Safety and Efficacy of Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Who Have Undergone Prior Allogeneic Stem Cell Transplant
Authors: Coutre Steven , O'Brien Susan , Byrd John C. , Hillmen Peter , Brown Jennifer R. , Dyer Martin JS , Mato Anthony R. , Miklos David B. , Keating Michael , Zhou Cathy , Fardis Maria , Styles Lori , Jaglowski Samantha 
Published: October 2019

Abstract
Introduction: Ibrutinib (Imbruvica®), a first-in-class Bruton’s tyrosine kinase inhibitor is a once-daily single-agent approved by the US FDA for patients with chronic lymphocytic leukemia (CLL) who have received ≥1 prior therapy, and for CLL with a 17p deletion. The phase III trial evaluating the efficacy and safety of ibrutinib in patients with relapsed/refractory CLL or small lymphocytic leukemia has previously been reported (Byrd et al. N Engl J Med, 2014). Allogeneic hematopoietic stem cell transplantation (HSCT) is also used to treat CLL, particularly in those who are at high risk. Patients with CLL who relapse after allogeneic HSCT are extremely difficult to treat with chemotherapy due to impaired hematopoietic reserve and/or infections. Furthermore, both B and T cells are known to play a role in the immunopathophysiology of graft-versus-host disease (GVHD), and in preclinical studies, ibrutinib, which inhibits both ITK and BTK, reversed established chronic GVHD. To evaluate whether ibrutinib is safe and effective in treating patients with CLL with a history of prior allogeneic HSCT, we evaluated the subset of patients enrolled in ibrutinib clinical trials who had undergone prior HSCT.
Methods: Data were collected for patients with relapsed/refractory CLL who had undergone allogeneic HSCT and had been treated with ibrutinib, either as a single agent or in combination with ofatumumab, in 1 of 4 clinical trials (PCYC-1102, PCYC-1109, PCYC-1112, and PCYC-1117). Two of the studies (PCYC-1112 and PCYC-1117) allowed only patients who were >6 months post-HSCT and without GVHD to enroll. Efficacy evaluations included assessment of overall response rate (ORR) by iwCLL criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety evaluations included reporting of adverse events (AEs), including serious AEs (SAEs).
Results: A total of 16 patients from 4 ibrutinib clinical trials had undergone prior allogeneic HSCT. Median patient age was 54.5 years (range, 43-68); 12.5% were ≥ 65 years of age, 11 were male, and all 16 patients had an ECOG performance status of 0 or 1. Chromosomal abnormalities del17p and del11q were reported in 10 and 3 patients, respectively. More than 4 prior therapies were reported for 12 patients. Of the 16 patients, 13 had received an intervening salvage therapy between allogeneic HSCT and the start of ibrutinib treatment. The median time since the most recent transplant was 27 months (range, 8-115). Baseline neutropenia, anemia, and thrombocytopenia were reported in 31%, 25%, and 38%, respectively. Median time on ibrutinib was 18.1 months (range, 0.4-38.8) including 12 patients who were treated with ibrutinib for >12 months. At the time of data cut-off, 11 patients were continuing treatment. Reasons for discontinuation included disease progression (n=2), AEs (n=2), and withdrawal of consent (n=1). No dose reductions were reported. Investigator-assessed responses included 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis, resulting in a best ORR of 87.5%. Median DOR, median PFS, and median OS were not reached at a median follow-up of 23 months. The 24-month PFS and OS rates were each 77% and 75%, respectively. Treatment-emergent grade ≥3 SAEs were observed in 11 patients and included infections (n=6), with the remaining events occurring in 1 patient each, including febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea. The only AE leading to discontinuation of ibrutinib was pneumonia in 2 patients; both were fatal events (at 0.9 and 2.3 months). Two additional deaths occurred on study due to disease progression at 24 and 28 months.
Conclusion: Ibrutinib was well tolerated in patients who had undergone prior allogeneic HSCT, with a safety profile similar to that observed in the overall population of patients with relapsed/refractory CLL. The best ORR of 87.5% in this subgroup was also consistent with the 90% reported for the broader relapsed/refractory population in the PCYC-1102 study of single-agent ibrutinib. These data support use of ibrutinib in CLL patients with previous allogeneic HSCT and exploration of ibrutinib treatment for chronic GVHD (ongoing clinical trial: clinicaltrials.gov NCT 02195869).

Disclosures
Coutre: Janssen, Pharmacyclics: Honoraria, Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Miklos:Pharmacyclics: Research Funding. Zhou:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Styles:Pharmacyclics: Employment. Jaglowski:Pharmacyclics: Research Funding.