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EMA recommends safety measures for idelalisib
Photo courtesy of
Gilead Sciences, Inc.
In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).
The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.
These trials have since been stopped.
Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.
These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.
In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.
Recommendations
The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.
Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.
Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.
And patients should be informed about the risk of serious infections with idelalisib.
All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.
Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.
The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.
Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.
About the review
The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.
The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states. 
Photo courtesy of
Gilead Sciences, Inc.
In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).
The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.
These trials have since been stopped.
Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.
These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.
In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.
Recommendations
The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.
Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.
Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.
And patients should be informed about the risk of serious infections with idelalisib.
All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.
Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.
The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.
Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.
About the review
The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.
The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
In light of recently reported safety concerns, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has issued provisional advice for doctors and patients using idelalisib (Zydelig).
The EMA recently began reviewing the safety of idelalisib because of serious adverse events, most of which were infection-related, that were reported in 3 clinical trials investigating idelalisib in combination with other drugs.
These trials have since been stopped.
Now, the PRAC is making provisional recommendations to ensure idelalisib is used as safely as possible outside of clinical trials.
These recommendations will be forwarded to the European Commission, which will issue a provisional legally binding decision applicable in all European Union (EU) member states.
In the EU, idelalisib is approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
Idelalisib is also approved for use in combination with rituximab to treat adults with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients considered unsuitable for chemo-immunotherapy.
Recommendations
The PRAC is recommending that previously untreated CLL patients with 17p deletion or TP53 mutation do not begin treatment with idelalisib. In addition, doctors should re-evaluate each patient taking idelalisib as first-line treatment for CLL and only continue treatment if the benefits outweigh the risks.
Idelalisib can continue to be used in combination, only with rituximab, in CLL patients who have received at least 1 prior therapy and as monotherapy in patients with follicular lymphoma that is refractory to 2 lines of treatment.
Patients with any evidence of ongoing systemic infection should not be started on treatment with idelalisib.
And patients should be informed about the risk of serious infections with idelalisib.
All patients who do receive idelalisib should take antibiotics to prevent Pneumocystis jirovecii pneumonia, and they should be monitored for respiratory signs and symptoms. Regular clinical and laboratory monitoring for cytomegalovirus infection is also recommended.
Patients should have regular blood tests to detect neutropenia. In case a patient has moderate or severe neutropenia, treatment with idelalisib may have to be interrupted, in line with the updated summary of product characteristics.
The EMA said further details on these provisional measures will be provided in writing to healthcare professionals, and the product information will be updated accordingly.
Likewise, further information on the review of idelalisib will be provided as necessary and once the review is finished.
About the review
The EMA’s review of idelalisib started after a higher rate of serious adverse events, including deaths, was seen in 3 clinical trials evaluating the addition of idelalisib to standard therapy in first-line CLL and relapsed indolent non-Hodgkin lymphoma (NHL).
Most of the deaths were related to infections such as Pneumocystis jirovecii pneumonia and cytomegalovirus infection. Other excess deaths were related mainly to respiratory events.
The NHL studies (NCT01732926 and NCT01732913) included patients with disease characteristics different from those covered by the currently approved indication for idelalisib and investigated combinations of drugs that are not currently approved in the EU—idelalisib plus rituximab for NHL and idelalisib plus bendamustine and rituximab for NHL.
The CLL trial (NCT01980888) involved patients who had not received previous treatment, some of whom had the 17p deletion or TP53 mutation. However, the trial also investigated a combination of drugs not currently approved in the EU—idelalisib plus bendamustine and rituximab.
At present, the PRAC is conducting the review. Once the PRAC is finished, its recommendations will be forwarded to the EMA’s Committee for Medicinal Products for Human Use, which will adopt a final opinion.
The European Commission will take this opinion into account and adopt a legally binding decision that is applicable in all EU member states.
Idelalisib use halted in six combo therapy trials, FDA announces
An increased rate of adverse events, including deaths, have been reported in clinical trials with idelalisib (Zydelig) in combination with other cancer medicines, the U.S. Food and Drug Administration announced.
Gilead Sciences, Inc. has confirmed that they are stopping six clinical trials in patients with chronic lymphocytic leukemia, small lymphocytic lymphoma and indolent non-Hodgkin lymphomas. The FDA is reviewing the findings of the clinical trials and will communicate new information as necessary, according to the FDA press release.
Idelalisib is not approved for previously untreated chronic lymphocytic leukemia. It is approved by the FDA for the treatment of:
• Relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
• Relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies.
• Relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies.
Adverse events involving idelalisib should be reported to the FDA MedWatch program, the release advised.
