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FDA approves rituximab + hyaluronidase human for FL, DLBCL, and CLL
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).
The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.
Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.
The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.
The combination is indicated for the following previously approved indications for rituximab:
- Relapsed or refractory FL as a single agent.
- Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
- Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
- Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
- Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.
The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.
Rituxan Hycela is marketed by Genentech.
Lenalidomide consolidation linked to extended overall survival in non-del(11q) CLL
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
[email protected]
On Twitter @maryjodales
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
[email protected]
On Twitter @maryjodales
CHICAGO – Lenalidomide consolidation therapy was associated with an extended survival plateau for patients with non-del(11q) chronic lymphocytic leukemia (CLL), based on results from the phase 2 CALGB 10404 trial.
This unique survival plateau indicates future studies should continue to examine the role of lenalidomide, compared with fludarabine plus rituximab therapy, as well as the incorporation of lenalidomide into other novel treatment regimens, Amy Ruppert, MAS, said at the annual meeting of the American Society of Clinical Oncology.
All patients received 6 months of FR or FCR therapy, then patients underwent full staging. At 10 months, patients who had been randomized to the FR + lenalidomide group received lenalidomide 5 mg on days 1-21 of the first 28 day cycle and lenalidomide 10 mg on days 1-21 of the subsequent 5 cycles. At 18 months, patients in the FR+L group underwent full staging, and all patients underwent full staging at 24 months.
Based on pretreatment central interphase cytogenetic screening, patients who had del(11q22.3) in at least 20% of their cells were excluded from the primary analysis of 2-year progression-free survival.
Median progression-free survival was significantly shorter with FR, compared with FR+L (P = .03) and FCR (P less than .01), at 43 months (95% CI, 33-50), 66 months (95% CI, 45-not reached), and 78 months (95% CI, 58-not reached), respectively.
Median overall survival has not been reached for any arm of the study. While overall survival was similar across all arms at 1, 2, and 3 years of follow-up, there was a plateau in overall survival with no events seen beyond 41 months in the FR+L arm. Events continued to occur in the FR and FCR arms, reported Ms. Ruppert of the Comprehensive Cancer Center at Ohio State University, Columbus. At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
[email protected]
On Twitter @maryjodales
AT ASCO 2017
Key clinical point:
Major finding: At 48 months, the hazard ratio for overall survival in FR+L vs. FR was 0.27 (95% CI, 0.10-0.70; P = .01).
Data source: Results from 342 patients in the phase 2 CALGB 10404 trial.
Disclosures: Ms. Ruppert had no financial disclosures. The study is sponsored by the National Cancer Institute and Celgene.
Sequential triple therapy produces high response rates in CLL
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
AT 14-ICML
Key clinical point: Sequential therapy with bendamustine, obinutuzumab, and venetoclax was associated with high response rates in patients with both treatment-naive and relapsed/refractory chronic lymphocytic leukemia.
Major finding: The overall response rate at the end of induction was 95%.
Data source: An open-label prospective study in 66 patients with CLL.
Disclosures: The study was sponsored by the German CLL study group. Dr. Cramer and her coauthors disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Hitting BTK, PI3K pays off in B-cell malignancies
LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.
One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).
“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.
In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.
Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.
All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.
For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.
Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.
One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.
The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.
The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.
The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.
The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.
One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).
“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.
In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.
Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.
All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.
For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.
Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.
One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.
The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.
The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.
The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.
The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
LUGANO, SWITZERLAND – A combination of ibrutinib and umbralisib, an investigational inhibitor of phosphatidylinostiol 3-kinase (PI3K), induced high response rates in patients with relapsed/refractory B-cell malignancies, with no dose-limiting toxicities, based on updated early efficacy results from a phase I/IB dose-escalation study.
One-year progression-free survival (PFS) was 88% for patients with chronic lymphocytic leukemia (CLL), and 1-year overall survival (OS) was 94%, reported Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston.
