Single-Agent Ibrutinib Versus Allogeneic Hematopoietic Cell Transplantation for Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and del(17p)

Background: Prognosis and treatment outcomes are inferior for patients with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) with del(17p) and TP53 mutations compared with patients without these abnormalities. Historically, these patients would undergo allogeneic hematopoietic cell transplantation (aHCT) early in the disease course. The introduction of targeted agents, such as ibrutinib, has significantly improved the survival rates for CLL/SLL, but differences in outcomes between patients with and without high-risk genetic features have been observed. To date, outcomes with ibrutinib versus aHCT have not been directly compared in patients with del(17p).Thisstudy aimed to provide comparative data of aHCT versus ibrutinib treatment in patients with CLL/SLL and del(17p).

Methods: This retrospective analysis used data from the Center for International Blood and Marrow Transplant Research (CIBMTR) observational registry and randomized clinical trials, RESONATE (NCT01578707) and RESONATE-17 (NCT01744691).Adults with relapsed/refractory CLL/SLL with del(17p) received either aHCT (reported to CIBMTR in 2008-2017) or single-agent ibrutinib (420 mg/day; enrollment dates: RESONATE, June 2012-April 2013; RESONATE-17, January 2013-June 2013).Main outcomes measured for patients who received aHCT or ibrutinib were overall survival (OS) and progression-free survival (PFS); additionally for patients with aHCT cumulative incidence of relapse/progression, incidence of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) were reported. Outcome comparisons were estimated by the inverse probability weighting to balance the important confounders: age, sex, race, bulky disease, Rai stage, prior treatment, Eastern Cooperative Oncology Group (ECOG) performance status score, time from diagnosis to treatment, del(11q), del(13q), and trisomy 12.

Results: Among qualified patients with relapsed/refractory CLL/SLL and del(17p), the median follow-up was capped at 60 months for the aHCT cohort (n=145); median follow-up for ibrutinib (n=196) was 64 and 33 months for RESONATE (n=53) and RESONATE-17 (n=143), respectively. Median age among patients in the aHCT versus ibrutinib cohort was 58.9 versus 64.5 years (P<0.001), and 70% versus 34% (P<0.001) had an ECOG performance status score of 0; the median time from diagnosis to treatment was 42 versus 70 months (P<0.001), and the proportion of patients with a bulky disease was 18% versus 52% (P<0.001). Of patients with aHCT, 77% underwent reduced-intensity or nonmyeloablative conditioning, 83% received calcineurin inhibitors with mycophenolate or methotrexate as GVHD prophylaxis, and 29% received antithymocyte globulin. At 60 months after aHCT, the cumulative incidence (95% CI) of disease relapse and NRM were both 37% (0.29-0.45); the cumulative incidence (95% CI) was 53% (0.45-0.61) for grade 2-4 acute GVHD and 67% (0.59-0.74) for chronic GVHD. After adjusting for confounders patients treated with ibrutinib had significantly longer OS (adjusted HR=0.39, 95% CI: 0.23-0.68, P=0.0008) and PFS (adjusted HR=0.43, 95% CI: 0.27-0.69, P=0.0005) versus those with aHCT.

Conclusion: This retrospective analysis suggests that ibrutinib treatment may offer improved OS and PFS outcomes over aHCT in patients with relapsed/refractory CLL/SLL and del(17p).

Awan:Dava Oncology: Consultancy; Loxo Oncology: Consultancy; AbbVie/Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy; Genmab: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Incyte: Consultancy. Liu:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Huang:Everest Clinical Research: Consultancy, Current Employment, Research Funding; AbbVie: Consultancy, Current Employment, Research Funding. Krigsfeld:Inovio: Current holder of stock options in a privately-held company; Dynavax: Current holder of stock options in a privately-held company; Moderna: Current holder of stock options in a privately-held company; Pharmacyclics LLC, an AbbVie Company: Current Employment, Other: travel, accommodations, expenses; BMS: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses; AbbVie: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses. Raz:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Wolfe:Curio Sciences: Other: Paid Lecture. Hamadani:Autolus: Consultancy; Caribou: Consultancy; Genmab: Consultancy; BMS: Consultancy; Omeros: Consultancy; Spectrum Pharmaceuticals: Research Funding; CRISPR: Consultancy; Allovir: Consultancy; Myeloid Therapeutics: Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; BeiGene: Speakers Bureau; Astellas Pharma: Research Funding; Takeda: Research Funding; Forte Biosciences: Consultancy; CRISPR: Speakers Bureau; AbbVie: Consultancy; Sanofi Genzyme: Speakers Bureau; DMC, Inc: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharma: Consultancy, Speakers Bureau; Byondis: Consultancy.