hormone (PMCH); ETS translocation variant 1 (ETV1); and tumor necrosis factor receptor superfamily, member 9 (TNFRSF9).
One of the genes showing greatest downregulation was the gene that encodes the cytoskeletal protein actinin (ACTN1), and the TILs indeed showed reduced motility when compared with the healthy T cells (P less than .025).
When cultured alone, healthy T cells did not express PMCH and had normal motility, but when cultured with follicular lymphoma cells, the T cells expressed this protein highly and had reduced motility (P = .0002).
The number of TILs expressing PMCH, ETV1, and NAMPT (nicotinamide phosphoribosyltransferase) and their locations in lymph nodes – in the malignant follicle (intrafollicular area), in the area between follicles (interfollicular area), and overall – as determined immunohistochemically, were significantly associated with both overall survival and time to transformation, the investigators said.
In multivariate analyses, the combination of the interfollicular-to-intrafollicular ratio of PMCH-expressing cells plus a high level of expression of NAMPT and a low level of expression of ETV1 in the intrafollicular area was the strongest predictor of longer time to transformation (hazard ratio, 0.19; P = .003).
Similarly, the combination of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the interfollicular-to-intrafollicular ratio of ETV1 cells was the strongest predictor of better overall survival (hazard ratio, 0.32; P = .007).
The study was supported by grants from Cancer Research UK and the National Cancer Institute. One of the investigators disclosed receiving honoraria from Roche/Genentech and Celgene.
The findings of the study by Dr. Kiaii and his colleagues are particularly important as novel T-cell–mediated therapies are being developed for B-cell malignancies.
Lymphoma cells often induce immune tolerance by deleting or inactivating tumor-specific T cells. One attempt at overcoming this phenomenon has been chimeric antigen receptor (CAR) therapy; however, best results have been restricted to patients who had a low tumor burden and received cytotoxic chemotherapy beforehand.
 |
|
The chemotherapy administered was likely to have not only depleted malignant cells but also decreased immunosuppressive cells. ... Malignant B cells, and the immunosuppressive tumor microenvironment they promote, may therefore remain a barrier to effective adoptive immunotherapy in B-cell lymphoma, particularly in patients with chemotherapy-resistant, bulky disease.
The data presented confirm that malignant B cells promote a profoundly immunosuppressive microenvironment and thereby protect themselves from being targeted by the immune system.
Future therapies in follicular lymphoma, including immunotherapies such as CAR T cells, will need to not only deplete malignant B cells but also inhibit the immunosuppressive mechanisms by which malignant B cells suppress the antitumor immune response. A dual approach that both depletes malignant cells and promotes immune function may subsequently result in a better clinical outcome for patients with follicular lymphoma.
Dr. Stephen M. Ansell is professor of medicine at the Mayo Clinic in Rochester, Minn. He made his remarks in an accompanying editorial (J. Clin. Oncol. 2013;31:2641-2). Dr. Ansell disclosed having no relevant conflicts of interest.
The findings of the study by Dr. Kiaii and his colleagues are particularly important as novel T-cell–mediated therapies are being developed for B-cell malignancies.
Lymphoma cells often induce immune tolerance by deleting or inactivating tumor-specific T cells. One attempt at overcoming this phenomenon has been chimeric antigen receptor (CAR) therapy; however, best results have been restricted to patients who had a low tumor burden and received cytotoxic chemotherapy beforehand.
|
|
The chemotherapy administered was likely to have not only depleted malignant cells but also decreased immunosuppressive cells. ... Malignant B cells, and the immunosuppressive tumor microenvironment they promote, may therefore remain a barrier to effective adoptive immunotherapy in B-cell lymphoma, particularly in patients with chemotherapy-resistant, bulky disease.
The data presented confirm that malignant B cells promote a profoundly immunosuppressive microenvironment and thereby protect themselves from being targeted by the immune system.
Future therapies in follicular lymphoma, including immunotherapies such as CAR T cells, will need to not only deplete malignant B cells but also inhibit the immunosuppressive mechanisms by which malignant B cells suppress the antitumor immune response. A dual approach that both depletes malignant cells and promotes immune function may subsequently result in a better clinical outcome for patients with follicular lymphoma.
Dr. Stephen M. Ansell is professor of medicine at the Mayo Clinic in Rochester, Minn. He made his remarks in an accompanying editorial (J. Clin. Oncol. 2013;31:2641-2). Dr. Ansell disclosed having no relevant conflicts of interest.
The findings of the study by Dr. Kiaii and his colleagues are particularly important as novel T-cell–mediated therapies are being developed for B-cell malignancies.
Lymphoma cells often induce immune tolerance by deleting or inactivating tumor-specific T cells. One attempt at overcoming this phenomenon has been chimeric antigen receptor (CAR) therapy; however, best results have been restricted to patients who had a low tumor burden and received cytotoxic chemotherapy beforehand.
|
|
The chemotherapy administered was likely to have not only depleted malignant cells but also decreased immunosuppressive cells. ... Malignant B cells, and the immunosuppressive tumor microenvironment they promote, may therefore remain a barrier to effective adoptive immunotherapy in B-cell lymphoma, particularly in patients with chemotherapy-resistant, bulky disease.
The data presented confirm that malignant B cells promote a profoundly immunosuppressive microenvironment and thereby protect themselves from being targeted by the immune system.
Future therapies in follicular lymphoma, including immunotherapies such as CAR T cells, will need to not only deplete malignant B cells but also inhibit the immunosuppressive mechanisms by which malignant B cells suppress the antitumor immune response. A dual approach that both depletes malignant cells and promotes immune function may subsequently result in a better clinical outcome for patients with follicular lymphoma.
Dr. Stephen M. Ansell is professor of medicine at the Mayo Clinic in Rochester, Minn. He made his remarks in an accompanying editorial (J. Clin. Oncol. 2013;31:2641-2). Dr. Ansell disclosed having no relevant conflicts of interest.
Tumor-induced genetic changes in the immune cells of lymph nodes predict outcomes in patients with follicular lymphoma, according to a study published in the Journal of Clinical Oncology.
Investigators performed gene expression profiling of tumor-infiltrating T cells (TILs) from lymph node biopsies at diagnosis in 172 treatment-naive patients with follicular lymphoma and of T cells from reactive tonsils and peripheral blood of 12 healthy donors.
Compared with the T cells from healthy donors, the TILs had marked upregulation of several genes and downregulation of others, as well as impaired motility. Moreover, similar changes could be induced in healthy T cells by exposing them to lymphoma cells, said Dr. Shahryar Kiaii of the Institute of Cancer and Barts and the London School of Medicine and Dentistry and his associates.
The numbers and locations within the lymph nodes of the TILs showing altered gene expression predicted both overall survival and the time to transformation to B-cell lymphoma – sometimes dramatically. Certain combinations were associated with 70%-80% reductions in the risks of these outcomes.
"These results contribute to our understanding of the complex interactions of lymphoma cells, TILs, and macrophages in their microenvironment and help us generate hypotheses. But until we have a better understanding of these interactions, it does not yet seem feasible to incorporate [immunohistochemistry] analysis of TILs in [follicular lymphoma] for prognosis," the investigators wrote.
"However, because nonmalignant infiltrating immune cells play a crucial role in outcomes in [follicular lymphoma], understanding the nature and impact of the abnormalities induced in TILs in these patients is vital before any immunotherapeutic strategies can be implemented to alter the immune microenvironment in [follicular lymphoma]," they added.
In the study, the investigators constructed tissue microarrays and used mRNA expression profiles, real-time polymerase chain reaction assays, and immunohistochemistry to assess gene expression in highly purified CD4 and CD8 T cells.