Single-agent ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase, is effective in patients with high-risk CLL or MCL, but the depth and durability of response are limited, he said. Umbralisib (TGR-1202) is a second-generation PI3K inhibitor with a high degree of specificity for the delta isoform of the kinase. It was designed to have a better safety profile than the first-in-class agent idelalisib (Zydelig).
“We hypothesized that inhibiting multiple BCR [B-cell receptor] pathways with kinase inhibitors may both deepen and prolong response and potentially overcome resistance mutations,” he said at the International Conference on Malignant Lymphoma.
In an ongoing, investigator-initiated phase I/IB trial, Dr. Davids and his colleagues enrolled 14 patients with MCL and 18 with CLL into parallel dose-escalation arms. Data were insufficient for the preliminary efficacy analysis.
Among patients with CLL, the objective response rate was 94% (16 of 17 patients). Of the 17 patients, 15 had a partial response or a partial response with lymphocytosis. One patient had a complete response, and three had radiographic complete responses, but these were not included in the objective response rate.
All three patients who had prior exposure to a PI3K inhibitor had responses, as did one of two patients with prior ibrutinib exposure.
For the patients with MCL, the objective response rate was 79% (11 of 14 patients); 10 had a partial response and 1 had a complete response. One other patient with a radiographic complete response was not included in the objective response rate.
Median follow-up among survivors was 14 months. As noted, the 1-year PFS and OS for patients with CLL were 88% and 94%, and the median PFS and OS for patients with MCL were 8.4 and 11.6 months.
One patient with CLL and five with MCL died of disease progression. A sixth patient with MCL did not have an adequate response to ibrutinib/umbralisib and died of toxicities related to the next line of therapy.
The safety analysis showed no dose-limiting toxicities, and the maximum tolerated dose was not identified with umbralisib at doses of 400 mg, 600 mg, or 800 mg daily in patients with either CLL or MCL.
The most common hematologic adverse events were grade 3/4 neutropenia in approximately 37% of patients in each arm, thrombocytopenia in 11% of CLL patients and 36% of MCL patients, and anemia in 15% and 29%, respectively.
The MCL arm of the study is still accruing patients, and correlative studies are in progress, Dr. Davids said.
The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
AT 14-ICML
Key clinical point:
Major finding: The objective response rate to the combination was 94% in 18 patients with chronic lymphocytic leukemia and 79% in 14 patients with mantle cell lymphoma.
Data source: A phase I/IB dose-escalation study.
Disclosures: The study is supported by TG Therapeutics, BCRP/LLS TAP, and grants from ASCO and the National Institutes of Health. Dr. Davids disclosed honoraria from Janssen and research funding to his institution from Phamarcyclics.
NOTCH1 mutation predicts reduced ofatumumab efficacy in CLL
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
AT iwCLL MEETING
Key clinical point:
Major finding: Ofatumumab was beneficial in patients with NOTCH1 wild-type, but not in patients with NOTCH1 mutation (hazard ratios, 0.64 and 0.86, respectively).
Data source: A mutation analysis of 325 DNA samples from patients in the phase III COMPLEMENT 2 trial.
Disclosures: Dr. Tausch reported receiving research support from Novartis.
iFCG achieves high MRD-negative remission in untreated CLL
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
AT THE IWCLL MEETING
Key clinical point:
Major finding: The overall response rate was 100%, and 83% of patients achieved MRD-negativity after three courses.
Data source: 29 patients from an investigator-initiated phase II trial.
Disclosures: Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis, Novimmune, and Adaptive Biotechnologies.
ECG finding predicts AFib in ibrutinib-treated CLL
NEW YORK – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.
ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD, said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.
Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.
Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.
Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.
“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.
On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).
“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.
The area under the ROC curve for this single predictor was 75%, he said.
The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.
The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.
Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.
Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.
To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.
The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.
Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.
Dr. Mato reported having no disclosures.
