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Division of Leukemia
Memorial Sloan Kettering Cancer Center
New York, New York
Anthony Mato, MD, MSCE, has disclosed that he has received funds for research support from AbbVie, Acerta/AstraZeneca, Adaptive, DTRM BioPharma, Johnson & Johnson, Loxo Oncology, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics and has received consulting fees from AbbVie, Acerta/AstraZeneca, Adaptive, Celgene, DTRM BioPharma, Johnson & Johnson, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem.
Professor of Medicine
Chief, Section of CLL
Department of Leukemia
The University of Texas MD Anderson Cancer Center
William G. Wierda, MD, PhD, has disclosed that he has received funds for research support from AbbVie, Acerta, Cyclacel, Genentech, Gilead Sciences, Janssen, Juno, Kite, Loxo, miRagen, Novartis, Oncternal, Pharmacyclics, Sunesis, and Xencor.
In this commentary, Anthony Mato, MD, MSCE, and William G. Wierda, MD, PhD, provide their thoughts on key studies in chronic lymphocytic leukemia (CLL) that were presented at ASCO 2021 and EHA 2021.
William G. Wierda, MD, PhD:
In recent years, numerous new agents have been approved for the management of CLL, and many have novel mechanisms of action. BTK inhibitors have been a significant step forward and have largely displaced chemoimmunotherapy. Venetoclax, combined with obinutuzumab, has also been a very successful regimen in the first-line setting, enabling fixed-duration treatment resulting in high undetectable minimal residual disease rates and long remissions off treatment. Now that these agents are approved, there is interest in developing optimal doublet or triplet regimen that incorporates BTK inhibitors plus venetoclax and CD20 antibodies.
Results from the phase III GLOW trial were recently reported at EHA 2021. GLOW was a first-line study of fixed-duration ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab in patients with previously untreated CLL (N = 211). This study followed the phase II CAPTIVATE trial, which demonstrated activity with first-line ibrutinib plus venetoclax.
Patients in GLOW were either 65 years of age or older or younger than 65 years of age with comorbidities; the median age was 71 years. This differed from the patient population in CAPTIVATE, which had a median age of 60 years. In GLOW, ibrutinib was given for 3 cycles as monotherapy, followed by 12 cycles of combined therapy with venetoclax, as in CAPTIVATE, and chlorambucil plus obinutuzumab was given for 6 cycles for the control arm in GLOW. The primary endpoint was progression-free survival (PFS).
The combined targeted therapy of ibrutinib plus venetoclax demonstrated superior PFS vs chlorambucil plus obinutuzumab (HR: 0.216; 95% CI: 0.131-0.357; P <.0001). For patients treated with ibrutinib plus venetoclax, the CR/CRi rate was 38.7%, which was significantly higher than the CR/CRi rate of 11.4% for those patients treated with chlorambucil plus obinutuzumab. Undetectable measurable residual disease (MRD) rates were also higher for patients treated with ibrutinib plus venetoclax in both the bone marrow and peripheral blood.
The CR/CRi and undetectable MRD rates were slightly lower with ibrutinib plus venetoclax in GLOW compared with those observed in CAPTIVATE. This may be due to the older age and presence of comorbidities for patients in GLOW, who may not have been able to tolerate as much treatment as those in CAPTIVATE. Regarding safety in GLOW, there was a slightly higher rate of neutropenia among patients who received chlorambucil plus obinutuzumab; more in-class toxicities associated with BTK inhibitors such as hypertension and atrial fibrillation were observed in the ibrutinib plus venetoclax arm. Overall, GLOW demonstrated that ibrutinib plus venetoclax appears to be a safe regimen, confirming what was seen in CAPTIVATE, and was clearly superior to chemoimmunotherapy.
Anthony Mato, MD, MSCE:
Both acalabrutinib and ibrutinib are BTK inhibitors approved by the FDA for patients with CLL/small lymphocytic lymphoma. Reported at ASCO 2021 were data from ELEVATE-RR, a head-to-head phase III trial comparing acalabrutinib with ibrutinib in 533 patients with previously treated high-risk relapsed/refractory CLL. In this trial, the definition of high-risk disease was presence of del(17p) or del(11q). The primary endpoint was noninferiority of independent review committee–assessed PFS, with secondary endpoints including any-grade atrial fibrillation/flutter, grade ≥3 infection, Richter transformation, and overall survival.
Regarding PFS, the HR was 1.00 (95% CI: 0.79-1.27), demonstrating that the efficacy of acalabrutinib was noninferior to that of ibrutinib in this study. The median PFS was 38.4 months in both treatment arms.
Looking at safety, this study was powered to detect differences in any-grade atrial fibrillation/flutter. The rate of any-grade atrial fibrillation/flutter in the acalabrutinib arm was 9.4% vs 16.0% in the ibrutinib arm, which was statistically significantly different. Hypertension occurred in 9.4% of patients receiving acalabrutinib vs 23.2% of those receiving ibrutinib. The rate of bleeding events was 38.0% in acalabrutinib-treated patients and 51.3% in ibrutinib-treated patients. The difference for both hypertension and bleeding events was significant. Looking at grade ≥3 adverse events, 4.9% experienced atrial fibrillation/flutter in the acalabrutinib arm vs 3.8% in the ibrutinib arm, with 4.1% vs 9.1% experiencing hypertension, respectively. The rate of second primary malignancies was slightly higher in the acalabrutinib group vs the ibrutinib group and the rate of infections was similar between treatment arms.
I think both acalabrutinib and ibrutinib remain very reasonable options because of the great efficacy data with both drugs. The data suggest more atrial fibrillation/hypertension with ibrutinib, so those may be considerations for specific patients. Discontinuation and adverse events rate differences have not yet translated into observable differences in PFS between agents, so both are options.
William G. Wierda, MD, PhD:
Interim analysis data from the randomized phase III ALPINE trial were also reported at EHA 2021. In this trial, zanubrutinib—a novel irreversible BTK inhibitor—was compared with ibrutinib for treating patients with relapsed/refractory CLL (N = 415 at this interim analysis). In this non-inferiority trial, the primary endpoint was investigator-assessed overall response rate.
A significantly higher overall response rate was observed for patients who received zanubrutinib vs ibrutinib (78.3% vs 62.5%; P = .0006). Of importance, ORR in this trial included partial and complete responders, and excluded partial responders with residual lymphocytosis. There appeared to be a trend in terms of improved PFS with zanubrutinib vs ibrutinib (12-month PFS rate: 94.9% vs 84.0%; HR: 0.40; P = .0007). It is important to highlight that this is relatively short follow-up that goes out to 18 months, so it will be interesting to see additional follow-up with this trial. Nevertheless, this observation is certainly intriguing. Similar to what was shown for acalabrutinib vs ibrutinib in ELEVATE-RR, there was a higher incidence of any-grade atrial fibrillation associated with ibrutinib compared with zanubrutinib (10.1% vs 2.5%).
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