Results showed that the TILs had an abnormal gene expression profile when compared with the healthy T cells, Dr. Kiaii and his associates said (J. Clin. Oncol. 2013;31:2654-61).
The genes showing the greatest upregulation were those for pro-melanin–concentrating hormone (PMCH); ETS translocation variant 1 (ETV1); and tumor necrosis factor receptor superfamily, member 9 (TNFRSF9).
One of the genes showing greatest downregulation was the gene that encodes the cytoskeletal protein actinin (ACTN1), and the TILs indeed showed reduced motility when compared with the healthy T cells (P less than .025).
When cultured alone, healthy T cells did not express PMCH and had normal motility, but when cultured with follicular lymphoma cells, the T cells expressed this protein highly and had reduced motility (P = .0002).
The number of TILs expressing PMCH, ETV1, and NAMPT (nicotinamide phosphoribosyltransferase) and their locations in lymph nodes – in the malignant follicle (intrafollicular area), in the area between follicles (interfollicular area), and overall – as determined immunohistochemically, were significantly associated with both overall survival and time to transformation, the investigators said.
In multivariate analyses, the combination of the interfollicular-to-intrafollicular ratio of PMCH-expressing cells plus a high level of expression of NAMPT and a low level of expression of ETV1 in the intrafollicular area was the strongest predictor of longer time to transformation (hazard ratio, 0.19; P = .003).
Similarly, the combination of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the interfollicular-to-intrafollicular ratio of ETV1 cells was the strongest predictor of better overall survival (hazard ratio, 0.32; P = .007).
The study was supported by grants from Cancer Research UK and the National Cancer Institute. One of the investigators disclosed receiving honoraria from Roche/Genentech and Celgene.
Tumor-induced genetic changes in the immune cells of lymph nodes predict outcomes in patients with follicular lymphoma, according to a study published in the Journal of Clinical Oncology.
Investigators performed gene expression profiling of tumor-infiltrating T cells (TILs) from lymph node biopsies at diagnosis in 172 treatment-naive patients with follicular lymphoma and of T cells from reactive tonsils and peripheral blood of 12 healthy donors.
Compared with the T cells from healthy donors, the TILs had marked upregulation of several genes and downregulation of others, as well as impaired motility. Moreover, similar changes could be induced in healthy T cells by exposing them to lymphoma cells, said Dr. Shahryar Kiaii of the Institute of Cancer and Barts and the London School of Medicine and Dentistry and his associates.
The numbers and locations within the lymph nodes of the TILs showing altered gene expression predicted both overall survival and the time to transformation to B-cell lymphoma – sometimes dramatically. Certain combinations were associated with 70%-80% reductions in the risks of these outcomes.
"These results contribute to our understanding of the complex interactions of lymphoma cells, TILs, and macrophages in their microenvironment and help us generate hypotheses. But until we have a better understanding of these interactions, it does not yet seem feasible to incorporate [immunohistochemistry] analysis of TILs in [follicular lymphoma] for prognosis," the investigators wrote.
"However, because nonmalignant infiltrating immune cells play a crucial role in outcomes in [follicular lymphoma], understanding the nature and impact of the abnormalities induced in TILs in these patients is vital before any immunotherapeutic strategies can be implemented to alter the immune microenvironment in [follicular lymphoma]," they added.
In the study, the investigators constructed tissue microarrays and used mRNA expression profiles, real-time polymerase chain reaction assays, and immunohistochemistry to assess gene expression in highly purified CD4 and CD8 T cells.
Results showed that the TILs had an abnormal gene expression profile when compared with the healthy T cells, Dr. Kiaii and his associates said (J. Clin. Oncol. 2013;31:2654-61).
The genes showing the greatest upregulation were those for pro-melanin–concentrating hormone (PMCH); ETS translocation variant 1 (ETV1); and tumor necrosis factor receptor superfamily, member 9 (TNFRSF9).
One of the genes showing greatest downregulation was the gene that encodes the cytoskeletal protein actinin (ACTN1), and the TILs indeed showed reduced motility when compared with the healthy T cells (P less than .025).
When cultured alone, healthy T cells did not express PMCH and had normal motility, but when cultured with follicular lymphoma cells, the T cells expressed this protein highly and had reduced motility (P = .0002).
The number of TILs expressing PMCH, ETV1, and NAMPT (nicotinamide phosphoribosyltransferase) and their locations in lymph nodes – in the malignant follicle (intrafollicular area), in the area between follicles (interfollicular area), and overall – as determined immunohistochemically, were significantly associated with both overall survival and time to transformation, the investigators said.
In multivariate analyses, the combination of the interfollicular-to-intrafollicular ratio of PMCH-expressing cells plus a high level of expression of NAMPT and a low level of expression of ETV1 in the intrafollicular area was the strongest predictor of longer time to transformation (hazard ratio, 0.19; P = .003).
Similarly, the combination of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the interfollicular-to-intrafollicular ratio of ETV1 cells was the strongest predictor of better overall survival (hazard ratio, 0.32; P = .007).
The study was supported by grants from Cancer Research UK and the National Cancer Institute. One of the investigators disclosed receiving honoraria from Roche/Genentech and Celgene.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Major finding: The combination of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the interfollicular-to-intrafollicular ratio of ETV1 cells was the strongest predictor of better overall survival (hazard ratio, 0.32; P = .007).
Data source: A gene expression profiling study in 172 patients with follicular lymphoma and 12 healthy individuals.
Disclosures: The study was supported by grants from Cancer Research UK and the National Cancer Institute. One of the investigators disclosed receiving honoraria from Roche/Genentech and Celgene.
Bendamustine-Rituximab Doubles Progression-Free Survival in Indolent Lymphomas
CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.
With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.
Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.
A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.
Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.
In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).
In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.
Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m2 on day 1 and 2) and rituximab (375 mg/m2 on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m2 on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).
In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).
Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.
Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).
Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.
Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.
Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.
CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.
With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.
Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.
A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.
Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.
In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).
In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.
Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m2 on day 1 and 2) and rituximab (375 mg/m2 on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m2 on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).
In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).
Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.
Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).
Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.
Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.
Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.
CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.
With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.
Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.
A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.
Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.
In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).
In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.
Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m2 on day 1 and 2) and rituximab (375 mg/m2 on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m2 on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).
In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).
Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.
Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).
Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.
Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.
Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
The Oncology Report Guide to Cancer Drugs and Devices in 2011
From an immunotherapy that improves melanoma survival to a device that zaps brain tumors, 2011 was a year of firsts from the FDA. This is our second annual guide to approvals of new cancer drugs, indications, and devices – along with a review of safety warnings and other actions affecting oncology practices.
(Click here for a PDF version of The Oncology Report Guide to Cancer Drugs and Devices in 2011.)
NEW DRUG APPROVALS
• Abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.). An androgen suppressant that decreases testosterone production for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. The fourth approval in late-stage prostate cancer since April 2010.
Basis: An international study of 1,195 men who had previously received chemotherapy containing docetaxel. Median overall survival was 14.8 months with abiraterone plus prednisone, vs. 10.9 months with prednisone alone.
• Asparaginase Erwinia chrysanthemi [Erwinaze for injection, EUSA Pharma (USA), Inc.] An asparagine-specific enzyme approved as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who developed hypersensitivity to E. coli-derived asparaginase. An orphan drug, it works by the same mechanism as the two previously approved treatments that block asparagine, a protein necessary for the proliferation of neoplastic cells.
Basis: In a single-arm, multicenter, open-label study of 58 patients, all 48 patients with available samples achieved threshold trough asparaginase levels shown to correlate with asparagine depletion and with serum levels that predict clinical efficacy.