NEW YORK – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.
ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD, said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.
Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.
Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.
Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.
“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.
On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).
“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.
The area under the ROC curve for this single predictor was 75%, he said.
The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.
The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.
Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.
Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.
To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.
The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.
Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.
Dr. Mato reported having no disclosures.
NEW YORK – A left atrial abnormality on a pretreatment electrocardiogram (ECG) is a moderately specific and sensitive finding that independently predicts risk for developing atrial fibrillation in chronic lymphocytic leukemia patients starting on ibrutinib, findings from a retrospective cohort study indicate.
ECGs are inexpensive and available in most physician’s offices. Routinely checking for a left atrial abnormality before starting ibrutinib would identify a patient subgroup that would benefit from increased monitoring and allow for proactive intervention strategies to reduce complications should atrial fibrillation develop, Anthony Mato, MD, said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Prior studies, including the RESONATE and RESONATE 2 trials, have clearly demonstrated a link between ibrutinib exposure and the development of AFib. Long-term follow-up data suggest an estimated incidence of 9% to 11%.
Dr. Mato and his colleagues used a case-control design within a two-center retrospective cohort study to test the hypothesis that pre-ibrutinib left atrial abnormality, as determined by the ECG, can identify patients at increased risk for AFib during ibrutinib-based therapy.
Of 153 consecutive CLL patients who were treated with ibrutinib 420 mg/day, 11% developed new AFib at a median of 7 months after starting treatment. Discontinuation of ibrutinib because of AFib was low, with less than 2% of the entire cohort discontinuing treatment.
Based on findings in 20 case patients and 24 controls with an available pretreatment ECG, the presence of a left atrial abnormality before ibrutinib therapy was associated with a nine times increased risk of subsequently developing AFib.
“We looked at baseline hypertension, coronary disease, diabetes, age, and sex, and, although hypertension, coronary disease, and age appeared to have some effect, they weren’t as significant as left atrial abnormality” for predicting risk of AFib, Dr. Mato noted.
On multivariate analysis, controlling for hypertension, coronary disease, and age, a left atrial abnormality continued to be a significant predictor of AFib (odds ratio, 6.6).
“We then wanted to make this more practical for clinicians who may potentially perform an ECG to estimate risk,” he said, noting that ECG test characteristics associated with left atrial abnormality were defined: Sensitivity was estimated to be 79%, specificity was 71%, positive and negative likelihood ratios were 2.7 and 0.3, respectively. Positive predictive value was 68%, and negative predictive value was 81%.
The area under the ROC curve for this single predictor was 75%, he said.
The median age of the cohort at CLL diagnosis was 61 years, and the median age at ibrutinib start was 70. Patients had undergone a median of 2 prior lines of therapy, and 87% were treated in the relapsed/refractory setting.
The median follow-up was 17 months, and the median time from CLL diagnosis to the start of ibrutinib was 73 months.
Cardiovascular characteristics prior to treatment included smoking or former smoking in 49%, hypertension in 42%, hyperlipidemia in 39%, diabetes in 17%, coronary artery disease in 12%, and valvular heart disease in 5%.
Controls were matched to cases on baseline characteristics, and only those with no pretreatment history of AFib, a pretreatment ECG, and therapeutic ibrutinib dosing (420 mg/day for at least 4 months) were included.
To minimize bias, all ECGs were reviewed by a cardio-oncologist blinded to clinical outcomes.
The findings need prospective validation, as they are limited by the retrospective study design, lack of balance with respect to cardiovascular characteristics among cases and controls, a small number of atrial fibrillation cases, and variable timing of pre-ibrutinib ECG, he said.
Patients should be educated about the signs and symptoms of AFib. “The development of AFib during ibrutinib treatment should not prevent its continuation. These patients should be managed medically,” he added.
Dr. Mato reported having no disclosures.
