User login
MDS patients with mutated IDH2 benefit from enasidenib
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial. 
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Photo courtesy of ASH
SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.
The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.
Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.
Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.
Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.
Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*
Study design
MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.
Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.
MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.
Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.
All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.
Patient characteristics
The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.
The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.
Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.
A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.
Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.
“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”
About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.
Adverse events
Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).
“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.
“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”
Investigators considered 9 of the AEs reported for 6 patients to be drug-related.
Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).
There were no treatment-related deaths.
Response and survival
Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).
One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.
Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.
Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.
The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.
Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.
Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.
The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.
At a median follow-up of 7.5 months, the median overall survival was not reached.
“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”
Co-occurring mutations
The investigators also analyzed co-occurring mutations in 13 MDS patients.
The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.
Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”
He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”
“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”
Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.
*Information in the abstract differs from the presentation.
Combo improves ORR, PFS in relapsed/refractory CLL
Image by Mary Ann Thompson
Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.
In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.
“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.
“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”
The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.
About otlertuzumab
Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.
Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.
According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.
Study design
This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.
Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.
Patients in both arms received intravenous bendamustine at 70 mg/m2 on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.
The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.
Patient characteristics
The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.
Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.
There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.
In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.
Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.
In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.
In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.
Response and survival
The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).
In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.
In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.
The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).
The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.
Safety
Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.
Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).
However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.
“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.
“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”
Image by Mary Ann Thompson
Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.
In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.
“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.
“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”
The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.
About otlertuzumab
Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.
Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.
According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.
Study design
This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.
Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.
Patients in both arms received intravenous bendamustine at 70 mg/m2 on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.
The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.
Patient characteristics
The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.
Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.
There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.
In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.
Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.
In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.
In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.
Response and survival
The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).
In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.
In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.
The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).
The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.
Safety
Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.
Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).
However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.
“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.
“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”
Image by Mary Ann Thompson
Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.
In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.
“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.
“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”
The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.
About otlertuzumab
Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.
Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.
According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.
Study design
This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.
Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.
Patients in both arms received intravenous bendamustine at 70 mg/m2 on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.
The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.
Patient characteristics
The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.
Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.
There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.
In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.
Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.
In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.
In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.
Response and survival
The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).
In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.
In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.
The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).
The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.
Safety
Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.
Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).
However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.
“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.
“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”
CHMP recommends authorization of rituximab biosimilar
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the rituximab biosimilar Truxima receive marketing authorization for the treatment of several conditions.
The CHMP said studies have shown that Truxima is comparable to the reference product, Mabthera, which was authorized for use in the European Union in 1998.
The active substance in both products is the anti-CD20 monoclonal antibody rituximab.
Truxima is being developed by Celltrion Healthcare Hungary Kft.
The CHMP’s recommendation for Truxima will be reviewed by the European Commission, which normally issues its decision on a product within 67 days of the time the CHMP adopts its opinion.
If the European Commission grants marketing authorization for Truxima, it will be available as a 500 mg concentrate for solution for infusion.
The CHMP has recommended marketing authorization for Truxima in the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.
The full indications are as follows.
Non-Hodgkin lymphoma
Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma.
Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
Chronic lymphocytic leukemia
Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.
The CHMP noted that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including Truxima, or patients refractory to previous Truxima plus chemotherapy.
Rheumatoid arthritis
Truxima in combination with methotrexate is indicated for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
The CHMP noted that Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active granulomatosis with polyangiitis and microscopic polyangiitis.
The CHMP proposed that Truxima be administered under the close supervision of an experienced healthcare professional and in an environment where full resuscitation facilities are immediately available.
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the rituximab biosimilar Truxima receive marketing authorization for the treatment of several conditions.
The CHMP said studies have shown that Truxima is comparable to the reference product, Mabthera, which was authorized for use in the European Union in 1998.
The active substance in both products is the anti-CD20 monoclonal antibody rituximab.
Truxima is being developed by Celltrion Healthcare Hungary Kft.
The CHMP’s recommendation for Truxima will be reviewed by the European Commission, which normally issues its decision on a product within 67 days of the time the CHMP adopts its opinion.
If the European Commission grants marketing authorization for Truxima, it will be available as a 500 mg concentrate for solution for infusion.
The CHMP has recommended marketing authorization for Truxima in the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.
The full indications are as follows.
Non-Hodgkin lymphoma
Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma.
Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
Chronic lymphocytic leukemia
Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.
The CHMP noted that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including Truxima, or patients refractory to previous Truxima plus chemotherapy.
Rheumatoid arthritis
Truxima in combination with methotrexate is indicated for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
The CHMP noted that Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active granulomatosis with polyangiitis and microscopic polyangiitis.
The CHMP proposed that Truxima be administered under the close supervision of an experienced healthcare professional and in an environment where full resuscitation facilities are immediately available.