On Twitter @maryjodales
An increased rate of adverse events, including deaths, have been reported in clinical trials with idelalisib (Zydelig) in combination with other cancer medicines, the U.S. Food and Drug Administration announced.
Gilead Sciences, Inc. has confirmed that they are stopping six clinical trials in patients with chronic lymphocytic leukemia, small lymphocytic lymphoma and indolent non-Hodgkin lymphomas. The FDA is reviewing the findings of the clinical trials and will communicate new information as necessary, according to the FDA press release.
Idelalisib is not approved for previously untreated chronic lymphocytic leukemia. It is approved by the FDA for the treatment of:
• Relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
• Relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies.
• Relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies.
Adverse events involving idelalisib should be reported to the FDA MedWatch program, the release advised.
On Twitter @maryjodales
An increased rate of adverse events, including deaths, have been reported in clinical trials with idelalisib (Zydelig) in combination with other cancer medicines, the U.S. Food and Drug Administration announced.
Gilead Sciences, Inc. has confirmed that they are stopping six clinical trials in patients with chronic lymphocytic leukemia, small lymphocytic lymphoma and indolent non-Hodgkin lymphomas. The FDA is reviewing the findings of the clinical trials and will communicate new information as necessary, according to the FDA press release.
Idelalisib is not approved for previously untreated chronic lymphocytic leukemia. It is approved by the FDA for the treatment of:
• Relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
• Relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies.
• Relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies.
Adverse events involving idelalisib should be reported to the FDA MedWatch program, the release advised.
On Twitter @maryjodales
AEs prompt EMA review of idelalisib
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Photo courtesy of
Gilead Sciences, Inc.
The European Medicines Agency (EMA) is reviewing the safety of idelalisib (Zydelig), a drug approved to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma in the European Union (EU).
The European Commission (EC) requested the review because of serious adverse events (AEs), including deaths, reported in 3 clinical trials investigating idelalisib in combination with other drugs.
The AEs were mostly infection-related.
The EMA is reviewing data from these studies to assess whether the findings have any consequences for the authorized uses of idelalisib.
In the meantime, the EMA advises that patients starting or already on treatment with idelalisib be carefully monitored for signs of infections. If the drug is well tolerated, treatment should not be stopped.
The EMA is considering whether any other immediate measures are necessary during the review period. The agency said it will communicate further and keep doctors and patients informed as appropriate.
About idelalisib
In the EU, idelalisib is approved for use in combination with rituximab to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment in the presence of 17p deletion or TP53 mutation in CLL patients unsuitable for chemo-immunotherapy.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
About the trials
The trials in which patients have experienced serious AEs involve patients with CLL and indolent non-Hodgkin lymphoma (NHL).
In one trial (NCT01732926), researchers are evaluating idelalisib in combination with bendamustine and rituximab for previously treated indolent NHL.
In another (NCT01732913), researchers are testing idelalisib in combination with rituximab for previously treated indolent NHL.
And in the third (NCT01980888), researchers are evaluating idelalisib in combination with bendamustine and rituximab in patients with previously untreated CLL.
The EMA noted that these studies are investigating combinations of drugs that are currently not approved in the EU and include patients with disease characteristics different from those covered by the approved indications for idelalisib.
About the review
The EMA has begun the review of idelalisib at the request of the EC, under Article 20 of Directive 2001/83/EC.
The review is being carried out by the EMA’s Pharmacovigilance Risk Assessment Committee, the committee responsible for the evaluation of safety issues for human medicines, which will make a set of recommendations.
Those recommendations will then be forwarded to the Committee for Medicinal Products for Human Use, which is responsible for questions concerning medicines for human use and will adopt a final opinion on the safety of idelalisib.
The final stage of the review procedure is the EC’s adoption of a legally binding decision that is applicable in all EU member states.
Follicular lymphoma: Quantitative PET/CT measures for detecting bone marrow involvement
Quantifying bone marrow uptake of FDG (18fluorodeoxyglucose) improved the diagnostic accuracy of PET/CT for predicting bone marrow involvement in patients with follicular lymphoma, based on the results of a retrospective study.
Visual evidence of focal increased uptake on PET/CT indicates marrow involvement in follicular lymphoma; however, diffuse uptake is a nonspecific finding. Measuring the mean bone marrow standardized uptake value (BM SUV mean) improves PET/CT diagnostic accuracy, Dr. Chava Perry and his colleagues at Tel Aviv Sourasky Medical Center reported in Medicine [(Baltimore). 2016 Mar;95(9):e2910].
