Citations

BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard therapy for younger patients with CLL. FCR therapy is particularly effective in patients with immunoglobulin heavy chain variable region (IGHV) mutated CLL. Approximately half of IGHV mutated patients are progression free 8 years after FCR therapy. At the ASH 2018 meeting, we reported the initial results of the ECOG 1912 (E1912) trial, a phase 3 trial comparing the FCR regimen to the combination of ibrutinib and rituximab (IR) for previously untreated CLL patients age 70 or younger who required therapy. With median follow-up of approximately 34 months, the trial demonstrated both a progression-free survival (PFS) and an overall survival (OS) benefit relative to FCR. On sub-set analysis by IGHV mutation status, the difference in PFS was statistically significant for IGHV unmutated patients but, with current follow-up, not IGHV mutated patients. Here, we present updated results for PFS in the E1912 trial. METHODS: As previously reported, eligible patients were treatment-naive individuals with CLL age 70 or younger. Patients with deletion 17p- were excluded from participating in the E1912 trial given their known poor response to FCR therapy. Patients were randomly assigned in a two-to-one ratio to receive ibrutinib (420 mg/day until disease progression or unacceptable toxicity) and rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and then 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 days 1-3), cyclophosphamide (250 mg/m2 days 1-3) and rituximab (50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and then 500 mg/m2 on day 1 of cycles 2-6) every 28-days. Adverse events (AEs) were graded according to the NCI Common Toxicity Criteria (version 4). Dose adjustments for cytopenias were based on the IWCLL CLL Working Group grading scale. The primary endpoint of the trial was PFS with OS a secondary endpoint. Analysis was by intention to treat. RESULTS: With median follow-up of 45 months, 257 (73%) of 354 patients randomized to IR remain on ibrutinib. With extended follow-up, grade 3 and above treatment-related AEs were observed in 70% of IR and 80% of FCR treated patients (OR=0.56; 95% CI 0.34 - 0.90; p=0.013). Among IR-treated patients, the median time on treatment is currently 43 months (range=0.2-61). Among the 95 patients who have discontinued ibrutinib, the reason for discontinuation was progression or death in 23 (7% of patients who started IR; 24% of those who discontinued treatment), AE or complication in 48 (14% of patients who started IR; 51% of those who discontinued treatment), and withdrawal of consent or other reasons in 24 (7% of patients who started IR; 25% of those who discontinued treatment). On multivariable Cox regression adjusting for Timed Up and Go test score, Cumulative Illness Rating Scale (CIRS) score, age, gender, ECOG performance status, creatinine clearance, and baseline anemia/thrombocytopenia, only CIRS score (range 0 - 14) predicted discontinuation of ibrutinib for a reason other than progression or death (HR=1.13 per unit increase; 95% CI 1.03 - 1.23; p=0.009). Among the 72 patients who discontinued ibrutinib for a reason other than progression or death, the median time on ibrutinib was 15.1 months (range 0.2-58.2 months). The median time from ibrutinib discontinuation to disease progression or death was 23 months. With current follow-up, we observed 110 PFS events. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.39; 95% CI 0.26-0.57; p<0.0001). Updated analysis of OS will be presented. On sub-group analysis by IGHV mutation status, IR was superior to FCR for IGHV unmutated patients (HR=0.28; 95% CI 0.17-0.48; p<0.0001). With current follow-up the difference is not significant in IGHV mutated patients (HR=0.42; 95% CI 0.16-1.16; p=0.086). Kaplan-Meier estimates for PFS are shown in Figure 1. CONCLUSIONS: Although less than 7% of ibrutinib treated patients progressed while on therapy, roughly 1 in 5 patients have discontinued ibrutinib for a reason other than progression or death. The only parameter significantly associated with discontinuation for a reason other than progression was increased baseline CIRS score. With extended follow-up, the combination of ibrutinib and rituximab continues to provide superior PFS compared to FCR for younger patients with previously untreated CLL. Disclosures Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract The targeted therapy ibrutinib inhibits B cell receptor signaling (BTK inhibitor) and has yielded high response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL). However, it