Byrd, John C.

7503 Background: Prior to use of novel targeted agents for CLL, debate existed regarding the best chemoimmunotherapy regimen to build upon in patients (pts) with non-del(11q) disease. The role of lenalidomide (L) was also not defined. CALGB 10404 was a randomized phase 2 study addressing these questions. Methods: Pts with untreated CLL requiring therapy were randomized to treatment with fludarabine + rituximab (FR), FR + 6 monthly consolidative treatments of L (5 mg days 1-21/28 x 1 then 10 mg days 1-21/28 x 5) (FR+L), or FR + cyclophosphamide (FCR). Based on pretreatment central interphase cytogenetic screening, pts with del(11q22.3) in at least 20% of cells were excluded from the primary analysis, testing whether 2-year progression-free survival (PFS) rate was improved in non-del(11q) pts within each arm. A target accrual of 103 non-del(11q) pts per arm provided at least 84% power to detect an increase in 2-year PFS rate from 60% to 73%; the critical value was 69% using a single stage design and type I error rate of 4%. Results: A total of 342 non-del(11q) CLL pts were randomized to treatment with FR (n = 123), FR+L (n = 109), or FCR (n = 110). Baseline characteristics were similar across arms. Two-year PFS rates with exact 90% CIs were 64% (57-71%) (FR), 71% (63-78%) (FR+L), and 74% (66-80%) (FCR). Median PFS was significantly shorter with FR compared to FR+L (p = 0.03) and FCR (p < 0.01): 43 (95% CI: 33-50), 66 (95% CI: 45-not reached), and 78 (95% CI: 58-not reached) months respectively. Median overall survival (OS) has not been reached for any arm. OS at 1, 2, and 3 years was similar across arms, although there was a plateau in OS with no events beyond 41 months in the FR+L arm, different from FR/FCR where events continued to occur. The most common adverse events were cytopenias and infections. Conclusions: FR+L and FCR met the protocol defined primary endpoint. FR+L extended PFS relative to FR and a plateau in survival differentiated this arm from the FR/FCR arms. Future studies comparing FR+L to FCR or incorporating L into other novel treatment regimens are justified. Support: U10CA180821, U10CA180882, Celgene. Clinical trial information: NCT00602459.

Key PointsBrief lenalidomide consolidation after chemoimmunotherapy is acceptably tolerated and extends PFS and OS in CLL. FCR has superior efficacy compared with FR chemoimmunotherapy for CLL.

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

Abstract Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients &lt;60 years of age, who also had less mutations in the methylation and spliceosome groups compared with patients ≥60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207–18. ©2016 AACR.

SummarySomatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ˂3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre‐treatment DNMT3A R882 and all other AML‐associated mutations to a variant allele frequency ˂3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients. There were no significant differences in disease‐free or overall survival between patients with and without DNMT3A R882 mutation clearance. Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease‐free survival (1·6 vs. 0·6 years, P = 0·06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML‐associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12). These data demonstrate that DNMT3A R882 mutations, as assessed by traditional NGS methods, persist in the majority of AML patients in CR.

Significance Long noncoding RNAs (lncRNAs) are involved in numerous biological roles including epigenetic regulation, apoptosis, and cell cycle. Whereas lncRNAs contribute to epigenetic gene regulation, metastasis, and prognosis in solid tumors, their role in acute myeloid leukemia (AML) has not been hitherto reported. Here, we show that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML. The identification of patients likely to achieve complete remission with standard therapy alone, based on lncRNA expression, is a significant advance potentially sparing such patients from other toxicities and focusing investigational approaches on postremission studies.

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.