AT THE IWCLL MEETING
Key clinical point:
Major finding: Left atrial abnormality as measured using ECG was a significant predictor of AFIB (adjusted odds ratio, 6.6).
Data source: A case-control study of 44 patients within a retrospective cohort.
Disclosures: Dr. Mato reported having no disclosures.
In good-candidate CLL, don’t wait too long for alloHCT
NEW YORK – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.
AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.
This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.
“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.
Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).
“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.
In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.
The more risk factors a patient had, the worse the outcome, he said.
Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.
Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.
“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.
In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.
In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).
High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.
Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.
Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.
Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.
For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.
“So, in conclusion ... good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.
The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.
“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”
As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.
In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.
“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”
Dr. van Gelder reported having no relevant disclosures.
NEW YORK – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.
AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.
This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.
“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.
Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).
“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.
In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.
The more risk factors a patient had, the worse the outcome, he said.
Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.
Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.
“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.
In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.
In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).
High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.
Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.
Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.
Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.
For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.
“So, in conclusion ... good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.
The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.
“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”
As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.
In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.
“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”
Dr. van Gelder reported having no relevant disclosures.
NEW YORK – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.
AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.
This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.
“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.
Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).
“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.
In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.
The more risk factors a patient had, the worse the outcome, he said.
Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.
Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.
“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.
In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.
In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).
High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.
Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.
Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.
Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.
For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.
“So, in conclusion ... good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.
The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.
“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”
As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.
In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.
“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”
Dr. van Gelder reported having no relevant disclosures.
AT THE IWCLL MEETING
Key clinical point:
Major finding: The predicted 2-year nonrelapse mortality was 12.1% for a patient who is a good transplant risk and predicted 8-year PFS was more than 50%.
Data source: An analysis of updated registry data for 197 patients.
Disclosures: Dr. van Gelder reported having no relevant disclosures
Ibrutinib response in CLL/SLL less affected by select risk factors
NEW YORK – Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.
In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.
In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.
In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.
In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.
“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.
In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.
Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.
In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.
In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.
In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.
The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.
Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.
At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.
“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.
The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.
“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.
Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.
The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.
“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.
Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
[email protected]
NEW YORK – Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.
In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.
In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.
In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.
In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.
“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.
In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.
Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.
In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.
In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.
In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.
The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.
Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.
At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.
“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.
The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.
“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.
Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.
The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.
“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.
Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
[email protected]
NEW YORK – Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.
In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.
In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.
In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.
In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.
“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.
In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.
Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.
In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.
In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.
In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.
The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.
Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.
At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.
“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.
The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.
“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.
Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.
The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.
“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.
Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
[email protected]
AT THE IWCLL MEETING
Key clinical point:
Major finding: In ibrutinib-treated patients, overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.
Data source: A pooled analysis of data from 1,210 patients from three randomized phase III trials.
Disclosures: Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.
Targeted drugs transform CLL management
NEW YORK – New, targeted treatments, especially ibrutinib (Imbruvica), have sharply shifted prognosis for patients with chronic lymphocytic leukemia (CLL) and raised new issues for managing these patients now that they survive years longer.
“Ibrutinib has produced a profound change in survival” of patients with CLL, Timothy G. Call, MD, a hematologist/oncologist at the Mayo Clinic in Rochester, Minn., said at a conference held by Imedex. It “has changed the playing field.” No other new agent so far “has produced the same level of progression-free survival in CLL.”
An analysis published in early 2017 projected a greater than 50% jump in U.S. patients living with CLL from 2011, before the advent of targeted oral drugs, to 2025, when the study predicted that there will be nearly 200,000 U.S. patients living with CLL (J Clin Oncol. 2017 January;35[2]:166-74). With targeted drugs like ibrutinib and idelalisib (Zydelig) costing about $130,000 per patient each year, the projected cost for managing the U.S. CLL population is on track to rise to more than $5 billion by 2025, a nearly sixfold increase, compared with CLL patient expenditures in 2011, according to this analysis.