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the rituximab biosimilar Truxima receive marketing authorization for the treatment of several conditions.
The CHMP said studies have shown that Truxima is comparable to the reference product, Mabthera, which was authorized for use in the European Union in 1998.
The active substance in both products is the anti-CD20 monoclonal antibody rituximab.
Truxima is being developed by Celltrion Healthcare Hungary Kft.
The CHMP’s recommendation for Truxima will be reviewed by the European Commission, which normally issues its decision on a product within 67 days of the time the CHMP adopts its opinion.
If the European Commission grants marketing authorization for Truxima, it will be available as a 500 mg concentrate for solution for infusion.
The CHMP has recommended marketing authorization for Truxima in the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.
The full indications are as follows.
Non-Hodgkin lymphoma
Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV follicular lymphoma.
Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.
Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.
Chronic lymphocytic leukemia
Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.
The CHMP noted that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies, including Truxima, or patients refractory to previous Truxima plus chemotherapy.
Rheumatoid arthritis
Truxima in combination with methotrexate is indicated for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.
The CHMP noted that Truxima has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active granulomatosis with polyangiitis and microscopic polyangiitis.
The CHMP proposed that Truxima be administered under the close supervision of an experienced healthcare professional and in an environment where full resuscitation facilities are immediately available.
Congenital CMV linked to increased risk of ALL
Photo by Vera Kratochvil
Newborns with congenital cytomegalovirus (CMV) infection may have an increased risk of developing acute lymphoblastic leukemia (ALL), according to a study published in Blood.
The data also suggest the risk may be particularly high among Hispanic children.
Researchers said this is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children.
To conduct this study, the researchers first identified all known infections present in the bone marrow of 127 children diagnosed with ALL and 38 children diagnosed with acute myeloid leukemia (AML).
The team found CMV infection was prevalent in children with ALL but rare in those with AML.
Next, the researchers looked for CMV in newborn blood samples from 268 children who went on to develop ALL. The team compared the samples with samples from 270 healthy children.
“Our goal in tracking CMV back from the time of diagnosis to the womb was to establish that this infection occurred well before initiation of disease,” said lead study author Stephen Francis, PhD, of the University of Nevada and University of California, San Francisco.
He and his colleagues found that children who went on to develop ALL were nearly 4 times more likely than control subjects to be CMV-positive at birth. The odds ratio was 3.71 (P=0.0016).
The odds ratio was 5.9 in Hispanic children and 2.1 in non-Hispanic whites. The researchers said this finding is particularly interesting because of the high rate of ALL observed in Hispanics.
“If it’s true that in utero CMV is one of the initiating events in the development of childhood leukemia, then control of the virus has the potential to be a prevention target,” Dr Francis said. “That’s the real take-home message.”
While this research is in the early stages, the researchers hope these results will inspire more studies that will validate these findings and lead to the development of a CMV vaccine.
“This is the first step, but if we do end up finding a causal link to the most common childhood cancer, we hope that will light a fire in terms of stopping mother-to-child transmission of CMV,” Dr Francis said.
Photo by Vera Kratochvil
Newborns with congenital cytomegalovirus (CMV) infection may have an increased risk of developing acute lymphoblastic leukemia (ALL), according to a study published in Blood.
The data also suggest the risk may be particularly high among Hispanic children.
Researchers said this is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children.
To conduct this study, the researchers first identified all known infections present in the bone marrow of 127 children diagnosed with ALL and 38 children diagnosed with acute myeloid leukemia (AML).
The team found CMV infection was prevalent in children with ALL but rare in those with AML.
Next, the researchers looked for CMV in newborn blood samples from 268 children who went on to develop ALL. The team compared the samples with samples from 270 healthy children.
“Our goal in tracking CMV back from the time of diagnosis to the womb was to establish that this infection occurred well before initiation of disease,” said lead study author Stephen Francis, PhD, of the University of Nevada and University of California, San Francisco.
He and his colleagues found that children who went on to develop ALL were nearly 4 times more likely than control subjects to be CMV-positive at birth. The odds ratio was 3.71 (P=0.0016).
The odds ratio was 5.9 in Hispanic children and 2.1 in non-Hispanic whites. The researchers said this finding is particularly interesting because of the high rate of ALL observed in Hispanics.
“If it’s true that in utero CMV is one of the initiating events in the development of childhood leukemia, then control of the virus has the potential to be a prevention target,” Dr Francis said. “That’s the real take-home message.”
While this research is in the early stages, the researchers hope these results will inspire more studies that will validate these findings and lead to the development of a CMV vaccine.
“This is the first step, but if we do end up finding a causal link to the most common childhood cancer, we hope that will light a fire in terms of stopping mother-to-child transmission of CMV,” Dr Francis said.
