Initial treatment of B‐cell prolymphocytic leukemia with ibrutinib
Authors: Jeremiah Moore, Andrea M. Baran, Philip J. Meacham, Andrew G. Evans, Paul M. Barr, Clive S. Zent
Journal: American Journal of Hematology (2020)

B-cell prolymphocytic leukemia (B-PLL) is a rare lymphoid neoplasm with an estimated 120 cases per year in the United States.1, 2 It is frequently characterized by TP53 dysfunction, can have an aggressive course, and prognosis was previously reported to be poor with a median overall survival of 3 years.3 There are no standard treatments and most patients are managed using regimens developed for chronic lymphocytic leukemia (CLL).4 Case reports have described response of B-PLL in patients treated with targeted drugs including ibrutinib, idelalisib, and venetoclax.3 We report a single center observational study of the initial treatment of six sequential B-PLL patients with ibrutinib containing regimens. B-PLL patients (three male, three female) were diagnosed according to the WHO criteria2 at a median age of 67.3 years (range 62.9-≥90). All patients had TP53 dysfunction (Table S1) and were negative for t(11;14) and cyclin D1 expression. Median time from diagnosis to first treatment for progressive B-PLL was 8 days (range 2-37). Initial treatment regimens were ibrutinib, rituximab and alemtuzumab (n = 2), ibrutinib and rituximab (n = 2), and ibrutinib monotherapy (n = 2) (Table S1). Response to therapy was evaluated using a modification of the CLL criteria defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).5 Because no patients had re-staging bone marrow biopsies or imaging, those patients meeting iwCLL clinical and laboratory complete remission criteria were considered to have a clinical complete remission (CCR). Partial response (PR), stable and progressive disease was defined using the iwCLL criteria. Progression free survival was defined as time from start of ibrutinib containing regimen to progression or death. Overall survival was defined as time from start of ibrutinib containing regimen to death from any cause. Patient follow up ranged from 2.6 to 59.9 months and time on an ibrutinib containing therapy ranged from 2.5 to 50.5 months (Figure 1). Treatment related adverse events included infections (recurrent urinary tract infections n = 1, cutaneous Nocardia infection n = 1, cytomegalovirus reactivation n = 1), musculoskeletal pain (n = 3), atrial fibrillation (n = 1) and stomatitis requiring dose reduction (n = 1). No patients discontinued therapy due to adverse events. Five patients responded to therapy (CCR n = 3 and PR n = 2) and one had stable disease. Median progression free survival (PFS) was 34.7 months (range 2.6-50.5) and median overall survival (OS) was not reached. Patient one had a CCR after treatment with rituximab, alemtuzumab and ibrutinib with disease relapse while still on ibrutinib therapy at 35 months (Figure 1). Molecular testing was negative for the Bruton tyrosine kinase (BTK) C481S and the phospholipase C gamma 2 (PLCG2) R665W mutations previously documented to cause ibrutinib resistance in CLL patients.6 Subsequently, he achieved a CCR on treatment with idelalisib and rituximab which was stopped at 5 months because of severe colitis, and the patient remains in remission 19 months later with no further treatment. Patient two achieved a CCR with ibrutinib and rituximab with an ongoing response of 50 months. Patient three had stable disease with ibrutinib and died after 2 months of therapy from progressive chronic obstructive pulmonary disease. Patient four achieved a short duration CCR after alemtuzumab, rituximab, ibrutinib, and splenectomy. Upon disease progression, therapy with venetoclax, rituximab and alemtuzumab was not effective and the patient died of progressive disease 1 month later. Patients five and six have achieved a PR on ibrutinib therapy which continues at 5, and 7 months respectively. To the best of our knowledge we report the largest cohort of patients receiving ibrutinib as initial therapy for B-PLL. Our data suggest that ibrutinib-containing therapy is tolerable and appears to improve PFS, and possibly also OS compared to historical data.3 Small molecule inhibitors of B cell receptor signaling could have a role in the management of this rare but serious disease. Funding for this study was provided Cadregari Endowment Fund (to C.S.Z.). A.G.E.: Consulting fees from H3Bio. C.S.Z.: Research funding to University of Rochester from Acerta/AstraZeneca and TGR Therapeutics. P.M.B.: Consulting for Pharmacyclics, Abbvie, Gilead, Genentech, Celgene, TG therapeutics, Merck, Seattle Genetics, Verastem, Morphosys. Other Authors declare no potential conflict of interest. J.M. designed the study, analyzed data, drafted the letter to the editor, and had full access to the data in the study. A.M.B., P.M.B. analyzed data. C.S.Z. designed the study, and drafted the letter to the editor. A.G.E., P.M.B. reviewed and provided substantial contributions during drafting of the letter. All authors approved the final draft of the letter and gave permission to submit to American Journal of Hematology. Table S1 Baseline patient characteristics and initial treatment Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.