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Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, non covalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma.MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a non covalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor.

Purpose: Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Patients and Methods: In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD. Results: Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively. Conclusions: The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

Purpose: Flavopiridol, the first clinically evaluated cyclin-dependent kinase inhibitor, shows activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.Experimental Design: A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early-phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.Results: Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy less than 10 cm or 10 cm or more during the first 2 treatments was 0.111 (SE% 13.0%) and 0.265 (SE% 17.9%), respectively, when flavo-G area under the plasma concentration versus time curve was at its median value in whole-patient group.Conclusions: This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine whether the associations between TLS, gender, and glucuronide metabolites are relevant in patients with chronic lymphocytic leukemia treated with other cyclin-dependent kinase inhibitors. Clin Cancer Res; 19(5); 1269–80. ©2012 AACR.

Purpose:Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).Patients and Methods:In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.Results:Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively.Conclusions:The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.

PDF file - 255 KB, Figure 1. Flavopiridol conditional weighted residuals vs. time with a smoothed loess line. Figure 2. Flavopiridol conditional weighted residuals vs. population predicted values with a smoothed loess line. Figure 3. Visual predictive check (VPC) plots for flavopiridol stratified by body weight. Open circles, observed data; grey solid line, median of observed data at nominal time; grey dashed line, 95% confidence interval (CI) of observed data at nominal time; black solid line, median of simulated data at nominal time; black dashed line, 95% prediction interval (PI) of simulated data at nominal time; grey area, 95% CI around median or 95% PI of simulated time. Figure 4. Flavopiridol-glucuronide (Flavo-G) conditional weighted residuals vs. time with a smoothed loess line. Figure 5. Flavopiridol-glucuronide (Flavo-G) conditional weighted residuals vs. population predicted values with a smoothed loess line. Figure 6. Predicted median TLS probability vs. observed TLS probability with a line of unity. Figure 7. TLS probability vs. median parent drug (flavopiridol) AUC.

Supplementary Data from Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study

PDF file - 51 KB

Supplementary Table S1 from Gene Expression Profiling Reveals Similarities between the In vitro and In vivo Responses of Immune Effector Cells to IFN-α

PDF file - 79 KB, Supplementary Table 1. Patient Characteristics Supplementary Table 2. Summary of drop-outs in Cycle 1

Purpose: The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the in vivo response to treatment with high-dose IFN-α.Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α.Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α in vitro for 18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-α-2b (20 MU/m2 i.v.) revealed significant up-regulation (>2-fold) of 21 genes (P < 0.001). Also, the gene expression profile of in vitro IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy.Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-α may be a useful predictor of the in vivo response of immune cells to IFN-α immunotherapy.

Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti–CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

PURPOSE Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)–adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET−) disease and intensifying treatment in patients with PET-positive (PET+) disease. METHODS Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2–, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation. RESULTS Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2– and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2– and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2− was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04). CONCLUSION Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

