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Frontline treatment with ibrutinib reduced the risk of progression or death by 84% compared with single-agent chlorambucil for elderly patients with chronic lymphocytic leukemia and small lymphocytic lymphoma.
Paul M. Barr, MD
Frontline treatment with ibrutinib reduced the risk of progression or death by 84% compared with single-agent chlorambucil for elderly patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to findings from the phase III RESONATE-2 trial presented at the 2016 International Congress on Hematologic Malignancies.
After a median follow-up of 18.4 months, median PFS was not yet reached with ibrutinib versus 18.9 months with chlorambucil (HR, 0.16; 95% CI, 0.09-0.28; P <.0001). The 18-month PFS rate was 90% with ibrutinib versus 52% with chlorambucil. Overall survival (OS) was improved by 84% with ibrutinib versus chlorambucil (HR, 0.16; 95% CI, 0.05-0.56; P = .001).
“While it's not a surprise that ibrutinib performed better than chlorambucil, the efficacy of ibrutinib in the first-line setting is worth noting,” said lead author of the poster Paul M. Barr, MD, medical director, clinical trial office, James P. Wilmot Cancer Center, University of Rochester Medical Center. “At 18 months median follow-up, the PFS and OS rates were 94% and 98%, respectively, justifying FDA approval for first-line use.”
In the trial, 269 patients with CLL/SLL were randomized in a 1:1 ratio to receive ibrutinib (n = 136) or chlorambucil (n = 133). Ibrutinib was administered once daily at 420 mg. Chlorambucil was administered 0.5-0.8 mg/kg on days 1 and 15 of a 28-day cycle. The primary endpoint of the study was PFS by iwCLL criteria. Secondary outcome measures included OS, objective response rate (ORR), and safety.
Those who experienced disease progression by independent review were treated in an extension study (PCYC-1116). In this arm, patients received investigator's choice of second-line therapy. Overall, 43 patients in the chlorambucil arm crossed over to receive second-line ibrutinib.
The median age of patients enrolled in the trial was ≥72 years, and 69% had at least 1 baseline comorbidity at the time of enrollment. Overall, 8% and 9% of patients had an ECOG PS of 2 and 31% and 33% had a CIRS score >6, in the ibrutinib and chlorambucil arms, respectively. Creatinine clearance was <60 mL/min for 44% of patients in the ibrutinib arm versus 50% in the chlorambucil group.
By investigator assessment, ibrutinib reduced the risk of progression or death by 91% versus chlorambucil. Median PFS in the ibrutinib arm was not yet reached versus 15.0 months with chlorambucil (HR, 0.09; 95% CI, 0.04-0.17; P <.0001). The 18-month PFS rates were 94% and 45% in the ibrutinib and chlorambucil arms, respectively. The 24-month OS rate was 98% with ibrutinib versus 85% with chlorambucil.
The ORR with ibrutinib was 90% versus 35% with chlorambucil. In the ibrutinib arm, 3% of responding patients experienced a partial response with lymphocytosis and 11% had a complete response. At 8 months, the ORR was 82% and 30% in the ibrutinib and chlorambucil arms, respectively.
PFS remained consistent across patient subgroups, including age, Rai stage, ECOG status, bulky disease, del11q, and unmutated IGHV. There were no cases of Richter's transformation in the ibrutinib arm versus 1 in the chlorambucil group. In the del11q and unmutated IGHV subgroups, PFS was improved by 98% and 94%, respectively. The 18-month PFS rate with ibrutinib in the IGHV-mutated group was 92% compared with 95% in the IGHV unmutated subgroup.
In patients with anemia and thrombocytopenia, there was a sustained improvement in hemoglobin and platelet counts with ibrutinib versus chlorambucil, suggesting improved bone marrow function. In those with anemia, hemoglobin was significantly improved for 84% of patients in the ibrutinib arm versus 45% in the chlorambucil group (P <.0001). In those with thrombocytopenia, platelet counts were improved by 77% versus 43% with ibrutinib and chlorambucil, respectively (P = .0054).
Overall, there were 3 deaths in the ibrutinib arm and 17 in the chlorambucil group. None of the deaths in the ibrutinib arm were attributed to disease progression. Of the deaths reported in the chlorambucil arm, 5 were from disease progression and 3 were related to infections. At the time of study completion, 87% of patients continued to receive ibrutinib.
Overall, dose reductions were required for 10% of those in the ibrutinib arm versus 19% with chlorambucil. Twelve patients discontinued ibrutinib due to adverse events (AEs), with one patient dying from pneumonia one month after discontinuation.
A majority of AEs were grade 1 in severity. Grade 3 events in the ibrutinib arm consisted of diarrhea, neutropenia, fatigue, nausea, peripheral edema, arthralgia, and neutropenia. However, fatigue, nausea, vomiting, and cytopenias were more common in the chlorambucil arm compared with ibrutinib.
Other all-grade AEs of note in the ibrutinib arm versus chlorambucil included hypertension (14% vs 0%), atrial fibrillation (6% vs 0%), and major hemorrhage (4% vs 2%). Grade 3 incidences of these events in the ibrutinib arm were 4%, 1%, and 3%, respectively. Overall, 19% of patients in the ibrutinib arm used anticoagulants and 47% received antiplatelet agents.
“There is still debate on whether some patients would be better served by receiving chemoimmunotherapy upfront, and ongoing randomized studies will address this question,” said Barr. “However, no one will debate that ibrutinib has transformed how we treat CLL.”
Clinical trials continue to assess ibrutinib across a number of settings, including in combination with monoclonal antibodies, such as obinutuzumab (Gazyva) and nivolumab (Opdivo). Additionally, the agent is being explored in combination with the Bcl-2 inhibitor venetoclax (ABT-199).
Since gaining initial approval for mantle cell lymphoma in 2013, ibrutinib’s indication has expanded to include the upfront treatment of CLL and for patients with Waldenström’s macroglobulinemia. In early March 2016, ibrutinib was granted a further approval as an upfront therapy for patients with CLL, based on the RESONATE-2 data.
Barr PM, Burger JA, Owen C, et al. Phase 3 study results from RESONATE-2: Ibrutinib Versus Chlorambucil in Patients 65 Years and Older with Treatment-naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Presented at: 20th Annual International Congress on Hematologic Malignancies; March 18—20, 2016; Miami Beach, FL. Poster #379.