Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis
Authors: Choi Michael Y. , Castro Januario E. , Hoff Sheila , Li Hongying , Rassenti Laura , James Danelle F. , Messer Karen , Kipps Thomas J. 
Published: October 2019

Abstract
Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL.

Methods
Patients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy.

Results
By April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q).
5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients.
Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype.

Conclusions
The combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes.

Disclosures:
Choi: Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.