CCTG CLC.2/Alliance A041202 demonstrated superior progression-free survival at 2 years with ibrutinib alone (87%; HR 0.39) or ibrutinib-rituximab (IR 88%; HR 0.38) compared to chemo-immunotherapy with bendamustine-rituximab (BR 74%) in treatment-naïve patients (pts) with chronic lymphocytic leukemia (CLL) who were 65 or older (Woyach NEJM 2018). We hypothesized that ibrutinib-based therapies would be more costly than BR but that costs would be offset by less toxicity and improved quality of life (QOL). We completed a prospective trial-based economic analysis to study the direct medical costs and quality-adjusted benefit associated with ibrutinib-based therapies compared to BR in the Canadian (CDN) subset of patients enrolled in CLC.2/Alliance 041202. All CDN pts were invited to participate in the companion analysis. Health utilities were collected using the EuroQOL EQ-5D and calculated using CDN population valuations (Bansback PLOS One 2012). Resource utilization forms were administered to collect off-protocol health care encounters. The planned analysis was a cost-utility analysis from the perspective of a public healthcare system, examining the costs and outcomes (quality-adjusted life years or QALYs) of ibrutinib-based therapy compared to BR. Unit costs were applied to resource data based on publicly available provincial/national databases; all costs were expressed in 2019 US dollars (1 CDN = 0.75 US dollar). Total and disaggregated direct medical costs are presented descriptively. Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months; derived utilities were used to calculate QALYs. A discount rate for costs and benefits (r=0.05) was applied. The analysis was based on estimation (with bootstrapping) of an incremental cost-effectiveness ratio (ICER) and/or direct medical costs. A total of 55 pts were enrolled; two pts who did not receive any treatment were censored at day 1 and 3 after randomization and excluded from analysis. Of the 53 analysed, pt demographics were well balanced between treatments and were reflective of the entire population: mean age was 71.6 (SD 6.34) in pts receiving ibrutinib alone (n=17), 72.2 (SD 3.85) in pts receiving IR (n=18), and 71.7 (SD 4.1) in pts receiving BR (n=18). A total of 3 pts, one in each arm, had 17p deletion. Progression-free survival at 2 years for CDN pts was 94% (95% CI 65-99%) for ibrutinib, 100% (95% CI 100-100%) for IR, and 72% (95% CI 45-87%) for BR (Figure 1). At 24 months, 1 pt on the BR arm had crossed over to ibrutinib (as per protocol); there was no overall survival difference between the three arms. On-protocol costs (including protocol treatment, ambulatory care, and imaging) and off-protocol costs (including hospitalizations, concomitant medications, and ambulatory care) are highlighted in Figure 2. On-protocol costs were higher for pts receiving ibrutinib (mean $142,001 USD; SD 48,417) and IR ($164,931; SD 46,208) compared to BR ($38,509; SD 10,351), driven by higher drug acquisition costs associated with ibrutinib (list price $6422 for 420mg/30 days). In contrast, off-protocol costs were modestly higher for pts on BR (mean $3050; SD 3812) compared to the ibrutinib ($2460; SD 3863) or IR ($2890; SD 4206); hospitalizations were the key off-protocol cost drivers and were highest for pts on IR and BR. Overall mean costs over the 2-year time horizon were $144,461 (SD 47,910) for pts on ibrutinib, $167,820 (SD 46,830) for pts on IR, and $41,560 (SD 11,849) for pts on BR. Discounted QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR. Given the similar quality-adjusted survival between arms at the time of this analysis, a formal ICER was not calculated. Direct medical costs are substantially higher for pts receiving continuous ibrutinib-based therapies, compared to chemo-immunotherapy of fixed duration, in frontline CLL management; the key cost driver is the cost of ibrutinib. The PFS benefit with ibrutinib-based therapy has not translated into an advantage in quality-adjusted survival to date; further follow-up may be required to demonstrate any cost or QOL benefits associated with fewer progression events for those on ibrutinib. Support: U10CA180821, U10CA180882; U10CA180863 and #704970 CCTG. https://acknowledgments.alliancefound.org ClinicalTrials.gov: NCT01886872 Figure Disclosures Owen: AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Lam:Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Crump:Servier: Consultancy; Kite/Gilead: Consultancy; Roche: Consultancy. Sperlich:Lundbeck Canada: Honoraria. Woyach:Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Hay:Roche: Research Funding; Janssen: Research Funding.

PURPOSE The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. PATIENTS AND METHODS This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. RESULTS The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. CONCLUSION The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

7511 Background: Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment (tx) of CLL and are associated with partial restoration of immune function with ongoing tx. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized. Methods: CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline (bl) and outcome data were collected including incidence (inc) of Richter’s transformation (RT), non-melanoma skin cancer (NMSC), and SPN. Standard inc ratio (SIR) with 95% confidence intervals (CI) were calculated using expected inc rates from the Surveillance, Epidemiology, and End Results Program, assuming a Poisson distribution for the observed inc. Cumulative inc (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up (f/u). SPN was correlated with bl data using the Fine-Gray model. Results: 691 pts were included; median age was 64 years (y), median prior lines of treatment (tx) was 2 (20% tx-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. At median f/u of 44 months, 68 pts (10%) were diagnosed (dx) with SPN (SIR 2.4, CI 1.9-3.0) including 13 lung (SIR 3.2, CI 1.7-5.5), 9 melanoma (SIR 6.9, CI 3.1-13), 9 prostate (SIR 1.4, CI 0.6-2.6), 7 bladder (SIR 5.2, CI 2.1-10.6) cancers. CIR of SPN at 3 y was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7-5.0, p < .01) and low bl CD8 count (HR 0.9 for 2-fold increase, CI 0.8-0.9, p < .01) were associated with higher inc of SPN. RT was dx in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 y overall survival of 79% (CI 76-82); the most common causes of death were CLL/RT (57%) and SPN (13%). Conclusions: The inc of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 y CIR of NMSC and SPN of 23% and 12%, these data support consideration of intensive cancer screening for CLL pts receiving BTKi. [Table: see text]

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia are associated with a favorable prognosis, whereas cytogenetic complexity (≥3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within 1 year of diagnosis of chronic lymphocytic leukemia and correlated these features with outcome and other clinical features including IGHV mutational status. Of 329 untreated patients, 53 (16.1%) had a complex karyotype, and 85 (25.8%) had a translocation. The median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (P3.5 mg/L, log-transformed white blood cell count, unmutated IGHV, a complex karyotype, a translocation, and trisomy 8, del(11q) or del(17p) detected by fluorescence in situ hybridization. In multivariable analysis, there was a significant effect modification of IGHV status on the relationship between translocation and TFT (P=0.002). In IGHV-mutated patients, those with a translocation had an over 3.5 times higher risk of starting treatment than those without a translocation (P