Photo by Vera Kratochvil
Newborns with congenital cytomegalovirus (CMV) infection may have an increased risk of developing acute lymphoblastic leukemia (ALL), according to a study published in Blood.
The data also suggest the risk may be particularly high among Hispanic children.
Researchers said this is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children.
To conduct this study, the researchers first identified all known infections present in the bone marrow of 127 children diagnosed with ALL and 38 children diagnosed with acute myeloid leukemia (AML).
The team found CMV infection was prevalent in children with ALL but rare in those with AML.
Next, the researchers looked for CMV in newborn blood samples from 268 children who went on to develop ALL. The team compared the samples with samples from 270 healthy children.
“Our goal in tracking CMV back from the time of diagnosis to the womb was to establish that this infection occurred well before initiation of disease,” said lead study author Stephen Francis, PhD, of the University of Nevada and University of California, San Francisco.
He and his colleagues found that children who went on to develop ALL were nearly 4 times more likely than control subjects to be CMV-positive at birth. The odds ratio was 3.71 (P=0.0016).
The odds ratio was 5.9 in Hispanic children and 2.1 in non-Hispanic whites. The researchers said this finding is particularly interesting because of the high rate of ALL observed in Hispanics.
“If it’s true that in utero CMV is one of the initiating events in the development of childhood leukemia, then control of the virus has the potential to be a prevention target,” Dr Francis said. “That’s the real take-home message.”
While this research is in the early stages, the researchers hope these results will inspire more studies that will validate these findings and lead to the development of a CMV vaccine.
“This is the first step, but if we do end up finding a causal link to the most common childhood cancer, we hope that will light a fire in terms of stopping mother-to-child transmission of CMV,” Dr Francis said.
Study reveals CML patients likely to benefit from HSCT long-term
Photo by Chad McNeeley
SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).
The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).
Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).
Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.
She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).
With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.
Patient population
The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.
About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.
Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).
Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.
Survival
The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.
The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.
HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.
“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.
Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.
Health outcomes
Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.
A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.
Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).
Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.
The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).
The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).
The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).
The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:
- Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
- Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
- Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).
(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).
Lower risk
To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.
The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).
The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).
The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).
“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”
Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.
However, she said data collection is ongoing, and the researchers hope to address some of these limitations.
*Information presented at the meeting differs from the abstract.
Photo by Chad McNeeley
SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).
The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).
Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).
Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.
She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).
With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.
Patient population
The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.
About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.
Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).
Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.
Survival
The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.
The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.
HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.
“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.
Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.
Health outcomes
Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.
A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.
Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).
Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.
The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).
The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).
The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).
The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:
- Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
- Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
- Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).
(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).
Lower risk
To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.
The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).
The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).
The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).
“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”
Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.
However, she said data collection is ongoing, and the researchers hope to address some of these limitations.
*Information presented at the meeting differs from the abstract.
Photo by Chad McNeeley
SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).
The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).
Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).
Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.
She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).
With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.
Patient population
The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.
About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.
Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).
Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.
Survival
The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.
The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.
HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.
“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.
Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.
Health outcomes
Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.
A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.
Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).
Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.
The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).
The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).
The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).
The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:
- Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
- Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
- Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).
(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).
Lower risk
To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.
The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).
The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).
The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).
“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”
Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.
However, she said data collection is ongoing, and the researchers hope to address some of these limitations.
*Information presented at the meeting differs from the abstract.
Platform could optimize treatment of ALL, other diseases
A digital health technology platform may prove useful for optimizing treatment of acute lymphoblastic leukemia (ALL), according to research published in SLAS Technology.
The platform is based on phenotypic personalized medicine (PPM), in which a patient’s response to treatment can be visually represented in the shape of a parabola.
The graph plots the drug dose along the horizontal axis and the patient’s response on the vertical axis.
Researchers said PPM has the ability to accurately identify a person’s optimal drug and dose combinations throughout an entire course of treatment.
“Phenotypic personalized medicine is like turbocharged artificial intelligence,” said study author Dean Ho, PhD, of the University of California, Los Angeles.
“It personalizes combination therapy to optimize efficacy and safety. The ability for our technology to continuously pinpoint the proper dosages of multiple drugs from such a large pool of possible combinations overcomes a challenge that is substantially more difficult than finding a needle in a haystack.”
In this study, Dr Ho and his colleagues used PPM to (retrospectively) individualize drug ratios/dosages in 2 pediatric patients with standard-risk ALL.
The researchers looked at the patients’ records to examine the administration of 4-drug maintenance regimens (dexamethasone, vincristine, mercaptopurine, and methotrexate).
The team said the drug doses served as the inputs, and maintaining absolute neutrophil counts and platelet counts within target ranges served as the outputs for optimization.
Using PPM, the researchers generated individualized 3-dimensional maps to determine the optimal drug ratios.
