Brown, Jennifer R.

7505 Background: Novel agents (NA) targeting B cell receptor kinases and Bcl-2 have substantially improved outcomes in CLL; however, the development of RS in CLL patients (pts) on NAs has been observed, and has not been systematically evaluated. Methods: We retrospectively reviewed pts at 9 academic centers diagnosed with pathologically-confirmed RS from 2011-16. Informed consent was provided through IRB-approved protocols. Descriptive statistics were utilized and overall survival (OS) was calculated from RS diagnosis (dx) to death or last follow-up by Kaplan-Meier. Results: 71 pts who developed RS on NAs for CLL were identified. Median age at CLL dx was 55 yrs (range 21-82), median of 3 therapies (range 0-12) prior to the NA. 68% pts were fludarabine-refractory, and 5 pts (7%) had relapsed post alloHCT. Median time from CLL dx to initiation of NA was 68.5 mo. (range 1.1-246.2). FISH at NA initiation: del(17p) 30/61 (49%), del(11q) 15/61 (25%), trisomy 12 15/61 (25%). Complex karyotype was present in 40/53 (75%). 46/52 (88%) were IGHV unmutated, VH1-69 10/43 (23%), VH4-39 4/43 (9%). 59 (83%) pts were on a BTK inhibitor, 6 (8%) PI3K inhibitor, 6 (8%) venetoclax. RS histology: DLBCL (87%), plasmablastic (6%), Hodgkin (4%), 3% other. RS Ki-67%: >90 (23%), 75-90 (25%), 50-75% (25%), <50% (28%). Median time from start of NA to RS dx was 9.1 mo (range 0.9-48.2), with 65% developing RS within 12 mo. of starting NA. In 56 pts, 19 different regimens were used as initial RS therapy, including: R-EPOCH (36%), R-CHOP (20%), checkpoint blockade (9%), OFAR (7%), or a different NA (7%). Of the 48 pts evaluable for response, ORR was 42% (15% CR, 27% PR). In 29 evaluable pts receiving R-EPOCH/CHOP, ORR was 48% (21% CR). With a median follow-up of 10.6 mo., median OS was only 3.3 mo. (95%CI 2.2-6.0), though none of the 7 pts who achieved CR has died. Conclusions: We report to our knowledge the largest series of CLL pts developing RS on NAs. Pts often had high risk CLL, particularly complex cytogenetics, and RS frequently developed within the first year of NA therapy. Substantial variation exists in treatment, and outcomes are poor for those who do not achieve CR. Identification of molecular drivers of RS and development of novel treatment strategies are urgently needed.

Abstract Background: Patients (pts) with CLL/SLL who use unmutated IGHV (u-CLL) have a less favorable outcome with standard chemotherapy than pts who use mutated IGHV (m-CLL). Ibrutinib (ibr) inhibits B-cell receptor signaling through Bruton’s tyrosine kinase and has robust clinical activity against CLL. This integrated analysis of 3 phase 3 studies examined the impact of IGHV status on ibr- and comparator (comp)-treated pts. Methods: Pooled data from 3 studies of ibr (420 mg/d) in CLL/SLL pts (RESONATE: relapsed/refractory [R/R] pts, ibr vs ≤ 24 weeks ofatumumab; RESONATE-2: treatment-naïve [TN] pts ≥ 65 yrs of age [no del17p], ibr vs ≤ 12 cycles chlorambucil; HELIOS: R/R pts [no del17p], ≤ 6 cycles bendamustine-rituximab with ibr vs placebo) were analyzed by IGHV status. Analyses included Kaplan-Meier method (overall survival [OS]; progression-free survival [PFS]); log-rank test (group comparisons); and Cox multivariate analysis (prognostic factors; Table). Results: For 491 ibr- (366 u-CLL, 125 m-CLL) and 494 comp-treated (351 u-CLL, 143 m-CLL) pts with IGHV data, baseline characteristics were similar for u-CLL vs m-CLL, except for the proportions of pts who were TN (17 vs 31%), had bulky disease (60 vs 37%), or had CLL cells with del11q (32 vs 16%). Median follow up was 21.4 mos for ibr and 20.6 mos for comp. PFS and OS were similar for u-CLL and m-CLL ibr-treated pts; u-CLL had poorer outcomes than m-CLL in comp-treated pts, which remained after adjustment for prognostic factors (Table). Ibr treatment was more effective than comp regardless of IGHV status. Incidence of adverse events (AEs) was similar between groups. For ibr vs comp pts (u-CLL/m-CLL): serious AEs: 49% (50%/47%) vs 36.5% (37%/35%); AEs that led to discontinuation: 12% (11%/15%) vs 13% (13%/14%); death within 30 days of last dose: 5% (6%/3%) vs 5% (6%/2%). Conclusions: U-CLL was an adverse predictor of outcome for comp-treated, but not for ibr-treated pts. Table.Efficacy Outcomes in Ibr- and Comparator-Treated Patients by IGHV Mutation StatusIbrutinib (N=491)Comparator (N =494)u-CLL (n=717)m-CLL (n=268)u-CLL(n=366): m-CLL(n=125)u-CLL(n=351): m-CLL(n=143)Ibr(n=366): Comp(n=351)Ibr (n=125): Comp (n=143)PFS24-month rate HR78%:81%10%:32%78%:10%81%:32%0.93a1.99a0.12b0.21bp = 0.78p &lt; 0.0001p &lt; 0.0001p &lt;0.0001Adjusted HRc1.02a1.94a0.11b0.17bp = 0.93p &lt; 0.0001p &lt; 0.0001p &lt; 0.0001OS24-month rate HR88%:89%78%:87%88%:78%89%:87%0.95a1.96a0.49b0.85b,ep = 0.86p = 0.02p &lt; 0.01p = 0.66Adjusted HRc1.21a2.10a0.49bNAp =0.57p = 0.01p &lt; 0.001Response ratesu-CLLm-CLLu-CLLm-CLLIbrCompIbrCompORR, %d8990475189479051p = 0.96p = 0.36p &lt; 0.0001p &lt; 0.0001CR, %d221546224156p = 0.10p = 0.44p &lt; 0.0001p = 0.01CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, overall response rate; NA, not applicable. aHR &lt; 1 favors unmutated. bHR &lt; 1 favors ibrutinib. cMultivariate Cox model adjusted for age, sex, current Rai stage, baseline ECOG performance status score, del11q, del17p, number of prior therapies, and cytopenias. dp value is from a Cochran-Mantel-Haenszel chi-square test. eInsufficient number of events prevents meaningful analysis, only 13 and 16 events observed in ibr and comp groups, respectively, and 46 (32%) pts in comp arm crossed over to ibr arm; interpret results with caution. Citation Format: Thomas J. Kipps, Graeme Fraser, Steven Coutre, Jennifer R. Brown, Jacqueline C. Barrientos, Paul M. Barr, John C. Byrd, Susan M. O'Brien, Marie-Sarah Dilhuydy, Stephen Devereux, Ulrich Jaeger, Carol Moreno, Paula Cramer, Stephan Stilgenbauer, Asher A. Chanan-Khan, Michelle Mahler, Mariya Salman, Mei Cheng, Anil Londhe, Joi Ninomoto, Angela Howes, Danelle James, Michael Hallek. Unmutated IGHV is not an adverse predictor of outcome to therapy with ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT158. doi:10.1158/1538-7445.AM2017-CT158