The researchers evaluated 68 consecutive patients with follicular lymphoma; 16 had bone marrow involvement – 13 had biopsy-proven involvement and 3 had a negative biopsy with increased medullary uptake that normalized after treatment. BM FDG uptake was diffuse in 8 of them and focal in the other 8.
While focal increased uptake is indicative of bone marrow involvement, diffuse uptake can be associated with false-positive results, as it was in the case of 17 patients (32.7% of those with diffuse uptake). Overall, visual assessment of scan results had a negative predictive value of 100% and a positive predictive value (PPV) of 48.5%.
On a quantitative assessment, however, BM SUV mean was significantly higher in patients with bone marrow involvement (SUV mean of 3.7 [1.7-6] vs. 1.4 [0.4-2.65]; P less than .001). On the receiver operator curve (ROC) analysis, a BM SUV mean exceeding 2.7 had a positive predictive value of 100% for bone marrow involvement (sensitivity of 68%). A BM SUV mean less than 1.7 had an negative predictive value of 100% (specificity of 73%).
A mean standardized uptake value (BM SUV mean) below 1.7 may spare the need for bone marrow biopsy while a BM SUV mean above 2.7 is compatible with bone marrow involvement, although biopsy may still be recommended to exclude large cell transformation, the researchers concluded.
On Twitter @maryjodales
Quantifying bone marrow uptake of FDG (18fluorodeoxyglucose) improved the diagnostic accuracy of PET/CT for predicting bone marrow involvement in patients with follicular lymphoma, based on the results of a retrospective study.
Visual evidence of focal increased uptake on PET/CT indicates marrow involvement in follicular lymphoma; however, diffuse uptake is a nonspecific finding. Measuring the mean bone marrow standardized uptake value (BM SUV mean) improves PET/CT diagnostic accuracy, Dr. Chava Perry and his colleagues at Tel Aviv Sourasky Medical Center reported in Medicine [(Baltimore). 2016 Mar;95(9):e2910].
The researchers evaluated 68 consecutive patients with follicular lymphoma; 16 had bone marrow involvement – 13 had biopsy-proven involvement and 3 had a negative biopsy with increased medullary uptake that normalized after treatment. BM FDG uptake was diffuse in 8 of them and focal in the other 8.
While focal increased uptake is indicative of bone marrow involvement, diffuse uptake can be associated with false-positive results, as it was in the case of 17 patients (32.7% of those with diffuse uptake). Overall, visual assessment of scan results had a negative predictive value of 100% and a positive predictive value (PPV) of 48.5%.
On a quantitative assessment, however, BM SUV mean was significantly higher in patients with bone marrow involvement (SUV mean of 3.7 [1.7-6] vs. 1.4 [0.4-2.65]; P less than .001). On the receiver operator curve (ROC) analysis, a BM SUV mean exceeding 2.7 had a positive predictive value of 100% for bone marrow involvement (sensitivity of 68%). A BM SUV mean less than 1.7 had an negative predictive value of 100% (specificity of 73%).
A mean standardized uptake value (BM SUV mean) below 1.7 may spare the need for bone marrow biopsy while a BM SUV mean above 2.7 is compatible with bone marrow involvement, although biopsy may still be recommended to exclude large cell transformation, the researchers concluded.
On Twitter @maryjodales
Quantifying bone marrow uptake of FDG (18fluorodeoxyglucose) improved the diagnostic accuracy of PET/CT for predicting bone marrow involvement in patients with follicular lymphoma, based on the results of a retrospective study.
Visual evidence of focal increased uptake on PET/CT indicates marrow involvement in follicular lymphoma; however, diffuse uptake is a nonspecific finding. Measuring the mean bone marrow standardized uptake value (BM SUV mean) improves PET/CT diagnostic accuracy, Dr. Chava Perry and his colleagues at Tel Aviv Sourasky Medical Center reported in Medicine [(Baltimore). 2016 Mar;95(9):e2910].
The researchers evaluated 68 consecutive patients with follicular lymphoma; 16 had bone marrow involvement – 13 had biopsy-proven involvement and 3 had a negative biopsy with increased medullary uptake that normalized after treatment. BM FDG uptake was diffuse in 8 of them and focal in the other 8.
While focal increased uptake is indicative of bone marrow involvement, diffuse uptake can be associated with false-positive results, as it was in the case of 17 patients (32.7% of those with diffuse uptake). Overall, visual assessment of scan results had a negative predictive value of 100% and a positive predictive value (PPV) of 48.5%.