• Brentuximab vedotin (Adcetris for injection, Seattle Genetics, Inc.). A CD30-directed antibody-drug conjugate for the treatment of Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen. The first new treatment approved for Hodgkin’s since 1977 and the first treatment approved for ALCL.
Basis: In a single-arm study of 102 patients treated with brentuximab, 73% had either a complete or partial response. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response.
Addendum: An accelerated approval, based on clinical data suggesting that treatment resulted in significant responses; conversion to full approval is contingent on confirmation of benefits in follow-up studies. (In January 2012, the FDA added a warning about the risk of a rare brain infection to the label.)
• Crizotinib (Xalkori Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene, as detected by the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), a companion diagnostic test approved at the same time.
Basis: In two single-arm studies of 255 patients with locally advanced or metastatic, ALK-positive NSCLC, most of whom had received prior chemotherapy, the overall response rate was 50% and 61%, with a median response duration of 42 and 48 weeks, respectively.
Addendum: An accelerated approval, so conversion to full approval is contingent on follow-up studies confirming clinical benefit.
• Deferiprone (Ferriprox Tablets, ApoPharma, Inc.). An oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.
Basis: A prospective pooled analysis of previously conducted studies of 236 patients (most had thalassemia syndromes) with transfusion-dependent iron overload, for which previous iron chelation therapy had failed or was considered inadequate because of poor tolerance. Within 1 year of starting treatment, 50% of the patients had at least a 20% decrease in serum ferritin levels.
Addendum: An accelerated approval. Safety and effectiveness not established for the treatment of transfusional iron overload due to other chronic anemias, including sickle cell disease. As a condition of approval, ApoPharma will conduct a study of safety and efficacy in patients with sickle cell disease and transfusional iron overload not adequately treated with available chelating agents.
• Hemacord (New York Blood Center). A hematopoietic progenitor cells–cord (HPC-C) preparation for allogenic hematopoietic stem cell transplantation. The first approval of a license for an umbilical cord blood therapy.
Basis: Safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements.
• Ipilimumab injection (Yervoy, Bristol-Myers Squibb). A human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody for the treatment of unresectable or metastatic melanoma. The first treatment proven to prolong survival in patients with metastatic melanoma.
Basis: An international study of 676 patients with previously treated unresectable stage III or IV melanoma whose disease had progressed, comparing ipilimumab plus an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab with or without the vaccine, vs. 6 months among those who received the vaccine alone.
Addendum: Approved with a Risk Evaluation and Mitigation Strategy (REMS) program addressing life-threatening toxicity and deaths associated with ipilimumab in the study. Acts slowly, and some patients may have tumor progression before therapy becomes effective.
• Ruxolitinib (Jakafi oral tablets, Incyte Corp.). A Janus-associated kinase (JAK) inhibitor for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. An orphan drug that is the first treatment approved for the rare blood disease – and the first approved JAK inhibitor.
Basis: Two randomized controlled trials of 528 patients with intermediate- or high-risk myelofibrosis. In one study, 42% of those on ruxolitinib had more than at least a 35% reduction in spleen volume vs. 1% of those on placebo at 24 weeks, and nearly half of those on treatment had achieved at least a 50% reduction in myelofibrosis symptoms, vs. 5% of those on placebo. In the second study, 29% of those on ruxolitinib had at least a 35% reduction in spleen size, vs. none of those on best available therapy after 48 weeks.
• Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP). A kinase inhibitor for the treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable, locally advanced, or metastatic disease. The first drug approved for this rare cancer.
Basis: An international study of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer. Median progression-free survival was at least 22.6 months with vandetanib vs. 16.4 months among with placebo, a highly significant difference.
Addendum: Approved with a REMS addressing the risk of QT interval prolongation and a note that use in patients with indolent, asymptomatic, or slowly progressing disease "should be carefully considered" because of treatment-associated risks, as well as a boxed warning and a restricted distribution program.
• Vemurafenib (Zelboraf tablets, Hoffmann-LaRoche, Inc.). A BRAF inhibitor for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic test approved at the same time. The second therapy found to prolong survival in patients with melanoma.
Basis: A study of 675 treatment-naive patients with unresectable or metastatic melanoma, positive for the BRAFV600E mutation. At the time of review, median survival was 7.9 months in a control group treated with dacarbazine, but had not been reached among those on vemurafenib. Median progression-free survival was 1.6 and 5.3 months, respectively.
Addendum: About half of melanoma patients have the BRAF mutation, and about half of them respond to vemurafenib. Approved with a medication guide to inform patients about the need for the diagnostic test and potential risks associated with treatment, including cutaneous squamous cell carcinoma. Roche and ipilimumab manufacturer Bristol-Meyers Squibb announced collaboration on a phase I/II study to determine whether combining the two agents is safe and effective in patients with BRAF mutations.
NEW DEVICES
• MelaFind (Mela Sciences). A noninvasive melanoma detection device for use "on clinically atypical cutaneous pigmented lesions with one or more clinical or historical characteristics of melanoma, excluding those with a clinical diagnosis of melanoma or likely melanoma."
Basis: The road to approval was controversial, with a split vote from an advisory panel, a citizens petition submitted by the manufacturer, and an agreement between the agency and manufacturer on how the device would be used and by whom.
• NovoTTF-100A System (NovoTTF, Novocure). A portable, battery-powered device that delivers electrical fields to the brain as a treatment for adults with glioblastoma multiforme that has recurred after chemotherapy.
Basis: In a randomized study of 237 patients whose GBM had recurred after surgery, radiation, and chemotherapy, median overall survival was 6.3 months with the approximately 6-pound device and 6.4 months with best available chemotherapy. The agency cited evidence suggesting better quality of life without chemotherapy side effects.
NEW INDICATIONS
• Cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly & Co. and Bristol-Myers Squibb). The epidermal growth factor receptor (EGFR) antagonist in combination with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional and/or metastatic squamous cell carcinoma of the head and neck.
Basis: A multicenter non-U.S. study of 442 patients not suitable for potentially curative treatment with surgery or radiation. Mean overall survival was 10.1 months with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil), vs. 7.4 months with chemotherapy alone.
Addendum: Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab used in this study, but the study results, pharmacokinetic data, and other clinical trial data "establish the efficacy" of cetuximab at the dose recommended, according to the prescribing information.
• Denosumab (Prolia, Amgen, Inc.). The RANK ligand (RANKL) inhibitor to increase bone mass in patients at high risk for fracture when receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.
Basis: Two international, randomized, double-blind placebo-controlled studies. In one study of 1,468 men with nonmetastatic prostate cancer receiving ADT, lumbar spine bone mineral density (BMD) at 2 years was significantly higher with denosumab vs. placebo (6.7% difference). At 3 years of treatment, the incidence of new vertebral fractures was 1.5% with denosumab vs. 3.9% with placebo, a risk reduction of 62%. In a study of 252 postmenopausal women with breast cancer on AI treatment, BMD at the lumbar spine was significantly higher with denosumab vs. placebo after 12 months of treatment (5.5% difference).
Addendum: Denosumab was initially approved in 2010. It is marketed as Prolia for treating postmenopausal women with osteoporosis at high risk of fracture, and as Xgeva for preventing skeletal-related events in patients with bone metastases from solid tumors; Xgeva is administered more frequently and at a higher dose for the latter indication.
• Everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corp.). The mammalian target of rapamycin (mTOR) inhibitor for progressive pancreatic neuroendocrine tumors (pNETs) that are unresectable, locally advanced, or metastatic. (Safety and effectiveness of everolimus for treating carcinoid tumors have not been established). The first new drug in about 30 years for the treatment of advanced pNET.
