Barrientos, Jacqueline C.

Abstract Introduction: Ibrutinib (Imbruvica®), an oral, first-in-class covalent BTK inhibitor, is a new treatment option approved by FDA for chronic lymphocytic leukemia (CLL) patients (pts) with ≥1 prior therapy. We previously reported results from the phase III trial, in which ibrutinib (ibr) significantly improved progression-free and overall survival vs ofatumumab (ofa) in pts with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) (Byrd et al. NEJM, 2014). Here, we report measures of patient well-being, including hematologic, immunologic, and quality of-life parameters, at interim analysis (IA). Methods: Pts with CLL/SLL after ≥1 prior therapy were randomized 1:1 to ibr 420 mg/day until progression or unacceptable toxicity, or to ofa for up to 24 weeks. At IA, secondary efficacy endpoints of hematologic improvement (sustained improvement ≥56 days without transfusions or growth factors) and FACiT-Fatigue (FACiT-F) outcomes were analyzed, along with exploratory endpoints assessing disease-related symptoms (DRS), serum immunoglobulin, patient-reported outcomes (PROs) by EORTC QLQ-C30, and medical resource utilization (MRU). Results: Of 391 enrolled pts (ibr n=195; ofa n=196), 63% had cytopenia(s) at baseline: 45% had anemia (hemoglobin ≤11 g/dL), 35% thrombocytopenia (platelets ≤100×109/L), and 20% neutropenia (absolute neutrophil counts [ANC] ≤1.5×109/L). On the ibr arm, 69% of pts with baseline cytopenias experienced sustained improvement in blood counts compared to 43% on ofa (P<0.0001, table). There was no decrement in serum immunoglobulins (IgA, IgG, IgM) during follow-up. IgA levels increased on the ibrutinib arm only (mean change from baseline: 41% at week 24). Immune cells CD4+ and CD8+ T-cell and NK-cell levels remained relatively stable during treatment. Mean change in FACiT-F score from baseline are shown in the figure for ibr and ofa arms. At week 24, clinically meaningful (≥3 points) improvement in FACiT-F occurred in more pts on ibr than ofa (59% vs 46%, P=0.06); clinically meaningful deterioration was reported by 14% vs 24% (P=0.08), respectively. A larger proportion of ibr vs ofa pts showed clinically meaningful improvement on EORTC-QLQ-C30 global health scores (46% vs 40%). Clinically meaningful improvement (≥10 points) from baseline to week 24 in ibr vs ofa pts was observed for fatigue (median 11 vs 0). A 50% reduction in lymph node based on IRC-assessed CT was observed in 93% (177/190 evaluable) of ibr pts compared with 17% (29/174 evaluable) of ofa pts (P< 0.0001). Splenic response based on IRC-assessed CT was reported for 85% (138/163 evaluable) of ibr pts compared with 54% (82/151 evaluable) of ofa pts. Baseline DRS were comparable between groups; however, improvement by at least 1 grade (G) post-baseline was observed in ibr relative to ofa pts for weight loss (100% vs 93%), fatigue (88% vs 72%), night sweats (95% vs 86%), and anorexia (100% vs 64%), respectively. Cumulative MRU was comparable for growth factors and transfusions, with ibr pts having longer median treatment duration: 8.6 months for ibr vs 5.3 for ofa. Hospitalizations in the first 30 days occurred in 2% ibr vs 15% ofa pts. After adjusting for treatment exposure duration, diarrhea, grade 1-2 bleeding events (e.g petechiae), and atrial fibrillation were among those noted to be more frequent on the ibrutinib arm while events such as fatigue, infusion reaction, and peripheral sensory neuropathy were seen more commonly with ofa. Major hemorrhage events were uncommon, observed in 2 patients on the ibr arm vs 3 on ofa arm without adjusting for exposure time. Exposure-adjusted analysis showed no difference in any-grade infection and a 43% relative reduction for grade 3 or higher infections for ibr. Conclusions: Ibr compared to ofa when administered to previously treated CLL/SLL pts led to improvements in hematologic function and disease burden. A survival benefit with ibr, together with sustained improvements in hematologic endpoints and PRO suggest that ibr enhances quality of life while prolonging survival. Table. Sustained hematologic improvement Parameter, n (%) ITT population Pts with cytopenias at baseline Ibr n=195 Ofa n=196 P value Ibr n=195 Ofa n=196 P value Platelets 60 (31) 19 (10) <0.0001 53/74 (72) 14/64 (22) <0.0001 ANC 52 (27) 19 (10) <0.0001 26/41 (63) 12/38 (32) 0.0047 Hemoglobin 42 (22) 32 (16) 0.1883 42/89 (47) 32/86 (37) 0.1815 Figure. Improvement in FACiT-F by treatment arm. Figure. Improvement in FACiT-F by treatment arm. Disclosures Barrientos: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulligan:Roche, Abbvie: Consultancy, Honoraria. Jaeger:Janssen Cilag: Honoraria. Devereux:Pharmacyclics, Janssen: Consultancy, Honoraria. Robak:Janssen: Consultancy, Research Funding. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Bloor:GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dearden:Roche, GSK, Gilead, Janssen, Napp: Honoraria. Jones:Pharmacyclics: Consultancy, Research Funding. Kierschniak:Pharmacyclics, GmbH: Employment. Eckert:Pharmacyclics: Employment. Suzuki:Pharmacyclics: Employment. Hsu:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding.