The team found their technology-suggested drug dosages were as much as 40% lower than clinical chemotherapy dosages, but they still maintained target neutrophil/platelet levels.
The parabolas showed that markedly different dosages of each drug were required to maintain normal cell counts for each patient.
The researchers said their results demonstrate a clear need to personalize ALL treatment and will serve as a foundation for a pending clinical trial to optimize multidrug chemotherapy.
“PPM has the ability to personalize combination therapy for a wide spectrum of diseases, making it a broadly applicable technology,” said study author Chih-Ming Ho, PhD, of the University of California, Los Angeles.
“The fact that we don’t need any information pertaining to a disease’s biological process in order to optimize and personalize treatment is a revolutionary advance. We’re at the interface of digital health and cancer treatment.”
The research team is planning to recruit patients for a prospective trial within the next year. The technology is approved for additional infectious disease and oncology studies.
A digital health technology platform may prove useful for optimizing treatment of acute lymphoblastic leukemia (ALL), according to research published in SLAS Technology.
The platform is based on phenotypic personalized medicine (PPM), in which a patient’s response to treatment can be visually represented in the shape of a parabola.
The graph plots the drug dose along the horizontal axis and the patient’s response on the vertical axis.
Researchers said PPM has the ability to accurately identify a person’s optimal drug and dose combinations throughout an entire course of treatment.
“Phenotypic personalized medicine is like turbocharged artificial intelligence,” said study author Dean Ho, PhD, of the University of California, Los Angeles.
“It personalizes combination therapy to optimize efficacy and safety. The ability for our technology to continuously pinpoint the proper dosages of multiple drugs from such a large pool of possible combinations overcomes a challenge that is substantially more difficult than finding a needle in a haystack.”
In this study, Dr Ho and his colleagues used PPM to (retrospectively) individualize drug ratios/dosages in 2 pediatric patients with standard-risk ALL.
The researchers looked at the patients’ records to examine the administration of 4-drug maintenance regimens (dexamethasone, vincristine, mercaptopurine, and methotrexate).
The team said the drug doses served as the inputs, and maintaining absolute neutrophil counts and platelet counts within target ranges served as the outputs for optimization.
Using PPM, the researchers generated individualized 3-dimensional maps to determine the optimal drug ratios.
The team found their technology-suggested drug dosages were as much as 40% lower than clinical chemotherapy dosages, but they still maintained target neutrophil/platelet levels.
The parabolas showed that markedly different dosages of each drug were required to maintain normal cell counts for each patient.
The researchers said their results demonstrate a clear need to personalize ALL treatment and will serve as a foundation for a pending clinical trial to optimize multidrug chemotherapy.
“PPM has the ability to personalize combination therapy for a wide spectrum of diseases, making it a broadly applicable technology,” said study author Chih-Ming Ho, PhD, of the University of California, Los Angeles.
“The fact that we don’t need any information pertaining to a disease’s biological process in order to optimize and personalize treatment is a revolutionary advance. We’re at the interface of digital health and cancer treatment.”
The research team is planning to recruit patients for a prospective trial within the next year. The technology is approved for additional infectious disease and oncology studies.
A digital health technology platform may prove useful for optimizing treatment of acute lymphoblastic leukemia (ALL), according to research published in SLAS Technology.
The platform is based on phenotypic personalized medicine (PPM), in which a patient’s response to treatment can be visually represented in the shape of a parabola.
The graph plots the drug dose along the horizontal axis and the patient’s response on the vertical axis.
Researchers said PPM has the ability to accurately identify a person’s optimal drug and dose combinations throughout an entire course of treatment.
“Phenotypic personalized medicine is like turbocharged artificial intelligence,” said study author Dean Ho, PhD, of the University of California, Los Angeles.
“It personalizes combination therapy to optimize efficacy and safety. The ability for our technology to continuously pinpoint the proper dosages of multiple drugs from such a large pool of possible combinations overcomes a challenge that is substantially more difficult than finding a needle in a haystack.”
In this study, Dr Ho and his colleagues used PPM to (retrospectively) individualize drug ratios/dosages in 2 pediatric patients with standard-risk ALL.
The researchers looked at the patients’ records to examine the administration of 4-drug maintenance regimens (dexamethasone, vincristine, mercaptopurine, and methotrexate).
The team said the drug doses served as the inputs, and maintaining absolute neutrophil counts and platelet counts within target ranges served as the outputs for optimization.
Using PPM, the researchers generated individualized 3-dimensional maps to determine the optimal drug ratios.
The team found their technology-suggested drug dosages were as much as 40% lower than clinical chemotherapy dosages, but they still maintained target neutrophil/platelet levels.
The parabolas showed that markedly different dosages of each drug were required to maintain normal cell counts for each patient.