LBA7008 Background: Treatment options for CLL/ SLL patients (pts) who fail chemoimmunotherapy are limited. We report interim results from a phase III randomized study of ibrutinib (ibr), a first in class covalent BTK inhibitor, vs ofatumumab (ofa) in R/R CLL/SLL. The Data Monitoring Committee recommended this analysis be considered final, based on meeting the primary and a key secondary endpoint. Methods: R/R CLL/SLL pts who failed ≥1 therapy received 420 mg oral ibr daily until progression or IV ofa 300/2000mg for 12 doses. Primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary endpoints included overall survival (OS), IRC assessed overall response rate (ORR) and safety. Results: Of 391 pts enrolled (median age 67 years; 40% ≥70 years; 57% Rai stage III/IV disease; 30% del 17p), 195 were randomized to ibr and 196 to ofa. Ibr pts had median 3 prior therapies vs 2 for ofa. Median follow-up was 9.4 months (m). Ibr significantly lengthened PFS (median not reached vs 8.1 m; HR 0.215, CI 0.146–0.317, p<0.0001; 78.5% risk reduction), and significantly improved OS (median not reached; HR 0.434, CI 0.238–0.789, p=0.0049) compared with ofa. ORR was 42.6 vs 4.1% (p<0.0001) and ORR+PR with lymphocytosis was 62.6 vs 4.1% for ibr vs ofa. Similar effects were seen in del17p and purine analog refractory subsets. In each arm 2 pts had confirmed Richter’s transformation. Most frequent adverse events (AE) for ibr vs ofa were diarrhea (47.7 vs 17.8%) fatigue (27.7 vs 29.8%), and nausea (26.2 vs 18.3%). Atrial fibrillation was more frequent with ibr (5.1 vs 0.5%). Major hemorrhages were reported in 1.0 vs 1.6% for ibr vs ofa. Drug discontinuation due to AE was 4.1 vs 3.6% for ibr vs ofa. 86% of ibr pts were continuing treatment. 57 pts randomized to ofa with confirmed PD had initiated ibr at cross-over. Conclusions: Compared with ofa, ibr significantly improved PFS, OS and ORR in pts with R/R CLL/SLL. The safety profile was comparable with that previously reported (Byrd NEJM 2013). These results support ibr as a beneficial therapy for R/R CLL patients irrespective of del 17p or purine analog refractory disease. Clinical trial information: NCT01578707.

Key Points The expression level of ROR1 on CLL cells varies between patients. High-level CLL-cell expression of ROR1 associates with more aggressive disease.

Key Points Methylation analysis at ZAP-70 CpG+223 in CLL provides superior prognostic information vs IGHV status or CD38 or ZAP-70 expression. A pyrosequencing method for the feasible assessment of CpG+223 methylation in CLL samples is provided.

AbstractLeukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70–negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70–positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years.

AbstractWe examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.