is widely believed that the addition of immune therapies to targeted drugs will be required to activate anti-tumor immunity and work towards curative therapy. Identifying effective combinations of targeted drugs and/or standard chemotherapy with immunotherapy is a priority research area and particularly relevant for CLL, as patients' T cells have been shown to exhibit profound tolerance/exhaustion and notably, no activity was reported in a recent trial of anti-PD-1 immunotherapy for relapsed disease. Ibrutinib has shown beneficial immunomodulatory activity in CLL by inhibiting IL-2-inducible T cell kinase (ITK) as well BTK that is associated with increased effector CD4+and CD8+ T cell numbers and decreased expression of inhibitory checkpoint receptors such as PD-1 on patient T cells. Here we have performed comparative immune bioassays from a randomized phase III trial comparing ibrutinib-based therapy to traditional FCR chemoimmunotherapy to assess the effects of treatments on anti-tumor T cell function. Viable peripheral blood mononuclear cell samples were collected serially (baseline, 6 months and 12 months) from CLL patients on the randomized phase III E1912 trial of ibrutinib and rituximab versus FCR for previously untreated disease to allow longitudinal batched immune analysis. Cytotoxicity assays revealed that highly purified CD3+ T cells from the FCR treated patients at 6 and 12-month time-points did not change their activated killing function against autologous baseline CD19+ CLL tumor B cells (acting as target antigen-presenting cells pulsed with superantigen, sAg) compared to pre-treatment/baseline exhausted T cells (n=22). In contrast, patients treated with ibrutinib-based therapy had a significant increase in activated anti-tumor T cell killing function (P<.01, n=22) at both 6-month (66% increase) and 12-month (89% increase) time-points. Flow cytometric analysis of circulating immune subsets revealed that the percentage of PD-1 and PD-L1 positive cells among CD8+ and CD4+ T cells (particularly effector compartments) were reduced with ibrutinib-based therapy, whereas only a partial reduction was detected following FCR treatment. However, patients' T cells from both treatment arms responded normally to T cell receptor engagement by upregulating these checkpoint molecules. This led us to explore ex vivo treatment of highly purified CD3+ T cells and CD19+ CLL B cells from both treatment arms with anti-PD-L1 or anti-PD-1 immunotherapy prior to cytotoxicity assays. Our functional data revealed that the T cells from both FCR time-points (6 and 12-months) were not sensitive to either anti-PD-L1 (n=14) or anti-PD-1 (n=14) treatment. In contrast, ibrutinib-based treatment sensitized anti-tumor T function (23% increase in killing) following anti-PD-L1 treatment (n=14) at the 6-month time-point only (P<.01) but not with anti-PD-1. To investigate the mechanism underlying these effector function differences, we compared the ability of highly purified CD3+ T cells from each treatment arm (n=45) time-point to form F-actin immunological synapses with baseline autologous CLL tumor B cells. Quantitative confocal image analysis revealed that ibrutinib-based therapy significantly (P<.01) enhanced polarization of F-actin, tyrosine-phosphorylated proteins and granzyme B at immune synapses with tumor cells at both 6 and 12-month time-points, whereas FCR treated patient T cells failed to mobilize these lytic synapse molecules. Importantly, our assays have revealed that T cells from both FCR treatment time-points formed "non-polarized" immune synapses with tumor cells, in keeping with cytotoxic dysfunction and insensitivity to additional checkpoint immunotherapy. In contrast, our functional correlative bioassays have revealed that ibrutinib-based therapy can reactivate exhausted cytolytic T cell function and suggest to us, a potential therapeutic window for anti-PD-L1 immunotherapy at the earlier 6-month time-point. We believe this data supports the concept of incorporating functional bioassays to immune-monitoring assays associated to clinical trials that should aid knowledge-led design of future combination immunotherapy. Disclosures Kay: Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: 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; Celgene: 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; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shanafelt:Pharmacyclics: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding. Ramsay:Celgene Corporation: Research Funding; Roche Glycart AG: Research Funding; MedImmune: Research Funding.