The researchers said their results demonstrate a clear need to personalize ALL treatment and will serve as a foundation for a pending clinical trial to optimize multidrug chemotherapy.
“PPM has the ability to personalize combination therapy for a wide spectrum of diseases, making it a broadly applicable technology,” said study author Chih-Ming Ho, PhD, of the University of California, Los Angeles.
“The fact that we don’t need any information pertaining to a disease’s biological process in order to optimize and personalize treatment is a revolutionary advance. We’re at the interface of digital health and cancer treatment.”
The research team is planning to recruit patients for a prospective trial within the next year. The technology is approved for additional infectious disease and oncology studies.
Novel trial aims to BEAT AML
SAN DIEGO – A multi-arm clinical trial aims to transform the treatment of acute myeloid leukemia, a deadly blood cancer whose standard of care has remained essentially unchanged for 4 decades.
Launched in October 2016, the multicenter BEAT AML Master Trial is based on a simple but radical goal – turn around genomic tests of bone marrow biopsies within 7 days to allow targeted therapy, said lead investigator Brian Druker, MD, of Oregon Health and Science University Knight Cancer Institute in Portland.
Speaking at a press conference at the annual meeting of the American Society of Hematology, he emphasized that rapid, accurate genomic testing is the only way to prescribe targeted agents for AML in time for them to help patients. “It really is about matching the right patient with the right drug,” he said. He also spoke about AML in a video interview at the conference.
That is a major departure from the current approach to treating AML, in which patients receive standard chemotherapy regimens that are toxic and largely ineffective. “Patients themselves call this barbaric therapy,” said John Byrd, MD, who is co-leading the trial on behalf of the Ohio State University Wexner Medical Center in Columbus. “In this trial, we’re going to move away from toxic therapy that is not potentially curative to give more targeted medicine instead.”
In addition to Dr. Druker’s and Dr. Byrd’s centers, Memorial Sloan Kettering Cancer Center, New York, and Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston, are onboard for the study. The lead investigators hope to add another six centers to the study group and to have 10 arms of the study underway by mid-2017.
Older patients with AML find chemotherapy especially hard to tolerate and typically respond poorly. Accordingly, the trial will enroll those aged 60 years and up regardless of their genomic profile, the researchers said. Patients lacking targetable markers will be offered investigational therapies showing broad activity in AML.
Another complexity of AML is that any patient can have a variety of mutations, including some affecting only a small subset of leukemia cells, Dr. Byrd noted. Targeting those mutations cannot eradicate disease, but past trials did not rank or choose therapies based on mutation prevalence. Thus, this trial is the first to ask “which mutation is in all of the cells, which gives you the opportunity to get rid of all the disease,” he emphasized. Again, patients – not individual markers or agents – are the priority.
The study also is meant to be nimble – arms can be quickly opened or closed if bench or clinical data are promising or lackluster. This design does not preclude FDA approvals, said Louis J. DeGennaro, PhD, of the Leukemia and Lymphoma Society, which is sponsoring the trial. “We have worked closely with FDA to design a unique protocol that we believe will change the paradigm of AML treatment and future clinical trials,” he added. “This is an unprecedented collaboration.”
Dr. Druker agreed. “If we do this correctly, we can potentially see large effects, and that can become the impetus for rapid FDA approval of these drugs for the right patients,” he said. “That one of the things this trial is designed to do.”
Dr. DeGennaro is president and chief executive officer of the Leukemia and Lymphoma Society, which is sponsoring the BEAT AML Master trial. Dr. Druker disclosed ties to a number of pharmaceutical companies. Dr. Byrd had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – A multi-arm clinical trial aims to transform the treatment of acute myeloid leukemia, a deadly blood cancer whose standard of care has remained essentially unchanged for 4 decades.
Launched in October 2016, the multicenter BEAT AML Master Trial is based on a simple but radical goal – turn around genomic tests of bone marrow biopsies within 7 days to allow targeted therapy, said lead investigator Brian Druker, MD, of Oregon Health and Science University Knight Cancer Institute in Portland.
Speaking at a press conference at the annual meeting of the American Society of Hematology, he emphasized that rapid, accurate genomic testing is the only way to prescribe targeted agents for AML in time for them to help patients. “It really is about matching the right patient with the right drug,” he said. He also spoke about AML in a video interview at the conference.
That is a major departure from the current approach to treating AML, in which patients receive standard chemotherapy regimens that are toxic and largely ineffective. “Patients themselves call this barbaric therapy,” said John Byrd, MD, who is co-leading the trial on behalf of the Ohio State University Wexner Medical Center in Columbus. “In this trial, we’re going to move away from toxic therapy that is not potentially curative to give more targeted medicine instead.”
