Alemtuzumab Consolidation Does Not Improve Outcome for CLL Patients with High Risk Genomic Features on Successive CALGB Trials.
Authors: Jones Jeffrey A. , Stark Amy , Zhao Weiqiang , Lin Thomas S. , Rai Kanti R , Marcucci Guido , Peterson Bercedis , Larson Richard A. , Heerema Nyla A. , Byrd John C. 
Published: October 2019

Abstract
Abstract 1791

Introduction:
Alemtuzumab (Al) consolidation has been investigated as a strategy to improve the quality and duration of remission after fludarabine (F)-based induction therapy for CLL. Whether pts with genomic high-risk disease, such as unmutated (unmut) immunoglobulin heavy chain genes (IGVH) and poor-risk interphase cytogenetic (cyto) abnormalities such as del(17p) and del(11q), benefit from this approach has not been systematically investigated. We retrospectively assessed the impact of these factors on induction outcome and survival from 2 completed Cancer and Leukemia Group B (CALGB) consolidation studies.

Methods:
CALGB 19901 and 10101 enrolled treatment naïve high-risk Rai stage III/IV or active Rai stage I/II CLL pts. Pts on CALGB 19901 received F 25 mg/m2/day IV × 5d every 4 wks for 4 mos. After a 2 mo. observation period, patients achieving complete (CR), partial remission (PR), or stable disease (SD) received Al at 30 mg/dose 3 × weekly for 6 wks, IV to the first 56 pts and subq to the next 29. Pts on CALGB 10101 received up to 6 cycles of F 25 mg/m2/day IV × 5d and rituximab (R) 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and 375 mg/m2 on day 1 of cycles 2 through 6. Pts with CR/PR/SD at 3 mos. post induction proceeded to Al 30 mg/dose 3 × weekly for 5 wks after a 1 wk dose escalation. Response was assessed by NCI 96 criteria immediately before and again 2 months post Al. Progression-free (PFS) and overall survival (OS) were assessed by genetic risk group: IGVH (mut v. unmut), del(17p)/del(11q) (absent v. present). A 2-sided alpha of 0.05 was used for all tests.

Results:
Of 187 pts treated on CALGB 19901 and CALGB 10101, 117 (63%) received at least 1 dose of Al, with 80 and 78 pts evaluated for IGVH and cyto, respectively. Among pts with IGVH, no significant differences in age, Rai stage, or sex were observed between mut and unmut pts (p>0.20). Induction response differed by IGVH status, with a lower fraction of responding mut pts (62% vs. 87%, p=0.02). Of those with PR or SD after induction, most improved response with Al, but the proportion of pts who improved their response was not associated with IGVH (mut 60% v. unmut 53%, p=0.62). PFS was similar in both IGVH groups (p=0.50), but OS was inferior in IGVH –unmut pts (p=0.02), emphasizing limited options for salvage in that group. In the subgroup of pts with cyto data, there were no significant differences in pt characteristics (p>0.20) or induction response rates (89% v. 83%) between those with or without del(17p)/del(11q). The proportion of improved responses with Al was similar between favorable and unfavorable cyto groups (52% v. 59%, p=0.78), although 2 non-responding unfavorable pts failed to convert to response with Al. Both PFS and OS tended to be worse in the unfavorable cyto group (p=0.05 and p=0.03, respectively), as has been observed historically. High-risk cyto remained moderately associated with inferior outcome when controlling for other prognostic factors, as did the negative association of IGVH-unmut with OS. Notably, induction response was not associated with PFS in either subgroup (p>0.50).

Conclusions:
Al consolidation can improve the quality of response in pts with high-risk CLL after F-based induction, but pts with IGVH-unmut or del(17p)/del(11q) continue to show inferior survival relative to pts without these markers, which must be balanced against the reported risk for serious infectious toxicity. Outcomes for these challenging pts remain poor, and consolidation and maintenance strategies remain appealing. Less immunosuppressive novel agents, such as kinase inhibitors and immunomodulatory drugs warrant exploration in this context.

Disclosures:
Off Label Use: Flavopiridol and lenalidomide are off-label for the treatment of CLL.