Novel Rituximab Combinations Highly Effective in CLL
The novel agents idelalisib and ABT-199 in combination with rituximab have demonstrated impressive activity with manageable toxicity for patients with relapsed or refractory chronic lymphocytic leukemia
Steven E. Coutre, MD
The novel agents idelalisib and ABT-199 in combination with rituximab have demonstrated impressive activity with manageable toxicity for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to two separate studies presented in a poster highlight session at the 2014 ASCO Annual Meeting.
Idelalisib Efficacy Established in Phase III
At the second interim analysis of the phase III Study 116 trial, the combination of the PI3K-delta inhibitor idelalisib and rituximab demonstrated an improvement in progression-free survival (PFS) of 82% and a 72% elevation in overall survival (OS). Abstract 7012
“[Study 116] clearly demonstrates that adding idelalisib to rituximab is superior. Patients have a longer duration of response and they live longer— a dramatic benefit from that standpoint,” said study author Steven E. Coutre, MD, a professor of medicine (hematology) at the Stanford University Medical Center. “If you’re a practicing oncologist and you think about the patients that you’ve treated with rituximab in this setting, then adding idelalisib to that would make sense based on these results.”
In the phase III study, 220 patients with a median age of 71 years were randomized in a 1:1 ratio to receive rituximab plus idelalisib (n = 110) or rituximab and placebo (n = 110).
Patients in the study had received three prior therapies, including prior treatment with rituximab.
Based on findings from the first analysis, the trial was halted and crossover was allowed following a positive risk—benefit review. At the second analysis of the study, the median PFS for idelalisib plus rituximab had not been reached, compared with 5.5 months with placebo plus rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression-free compared with 50% with placebo.
The ORR with idelalisib was 77% versus 15% with placebo. Of evaluable patients, 92% treated with idelalisib experienced a greater than 50% reduction in lymph node size compared with 6% with placebo.
Adverse events of any grade occurred in 95% of patients in both arms of the trial. The incidence of grade 3/4 adverse events was 64% with idelalisib versus 52% with placebo. The discontinuation rate associated with adverse events was 5% in the idelalisib arm and 6% in the placebo group.
The FDA has approved idelalisib in combination with rituximab for patients with high-risk relapsed or refractory CLL and as a single agent for two types of indolent non-Hodgkin lymphoma (iNHL).
ABT-199 Shows Early Promise
ABT-199 demonstrated promising efficacy in patients who received the drug in combination with rituximab in a phase Ib study, demonstrating an overall response rate (ORR) of 84% when it was combined with rituximab. Patients in the study had a median age of 69 years and had received a median of two prior therapies, including rituximab (91%) and fludarabine (47%). Altogether, 24% of patients entering the trial were refractory to rituximab. Abstract 7013
In 25 evaluable patients, the ORR was 84%, with 36% achieving a complete response (CR) and 48% with a partial response. Lymph node size was reduced by 50% in 94% of patients treated with ABT-199, with a median time to reduction of 12 weeks. Seven patients with a CR were analyzed for minimal residual disease (MRD), of which 5 (71%) were deemed MRD negative.
The initial dose of ABT-199 in the trial began at 50 mg but was modified to 20 mg as a result of a fatal episode of tumor lysis syndrome (TLS) that occurred during the lead-in period. Following this modification and increased monitoring, further TLS events did not occur. These events were not considered to be dose limiting. The final dose selected for phase II studies with induction was 400 mg.
In all 45 patients in the study, the most common all-grade adverse events were neutropenia (51%), nausea (38%), and diarrhea (33%). The most common serious adverse events were neutropenia (47%), anemia (16%), and thrombocytopenia (13%). Febrile neutropenia occurred in 7% of patients.
Phyllis McKiernan, MSN, APN, OCN
Blood and Marrow Transplant Program
John Theurer Cancer Center
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world, and anti- CD20 therapy with monoclonal antibodies has been an effective treatment strategy. Rituximab given in conjunction with chemotherapy is standard first-line treatment for CLL, but can have toxic effects. Combining rituximab with novel agents that target other cell pathways now holds promise for CLL treatment. The key is improving response and survival without increasing toxicity.
In the phase III study presented at ASCO, adding idelalisib to rituximab resulted in superior outcomes for patients with CLL. The results were so striking, the randomization was halted and patients were allowed to cross over from the placebo arm to the idelalisib arm. Although the incidence of grade 3/4 adverse events was slightly higher in the idelalisib arm, the discontinuation rate was low and similar in both arms, indicating no increased toxicity. However, since the study was stopped early, late adverse effects such as diarrhea may develop in some patients. Interestingly, there was a decrease in rituximab-related infusion reactions in the idelalisib arm, a benefit to patients and nurses administering therapy (NEJM. 2014;370(11):997-1007).
ABT-199 is an oral Bcl-2 inhibitor presently being studied in CLL and small lymphocytic lymphoma. In the phase I study, the combination of ABT-199 with rituximab showed very good response rates in patients with previously treated CLL. The most common adverse effects were hematologic, and the combination appears to be well tolerated.
Both novel agents administered with rituximab show efficacy in the treatment of heavily pretreated patients with CLL, some of whom were refractory to rituximab. Thus far, there appears to be no added toxicity, but further study and long-term follow up are needed.
These new combinations may become impressive additions to the therapeutic options for patients with CLL.