Addition of venetoclax at time of progression in ibrutinib‐treated patients with chronic lymphocytic leukemia: Combination therapy to prevent ibrutinib flare
Authors: Paul J. Hampel, Timothy G. Call, Wei Ding, Eli Muchtar, Saad S. Kenderian, Yucai Wang, Jose F. Leis, Thomas E. Witzig, Amber B. Koehler, Amie L. Fonder, Susan M. Schwager, Kari G. Rabe, Daniel L. Van Dyke, Esteban Braggio, Susan L. Slager, Neil E. Kay, Sameer A. Parikh
Journal: American Journal of Hematology (2019)

To the Editor: The outcomes of patients with chronic lymphocytic leukemia (CLL) have dramatically improved with the introduction of novel agents. Final analysis of the phase III RESONATE trial reported a median progression free survival (PFS) of 44 months in relapsed/refractory CLL patients treated with ibrutinib.1 Venetoclax is effective in CLL following progression on ibrutinib, with an overall response rate (ORR) of 65% and estimated 12-month PFS of 75%.2 Due to concerns for tumor lysis syndrome, the dose of venetoclax is increased on a weekly ramp-up schedule per package insert. We have previously reported that the rapid flare of disease is common in CLL patients when they discontinue ibrutinib at disease progression (ie, progressive CLL or Richter's transformation [RT]).3 In this study, we sought to evaluate the role of continuing ibrutinib beyond the start of salvage venetoclax in CLL patients progressing on ibrutinib monotherapy. We identified CLL patients seen at Mayo Clinic who had disease progression on ibrutinib where venetoclax was added as subsequent treatment while continuing ibrutinib. Ibrutinib flare was as previously defined.3 All patients started venetoclax according to the weekly ramp-up per the package insert. Overall survival (OS) was defined from the start of venetoclax therapy until last known alive date. Event free survival (EFS) was defined from the start of the venetoclax therapy until disease progression, death, or subsequent treatment, whichever occurred first. Eighteen patients with progressive disease (14 progressive CLL, 4 RT of CLL) who started venetoclax while continuing ibrutinib were identified. See Table 1 for baseline characteristics. The target venetoclax dose of 400 mg daily (200 mg in one patient due to a drug metabolism interaction) was reached by 5 weeks in 13 patients; reasons for delaying or stopping dose escalation included diarrhea (n = 2), sepsis (n = 2), and neutropenia (n = 1). No patient experienced a disease flare during venetoclax ramp-up. Anti-CD20 therapy (six rituximab, one obinutuzumab) was added to combination ibrutinib and venetoclax during the treatment course in seven patients (five CLL progression and two RT) after a median 87 days (range 0-133 days). See Table S1 for toxicities with combination therapy. The median duration of combination ibrutinib and venetoclax was 3 months (range, 0-14 months). Of the 18 patients who started combination therapy with ibrutinib and venetoclax, ibrutinib was discontinued in 10 patients (median overlap of 2 months). Reasons for discontinuation included four planned discontinuations after achievement of target dose of venetoclax, two allogeneic stem cell transplants (HSCT), two due to toxicities (one neutropenia and one immune thrombocytopenia), one for financial reasons, and one for death secondary to pneumonia. Among the patients who discontinued ibrutinib, only one experienced ibrutinib flare, occurring after a planned abrupt discontinuation of ibrutinib. This patient had overlapped treatment for 41 days, resulting in normalization of clinical and hematologic parameters, and was tolerating venetoclax 400 mg daily at time of ibrutinib discontinuation. Management with re-initiation of ibrutinib was effective in regaining disease control, and combination therapy was continued until proceeding to HSCT 4 months later. Of the remaining eight patients who stopped ibrutinib and did not develop ibrutinib flare, four patients tapered ibrutinib over 2-8 weeks, two patients received corticosteroids (prednisone 60 mg daily for 1 week followed by a taper) at the time of ibrutinib discontinuation, and two patients discontinued without an ibrutinib taper or steroids. Among the other eight patients (six CLL progression and two RT) who did not discontinue ibrutinib, six patients remain on the combination with venetoclax (median duration 6.5 months, range 3-14 months). Two patients (one CLL progression, one RT) continued on ibrutinib monotherapy following venetoclax discontinuation due to disease progression. The ORR of combination therapy was 81% (92% in CLL progression; 33% in RT); CR/clinical CR in 56% (61% in CLL progression; 33% in RT), partial response in 25% (31% in CLL progression; 0% in RT), stable disease in 6% (8% in CLL progression; 0% in RT), and primary refractory disease in 13% (0% in CLL progression; 67% in RT). The estimated 12-month EFS and OS (Figure S1) were 54% (95%CI 33-87%) and 79% (95% CI 60-100%), respectively, and were similar in cases of CLL progression and RT (data not shown). Previous reports from clinical trial4 and real-world3 settings have described rapid progression of disease, following ibrutinib discontinuation in patients who are showing signs of progression on ibrutinib. Among patients with progression, many have developed resistance via mutations in BTK or PLCG2,5 which has been considered potentially causative for the flare phenomenon through mechanisms including autonomous B cell receptor signaling and enhanced downstream expression of pro-survival signaling pathways, manifesting as more biologically aggressive disease.6 In our current report, we demonstrated the importance of continuing ibrutinib when starting venetoclax in patients progressing on ibrutinib. This markedly reduced the rate of flare, which occurred in only one patient in this cohort. Additional tactics employed included tapering off ibrutinib after a period of overlap and corticosteroids at time of discontinuation; these may serve as beneficial adjuncts in patients considered particularly high risk. An accelerated ramp-up dosing schedule for venetoclax initiation is another strategy to prevent ibrutinib withdrawal, as described by Jones and colleagues for patients with a high tumor burden and signs of rapid progression on ibrutinib.2 Limitations of the current analysis include the small number of patients and a cohort comprised of patients with both CLL and RT. The financial logistics of reimbursement for both agents outside a clinical trial represents a challenge since this combination is not yet approved by the Food and Drug Administration. Our report has important clinical implications for practicing hematologists/oncologists as well as clinical trials. Without evidence from controlled trials, we recommend either continuing ibrutinib in addition to venetoclax or rapid dose escalation of venetoclax in patients progressing on ibrutinib monotherapy as reasonable strategies to prevent ibrutinib flare at the time of transitioning treatment. Trial design must minimize protocol-mandated washout periods for patients with relapsed/refractory CLL to allow for overlap and facilitate participation of patients in this clinical scenario. Guidelines for preventing ibrutinib flare will need to be refined as further evidence accumulates. Presented as an abstract at the 24th Congress of the European Hematology Association. None. PJH, KGB, and SAP designed the research, collected, analyzed, and interpreted data, and wrote the manuscript; TGC, WD, EM, TEW, ABK, and ALF cared for the patients, analyzed data, and critically reviewed the manuscript; SSK, YW, JFL, DLVD, EB, and NEK analyzed data and critically reviewed the manuscript; SMS collected data for statistical analysis; KGB and SLS analyzed data, conducted statistical analyses, and critically reviewed the manuscript; All authors approved the manuscript in its final format. Table S1. Toxicities with combination therapy Figure S1: 12-month Event Free (A) and Overall (B) Survival. 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