Basis: A randomized controlled study of 410 patients, all of whom also received best supportive care. Median progression-free survival was 11 months with everolimus, vs. 4.6 months with placebo. In an interim analysis, overall survival was not different between the two groups.
• Peg-interferon alfa-2b (Sylatron, Schering Corp.). An alpha interferon for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.
Basis: An open-label multicenter study of 1,256 patients. Median relapse-free survival was 34.8 months among those treated with peg-interferon alfa-2b, vs. 25.5 months with observation.
• Rituximab (Rituxan, Genentech, Inc.). The CD20-directed cytolytic antibody for maintenance therapy in people with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.
Basis: An international study of 1,217 previously untreated patients with advanced follicular lymphoma; it randomized 1,018 patients who had a complete or partial response with rituximab and chemotherapy. Maintenance treatment with rituximab reduced the risk of progression by 46% compared with observation only.
• Sunitinib (Sutent Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease; it was approved soon after everolimus for this indication.
Basis: A randomized controlled study of 171 patients with unresectable, locally advanced or well-differentiated pNET; treatment with somatostatin analogues was allowed. Median progression-free survival was 10.2 months with sunitinib, vs. 5.4 months with placebo.
WARNINGS AND LABEL CHANGES
• Bevacizumab (Avastin, Genentech, Inc.). Revised prescribing information includes the risk of ovarian failure in premenopausal women treated with bevacizumab and chemotherapy; postmarketing reports of osteonecrosis of the jaw in patients treated with bevacizumab but not bisphosphonates; and information from a clinical trial about the risk of venous thromboembolic events and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.
• Dasatinib (Sprycel, Bristol-Myers Squibb). Information on increased risk for pulmonary arterial hypertension added to prescribing information.
• Fentanyl. A classwide risk management program approved for all transmucosal immediate-release fentanyl formulations.
• IV methotrexate and proton pump inhibitors (PPIs). A warning added to the methotrexate label advises caution when high-dose methotrexate is administered to patients taking a PPI, because concomitant administration may result in elevated and prolonged serum levels of methotrexate and/or its metabolite hydroxymethotrexate, with possible toxic effects.
• Lenalidomide (Revlimid, Celgene). Advisory informed the public that the FDA is monitoring the risk of secondary cancers in patients treated for myelodysplastic syndromes or multiple myeloma.
• Ondansetron (Zofran, GlaxoSmithKline, and generic formulations). Following a review of information on the risk of QT prolongation, label now recommends ECG monitoring in patients who are treated with ondansetron and have an electrolyte abnormality, congestive heart failure, or bradyarrhythmias; and in patients taking other medications that prolong the QT interval – who are at an increased risk of developing torsades de pointes. Label recommends against use in patients with congenital long QT syndrome. Safety review ongoing.
• Opioids. Draft issued for opioid prescriber education program, as part of the Risk Evaluation and Mitigation Strategy (REMS) now in place for brand-name and generic long-acting and extended-release opioids.
• Pioglitazone. Bladder cancer warning risk added to the label for type 2 diabetes drug marketed as Actos (or in combination with metformin as Actoplus Met, and with glimepiride as Duetact).
• Romiplostim (Nplate for subcutaneous injection, Amgen, Inc.) and eltrombopag (Promacta tablets, GlaxoSmithKline LLC). Elements of the REMS for the two thrombopoietin receptor agonists were dropped, including the restricted distribution program that required health care professionals, hospitals, and patients to be enrolled in order to prescribe, dispense, or receive these drugs. Clinicians no longer need to file periodic safety forms for their patients on these treatments.
• Tumor necrosis factor (TNF) blockers. Manufacturers asked to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them.
OTHER ACTIONS
• Bevacizumab (Avastin, Genentech, Inc.). FDA Commissioner Margaret Hamburg withdrew bevacizumab’s indication in metastatic breast cancer. She cited a lack of data establishing benefit and serious risks associated with treatment. The decision followed a July hearing, where the Oncologic Drugs Advisory Committee unanimously voted that the indication be withdrawn despite emotional testimony from patients who said they benefited from the monoclonal antibody.
• Drug shortages. A new rule requires some manufacturers to give early warning of shortages. The agency also held a workshop on the crisis and is working to avert and/or resolve shortages.
• Office of Oncology Products. Many New Drug Applications, Biologic License Applications, and Investigational New Drug Applications for cancer drugs are being reassigned to new review divisions as part of a reorganization.
From an immunotherapy that improves melanoma survival to a device that zaps brain tumors, 2011 was a year of firsts from the FDA. This is our second annual guide to approvals of new cancer drugs, indications, and devices – along with a review of safety warnings and other actions affecting oncology practices.
(Click here for a PDF version of The Oncology Report Guide to Cancer Drugs and Devices in 2011.)
NEW DRUG APPROVALS
• Abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.). An androgen suppressant that decreases testosterone production for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. The fourth approval in late-stage prostate cancer since April 2010.
Basis: An international study of 1,195 men who had previously received chemotherapy containing docetaxel. Median overall survival was 14.8 months with abiraterone plus prednisone, vs. 10.9 months with prednisone alone.
• Asparaginase Erwinia chrysanthemi [Erwinaze for injection, EUSA Pharma (USA), Inc.] An asparagine-specific enzyme approved as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who developed hypersensitivity to E. coli-derived asparaginase. An orphan drug, it works by the same mechanism as the two previously approved treatments that block asparagine, a protein necessary for the proliferation of neoplastic cells.
Basis: In a single-arm, multicenter, open-label study of 58 patients, all 48 patients with available samples achieved threshold trough asparaginase levels shown to correlate with asparagine depletion and with serum levels that predict clinical efficacy.
• Brentuximab vedotin (Adcetris for injection, Seattle Genetics, Inc.). A CD30-directed antibody-drug conjugate for the treatment of Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen. The first new treatment approved for Hodgkin’s since 1977 and the first treatment approved for ALCL.
Basis: In a single-arm study of 102 patients treated with brentuximab, 73% had either a complete or partial response. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response.
Addendum: An accelerated approval, based on clinical data suggesting that treatment resulted in significant responses; conversion to full approval is contingent on confirmation of benefits in follow-up studies. (In January 2012, the FDA added a warning about the risk of a rare brain infection to the label.)
• Crizotinib (Xalkori Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene, as detected by the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), a companion diagnostic test approved at the same time.
Basis: In two single-arm studies of 255 patients with locally advanced or metastatic, ALK-positive NSCLC, most of whom had received prior chemotherapy, the overall response rate was 50% and 61%, with a median response duration of 42 and 48 weeks, respectively.
Addendum: An accelerated approval, so conversion to full approval is contingent on follow-up studies confirming clinical benefit.
• Deferiprone (Ferriprox Tablets, ApoPharma, Inc.). An oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.
Basis: A prospective pooled analysis of previously conducted studies of 236 patients (most had thalassemia syndromes) with transfusion-dependent iron overload, for which previous iron chelation therapy had failed or was considered inadequate because of poor tolerance. Within 1 year of starting treatment, 50% of the patients had at least a 20% decrease in serum ferritin levels.
Addendum: An accelerated approval. Safety and effectiveness not established for the treatment of transfusional iron overload due to other chronic anemias, including sickle cell disease. As a condition of approval, ApoPharma will conduct a study of safety and efficacy in patients with sickle cell disease and transfusional iron overload not adequately treated with available chelating agents.