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. Over the last 15 years, a series of phase 3 trials have established that chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression free survival (PFS) and overall survival (OS) compared with chemotherapy alone. FCR is the gold standard for young fit patients with treatment naïve CLL. In parallel with the advances in CIT, a profound increase in the understanding of CLL B-cell biology led to new therapeutic approaches.1 Among these, ibrutinib (an irreversible inhibitor of Bruton's Tyrosine Kinase [BTK]) has had the largest impact on clinical practice to date. Initial trials of ibrutinib demonstrated robust and durable efficacy in patients with relapsed/refractory disease. Subsequent phase 3 trials showed improved PFS and OS with ibrutinib relative to chlorambucil in previously untreated, older CLL patients. Despite these advances, the efficacy of ibrutinib as a first-line treatment for younger CLL patients (i.e. <70) relative to the most efficacious CIT regimens, such as FCR, is unknown. METHODS: Eligible patients were treatment-naive individuals with CLL who were age <70 and required therapy. Patients with deletion 17p- were excluded from participating given the poor response of these patients to FCR therapy. Participants were randomly assigned in a 2:1 ratio to receive ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days. The planned accrual was 519 patients. Hematologic toxicity was graded according to the 2008 IWCLL Working Group scale. All other adverse events were graded according to the NCI Common Toxicity Criteria (version 4). The primary endpoint was PFS with a secondary endpoint of overall survival (OS). Analysis was by intention to treat. The first planed interim analysis for PFS was scheduled to occur 24-27 months after full accrual with the first interim analysis for OS scheduled to occur if the boundary for PFS was crossed. The primary analysis was a stratified logrank test applied to all patients as randomized. Treatment effect p-values are one-sided. The study was approved by the Central Institutional Review Board for the National Cancer Institute, conducted in accordance with the principles of the Declaration of Helsinki, and registered with ClinicalTrials.gov (NCT02048813). RESULTS: A total of 529 patients were accrued between January 31, 2014 and June 9, 2016. 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to FCR. Nineteen patients did not start protocol therapy. The first interim analysis was performed September 2018. With median follow-up of 33.4 months, we observed 77 PFS events and 14 deaths. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.352; 95% CI 0.223-0.558; p<0.0001) which crossed the pre specified boundary. The HR for OS also favored the IR arm (HR=0.168, 95% CI 0.053-0.538; p=0.0003, pre-specified boundary for superiority p=0.0005). Kaplan-Meier estimates for PFS and OS are shown in Figure 1A and 1B. In subgroup analysis for PFS, IR was superior to FCR independent of age, sex, performance status, disease stage or the presence/absence of del11q23. With current follow-up, IR was also superior to FCR for IGHV unmutated patients (HR=0.262; 95% CI 0.137-0.498; p<0.0001) but not IGHV mutated patients (HR=0.435; 95% CI 0.140-0.1350; p=0.07). Grade 3 and 4 treatment-related adverse events were observed in 58% of IR and 72% of FCR treated patients (p=0.0042). Specifically, FCR was more frequently associated with grade 3 and 4 neutropenia (FCR: 69 [44%] of 158 vs. IR: 80 [23%] of 352; p<0·0001) and infectious complications (FCR: 28/158 [17.7%] vs. IR: 25/352 [7.1%]; p<0.0001). CONCLUSIONS: The combination of ibrutinib and rituximab provides superior PFS and OS relative to FCR for patients with previously untreated CLL age <70. These findings have immediate practice changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL. Disclosures Shanafelt: Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees. O'Brien:Amgen: Consultancy; Astellas: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Abbvie: Consultancy; Alexion: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding. Barrientos:Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Janssen: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; MacroGenics: Consultancy; MacroGenics: Consultancy; Amgen: Research Funding; Takeda/Millenium: Research Funding; Amgen: Research Funding; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding; Juno: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding. Stone:Juno: Consultancy; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; FujiFilm: Consultancy; Sumitomo: Consultancy; Ono/Theradex: Consultancy; Otzuka/Astex: Consultancy; Pfizer: Consultancy; Roche: Consultancy; AbbVie: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Celator / Jazz: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board; AbbVie: Research Funding; Cellerant: Research Funding; AROG: Research Funding; Orsenix: Other: Advisory board.

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.

AbstractHairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti‐CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8‐12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m2 weekly)(n = 16) or low dose (20 mg/m2 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression‐free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti‐CD20 mAb therapy as a potentially more effective use of anti‐CD20 mAb in the treatment of CLL. Am. J. Hematol. 91:308–312, 2016. © 2015 Wiley Periodicals, Inc.