Favorable Patient Survival after Failure of Venetoclax (ABT-199/ GDC-0199) Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Authors: Tam Constantine , Anderson Mary Ann , Ritchie David S. , Januszewicz E. Henry , Carney Dennis , Roberts Andrew W. , Seymour John F. 
Published: October 2019

Abstract
Introduction
Targeted inhibitors of BTK, PI3K or BCL-2 all induce durable responses in patients with chemotherapy-refractory CLL. In the case of the BTK inhibitor ibrutinib, two patterns of resistance have emerged: early (<12 - 24 months) progression with RichterÕs Syndrome (RS), and late progression with CLL often carrying BTK and/or PLCγ mutations. The survival of patients with disease progression after ibrutinib is reported to be poor, particularly for those with RS (median overall survival (OS) 2.6 - 3.5 months)(Blood 2015:2062, JAMA Oncol 2015:80). There are no available data in the context of venetoclax failure.
Methods
We analyzed our institutional experiences with 70 patients with relapsed / refractory CLL enrolled across 3 venetoclax studies between 2011 and 2015 (2 single agent, 1 rituximab combination). Twenty-eight patients (40%) ceased venetoclax for reasons other than voluntary drug hold after achieving complete remission; these patients had received a median 7.5 (range, 1 - 38) months of venetoclax therapy prior to cessation.
Results
Of 28 patients, 7 (25%) had CLL progression, 16 (57%) developed RS (3 Hodgkin, 13 DLBCL), and 5 (18%) ceased for other reasons. Patients who ceased therapy typically had high-risk disease characteristics including del(17p)/TP53 mutation or complex cytogenetics in 70%, unmutated IgHV in 88%, and a median of 4 (range 1 - 12) prior therapies before venetoclax. After a median survivor follow-up of 12.5 months (range 0 - 34), the median post-progression survival of patients who progressed with CLL and RS were: not reached (1 year OS 69%) and 12 months, respectively (p=0.88, Figure). Post-progression survival did not statistically differ by any of the following factors: response to venetoclax, progression on venetoclax before or after 12 months, cytogenetic risk, or the number of prior therapies (all p-values >0.18). Of the 7 patients with CLL progression, 5 remain alive on next-line ibrutinib (n=4) or corticosteroids (1). Of the 16 patients with RS, 15 received salvage therapy; R-CHOP (n=6) and R-ICE (3) being the most commonly used regimens. 4 received consolidation with stem cell transplantation. One allogeneic stem cell recipient died at 12 months from transplant-related complications, and the other remains alive and free of disease at 34 months. Both autologous transplant recipients have relapsed with CLL and were successful salvaged with BTK inhibitors.
Conclusion
Failure of venetoclax does not automatically portend a poor prognosis. The survival of patients who progress with CLL or RS on venetoclax therapy may be superior to that reported for BTK inhibitors.
Figure 1. Figure 1.

Disclosures
Tam: Janssen: Consultancy, Honoraria, Research Funding. Off Label Use: Venetoclax is not licensed for treatment of CLL. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Seymour:Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.