On a quantitative assessment, however, BM SUV mean was significantly higher in patients with bone marrow involvement (SUV mean of 3.7 [1.7-6] vs. 1.4 [0.4-2.65]; P less than .001). On the receiver operator curve (ROC) analysis, a BM SUV mean exceeding 2.7 had a positive predictive value of 100% for bone marrow involvement (sensitivity of 68%). A BM SUV mean less than 1.7 had an negative predictive value of 100% (specificity of 73%).
A mean standardized uptake value (BM SUV mean) below 1.7 may spare the need for bone marrow biopsy while a BM SUV mean above 2.7 is compatible with bone marrow involvement, although biopsy may still be recommended to exclude large cell transformation, the researchers concluded.
On Twitter @maryjodales
FROM MEDICINE
Key clinical point: Measuring the mean standardized uptake value of 18fluorodeoxyglucose in the bone marrow of patients with follicular lymphoma improves the diagnostic accuracy of PET/CT.
Major finding: In this study, diffuse uptake was associated with 17 (32.7%) false positive cases.
Data source: Retrospective study of 68 consecutive patients with follicular lymphoma.
Disclosures: The authors had no funding and conflicts of interest to disclose.
Germline mutations linked to hematologic malignancies
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
Teens’ weight, height linked to risk of NHL
A new analysis indicates that having a higher body weight and taller stature during adolescence may increase the risk of developing non-Hodgkin lymphoma (NHL).
Global rates of NHL have been on the rise in recent years, and research suggests that rising rates of obesity may be contributing to this trend.
With this in mind, investigators examined whether adolescent weight and height might be associated with the risk of developing NHL later in life.
They reported their results in Cancer.
The study included 2,352,988 subjects, ages 16 to 19, who were examined between 1967 and 2011. Their information was linked to the Israel National Cancer Registry, which included 4021 cases of NHL from 1967 through 2012.
The data showed that being overweight or obese in adolescence was associated with an increased risk of NHL later in life. When compared to adolescents of normal weight, the hazard ratio (HR) was 1.25 for subjects who were overweight or obese. The HR for underweight individuals was 0.98.
Being overweight or obese in adolescence was a significant predictor for marginal zone lymphoma (HR=1.70), primary cutaneous lymphoma (PCL, HR=1.44), and diffuse large B-cell lymphoma (DLBCL, HR=1.31). Excess weight was a borderline predictor for follicular lymphoma (HR=1.28).
“It is important to be aware that overweight and obesity are not risk factors only for diabetes and cardiovascular disease but also for lymphomas,” said study author Merav Leiba, MD, of the Sheba Medical Center in Israel.
Dr Leiba and her colleagues also observed an increased risk of NHL corresponding with increases in subjects’ height. When compared with the mid-range height category, shorter individuals had an HR of 1.25, and the tallest individuals had an HR of 1.28.
The strongest associations between taller height and NHL were observed for primary cutaneous lymphoma and diffuse large B-cell lymphoma. The HRs for the tallest group, compared to the shortest group, were 3.19 for PCL and 2.21 for DLBCL.
The investigators said additional research is needed to help explain the links between height, weight, and NHL.
A new analysis indicates that having a higher body weight and taller stature during adolescence may increase the risk of developing non-Hodgkin lymphoma (NHL).
Global rates of NHL have been on the rise in recent years, and research suggests that rising rates of obesity may be contributing to this trend.
With this in mind, investigators examined whether adolescent weight and height might be associated with the risk of developing NHL later in life.
They reported their results in Cancer.
The study included 2,352,988 subjects, ages 16 to 19, who were examined between 1967 and 2011. Their information was linked to the Israel National Cancer Registry, which included 4021 cases of NHL from 1967 through 2012.
The data showed that being overweight or obese in adolescence was associated with an increased risk of NHL later in life. When compared to adolescents of normal weight, the hazard ratio (HR) was 1.25 for subjects who were overweight or obese. The HR for underweight individuals was 0.98.
Being overweight or obese in adolescence was a significant predictor for marginal zone lymphoma (HR=1.70), primary cutaneous lymphoma (PCL, HR=1.44), and diffuse large B-cell lymphoma (DLBCL, HR=1.31). Excess weight was a borderline predictor for follicular lymphoma (HR=1.28).
“It is important to be aware that overweight and obesity are not risk factors only for diabetes and cardiovascular disease but also for lymphomas,” said study author Merav Leiba, MD, of the Sheba Medical Center in Israel.
Dr Leiba and her colleagues also observed an increased risk of NHL corresponding with increases in subjects’ height. When compared with the mid-range height category, shorter individuals had an HR of 1.25, and the tallest individuals had an HR of 1.28.
The strongest associations between taller height and NHL were observed for primary cutaneous lymphoma and diffuse large B-cell lymphoma. The HRs for the tallest group, compared to the shortest group, were 3.19 for PCL and 2.21 for DLBCL.