Abstract Introduction: The therapy of relapsed/refractory AML remains poor and new treatment options are sorely needed. The Leukemia Committee of ECOG devised a randomized phase II trial of 3 novel regimens to determine overall response rates could be improved. Methods: Patients between the ages of 18 and 70 years with a prior diagnosis of AML who relapsed <1 year after initial achievement of complete remission (CR) or who were refractory to initial induction therapy (<2 courses) or to first reinduction after a relapse (<1 course) were eligible for this trial. Eligible patients were randomized equally to one of three regimens described in Table 1 below. The primary endpoint was achievement of a morphologic complete remission (CR) or a CR with incomplete blood count recovery (CRi). A 2 stage statistical design was planned with 18 patients (assuming 16 eligible) to be accrued in the first stage. If at least 3 CR+CRi were seen among the 16 eligible patients, an additional 19 patients (assuming 17 eligible) would be entered in the second stage. If 8 or more CR+CRi were seen in the 33 eligible patients, this would be considered evidence of a promising response rate. Results: This study activated October 16, 2008 and closed August 2, 2013 with a total of 92 patients accrued (91 eligible). The eligibility criteria were amended during the study to lower the upper age limit from 70 to 65 years because 6 treatment related deaths occurred in the initial 27 patients accrued to the FLAM regimen. All of these patients died of septic shock or multi-organ failure and 5 of the 6 died within 1 month of the start of therapy. Most of these patients were over age 65 ( 53, 62, 67, 68, 69 and 69 years). At the first stage analysis, of the first 16 eligible patients accrued to each arm there were 2 CR and 2 CRi in the CT arm, 2 CR and 2 CRi in the FLAM arm and 2 CR in the sirolimus-MEC arm. Thus, the sirolimus-MEC arm was closed to accrual with a total of 20 eligible patients and second stage accrual continued for the CT and FLAM arms. Among the 35, 36 and 20 eligible patients accrued to arms A, B and C, respectively, there were 2 CR and 3 CRi in the CT arm, 6 CR and 4 CRi in the FLAM arm, and 2 CR and 1 CRi in the sirolimus-MEC arm. All 10 CR or CRi of the FLAM arm were among the first 33 eligible patients, therefore FLAM was the only regimen to achieve our target. The overall response rates for arms A, B and C were 14% (90% CI 7.1% - 34.7%), 28% (90% CI 16.1% - 43.0%) and 15% (90% CI 4.2% - 34.4%), respectively. Among the 92 patients accrued, there were 5, 10 and 2 grade 5 events within 30 days of the end of therapy in arms A, B and C, respectively. The vast majority of these deaths were attributed to infection and multi-organ failure except two which were secondary to disease. Conclusion: In this high risk group of AML patients the FLAM regimen showed an encouraging response rate. A randomized phase II trial has also recently been completed exploring its use in the front-line setting with newly diagnosed high-risk AML. While the FLAM regimen was excessively toxic in elderly patients with relapsed or refractory disease, it is a suitable option for younger patients in this setting. Arm A: CT Carboplatin 150 mg/m2/day over 24 hours by continuous infusion IV for 5 days (days 1-5) Topotecan 1.6 mg/m2/day over 24 hours by continuous infusion IV for 5 days (days 1-5) Arm B: FLAM Flavopiridol 30 mg/m2 for ½ hour followed by 60 mg/m2 over 4 hours IV per day for 3 days Cytarabine 667 mg/m2 over 24 hours by continuous infusion IV for 3 days (days 6-8) Mitoxantrone 40 mg/m2 IV over 1-2 hours (day 9) Arm C: Sirolimus-MEC Sirolimus 12 mg by mouth on day 1, followed by 4 mg by mouth daily for 8 days (days 2-9) Mitoxantrone 8 mg/m2/day over 15 minutes IV for 5 days (days 4-8) Etoposide 100 mg/m2/day over 1 hour IV for 5 days (days 4-8) Cytarabine 1000 mg/m2/day over 3 hours IV for 5 days (days 4-8) Table 2. Responses Table 1. Chemotherapy Regimens Regimen n Median age (range), years Responses (%) Deaths (first 30 days) (%) CT 35 55 (23-67) 5 (14%) 5 (14%) FLAM 36 62 (19-69) 10 (28%) 10 (28%) Sirolimus-MEC 20 52 (22-68) 3 (15%) 2 (10%) Disclosures Off Label Use: Sirolimus-potentiate chemotherapy Carboplatin-chemotherapy for AML treatment Topotecan-chemotherapy for AML treatment.

Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse > 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses< 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse > 3 yearsRelapse > 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.

Abstract Introduction: High-dose cytarabine consolidation chemotherapy for acute myeloid leukemia (AML) induces profound transient myelosuppression. Thrombocytopenia is a limiting factor in chemotherapy administration for maintaining dose intensity and schedule as thrombocytopenic-related hemorrhage may contribute to significant morbidity and mortality. Therapeutic and prophylactic platelet (plt) transfusions remain the treatment of choice but the benefits typically last only 3-7 days, are expensive, time consuming, and may induce alloimmunization and transmit infection. PrE0901 was a phase I multi-center study to evaluate the safety and toxicity of eltrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, for plt recovery in AML patients (pts) receiving consolidation therapy. Methods: The primary objectives were to determine the safety, tolerability, and optimal dosing of eltrombopag while describing the kinetics of plt recovery in AML pts receiving intensive consolidation. Plt recovery was defined as a sustained plt count of ≥ 20 x 109/L following the nadir with no plt transfusions in prior 7 days or a continued upward trend in plt count for at least 2 successive measurements despite no plt transfusions in 48 hours. We used a standard 3+3 design utilizing a novel dose escalation/de-escalation strategy for pts in either first or second complete remission, ≥18 and ≤70 years of age, who had an ECOG performance status of 0-2. Cytarabine was administered at 3 g/m2 (1.5 g/m2 for pts >60 years) IV over 3 hours twice daily on days 1,3,5. Eltrombopag at assigned dose was administered with a first cycle of cytarabine only. Planned eltrombopag dose levels -2, -1, 1, 2, 3, 4, and 5 were 50, 100, 150, 150, 150, 200, and 300 mg, respectively (Table 1). Eltrombopag was to start on days X, X, 3, -1, -5, -5, and -5 relative to day of cytarabine start and levels -2, -1, 1, 2, 3, 4, and 5, respectively, with day X being variable depending on timing of observed dose limiting toxicities (DLTs). The eltrombopag was continued until plt recovery or for up to 35 consecutive days, whichever occurred first. An exploratory objective was to determine if eltrombopag had an effect on TPO and EPO blood concentrations in this setting. Results: Accrual began on July 31, 2012 and the trial closed on January 8, 2016 upon recommendation after an independent Data and Monitoring Committee reviewed a separate trial of eltrombopag therapy in MDS which demonstrated futility. 104 pts were screened. 54 declined participation and 35 were deemed medically ineligible. A total of 15 eligible pts were enrolled; 14 were treated on study with one pt being withdrawn prior to starting treatment due to infection. Three pts were treated at each of dose levels 1-4 and two were treated on dose level 5. No DLTs were observed. Median time to plt recovery of all pts treated on study was 22.5 (range 16-43) days. Pts in cohort 1 dosed with eltrombopag 150 mg daily starting on day 3 of consolidation demonstrated the fastest plt recovery (median =19 days; range 19, 19, 19) compared to cohort 2 who received 150 mg daily starting on day -1 of consolidation and recovered the slowest (median 23 days; range 16, 23, 43). Dose escalation in terms of starting eltrombopag further in advance of chemotherapy exposure as within cohort 3 (150 mg starting day -5) was associated with a median plt recovery of 27 (range 22, 27, 27) days. Eltrombopag dose intensification with cohort 4 at 200 mg daily and cohort 5 at 300 mg daily was associated with median plt recoveries of 24 (range 18, 24, 26) and 23 (range 19, 27) days, respectively. Kinetics of plt recovery for all cohorts are represented in Figure 1 and duration of eltrombopag exposure for each individual patient is represented in Table 2. Conclusions: Endogenous cytokine (TPO and EPO) levels varied inversely with plt and hematocrit values and did not appear to be affected by eltrombopag dose / schedule (details to be provided at ASH Annual Mtg). Unusually high screen fail numbers warrant examination to guide future trial design in the post-remission setting. The addition of eltrombopag to high-dose cytarabine consolidation therapy was well-tolerated and no DLTs were observed. The results for cohort 1 [eltrombopag 150 mg daily starting on day 3 of consolidation] demonstrated the fastest plt recovery. Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding.