The impact of the higher cost of treatment is already being felt more acutely by many patients because of recent cuts in assistance from the Patient Access Network, which helps patients with copays but recently had to put a lid on CLL assistance availability when its funding availability hit a wall, Dr. Call said.
On the clinical side, there are new considerations triggered by greater patient longevity. “As we make patients live longer with CLL, we need to double down on the diagnosis and treatment of its complications,” such as watching for development of secondary cancers, Dr. Call said in an interview. This stems from the reduced immunosurveillance in patients with CLL and their resulting increased susceptibility to developing environmentally-triggered malignancies like lung and skin cancers. Other long-term implications of impaired immunosurveillance include increased infection susceptibility, an ongoing risk for Richter’s or Hodgkin lymphoma transformation, and a risk for autoimmune complications, such as red blood cell aplasia and transfusion-associated graft versus host disease.
Patients with CLL can also be susceptible to complications from long-term use of the targeted drug they’re on. The new targeted agents can trigger bruising and bleeding, diarrhea, rash, fatigue, muscle and joint aches, and arrhythmia, he noted.
Potential adverse effects, specifically from ibrutinib, include a 3% risk for a major bleed, a 10% rate of new-onset atrial fibrillation, and a 20% risk for new hypertension, Dr. Call said. Before starting ibrutinib, patients should undergo screening for hepatitis B virus infection and receive prophylaxis against herpes zoster activation with acyclovir or valacyclovir. If the patient starts with a CD4 cell count below 200 cells/mm3, it might be prudent to prophylax the patient against Pneumocystis jirovecii pneumonia.
However, even if a toxicity develops on ibrutinib, Dr. Call recommended reducing the dosage rather than discontinuing the drug. “I rarely see a loss in response from a reduced dosage of ibrutinib,” he said.
Because ibrutinib is primarily metabolized via the liver enzyme cytochrome P450 3A (CYP3A), other drugs that enhance or reduce the activity of this enzyme produce significant changes in ibrutinib levels. The Food and Drug Administration considers ibrutinib a “sensitive substrate” for fluctuations in CYP3A activity. Strong CYP3A inhibitors include clarithromycin, ketoconazole, and various anti-HIV medications; moderate CYP3A4 inhibitors include ciprofloxacin, and verapamil; and inducers of CYP3A include phenytoin and rifampin. A more complete list of the drugs that inhibit or induce CYP3A activity can be found at the FDA website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2.
Dr. Call presented the combined experience from several U.S. Mayo Clinic centers for 118 patients treated with ibrutinib after the drug received FDA marketing approval in November 2013. The clinicians identified 75 patients (64%) who were on a concurrent medication that could potentially increase the risk for ibrutinib toxicity and 4 patients (3%) who were on a concurrent drug with the potential to reduce ibrutinib efficacy (Leukemia Lymphoma, 2017;58[6]:1376-83).
“We don’t change the dosage of ibrutinib when the patient is on a CYP3A inducer, but, if the patient is getting a CYP3A inhibitor, we change that to another drug or reduce the ibrutinib dosage,” Dr. Call said.
Dr. Call had no disclosures.
[email protected]
On Twitter @mitchelzoler
NEW YORK – New, targeted treatments, especially ibrutinib (Imbruvica), have sharply shifted prognosis for patients with chronic lymphocytic leukemia (CLL) and raised new issues for managing these patients now that they survive years longer.
“Ibrutinib has produced a profound change in survival” of patients with CLL, Timothy G. Call, MD, a hematologist/oncologist at the Mayo Clinic in Rochester, Minn., said at a conference held by Imedex. It “has changed the playing field.” No other new agent so far “has produced the same level of progression-free survival in CLL.”