• Hemacord (New York Blood Center). A hematopoietic progenitor cells–cord (HPC-C) preparation for allogenic hematopoietic stem cell transplantation. The first approval of a license for an umbilical cord blood therapy.
Basis: Safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements.
• Ipilimumab injection (Yervoy, Bristol-Myers Squibb). A human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody for the treatment of unresectable or metastatic melanoma. The first treatment proven to prolong survival in patients with metastatic melanoma.
Basis: An international study of 676 patients with previously treated unresectable stage III or IV melanoma whose disease had progressed, comparing ipilimumab plus an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab with or without the vaccine, vs. 6 months among those who received the vaccine alone.
Addendum: Approved with a Risk Evaluation and Mitigation Strategy (REMS) program addressing life-threatening toxicity and deaths associated with ipilimumab in the study. Acts slowly, and some patients may have tumor progression before therapy becomes effective.
• Ruxolitinib (Jakafi oral tablets, Incyte Corp.). A Janus-associated kinase (JAK) inhibitor for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. An orphan drug that is the first treatment approved for the rare blood disease – and the first approved JAK inhibitor.
Basis: Two randomized controlled trials of 528 patients with intermediate- or high-risk myelofibrosis. In one study, 42% of those on ruxolitinib had more than at least a 35% reduction in spleen volume vs. 1% of those on placebo at 24 weeks, and nearly half of those on treatment had achieved at least a 50% reduction in myelofibrosis symptoms, vs. 5% of those on placebo. In the second study, 29% of those on ruxolitinib had at least a 35% reduction in spleen size, vs. none of those on best available therapy after 48 weeks.
• Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP). A kinase inhibitor for the treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable, locally advanced, or metastatic disease. The first drug approved for this rare cancer.
Basis: An international study of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer. Median progression-free survival was at least 22.6 months with vandetanib vs. 16.4 months among with placebo, a highly significant difference.
Addendum: Approved with a REMS addressing the risk of QT interval prolongation and a note that use in patients with indolent, asymptomatic, or slowly progressing disease "should be carefully considered" because of treatment-associated risks, as well as a boxed warning and a restricted distribution program.
• Vemurafenib (Zelboraf tablets, Hoffmann-LaRoche, Inc.). A BRAF inhibitor for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic test approved at the same time. The second therapy found to prolong survival in patients with melanoma.
Basis: A study of 675 treatment-naive patients with unresectable or metastatic melanoma, positive for the BRAFV600E mutation. At the time of review, median survival was 7.9 months in a control group treated with dacarbazine, but had not been reached among those on vemurafenib. Median progression-free survival was 1.6 and 5.3 months, respectively.
Addendum: About half of melanoma patients have the BRAF mutation, and about half of them respond to vemurafenib. Approved with a medication guide to inform patients about the need for the diagnostic test and potential risks associated with treatment, including cutaneous squamous cell carcinoma. Roche and ipilimumab manufacturer Bristol-Meyers Squibb announced collaboration on a phase I/II study to determine whether combining the two agents is safe and effective in patients with BRAF mutations.
NEW DEVICES
• MelaFind (Mela Sciences). A noninvasive melanoma detection device for use "on clinically atypical cutaneous pigmented lesions with one or more clinical or historical characteristics of melanoma, excluding those with a clinical diagnosis of melanoma or likely melanoma."
Basis: The road to approval was controversial, with a split vote from an advisory panel, a citizens petition submitted by the manufacturer, and an agreement between the agency and manufacturer on how the device would be used and by whom.
• NovoTTF-100A System (NovoTTF, Novocure). A portable, battery-powered device that delivers electrical fields to the brain as a treatment for adults with glioblastoma multiforme that has recurred after chemotherapy.
Basis: In a randomized study of 237 patients whose GBM had recurred after surgery, radiation, and chemotherapy, median overall survival was 6.3 months with the approximately 6-pound device and 6.4 months with best available chemotherapy. The agency cited evidence suggesting better quality of life without chemotherapy side effects.
NEW INDICATIONS
• Cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly & Co. and Bristol-Myers Squibb). The epidermal growth factor receptor (EGFR) antagonist in combination with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional and/or metastatic squamous cell carcinoma of the head and neck.
Basis: A multicenter non-U.S. study of 442 patients not suitable for potentially curative treatment with surgery or radiation. Mean overall survival was 10.1 months with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil), vs. 7.4 months with chemotherapy alone.
Addendum: Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab used in this study, but the study results, pharmacokinetic data, and other clinical trial data "establish the efficacy" of cetuximab at the dose recommended, according to the prescribing information.
• Denosumab (Prolia, Amgen, Inc.). The RANK ligand (RANKL) inhibitor to increase bone mass in patients at high risk for fracture when receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.
Basis: Two international, randomized, double-blind placebo-controlled studies. In one study of 1,468 men with nonmetastatic prostate cancer receiving ADT, lumbar spine bone mineral density (BMD) at 2 years was significantly higher with denosumab vs. placebo (6.7% difference). At 3 years of treatment, the incidence of new vertebral fractures was 1.5% with denosumab vs. 3.9% with placebo, a risk reduction of 62%. In a study of 252 postmenopausal women with breast cancer on AI treatment, BMD at the lumbar spine was significantly higher with denosumab vs. placebo after 12 months of treatment (5.5% difference).
Addendum: Denosumab was initially approved in 2010. It is marketed as Prolia for treating postmenopausal women with osteoporosis at high risk of fracture, and as Xgeva for preventing skeletal-related events in patients with bone metastases from solid tumors; Xgeva is administered more frequently and at a higher dose for the latter indication.
• Everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corp.). The mammalian target of rapamycin (mTOR) inhibitor for progressive pancreatic neuroendocrine tumors (pNETs) that are unresectable, locally advanced, or metastatic. (Safety and effectiveness of everolimus for treating carcinoid tumors have not been established). The first new drug in about 30 years for the treatment of advanced pNET.
Basis: A randomized controlled study of 410 patients, all of whom also received best supportive care. Median progression-free survival was 11 months with everolimus, vs. 4.6 months with placebo. In an interim analysis, overall survival was not different between the two groups.
• Peg-interferon alfa-2b (Sylatron, Schering Corp.). An alpha interferon for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.
Basis: An open-label multicenter study of 1,256 patients. Median relapse-free survival was 34.8 months among those treated with peg-interferon alfa-2b, vs. 25.5 months with observation.
• Rituximab (Rituxan, Genentech, Inc.). The CD20-directed cytolytic antibody for maintenance therapy in people with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.
Basis: An international study of 1,217 previously untreated patients with advanced follicular lymphoma; it randomized 1,018 patients who had a complete or partial response with rituximab and chemotherapy. Maintenance treatment with rituximab reduced the risk of progression by 46% compared with observation only.
• Sunitinib (Sutent Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease; it was approved soon after everolimus for this indication.
Basis: A randomized controlled study of 171 patients with unresectable, locally advanced or well-differentiated pNET; treatment with somatostatin analogues was allowed. Median progression-free survival was 10.2 months with sunitinib, vs. 5.4 months with placebo.
WARNINGS AND LABEL CHANGES
• Bevacizumab (Avastin, Genentech, Inc.). Revised prescribing information includes the risk of ovarian failure in premenopausal women treated with bevacizumab and chemotherapy; postmarketing reports of osteonecrosis of the jaw in patients treated with bevacizumab but not bisphosphonates; and information from a clinical trial about the risk of venous thromboembolic events and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.
• Dasatinib (Sprycel, Bristol-Myers Squibb). Information on increased risk for pulmonary arterial hypertension added to prescribing information.
• Fentanyl. A classwide risk management program approved for all transmucosal immediate-release fentanyl formulations.