Abstract The ECOG-ACRIN Cancer Research Group Led Trial, E2902, was a randomized phase III North American Leukemia Intergroup trial of the Farnesyl Transferase Inhibitor , R115777(Tipifarnib), as maintenance therapy for acute myeloid leukemia (AML). Patients (pts) with AML in remission after requiring salvage therapy (primary induction failure or second or subsequent remission) or over the age of 60 in first remission were eligible. Pts were eligible if they were in a complete remission (CR) or complete remission without platelet recovery (CRp) as confirmed by bone marrow examination within 2 weeks prior to randomization. Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Adequate blood counts (absolute neutrophil count >= 1000/mm3 and platelet count >=50,000/mm3), and normal renal, and hepatic function were required within 2 weeks of randomization. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. Pts were stratified by remission ( CR1 vs > CR1) and whether or not they received consolidation therapy in the current remission. The main objective of this study was to compare disease free survival(DFS) in the two groups. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts was 69 (range 28-86). Seventy-three pts (51%) were male and 135 pts (94%) were white. The majority of pts enrolled on the study (70%) were in first CR, and had post remission chemotherapy (56%) prior to randomization. Seventy-three pts were enrolled onto the treatment arm (Arm A) and 71 pts were enrolled onto the observation arm (Arm B). When the study was initially opened, pts on Arm A were treated with tipifarnib at a dose of 400 mg BID with dose reductions and interruptions defined per protocol for toxicity. After the first planned interim analysis, based on toxicity data, the ECOG Data Monitoring Committee recommended that the starting dose be decreased to 300 mg BID. While non-hematologic toxicity was acceptable, significant hematologic toxicity was seen in pts treated at an initial dose of either 400 mg or 300 mg BID. Of note, hematologic toxicity was also seen on the observation arm although less frequently than with both treatment doses. The primary endpoint of the study was analysis of DFS on an intent to treat basis. The median DFS for arms A and B are 8.87 months and 5.26 months respectively ( p=0.058, HR 0.760). When restricted to eligible patients only(n=134 ), the DFS for arms A and B are 10.81 vs 5.26 months, respectively ( p=0.019, HR 0.690). An unplanned subgroup analysis was performed by gender. The median DFS for male pts (n=73) is 5.36 vs 5.91 months for arms A and B respectively (p=0.868, HR 1.320) and 12.09 vs 3.91 months for female pts (n=71)(p=0.0002, HR=0.408) In a multivariate Cox proportional hazards model to adjust for baseline clinical variables, there is a significant interaction between treatment and gender. (Table 1) Similar results were noted for OS (Figure 1). ECOG ACRIN Trial E2902 evaluated the potential role of Tipifarnib ( R115777) in patients with AML in remission with a high risk of relapse. While the primary endpoint for improved DFS was not reached when evaluating all randomized pts, when restricted to eligible patients only, there is a statistically significant improvement in DFS seen. Moreover, an unplanned subgroup analysis by gender demonstrates an improvement in DFS and OS for females who were enrolled on the study which persists on multivariate analysis. Possible explanations include the use of flat dosing rather than BSA based dosing on this study. However futher evaluation of patient and disease characteristics, dosing and toxicity profiles of responders and nonresponders is needed. Given what appears to be a potentially clinically relevant benefit, further evaluation of this agent is warranted. Table 1. Multivariate Cox Proportional Hazards Model for DFS: All Randomized Patients Hazard Ratio (95% CI) P value Arm B vs A 2.559(1.547,4.236) 0.00025 Male vs Female 2.005(1.228,3.274) 0.00544 CR1 vs >CR1 0.447 (0.305,0.656) 0.00004 Figure 1. (A) DFS (B) OS in Female Patients Figure 1. (A) DFS (B) OS in Female Patients Disclosures Rowe: BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BioLineRx Ltd.: Consultancy. Larson:Astellas: Consultancy, Research Funding.