An analysis published in early 2017 projected a greater than 50% jump in U.S. patients living with CLL from 2011, before the advent of targeted oral drugs, to 2025, when the study predicted that there will be nearly 200,000 U.S. patients living with CLL (J Clin Oncol. 2017 January;35[2]:166-74). With targeted drugs like ibrutinib and idelalisib (Zydelig) costing about $130,000 per patient each year, the projected cost for managing the U.S. CLL population is on track to rise to more than $5 billion by 2025, a nearly sixfold increase, compared with CLL patient expenditures in 2011, according to this analysis.
The impact of the higher cost of treatment is already being felt more acutely by many patients because of recent cuts in assistance from the Patient Access Network, which helps patients with copays but recently had to put a lid on CLL assistance availability when its funding availability hit a wall, Dr. Call said.
On the clinical side, there are new considerations triggered by greater patient longevity. “As we make patients live longer with CLL, we need to double down on the diagnosis and treatment of its complications,” such as watching for development of secondary cancers, Dr. Call said in an interview. This stems from the reduced immunosurveillance in patients with CLL and their resulting increased susceptibility to developing environmentally-triggered malignancies like lung and skin cancers. Other long-term implications of impaired immunosurveillance include increased infection susceptibility, an ongoing risk for Richter’s or Hodgkin lymphoma transformation, and a risk for autoimmune complications, such as red blood cell aplasia and transfusion-associated graft versus host disease.
Patients with CLL can also be susceptible to complications from long-term use of the targeted drug they’re on. The new targeted agents can trigger bruising and bleeding, diarrhea, rash, fatigue, muscle and joint aches, and arrhythmia, he noted.
Potential adverse effects, specifically from ibrutinib, include a 3% risk for a major bleed, a 10% rate of new-onset atrial fibrillation, and a 20% risk for new hypertension, Dr. Call said. Before starting ibrutinib, patients should undergo screening for hepatitis B virus infection and receive prophylaxis against herpes zoster activation with acyclovir or valacyclovir. If the patient starts with a CD4 cell count below 200 cells/mm3, it might be prudent to prophylax the patient against Pneumocystis jirovecii pneumonia.
However, even if a toxicity develops on ibrutinib, Dr. Call recommended reducing the dosage rather than discontinuing the drug. “I rarely see a loss in response from a reduced dosage of ibrutinib,” he said.
Because ibrutinib is primarily metabolized via the liver enzyme cytochrome P450 3A (CYP3A), other drugs that enhance or reduce the activity of this enzyme produce significant changes in ibrutinib levels. The Food and Drug Administration considers ibrutinib a “sensitive substrate” for fluctuations in CYP3A activity. Strong CYP3A inhibitors include clarithromycin, ketoconazole, and various anti-HIV medications; moderate CYP3A4 inhibitors include ciprofloxacin, and verapamil; and inducers of CYP3A include phenytoin and rifampin. A more complete list of the drugs that inhibit or induce CYP3A activity can be found at the FDA website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2.
Dr. Call presented the combined experience from several U.S. Mayo Clinic centers for 118 patients treated with ibrutinib after the drug received FDA marketing approval in November 2013. The clinicians identified 75 patients (64%) who were on a concurrent medication that could potentially increase the risk for ibrutinib toxicity and 4 patients (3%) who were on a concurrent drug with the potential to reduce ibrutinib efficacy (Leukemia Lymphoma, 2017;58[6]:1376-83).
“We don’t change the dosage of ibrutinib when the patient is on a CYP3A inducer, but, if the patient is getting a CYP3A inhibitor, we change that to another drug or reduce the ibrutinib dosage,” Dr. Call said.
Dr. Call had no disclosures.
[email protected]
On Twitter @mitchelzoler
NEW YORK – New, targeted treatments, especially ibrutinib (Imbruvica), have sharply shifted prognosis for patients with chronic lymphocytic leukemia (CLL) and raised new issues for managing these patients now that they survive years longer.
“Ibrutinib has produced a profound change in survival” of patients with CLL, Timothy G. Call, MD, a hematologist/oncologist at the Mayo Clinic in Rochester, Minn., said at a conference held by Imedex. It “has changed the playing field.” No other new agent so far “has produced the same level of progression-free survival in CLL.”