The investigators said additional research is needed to help explain the links between height, weight, and NHL.
A new analysis indicates that having a higher body weight and taller stature during adolescence may increase the risk of developing non-Hodgkin lymphoma (NHL).
Global rates of NHL have been on the rise in recent years, and research suggests that rising rates of obesity may be contributing to this trend.
With this in mind, investigators examined whether adolescent weight and height might be associated with the risk of developing NHL later in life.
They reported their results in Cancer.
The study included 2,352,988 subjects, ages 16 to 19, who were examined between 1967 and 2011. Their information was linked to the Israel National Cancer Registry, which included 4021 cases of NHL from 1967 through 2012.
The data showed that being overweight or obese in adolescence was associated with an increased risk of NHL later in life. When compared to adolescents of normal weight, the hazard ratio (HR) was 1.25 for subjects who were overweight or obese. The HR for underweight individuals was 0.98.
Being overweight or obese in adolescence was a significant predictor for marginal zone lymphoma (HR=1.70), primary cutaneous lymphoma (PCL, HR=1.44), and diffuse large B-cell lymphoma (DLBCL, HR=1.31). Excess weight was a borderline predictor for follicular lymphoma (HR=1.28).
“It is important to be aware that overweight and obesity are not risk factors only for diabetes and cardiovascular disease but also for lymphomas,” said study author Merav Leiba, MD, of the Sheba Medical Center in Israel.
Dr Leiba and her colleagues also observed an increased risk of NHL corresponding with increases in subjects’ height. When compared with the mid-range height category, shorter individuals had an HR of 1.25, and the tallest individuals had an HR of 1.28.
The strongest associations between taller height and NHL were observed for primary cutaneous lymphoma and diffuse large B-cell lymphoma. The HRs for the tallest group, compared to the shortest group, were 3.19 for PCL and 2.21 for DLBCL.
The investigators said additional research is needed to help explain the links between height, weight, and NHL.
NICE issues draft guideline for NHL
a cancer patient
Photo courtesy of NCI/
Mathews Media Group
The National Institute for Health and Care Excellence (NICE) has issued a draft guideline for the diagnosis and management of non-Hodgkin lymphoma (NHL).
The guideline, which is open for consultation, covers adults and young people who are referred to secondary care with suspected NHL or who have newly diagnosed or relapsed NHL.
It contains recommendations for the management of 6 different NHL subtypes—diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, MALT lymphoma, Burkitt lymphoma, and peripheral T-cell lymphoma.
The guideline considers which method of biopsy is most appropriate, which diagnostic test most suitable, how the stage of disease is best assessed, and what treatment is likely to be most effective.
It also proposes recommendations for how best to support patients who complete their treatment. These include the provision of end-of-treatment summaries to be discussed with the patient and an increase in education on the possible relapse/late side-effects of their treatment.
“This draft guideline is now open for consultation,” said Mark Baker, director of the Centre of Clinical Practice at NICE.
“We want to hear from patients and all those who provide care for people with non-Hodgkin’s lymphoma in the NHS [National Health Service] so that we can produce a guideline which will support everyone who diagnoses, treats, and has to live with this disease.”
The consultation closes on March 11, 2016, with the final guideline expected in the summer.
a cancer patient
Photo courtesy of NCI/
Mathews Media Group
The National Institute for Health and Care Excellence (NICE) has issued a draft guideline for the diagnosis and management of non-Hodgkin lymphoma (NHL).
The guideline, which is open for consultation, covers adults and young people who are referred to secondary care with suspected NHL or who have newly diagnosed or relapsed NHL.
It contains recommendations for the management of 6 different NHL subtypes—diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, MALT lymphoma, Burkitt lymphoma, and peripheral T-cell lymphoma.
The guideline considers which method of biopsy is most appropriate, which diagnostic test most suitable, how the stage of disease is best assessed, and what treatment is likely to be most effective.
It also proposes recommendations for how best to support patients who complete their treatment. These include the provision of end-of-treatment summaries to be discussed with the patient and an increase in education on the possible relapse/late side-effects of their treatment.
“This draft guideline is now open for consultation,” said Mark Baker, director of the Centre of Clinical Practice at NICE.
“We want to hear from patients and all those who provide care for people with non-Hodgkin’s lymphoma in the NHS [National Health Service] so that we can produce a guideline which will support everyone who diagnoses, treats, and has to live with this disease.”
The consultation closes on March 11, 2016, with the final guideline expected in the summer.
a cancer patient
Photo courtesy of NCI/
Mathews Media Group
The National Institute for Health and Care Excellence (NICE) has issued a draft guideline for the diagnosis and management of non-Hodgkin lymphoma (NHL).