Abstract Sequencing studies have significantly improved our understanding of the CLL genetic landscape and allowed the identification of the first associations between specific mutations and clinical outcome. Hence, mutations in TP53, NOTCH1, SF3B1, BIRC3 and MYD88 are known to be associated with differential prognosis and have been incorporated in CLL risk stratification models. Despite the work performed on these 5 genes, several additional putative tumor-driver genes are recurrently mutated in CLL, but their clinical impact remains unclear. In order to gain further understanding, we performed targeted sequencing in baseline samples of 308 CLL patients (pts) participating in the North American Intergroup study (NAIG) designated as E1912 and led by ECOG. This trial is a randomized Phase III of Ibrutinib (Ibr) and Rituximab (R) vs FCR in previously untreated CLL. Besides the 5 genes aforementioned, we screened another 19 genes recurrently mutated in CLL, and 2 genes (BTK and PLCy2) recently associated with Ibr resistance. The CD5+/CD19+ B lymphocyte population of these pts was flow-sorted. All coding regions were amplified using customized oligos. Libraries were templated and enriched using IonOneTouch2 and IonOneTouch ES systems, respectively. Samples were run on an IonTorrent sequencer using 318TM chips. Variants were called using IonTorrent Somatic VariantCaller. VCF files were annotated using BioR, which provides annotation from NCBI/Ensembl, UCSC, dbSNP, HapMap, 1000Genomes, COSMIC, SIFT, and PolyPhen-2. Somatic variants with a Mapping Quality <20 or read depth <5X were removed. Variants of interest were inspected using Integrative Genomics Viewer. The mutational status of genes and pathways was analyzed for association with chromosomal abnormalities detected by FISH, expression of CD38, CD49d and ZAP70, Rai stage, age and gender. We were not able to evaluate associations to clinical responses for the different arms as this trial is still underway and remains blinded for clinical outcome. We found 511 SNVs (442 missense, 45 nonsense and 24 splice sites) and 115 indels. An average coverage of 770X depth was obtained, allowing the detection of minor subclonal mutations (<10% of reads) in almost 35% (218/626 mutations). Overall, 215 pts (70%) carried at least one mutated gene, 102 (33%) carried 2 or more and 32 (10%) 3 or more mutated genes. The most commonly mutated gene was SF3B1 (22%), followed by NOTCH1 (19%), ATM (12%), XPO1 (11%), BIRC3 (9%), KRAS (7%), BRAF, DDX3X, EGR2, POT1 and TP53 (6% each). No BTK or PLCy2 mutations were found in progressive but untreated CLLs. In contrast to a recent report (Nature 2015;526:525-30), we found BRAF mutations located in the canonical hotspot p.V600E (25% of total mutations). Another 13% were located in amino acid K601 (p.K601E/N) and the remaining in the kinase domain (p.G469A, p.D594G, p.F595L, p.G596R, p.L597Q).Nearly 27% of cases with activating mutations in the RAS pathway (BRAF, KRAS, NRAS), showed >1 mutation affecting one or more genes of the pathway. Similar observations were found in mutational hotspots of BIRC3 (30% of mutated cases showed >1 mutation), MED12 (18%), SF3B1 (7%), XPO1 (6%), and NOTCH1 (5%), suggesting the existence of genetic subclones showing convergent evolution in a substantial number of CLL. We found multiple associations between mutations and known prognostic and clinical parameters. These included mutations in NOTCH1 associated with +12 (p=0.005), and expression of ZAP70 (p=0.01), CD38 (p=0.001) and CD49d (p=0.004). Mutant BIRC3 was associated with +12 (p<0.001) and CD38 expression (p=0.01). Mutations in RAS pathway, with +12 (<0.001), and expression of CD38 (p=0.002) and CD49d (p=0.05). ATM (p=0.007) and EGR2 (p=0.002) with -11q; POT1 with CD49d expression (p=0.01), and MYD88 with -13q (p=0.04) and lack of CD38 (p=0.01) and CD49d (p=0.01) expression. This study, performed on a large cohort of untreated but progressive CLLs, provides novel data about the mutation status of driver genes and their associations with clinical and prognostic parameters. Our data indicate that convergent evolution is a common event in CLL, affecting several driver genes. Furthermore, it reinforces that BTK and PLCy2 mutations are not found in Ibr-naive pts. Finally, this study provides the genetic groundwork for subsequent prospective comparative analyses of the clinical outcome for CLL cohorts treated with Ibr-R vs FCR in this phase 3 NAIG trial. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Fonseca:Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Janssen: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Cephalon: Research Funding; Hospira: 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.

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.