An analysis published in early 2017 projected a greater than 50% jump in U.S. patients living with CLL from 2011, before the advent of targeted oral drugs, to 2025, when the study predicted that there will be nearly 200,000 U.S. patients living with CLL (J Clin Oncol. 2017 January;35[2]:166-74). With targeted drugs like ibrutinib and idelalisib (Zydelig) costing about $130,000 per patient each year, the projected cost for managing the U.S. CLL population is on track to rise to more than $5 billion by 2025, a nearly sixfold increase, compared with CLL patient expenditures in 2011, according to this analysis.
The impact of the higher cost of treatment is already being felt more acutely by many patients because of recent cuts in assistance from the Patient Access Network, which helps patients with copays but recently had to put a lid on CLL assistance availability when its funding availability hit a wall, Dr. Call said.
On the clinical side, there are new considerations triggered by greater patient longevity. “As we make patients live longer with CLL, we need to double down on the diagnosis and treatment of its complications,” such as watching for development of secondary cancers, Dr. Call said in an interview. This stems from the reduced immunosurveillance in patients with CLL and their resulting increased susceptibility to developing environmentally-triggered malignancies like lung and skin cancers. Other long-term implications of impaired immunosurveillance include increased infection susceptibility, an ongoing risk for Richter’s or Hodgkin lymphoma transformation, and a risk for autoimmune complications, such as red blood cell aplasia and transfusion-associated graft versus host disease.
Patients with CLL can also be susceptible to complications from long-term use of the targeted drug they’re on. The new targeted agents can trigger bruising and bleeding, diarrhea, rash, fatigue, muscle and joint aches, and arrhythmia, he noted.
Potential adverse effects, specifically from ibrutinib, include a 3% risk for a major bleed, a 10% rate of new-onset atrial fibrillation, and a 20% risk for new hypertension, Dr. Call said. Before starting ibrutinib, patients should undergo screening for hepatitis B virus infection and receive prophylaxis against herpes zoster activation with acyclovir or valacyclovir. If the patient starts with a CD4 cell count below 200 cells/mm3, it might be prudent to prophylax the patient against Pneumocystis jirovecii pneumonia.
However, even if a toxicity develops on ibrutinib, Dr. Call recommended reducing the dosage rather than discontinuing the drug. “I rarely see a loss in response from a reduced dosage of ibrutinib,” he said.
Because ibrutinib is primarily metabolized via the liver enzyme cytochrome P450 3A (CYP3A), other drugs that enhance or reduce the activity of this enzyme produce significant changes in ibrutinib levels. The Food and Drug Administration considers ibrutinib a “sensitive substrate” for fluctuations in CYP3A activity. Strong CYP3A inhibitors include clarithromycin, ketoconazole, and various anti-HIV medications; moderate CYP3A4 inhibitors include ciprofloxacin, and verapamil; and inducers of CYP3A include phenytoin and rifampin. A more complete list of the drugs that inhibit or induce CYP3A activity can be found at the FDA website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table2-2.
Dr. Call presented the combined experience from several U.S. Mayo Clinic centers for 118 patients treated with ibrutinib after the drug received FDA marketing approval in November 2013. The clinicians identified 75 patients (64%) who were on a concurrent medication that could potentially increase the risk for ibrutinib toxicity and 4 patients (3%) who were on a concurrent drug with the potential to reduce ibrutinib efficacy (Leukemia Lymphoma, 2017;58[6]:1376-83).
“We don’t change the dosage of ibrutinib when the patient is on a CYP3A inducer, but, if the patient is getting a CYP3A inhibitor, we change that to another drug or reduce the ibrutinib dosage,” Dr. Call said.
Dr. Call had no disclosures.
[email protected]
On Twitter @mitchelzoler