The guideline, which is open for consultation, covers adults and young people who are referred to secondary care with suspected NHL or who have newly diagnosed or relapsed NHL.
It contains recommendations for the management of 6 different NHL subtypes—diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, MALT lymphoma, Burkitt lymphoma, and peripheral T-cell lymphoma.
The guideline considers which method of biopsy is most appropriate, which diagnostic test most suitable, how the stage of disease is best assessed, and what treatment is likely to be most effective.
It also proposes recommendations for how best to support patients who complete their treatment. These include the provision of end-of-treatment summaries to be discussed with the patient and an increase in education on the possible relapse/late side-effects of their treatment.
“This draft guideline is now open for consultation,” said Mark Baker, director of the Centre of Clinical Practice at NICE.
“We want to hear from patients and all those who provide care for people with non-Hodgkin’s lymphoma in the NHS [National Health Service] so that we can produce a guideline which will support everyone who diagnoses, treats, and has to live with this disease.”
The consultation closes on March 11, 2016, with the final guideline expected in the summer.
Mutations could be therapeutic target for FL
Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.
They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.
And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.
Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.
“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.
“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”
Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.
In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.
Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.
“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”
The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.
“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”
Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.
They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.
And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.
Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.
“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.
“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”
Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.
In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.
Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.
“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”
The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.
“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”
Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.
They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.
And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.
Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.
“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.
“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”
Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.
In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.
Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.
“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”
The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.
“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”
EZH2 inhibitor can produce durable responses
ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).
The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.
In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.
The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.
At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.
The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.
The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.
Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.
Safety
At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.
Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).
There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.
Efficacy
Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).
Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.
Four responders remain on study—2 with DLBCL and 2 with FL.
One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.
Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.
*Data in the abstract differ from the presentation.
ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).
The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.
In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.
The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.
At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.
The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.
The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.
Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.
Safety
At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.
Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).
There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.
Efficacy
Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).
Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.
Four responders remain on study—2 with DLBCL and 2 with FL.
One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.
Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.
*Data in the abstract differ from the presentation.
ORLANDO, FL—Updated results of a phase 1 study suggest the EZH2 inhibitor tazemetostat (EPZ-6438) can produce durable responses in patients with advanced non-Hodgkin lymphoma (NHL).
The drug has demonstrated activity against diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
The overall response rate among NHL patients in this study was 56%, and 1 patient has maintained a response for more than 21 months.
In addition, the drug’s safety profile is “still acceptable,” according to Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.
Dr Ribrag presented the results of this study at the 2015 ASH Annual Meeting (abstract 473*). The research, which was previously presented at the 13th International Conference on Malignant Lymphoma, was sponsored by Epizyme, Inc., the company developing tazemetostat.
The trial has enrolled 58 patients, 21 with relapsed or refractory B-cell NHL and 37 with advanced solid tumors. The NHL cohort includes 5 patients with germinal center B-cell (GCB) DLBCL, 6 cases of non-GCB DLBCL, 3 DLBCL cases of an undetermined subtype, 6 patients with FL, and 1 case of MZL.
At baseline, the NHL patients had a median age of 63 (range, 24-84) and were heavily pretreated. Eighty-five percent of patients had received 3 or more prior therapies, and 33% had received 5 or more. Thirty-eight percent of patients had undergone an autologous transplant, and 57% had received radiotherapy.
The patients received tazemetostat twice daily at a range of doses. For the dose-escalation portion of the trial, they received 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. For the dose-expansion phase, they received 800 mg or 1600 mg.
The researchers are now conducting a drug-drug interaction substudy in which patients receive 800 mg of tazemetostat twice daily and a food-effect substudy in which patients receive the drug at 400 mg twice daily.
Dr Ribrag said the recommended phase 2 dose of tazemetostat is 800 mg twice daily.
Safety
At the data cutoff point (November 7, 2015), 55 patients—20 with NHL and 35 with solid tumors—were evaluable for safety.
Treatment-related adverse events in these patients included asthenia (n=13), nausea (n=8), thrombocytopenia (n=7), dysgeusia (n=5), vomiting (n=5), dry skin (n=4), decreased appetite (n=4), diarrhea (n=4), muscle spasms (n=3), neutropenia (n=3), anemia (n=3), night sweats (n=3), hypertension (n=2), constipation (n=2), peripheral edema (n=2), hypophosphatemia (n=1), anxiety (n=1), depression (n=1), abdominal pain (n=1), and hepatocellular injury (n=1).
There were 4 grade 3 or higher adverse events that were considered treatment-related, including nausea, hypertension, neutropenia, and hepatocellular injury.