In addition to Dr. Druker’s and Dr. Byrd’s centers, Memorial Sloan Kettering Cancer Center, New York, and Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston, are onboard for the study. The lead investigators hope to add another six centers to the study group and to have 10 arms of the study underway by mid-2017.
Older patients with AML find chemotherapy especially hard to tolerate and typically respond poorly. Accordingly, the trial will enroll those aged 60 years and up regardless of their genomic profile, the researchers said. Patients lacking targetable markers will be offered investigational therapies showing broad activity in AML.
Another complexity of AML is that any patient can have a variety of mutations, including some affecting only a small subset of leukemia cells, Dr. Byrd noted. Targeting those mutations cannot eradicate disease, but past trials did not rank or choose therapies based on mutation prevalence. Thus, this trial is the first to ask “which mutation is in all of the cells, which gives you the opportunity to get rid of all the disease,” he emphasized. Again, patients – not individual markers or agents – are the priority.
The study also is meant to be nimble – arms can be quickly opened or closed if bench or clinical data are promising or lackluster. This design does not preclude FDA approvals, said Louis J. DeGennaro, PhD, of the Leukemia and Lymphoma Society, which is sponsoring the trial. “We have worked closely with FDA to design a unique protocol that we believe will change the paradigm of AML treatment and future clinical trials,” he added. “This is an unprecedented collaboration.”
Dr. Druker agreed. “If we do this correctly, we can potentially see large effects, and that can become the impetus for rapid FDA approval of these drugs for the right patients,” he said. “That one of the things this trial is designed to do.”
Dr. DeGennaro is president and chief executive officer of the Leukemia and Lymphoma Society, which is sponsoring the BEAT AML Master trial. Dr. Druker disclosed ties to a number of pharmaceutical companies. Dr. Byrd had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – A multi-arm clinical trial aims to transform the treatment of acute myeloid leukemia, a deadly blood cancer whose standard of care has remained essentially unchanged for 4 decades.
Launched in October 2016, the multicenter BEAT AML Master Trial is based on a simple but radical goal – turn around genomic tests of bone marrow biopsies within 7 days to allow targeted therapy, said lead investigator Brian Druker, MD, of Oregon Health and Science University Knight Cancer Institute in Portland.
Speaking at a press conference at the annual meeting of the American Society of Hematology, he emphasized that rapid, accurate genomic testing is the only way to prescribe targeted agents for AML in time for them to help patients. “It really is about matching the right patient with the right drug,” he said. He also spoke about AML in a video interview at the conference.
That is a major departure from the current approach to treating AML, in which patients receive standard chemotherapy regimens that are toxic and largely ineffective. “Patients themselves call this barbaric therapy,” said John Byrd, MD, who is co-leading the trial on behalf of the Ohio State University Wexner Medical Center in Columbus. “In this trial, we’re going to move away from toxic therapy that is not potentially curative to give more targeted medicine instead.”
In addition to Dr. Druker’s and Dr. Byrd’s centers, Memorial Sloan Kettering Cancer Center, New York, and Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston, are onboard for the study. The lead investigators hope to add another six centers to the study group and to have 10 arms of the study underway by mid-2017.
Older patients with AML find chemotherapy especially hard to tolerate and typically respond poorly. Accordingly, the trial will enroll those aged 60 years and up regardless of their genomic profile, the researchers said. Patients lacking targetable markers will be offered investigational therapies showing broad activity in AML.
Another complexity of AML is that any patient can have a variety of mutations, including some affecting only a small subset of leukemia cells, Dr. Byrd noted. Targeting those mutations cannot eradicate disease, but past trials did not rank or choose therapies based on mutation prevalence. Thus, this trial is the first to ask “which mutation is in all of the cells, which gives you the opportunity to get rid of all the disease,” he emphasized. Again, patients – not individual markers or agents – are the priority.
The study also is meant to be nimble – arms can be quickly opened or closed if bench or clinical data are promising or lackluster. This design does not preclude FDA approvals, said Louis J. DeGennaro, PhD, of the Leukemia and Lymphoma Society, which is sponsoring the trial. “We have worked closely with FDA to design a unique protocol that we believe will change the paradigm of AML treatment and future clinical trials,” he added. “This is an unprecedented collaboration.”
Dr. Druker agreed. “If we do this correctly, we can potentially see large effects, and that can become the impetus for rapid FDA approval of these drugs for the right patients,” he said. “That one of the things this trial is designed to do.”
Dr. DeGennaro is president and chief executive officer of the Leukemia and Lymphoma Society, which is sponsoring the BEAT AML Master trial. Dr. Druker disclosed ties to a number of pharmaceutical companies. Dr. Byrd had no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
Lenalidomide improves PFS after 1st and 2nd line CLL therapy
SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.
Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.
Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.
“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.
Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).
The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
Maintenance after first-line therapy
In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).
Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10-2 cells, or MRD levels from 10-4 to less than 10-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.
Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.
Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.
The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.
Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.
At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.
Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10-2 but more than 10-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10-2 (HR 0.165).
There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
Maintenance after second-line therapy
In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).
This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.
At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).
The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).
In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.
Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.
CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.
SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.
Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.
Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.
“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.
Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).
The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
Maintenance after first-line therapy
In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).
Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10-2 cells, or MRD levels from 10-4 to less than 10-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.
Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.
Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.
The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.
Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.
At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.
Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10-2 but more than 10-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10-2 (HR 0.165).
There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
Maintenance after second-line therapy
In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).
This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.
At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).
The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).
In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.
Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.
CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.
SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.
Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.
Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.
“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.
Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).
The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
Maintenance after first-line therapy
In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).
Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10-2 cells, or MRD levels from 10-4 to less than 10-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.
Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.
Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.
The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.
Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.
At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.
Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10-2 but more than 10-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10-2 (HR 0.165).
There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
Maintenance after second-line therapy
In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).
This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.
At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).
The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).
In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.
Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.
CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.
AT ASH 2016
Key clinical point: Lenalidomide (Revlimid) maintenance improves progression free survival following first- and second-line therapies for chronic lymphocytic leukemia.
Major finding: Median PFS vs. placebo was not reached vs. 13.3 months in CLLM1, and 33.9 vs. 9.2 months in CONTINUUM.
Data source: Phase III randomized studies of lenalidomide maintenance following first-line therapy (CLLM1) and second-line therapy (CONTINUUM).
Disclosures: CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from Celgene, and travel grants and honoraria from other drug companies. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.
How old is too old to be on a kids’ protocol for ALL?
Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
Photo by Bill Branson
SAN DIEGO—In recent years, pediatric or pediatric-inspired protocols have become the preferred treatment approach for younger adults with acute lymphoblastic leukemia (ALL).
These protocols include higher doses of steroids, vincristine, methotrexate, and L-asparaginase.
However, the upper age limit for this strategy has not been defined.
With the GRAALL-2005 study, investigators set out to determine how old is too old to be treated on pediatric protocols.
Their results suggest 55 is likely the upper age limit for patients with Ph-negative ALL.
The investigators also evaluated a hyper-fractionated (hyper-C) versus standard dose (standard-C) of cyclophosphamide during induction and late intensification.
They found that hyper-C did not provide an event-free survival (EFS) benefit in the overall study population, but patients age 55 and older did appear to benefit from hyper-C.
Françoise Huguet, MD, of the Institut Universitaire du Cancer de Toulouse in Toulouse, France, presented these findings at the 2016 ASH Annual Meeting (abstract 762).
GRAALL investigators had previously evaluated a pediatric-inspired protocol for adult patients in the GRAALL-2003 study, which validated the approach.
Study design
Patients with newly diagnosed, Ph-negative ALL were eligible to enroll if they were 18 to 59 years of age.
Treatment comprised a steroid pre-phase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance phase.
Patients could proceed to allogeneic transplant in first complete remission (CR) if eligible.
During induction and late intensification, patients received cyclophosphamide at 750 mg/m2 on day 1 and were then randomized to hyper-C (300 mg/m2/every 12 hours on days 15 to 17) or standard-C (750 mg/m2 on day 15).
The primary endpoint was EFS.
Patient population
Investigators randomized 787 evaluable patients—398 in the standard-C arm and 389 in the hyper-C arm.
Their median age was 36 years, 67% of patients had B-cell precursor ALL, and 33% had T-ALL.
Most had high-risk ALL, 72% of them receiving standard-C and 66% receiving hyper-C.
About a third of the patients in each arm proceeded to allogeneic stem cell transplant in first CR.
Results
The CR rate after induction therapy was 90.2% in the standard-C arm and 93.6% in the hyper-C arm, for an overall CR rate of 92%.
Most patients—87.5% in the standard-C arm and 91.8% in the hyper-C arm—achieved a response in 1 course of therapy.
Sixty percent of patients tested in the standard-C arm and 66% of those tested in the hyper-C arm were minimal residual disease negative at less than 10-4.
There were 26 (6.5%) deaths in the standard-C arm and 18 (4.6%) in the hyper-C arm.
The 5-year EFS rate was 52% overall, and hyper-C treatment had no impact on EFS (hazard ratio=0.89 [range, 0.7-1.1]; P=0.26).
Impact of age
Investigators conducted a post-hoc subgroup analysis of 5 age groups—18-24 years (n=200), 25-34 (n=172), 35-44 (n=171), 45-54 (n=151), and 55+ (n=93).
Overall, the CR rate tended to decrease with age. The rates were 98.5% (18-24), 95.3% (25-34), 87.7% (35-44), 89.4% (45-54), and 79.6% (55+).