• IV methotrexate and proton pump inhibitors (PPIs). A warning added to the methotrexate label advises caution when high-dose methotrexate is administered to patients taking a PPI, because concomitant administration may result in elevated and prolonged serum levels of methotrexate and/or its metabolite hydroxymethotrexate, with possible toxic effects.
• Lenalidomide (Revlimid, Celgene). Advisory informed the public that the FDA is monitoring the risk of secondary cancers in patients treated for myelodysplastic syndromes or multiple myeloma.
• Ondansetron (Zofran, GlaxoSmithKline, and generic formulations). Following a review of information on the risk of QT prolongation, label now recommends ECG monitoring in patients who are treated with ondansetron and have an electrolyte abnormality, congestive heart failure, or bradyarrhythmias; and in patients taking other medications that prolong the QT interval – who are at an increased risk of developing torsades de pointes. Label recommends against use in patients with congenital long QT syndrome. Safety review ongoing.
• Opioids. Draft issued for opioid prescriber education program, as part of the Risk Evaluation and Mitigation Strategy (REMS) now in place for brand-name and generic long-acting and extended-release opioids.
• Pioglitazone. Bladder cancer warning risk added to the label for type 2 diabetes drug marketed as Actos (or in combination with metformin as Actoplus Met, and with glimepiride as Duetact).
• Romiplostim (Nplate for subcutaneous injection, Amgen, Inc.) and eltrombopag (Promacta tablets, GlaxoSmithKline LLC). Elements of the REMS for the two thrombopoietin receptor agonists were dropped, including the restricted distribution program that required health care professionals, hospitals, and patients to be enrolled in order to prescribe, dispense, or receive these drugs. Clinicians no longer need to file periodic safety forms for their patients on these treatments.
• Tumor necrosis factor (TNF) blockers. Manufacturers asked to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them.
OTHER ACTIONS
• Bevacizumab (Avastin, Genentech, Inc.). FDA Commissioner Margaret Hamburg withdrew bevacizumab’s indication in metastatic breast cancer. She cited a lack of data establishing benefit and serious risks associated with treatment. The decision followed a July hearing, where the Oncologic Drugs Advisory Committee unanimously voted that the indication be withdrawn despite emotional testimony from patients who said they benefited from the monoclonal antibody.
• Drug shortages. A new rule requires some manufacturers to give early warning of shortages. The agency also held a workshop on the crisis and is working to avert and/or resolve shortages.
• Office of Oncology Products. Many New Drug Applications, Biologic License Applications, and Investigational New Drug Applications for cancer drugs are being reassigned to new review divisions as part of a reorganization.
From an immunotherapy that improves melanoma survival to a device that zaps brain tumors, 2011 was a year of firsts from the FDA. This is our second annual guide to approvals of new cancer drugs, indications, and devices – along with a review of safety warnings and other actions affecting oncology practices.
(Click here for a PDF version of The Oncology Report Guide to Cancer Drugs and Devices in 2011.)
NEW DRUG APPROVALS
• Abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.). An androgen suppressant that decreases testosterone production for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. The fourth approval in late-stage prostate cancer since April 2010.
Basis: An international study of 1,195 men who had previously received chemotherapy containing docetaxel. Median overall survival was 14.8 months with abiraterone plus prednisone, vs. 10.9 months with prednisone alone.
• Asparaginase Erwinia chrysanthemi [Erwinaze for injection, EUSA Pharma (USA), Inc.] An asparagine-specific enzyme approved as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who developed hypersensitivity to E. coli-derived asparaginase. An orphan drug, it works by the same mechanism as the two previously approved treatments that block asparagine, a protein necessary for the proliferation of neoplastic cells.
Basis: In a single-arm, multicenter, open-label study of 58 patients, all 48 patients with available samples achieved threshold trough asparaginase levels shown to correlate with asparagine depletion and with serum levels that predict clinical efficacy.
• Brentuximab vedotin (Adcetris for injection, Seattle Genetics, Inc.). A CD30-directed antibody-drug conjugate for the treatment of Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen. The first new treatment approved for Hodgkin’s since 1977 and the first treatment approved for ALCL.
Basis: In a single-arm study of 102 patients treated with brentuximab, 73% had either a complete or partial response. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response.
Addendum: An accelerated approval, based on clinical data suggesting that treatment resulted in significant responses; conversion to full approval is contingent on confirmation of benefits in follow-up studies. (In January 2012, the FDA added a warning about the risk of a rare brain infection to the label.)
• Crizotinib (Xalkori Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene, as detected by the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), a companion diagnostic test approved at the same time.
Basis: In two single-arm studies of 255 patients with locally advanced or metastatic, ALK-positive NSCLC, most of whom had received prior chemotherapy, the overall response rate was 50% and 61%, with a median response duration of 42 and 48 weeks, respectively.
Addendum: An accelerated approval, so conversion to full approval is contingent on follow-up studies confirming clinical benefit.
• Deferiprone (Ferriprox Tablets, ApoPharma, Inc.). An oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.
Basis: A prospective pooled analysis of previously conducted studies of 236 patients (most had thalassemia syndromes) with transfusion-dependent iron overload, for which previous iron chelation therapy had failed or was considered inadequate because of poor tolerance. Within 1 year of starting treatment, 50% of the patients had at least a 20% decrease in serum ferritin levels.
Addendum: An accelerated approval. Safety and effectiveness not established for the treatment of transfusional iron overload due to other chronic anemias, including sickle cell disease. As a condition of approval, ApoPharma will conduct a study of safety and efficacy in patients with sickle cell disease and transfusional iron overload not adequately treated with available chelating agents.
• Hemacord (New York Blood Center). A hematopoietic progenitor cells–cord (HPC-C) preparation for allogenic hematopoietic stem cell transplantation. The first approval of a license for an umbilical cord blood therapy.
Basis: Safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements.
• Ipilimumab injection (Yervoy, Bristol-Myers Squibb). A human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody for the treatment of unresectable or metastatic melanoma. The first treatment proven to prolong survival in patients with metastatic melanoma.
Basis: An international study of 676 patients with previously treated unresectable stage III or IV melanoma whose disease had progressed, comparing ipilimumab plus an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab with or without the vaccine, vs. 6 months among those who received the vaccine alone.
Addendum: Approved with a Risk Evaluation and Mitigation Strategy (REMS) program addressing life-threatening toxicity and deaths associated with ipilimumab in the study. Acts slowly, and some patients may have tumor progression before therapy becomes effective.
• Ruxolitinib (Jakafi oral tablets, Incyte Corp.). A Janus-associated kinase (JAK) inhibitor for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. An orphan drug that is the first treatment approved for the rare blood disease – and the first approved JAK inhibitor.
Basis: Two randomized controlled trials of 528 patients with intermediate- or high-risk myelofibrosis. In one study, 42% of those on ruxolitinib had more than at least a 35% reduction in spleen volume vs. 1% of those on placebo at 24 weeks, and nearly half of those on treatment had achieved at least a 50% reduction in myelofibrosis symptoms, vs. 5% of those on placebo. In the second study, 29% of those on ruxolitinib had at least a 35% reduction in spleen size, vs. none of those on best available therapy after 48 weeks.
• Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP). A kinase inhibitor for the treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable, locally advanced, or metastatic disease. The first drug approved for this rare cancer.
Basis: An international study of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer. Median progression-free survival was at least 22.6 months with vandetanib vs. 16.4 months among with placebo, a highly significant difference.