Efficacy
Sixteen of the NHL patients were evaluable for efficacy. Nine patients responded to treatment, 2 with complete responses (CRs) and 7 with partial responses (PRs).
Five of the 10 DLBCL patients responded, 4 with PRs and 1 with a CR. Three of the 5 FL patients responded, 2 with PRs and 1 with a CR. The patient with MZL achieved a PR.
Four responders remain on study—2 with DLBCL and 2 with FL.
One DLBCL patient with an EZH2 mutation (Y646H) had relapsed after or was refractory to 6 previous treatment regimens. This patient achieved a PR after 16 weeks of tazemetostat. The patient is still in PR at week 44 and remains on study.
Based on these results, Epizyme is currently enrolling patients in a phase 2 study of tazemetostat monotherapy. The trial is open to patients with DLBCL or FL in France, Australia, and the UK.
*Data in the abstract differ from the presentation.
Triplet disappoints in follicular lymphoma trial
Photo courtesy of ASH
ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.
In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.
But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.
Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*
“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.
She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.
In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.
Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.
In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.
With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.
Study design
The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.
They received 4 doses of rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m2) on day 1 of cycles 4, 6, 8, and 10.
The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.
The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.
Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.
The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.
Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.
Patients and treatment
Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.
Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.
Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.
However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.
Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)
Adverse events
Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).
The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.
Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.
Rash
“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”
Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.
The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.
“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”
“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”
Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.
All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.
Response and survival
The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.
The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).
The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).
At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.
“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.
In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.
But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.
Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*
“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.
She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.
In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.
Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.
In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.
With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.
Study design
The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.
They received 4 doses of rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m2) on day 1 of cycles 4, 6, 8, and 10.
The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.
The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.
Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.
The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.
Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.
Patients and treatment
Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.
Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.
Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.
However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.
Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)
Adverse events
Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).
The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.
Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.
Rash
“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”
Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.
The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.
“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”
“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”
Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.
All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.
Response and survival
The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.
The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).
The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).
At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.
“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”
*Data in the abstract differ from data presented at the meeting.
Photo courtesy of ASH
ORLANDO, FL—A 3-drug regimen is likely not worth pursuing as a first-line treatment option for follicular lymphoma (FL), according to a presentation at the 2015 ASH Annual Meeting.
In a phase 1 study, combination ibrutinib, rituximab, and lenalidomide did not provide any response benefit over that previously observed with rituximab and lenalidomide.
But the triplet increased toxicity—particularly the incidence of rash—and necessitated dose modifications.
Chaitra S. Ujjani, MD, of Georgetown University Hospital in Washington, DC, presented these results at the meeting as abstract 471.*
“The combination of rituximab and lenalidomide has demonstrated remarkable activity in follicular lymphoma,” Dr Ujjani began.
She noted that, in the CALGB 50401 trial of relapsed FL (Leonard et al. JCO 2015), the combination elicited an overall response rate (ORR) of 76% and a complete response (CR) rate of 39%, and the 2-year time to progression was 52%.
In the CALGB 50803 trial of previously untreated FL (Martin et al. ASCO 2014, 8521), the regimen produced an ORR of 96%, a CR rate of 71%, and a 2-year progression-free survival (PFS) of 89%. In another trial of previously untreated FL (Fowler et al. Lanc Onc 2014), the ORR was 90%, the CR rate was 80%, and the 3-year PFS was 79%.
Ibrutinib has also demonstrated activity in FL, Dr Ujjani pointed out. In a phase 1 study of relapsed FL (Fowler et al. ASH 2012), the drug produced an ORR of 55%, 3 of 11 patients achieved a CR, and the median PFS was 13.4 months.
In a phase 2 study of ibrutinib in relapsed FL (Bartlett et al. ASH 2014, 800), the ORR was 30%, 1 of 40 patients achieved a CR, and the median PFS was 9.9 months.
With this in mind, Dr Ujjani and her colleagues conducted the A051103 trial to determine the activity and tolerability of rituximab, lenalidomide, and ibrutinib in previously untreated patients with FL.
Study design
The study enrolled patients with grade 1-3a FL; stage III, IV, or bulky stage II disease; an ECOG performance status less than 2; and adequate organ function.
They received 4 doses of rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28 days). They received 4 additional doses (375 mg/m2) on day 1 of cycles 4, 6, 8, and 10.
The patients received lenalidomide according to their assigned dosing cohort on days 1 to 21 for 18 cycles. They received daily ibrutinib according to their assigned dosing cohort until progression or unacceptable toxicity.