Induction death rates increased from 0.5% in the youngest group to 18.3% in the oldest, but the rate of cumulative incidences of failure at 5 years was similar among all the age groups.
The cumulative incidence of treatment-related mortality, without censoring for transplant, ranged from 7.6% in the youngest group to 39.7% in the oldest.
And the 5-year EFS for the youngest patients was 60%, while, for the oldest, it was 26%.
“Above 50 years, the increase in age became highly significant,” Dr Huguet emphasized. “There were fewer CRs and lower survival.”
Treatment compliance
In terms of treatment compliance and median dose received in the induction course, patients aged 55-59 received significantly less L-asparaginase than those aged 18-54 (P<0.001).
During all 3 consolidation phases, patients aged 55-59 received significantly lower median doses of all medications—cytarabine, methotrexate, cyclophosphamide—than patients aged 18-54.
And in late intensification, patients aged 55-59 received significantly lower median doses of vincristine, prednisone, daunorubicin, and hyper-C than all other patients. The median doses of L-asparaginase and standard-C received were lower in the older patients but not significantly so.
EFS by age and randomization
The 5-year EFS for patients aged 18-54 was 57% with hyper-C, compared with 55% in the standard-C arm (P=0.66).
However, for older patients, there was a significant advantage for those receiving hyper-C. The 5-year EFS was 38% with hyper-C, compared to 12% with standard-C (P=0.007).
Dr Huguet explained that inferior compliance in patients 55 and older “might explain why a benefit associated with early hyper-C reinforcement became apparent in these older patients only.”
Dr Huguet concluded that the results “suggest that 55 years is likely to be the upper age limit to tolerate a pediatric-like therapy for younger adults with Ph-negative ALL.”
She added that patients over 54 might benefit from alternative front-line strategies.
Accordingly, investigators are planning to use new agents, such as blinatumomab or inotuzumab ozogamicin, in the next European Working Group on Adult ALL studies.
Two mutations may help drive CBF-AML
2016 ASH Annual Meeting
SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).
The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.
However, the fusion genes alone are not capable of causing CBF-AML.
“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.
“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”
Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).
A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.
For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.
The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.
Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.
The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.
CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.
The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.
In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.
“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”
2016 ASH Annual Meeting
SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).
The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.
However, the fusion genes alone are not capable of causing CBF-AML.
“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.
“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”
Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).
A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.
For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.
The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.
Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.
The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.
CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.
The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.
In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.
“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”
2016 ASH Annual Meeting
SAN DIEGO—Researchers have found evidence to suggest that mutations in the CCND1 and CCND2 genes may contribute to the development of core-binding factor acute myeloid leukemia (CBF-AML).
The team noted that CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11.
However, the fusion genes alone are not capable of causing CBF-AML.
“The hematology community has long sought to determine what other factors in addition to the fusion genes occur in this special type of leukemia,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.
“We are now the first to describe that mutations in CCND1—and among the first to describe that mutations in the sister gene CCND2—are unique features of CBF-AML with t(8;21). In addition, we have collected the first evidence that mutations in CCND2 lead to more aggressive growth of leukemia cell lines.”
Dr Eisfeld and her colleagues reported these findings in a paper published in Leukemia and in a poster presented at the 2016 ASH Annual Meeting (abstract 2740).
A previous study of genetic mutations in CBF-AML revealed the presence of at least 1 mutation in 85% of patients studied. This meant the remaining 15% of patients harbored other, undiscovered mutations.
For the current study, Dr Eisfeld and her colleagues searched CBF-AML samples for the missing mutations that, together with the fusion genes, might contribute to the leukemia in this subgroup of cases.
The team analyzed pretreatment bone marrow and peripheral blood samples from 177 adult CBF-AML patients who received similar treatment through a clinical trial conducted at multiple centers across the US.
Using a targeted, next-generation sequencing approach, the researchers looked for mutations in 84 leukemia- and/or cancer-associated genes. They also performed tests on blood or bone marrow cells to look for chromosomal irregularities.
The team discovered 2 significant mutations in the CCND1 and CCND2 genes, representing the first dual evidence of these recurrent mutations in patients with t(8;21)-positive CBF-AML.
CCND1 and CCND2 mutations were found in 15% (n=10) of patients with t(8;21)-positive CBF-AML. Two patients had mutations in CCND1, and 8 had mutations in CCND2.
The researchers also found a single CCND2 mutation in 1 (0.9%) patient with inv(16)-positive CBF-AML.
In comparison, the incidence of CCND1 and CCND2 mutations was 0.77% (n=11) in a cohort of 1426 patients with non-CBF-AML.
“This is extremely valuable information that was previously unknown,” Dr Eisfeld said, “and it might help us develop targeted therapies more likely to help patients with [CBF-AML] in the near future.”