Addendum: Approved with a REMS addressing the risk of QT interval prolongation and a note that use in patients with indolent, asymptomatic, or slowly progressing disease "should be carefully considered" because of treatment-associated risks, as well as a boxed warning and a restricted distribution program.
• Vemurafenib (Zelboraf tablets, Hoffmann-LaRoche, Inc.). A BRAF inhibitor for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic test approved at the same time. The second therapy found to prolong survival in patients with melanoma.
Basis: A study of 675 treatment-naive patients with unresectable or metastatic melanoma, positive for the BRAFV600E mutation. At the time of review, median survival was 7.9 months in a control group treated with dacarbazine, but had not been reached among those on vemurafenib. Median progression-free survival was 1.6 and 5.3 months, respectively.
Addendum: About half of melanoma patients have the BRAF mutation, and about half of them respond to vemurafenib. Approved with a medication guide to inform patients about the need for the diagnostic test and potential risks associated with treatment, including cutaneous squamous cell carcinoma. Roche and ipilimumab manufacturer Bristol-Meyers Squibb announced collaboration on a phase I/II study to determine whether combining the two agents is safe and effective in patients with BRAF mutations.
NEW DEVICES
• MelaFind (Mela Sciences). A noninvasive melanoma detection device for use "on clinically atypical cutaneous pigmented lesions with one or more clinical or historical characteristics of melanoma, excluding those with a clinical diagnosis of melanoma or likely melanoma."
Basis: The road to approval was controversial, with a split vote from an advisory panel, a citizens petition submitted by the manufacturer, and an agreement between the agency and manufacturer on how the device would be used and by whom.
• NovoTTF-100A System (NovoTTF, Novocure). A portable, battery-powered device that delivers electrical fields to the brain as a treatment for adults with glioblastoma multiforme that has recurred after chemotherapy.
Basis: In a randomized study of 237 patients whose GBM had recurred after surgery, radiation, and chemotherapy, median overall survival was 6.3 months with the approximately 6-pound device and 6.4 months with best available chemotherapy. The agency cited evidence suggesting better quality of life without chemotherapy side effects.
NEW INDICATIONS
• Cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly & Co. and Bristol-Myers Squibb). The epidermal growth factor receptor (EGFR) antagonist in combination with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional and/or metastatic squamous cell carcinoma of the head and neck.
Basis: A multicenter non-U.S. study of 442 patients not suitable for potentially curative treatment with surgery or radiation. Mean overall survival was 10.1 months with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil), vs. 7.4 months with chemotherapy alone.
Addendum: Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab used in this study, but the study results, pharmacokinetic data, and other clinical trial data "establish the efficacy" of cetuximab at the dose recommended, according to the prescribing information.
• Denosumab (Prolia, Amgen, Inc.). The RANK ligand (RANKL) inhibitor to increase bone mass in patients at high risk for fracture when receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.
Basis: Two international, randomized, double-blind placebo-controlled studies. In one study of 1,468 men with nonmetastatic prostate cancer receiving ADT, lumbar spine bone mineral density (BMD) at 2 years was significantly higher with denosumab vs. placebo (6.7% difference). At 3 years of treatment, the incidence of new vertebral fractures was 1.5% with denosumab vs. 3.9% with placebo, a risk reduction of 62%. In a study of 252 postmenopausal women with breast cancer on AI treatment, BMD at the lumbar spine was significantly higher with denosumab vs. placebo after 12 months of treatment (5.5% difference).
Addendum: Denosumab was initially approved in 2010. It is marketed as Prolia for treating postmenopausal women with osteoporosis at high risk of fracture, and as Xgeva for preventing skeletal-related events in patients with bone metastases from solid tumors; Xgeva is administered more frequently and at a higher dose for the latter indication.
• Everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corp.). The mammalian target of rapamycin (mTOR) inhibitor for progressive pancreatic neuroendocrine tumors (pNETs) that are unresectable, locally advanced, or metastatic. (Safety and effectiveness of everolimus for treating carcinoid tumors have not been established). The first new drug in about 30 years for the treatment of advanced pNET.
Basis: A randomized controlled study of 410 patients, all of whom also received best supportive care. Median progression-free survival was 11 months with everolimus, vs. 4.6 months with placebo. In an interim analysis, overall survival was not different between the two groups.
• Peg-interferon alfa-2b (Sylatron, Schering Corp.). An alpha interferon for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.
Basis: An open-label multicenter study of 1,256 patients. Median relapse-free survival was 34.8 months among those treated with peg-interferon alfa-2b, vs. 25.5 months with observation.
• Rituximab (Rituxan, Genentech, Inc.). The CD20-directed cytolytic antibody for maintenance therapy in people with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.
Basis: An international study of 1,217 previously untreated patients with advanced follicular lymphoma; it randomized 1,018 patients who had a complete or partial response with rituximab and chemotherapy. Maintenance treatment with rituximab reduced the risk of progression by 46% compared with observation only.
• Sunitinib (Sutent Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease; it was approved soon after everolimus for this indication.
Basis: A randomized controlled study of 171 patients with unresectable, locally advanced or well-differentiated pNET; treatment with somatostatin analogues was allowed. Median progression-free survival was 10.2 months with sunitinib, vs. 5.4 months with placebo.
WARNINGS AND LABEL CHANGES
• Bevacizumab (Avastin, Genentech, Inc.). Revised prescribing information includes the risk of ovarian failure in premenopausal women treated with bevacizumab and chemotherapy; postmarketing reports of osteonecrosis of the jaw in patients treated with bevacizumab but not bisphosphonates; and information from a clinical trial about the risk of venous thromboembolic events and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.
• Dasatinib (Sprycel, Bristol-Myers Squibb). Information on increased risk for pulmonary arterial hypertension added to prescribing information.
• Fentanyl. A classwide risk management program approved for all transmucosal immediate-release fentanyl formulations.
• IV methotrexate and proton pump inhibitors (PPIs). A warning added to the methotrexate label advises caution when high-dose methotrexate is administered to patients taking a PPI, because concomitant administration may result in elevated and prolonged serum levels of methotrexate and/or its metabolite hydroxymethotrexate, with possible toxic effects.
• Lenalidomide (Revlimid, Celgene). Advisory informed the public that the FDA is monitoring the risk of secondary cancers in patients treated for myelodysplastic syndromes or multiple myeloma.
• Ondansetron (Zofran, GlaxoSmithKline, and generic formulations). Following a review of information on the risk of QT prolongation, label now recommends ECG monitoring in patients who are treated with ondansetron and have an electrolyte abnormality, congestive heart failure, or bradyarrhythmias; and in patients taking other medications that prolong the QT interval – who are at an increased risk of developing torsades de pointes. Label recommends against use in patients with congenital long QT syndrome. Safety review ongoing.
• Opioids. Draft issued for opioid prescriber education program, as part of the Risk Evaluation and Mitigation Strategy (REMS) now in place for brand-name and generic long-acting and extended-release opioids.
• Pioglitazone. Bladder cancer warning risk added to the label for type 2 diabetes drug marketed as Actos (or in combination with metformin as Actoplus Met, and with glimepiride as Duetact).
• Romiplostim (Nplate for subcutaneous injection, Amgen, Inc.) and eltrombopag (Promacta tablets, GlaxoSmithKline LLC). Elements of the REMS for the two thrombopoietin receptor agonists were dropped, including the restricted distribution program that required health care professionals, hospitals, and patients to be enrolled in order to prescribe, dispense, or receive these drugs. Clinicians no longer need to file periodic safety forms for their patients on these treatments.
• Tumor necrosis factor (TNF) blockers. Manufacturers asked to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them.