The study had a 3+3 dose-escalation design. Dose level (DL) 0 was lenalidomide at 15 mg and ibrutinib at 420 mg, DL1 was lenalidomide at 15 mg and ibrutinib at 560 mg, and DL2 was lenalidomide at 20 mg and ibrutinib at 560 mg.
Patients also received allopurinol at 300 mg daily for tumor lysis prophylaxis and aspirin as thromboprophylaxis while on lenalidomide.
The researchers assessed dose-limiting toxicities (DLTs) weekly during cycle 1. Given the known incidence of rash with lenalidomide, grade 3 rash that resolved to less than grade 2 within 10 days was not included as a DLT.
Once the maximum-tolerated dose was determined, there was a 10-patient expansion cohort.
Patients and treatment
Twenty-two patients were enrolled between June 2013 and May 2015. Their median age was 53.5 years (range, 36-81), and 68% were male.
Seventy-three percent of patients had grade 1/2 disease, and 77% had stage IV disease. By FLIPI, 18% of patients were low-risk, 55% were intermediate-risk, and 27% were high-risk.
Three patients were treated at DL0, 3 at DL1, and 16 at DL2. There were no DLTs reported at any dose level.
However, 11 patients required dose reductions due to toxicity (7 due to rash), and 12 patients ultimately discontinued treatment.
Reasons for discontinuation included progression (n=2), new diagnosis of carcinoma requiring systemic therapy (n=2), patient decision (n=3), and adverse events (n=6), including grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1), hypertension (n=1), and depression (n=1). (One patient discontinued due to rash and progression.)
Adverse events
Dr Ujjani said the hematologic toxicity profile was similar to that observed with rituximab and lenalidomide in the front-line setting. Grade 3/4 hematologic toxicities included neutropenia (18.2%), thrombocytopenia (4.5%), anemia (4.5%), and lymphopenia (4.5%).
The most common non-hematologic toxicities (occurring in more than 20% of patients) were rash, diarrhea, fatigue, infusion-related reactions, nausea, infection, and neoplasms. There were no grade 4 non-hematologic toxicities.
Compared to rituximab and lenalidomide, the triplet was associated with an increase in rash, diarrhea, arthralgia, and neoplasm. There were 2 cutaneous neoplasms and 3 carcinomas.
Rash
“While no protocol-defined DLTs were observed, the regimen was associated with clinically significant rash,” Dr Ujjani noted. “Rash may have been related to individual study drugs or drug-drug interactions.”
Rash occurred in 82% of patients overall, 100% of patients treated at DL0, 67% at DL1, and 81% at DL2. The incidence of grade 1/2 rash was 46% overall, 67% at DL0, 33% at DL1, and 44% at DL2. The incidence of grade 3 rash was 36% overall, 33% at DL0 and DL1, and 38% at DL2.
The incidence of rash was similar whether or not patients received allopurinol. Ten of 11 patients on allopurinol had a rash, and 8 of 11 patients not on allopurinol had a rash.
“The time of [rash] onset was typically during cycle 1 but was seen as late as cycle 5,” Dr Ujjani said. “Grade 1 and 2 rashes resolved spontaneously without dose modification. The incidence of these milder rashes were comparable to our prior reports of rituximab and lenalidomide.”
“Grade 3 rash, however, occurred in 36% of patients, which is significantly higher than [with] rituximab and lenalidomide, [which is] typically 7% to 8%, or single-agent ibrutinib, which is about 3% to 4%.”
Patients with grade 3 rash were managed with supportive care, including acetaminophen, diphenhydramine, and oral corticosteroids.
All but 1 patient (7/8) had dose delays and reductions due to rash. One patient withdrew from the study because of rash, and 1 patient withdrew because of disease progression that occurred during a dose delay for rash.
Response and survival
The ORR was 95% for the entire cohort, 100% at DL0 and DL1 and 94% at DL2. The CR/unconfirmed CR rate was 63% overall, 67% at DL0, 33% at DL1, and 69% at DL2.
The partial response rate was 32% overall, 33% at DL0, 67% at DL1, and 25% at DL2. Five percent of patients had stable disease, all at DL2 (6% of this group).
The median time to first response was 2.3 months (range, 1.9 to 11.1). And the median time to best response was 5.5 months (range, 1.9 to 20.2).
At a median follow-up of 12.3 months, all patients are still alive. The 12-month PFS is 84%.
“Preliminary response data were similar to the prior CALGB/Alliance study of rituximab and lenalidomide,” Dr Ujjani noted. “However, given the increased toxicity and required dose modifications, the additional benefit of a third agent is not apparent, and further investigation of the triplet in this setting seems unwarranted.”
*Data in the abstract differ from data presented at the meeting.