OTHER ACTIONS
• Bevacizumab (Avastin, Genentech, Inc.). FDA Commissioner Margaret Hamburg withdrew bevacizumab’s indication in metastatic breast cancer. She cited a lack of data establishing benefit and serious risks associated with treatment. The decision followed a July hearing, where the Oncologic Drugs Advisory Committee unanimously voted that the indication be withdrawn despite emotional testimony from patients who said they benefited from the monoclonal antibody.
• Drug shortages. A new rule requires some manufacturers to give early warning of shortages. The agency also held a workshop on the crisis and is working to avert and/or resolve shortages.
• Office of Oncology Products. Many New Drug Applications, Biologic License Applications, and Investigational New Drug Applications for cancer drugs are being reassigned to new review divisions as part of a reorganization.
Is the US running too many T-cell lymphoma trials?
SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.
Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.
Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.
The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.
“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”
As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.
But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.
“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”
As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.
For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.
And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.
“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”
SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.
Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.
Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.
The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.
“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”
As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.
But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.
“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”
As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.
For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.
And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.
“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”
SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.
Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.
Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.
The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.
“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”
As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.
But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.
“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”
As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.
For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.
And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.
“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”
Pregnant Women With Lymphoma Can Have Good Outcomes
SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.
Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.
All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).
The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.
Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.
Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.
"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.
Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.
Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.
He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.
Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).
Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.
The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).
A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).
Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.
All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.
Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.
"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.
Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.
Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.
There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.
One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.
Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.
The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.
Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.
The study was funded by the participating centers. The authors reported no relevant conflicts of interest.
SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.
Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.
All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).
The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.
Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.
Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.
"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.
Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.
Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.
He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.
Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).
Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.
The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).
A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).
Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.
All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.
Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.
"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.
Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.
Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.
There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.
One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.
Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.
The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.
Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.
The study was funded by the participating centers. The authors reported no relevant conflicts of interest.
SAN DIEGO – Women diagnosed with lymphoma during pregnancy stand a good chance of carrying a healthy child to term even when they opt for treatment during the second or third trimester, according to a retrospective multicenter analysis.
Among 82 women diagnosed with either Hodgkin’s or non-Hodgkin’s lymphoma during pregnancy, 48 opted to start therapy during pregnancy rather than defer it until after delivery, investigators reported at the annual meeting of the American Society of Hematology.
All but one woman had a normal birth, the exception being a severe malformation: microcephaly in the fetus of a woman who had received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for diffuse large B-cell lymphoma (DLBCL).
The timing of therapy did not appear to affect overall survival, with the 3-year progression-free survival (PFS) rate being 76% among women who underwent treatment during pregnancy, compared with 79% for those who deferred it, said Dr. Andrew M. Evens of the University of Massachusetts in Worcester.
Respective overall survival rates were 92% and 83%, he reported. For the six women who elected to terminate their pregnancies, the 3-year PFS rate and overall survival rate were each 100%.
Among 39 women with Hodgkin’s lymphoma (HL), the 3-year PFS rate was 90%, and overall survival was 95%. Among 33 patients with B-cell non-Hodgkin’s lymphomas (NHL), 73% were progression free at 3 years; the overall survival rate was 82%. For 10 women with NHL of T-cell histology, the respective figures were 50% and 90%.
"We conclude that standard chemotherapy – non-antimetabolite chemotherapy – and radiation in select cases, in particular localized disease likely above the diaphragm during the second and third trimester, were associated with expected maternal complications and fetal detriment," Dr. Evens said.
Women with low-risk disease, such as indolent NHL, or a diagnosis late in gestation may be able to defer therapy until after delivery, he added.
Cancers in Pregnancy Uncommon. Cancer diagnoses during pregnancy are uncommon, occurring in about 3,500 women annually in the United States. The estimated prevalence is 1 in 1,000 gestations. Hematologic malignancies, primarily lymphomas, account for about 20% of all cancers diagnosed in pregnancy, Dr. Evens said.
He and his colleagues at nine academic medical centers conducted a descriptive retrospective analysis looking at histology, disease characteristics, therapy received, and maternal and fetal complications among pregnant women diagnosed with lymphomas from 1998 through 2011.
Of the 82 women identified for whom follow-up data were available, 43 (52%) were diagnosed with NHL (83% B-cell and 17% T-cell histologies) and 39 (48%) with HL. The median time of diagnosis was at 24 weeks gestation (range 5-40 weeks).
Six patients (4 with NHL and 2 with HL) decided to terminate the pregnancies to have immediate chemotherapy. Five of these patients were diagnosed in the first trimester and required systemic therapy.
The remaining patient was diagnosed early in the second trimester with lymphoma involving the central nervous system and requiring high-dose methotrexate, an antimetabolite in FDA pregnancy category X (positive evidence of fetal harm from animal or human studies and/or clinical experience; contraindicated). Other antimetabolites are classified in category D (positive evidence of fetal risk, but the benefits may warrant use in pregnant women).
A total of 28 patients (34%) chose to defer therapy, including 15 with HL, 5 with follicular lymphoma, 4 with DLBCL, 3 with T-cell lymphoma, and 1 with Burkitt’s lymphoma. The median gestation time at diagnosis in these patients was 34 weeks (range 6-38).
Of the 48 patients who chose to start therapy during pregnancy, 27 patients with NHL received therapy with CHOP, CHOP plus rituximab (Rituxan), modified hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), or similar regimens.
All but 2 patients with HL received the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), and 4 of these patients also received partial-dose radiation therapy with shielding of the fetus. One patient received AVD (no bleomycin), and 1 received ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone). Treatments ranged from the 13th to the 33rd week of gestation.
Among the 48 treated patients, gestation reached full term in 73% with delivery at a median of 37 weeks (range 31-40); most of the deliveries occurred at or after 35 weeks. Among the 28 patients who deferred therapy, delivery was at a median of 38 weeks (range 26-40), and 86% of these women were able to carry their pregnancies to term.
"The goal in every patient, whether they received therapy or not, was to try and deliver as close to term as possible," Dr. Evens said.
Among all patients, 72% had vaginal delivery, and 28% had cesarean sections.
Labor Induced in Nearly Half of Patients. The most common preterm complication was the need for induction of labor in 45%. Preeclampsia occurred in 8%, 5% had spontaneous rupture of membranes, and 4% had gestational diabetes. There were no reported cases of endometritis or chorioamnionitis. There were no significant differences in preterm events between patients who were treated or deferred therapy.
There was one stillbirth, occurring in a 34-year-old woman with double-hit (two-mutation) NHL at 19 weeks after one cycle of R-CHOP.
One woman died before giving birth. She had very-high-risk DLBCL with significant metastases to the liver. She had been diagnosed at week 29 and died at week 32 from encephalopathy, but delivered a healthy infant before her death.
Outcomes for the fetuses of the 76 women who opted to continue their pregnancies included the aforementioned stillbirth and 1 case of microcephaly in a woman who had received four cycles of CHOP for DLBCL.
The median birth weight of neonates was 2,427 g (range 1,005-5,262 g), and there were no differences between the children of women who underwent antepartum chemotherapy or deferred therapy.
Dr. Evens noted that the investigators looked only at acute fetal outcomes, and have not evaluated long-term developmental measures.
The study was funded by the participating centers. The authors reported no relevant conflicts of interest.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY
Major Finding: Among women with lymphomas diagnosed during pregnancy, the 3-year progression-free survival rates were 76% in women who underwent immediate treatment and 79% for those who deferred it until after delivery. Respective overall survival rates were 92% and 83%.
Data Source: Retrospective analysis of 82 cases from nine academic health centers.
Disclosures: The study was funded by the participating centers. The authors reported no relevant conflicts of interest.