With the launch of the National Cancer Institute’s Precision Medicine Initiative in 2015, there has been a shift to trial designs that tailor health care solutions to individual patients by using a screening platform and by moving away from the one-trial/one-biomarker-at-a-time approach. To make precision medicine a reality, it is critical to identify and validate potential biomarkers to help select patients who will truly benefit from a targeted therapy. In this article, we discuss five trial designs: enrichment, umbrella, basket, subgroup, and window of opportunity. For each trial design, we describe the design characteristics, use ongoing or completed trials as case studies, provide any recent advances to the trial design, and discuss advantages and disadvantages of each design.

The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo-HSCT for hematologic malignancies and received r-ATG (4.5 mg/kg, 141 patients) versus R-ATG (6 mg/kg, 216 patients). There was a higher incidence of cytomegalovirus (P.001) and Epstein-Barr virus viremia (P =.03) in the R-ATG group than in the r-ATG group. The cumulative incidences of acute graft-versus-host disease (aGVHD) grades II to IV at day 180 in the r-ATG and R-ATG groups were 59% and 44% (P = .006) and grades III to IV 20% and 12% (P = .029), respectively. In multivariable models adjusting for disease diagnosis, the risk of aGVHD grades III to IV did not reach statistical significance (P = .087). The respective cumulative incidences of chronic GVHD in the r-ATG and R-ATG groups were 26% and 15% (P = .10), respectively. There were no significant differences in relapse rate (P = .24), nonrelapse mortality (P = .96), progression-free survival (P = .24), overall survival (P = .70), and GVHD-free relapse-free survival (P = .24). In this retrospective analysis, aGVHD incidence was higher in those treated with r-ATG compared with R-ATG, but this did not translate into significant differences of clinical outcome. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials.

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m(2), in adults with R/R AML and in older (age ≥60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60mg (~35 mg/m(2)) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.

Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

A diagnosis of leukemia can have a profound effect on patients' health-related quality of life (HRQoL), however this has not been measured prospectively in patients with hairy cell leukemia (HCL). At the request of patients living with HCL who had identified this gap in knowledge about the disease, we conducted a longitudinal study of HRQoL among patients enrolled in the HCL Patient Data Registry (PDR). From September 1, 2018 to September 1, 2020, 165 patients were enrolled in the study and completed the baseline survey. The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) was used to measure patients' HRQoL. Results show that newly diagnosed HCL patients reported the lowest HRQoL, followed by patients in relapse and those on "watch and wait." Factors associated with higher (better) FACT-Leu total scores in the multivariable analysis included older age, higher social support, and greater physical activity. These same factors were associated with lower levels of fatigue. In rare diseases where it is difficult to perform large prospective studies, patient/researcher collaborations are critical for the identification of studies that are of importance to patients and their families in order to maximize the benefits of the research and improve the lives of patients living with HCL.

7507 Background: Bulky disease is associated with inferior outcomes in patients with early stage cHL. Historically, most patients (pts) receive chemotherapy followed by radiotherapy (RT), which is associated with long-term toxicity. We tested a PET-adapted approach to reduce the need for RT in pts with early PET-negative (PET-) disease and escalate therapy in pts with PET-positive (PET+) disease. Methods: Eligible pts aged 18-60 years (yrs) had stage IA-IIB cHL with disease bulk >10 cm or >.33 max intrathoracic diameter on chest x-ray. Pts received 2 cycles of doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) followed by centrally reviewed PET. PET- was defined as Deauville of 1-3. Pts who achieved a negative PET scan (PET2-) received 4 additional cycles of ABVD. PET2+ pts received 4 cycles of escBEACOPP plus 30 Gy involved-site radiation therapy. The primary endpoint was progression-free survival (PFS) estimated from PET2. With 93 pts and assuming 30% PET2+, there was 80% power to rule out that PFS of PET2+ pts was substantially inferior to PFS of PET2- pts (HR 4.1, 3-yr PFS 40% vs 80%) if the true PFS of PET2+ pts was closer to that of PET2- pts (HR 2.29, 3-yr PFS 60% vs 80%) with one-sided alpha=0.15. With few events and mature follow-up, we report results 3 yrs after the last pt was enrolled. Results: Between May 2010 and October 2017, 101 pts enrolled. Excluding 6 ineligible pts (3 without baseline DLCO, 2 did not meet definition of bulk, 1 stage IIIB) and 1 pt without PET2, 94 were evaluable. 78% of pts were PET2- (73 PET2-, 21 PET2+). Median age was 30 yrs (range: 18 to 58) and 53.2% were female. Distribution of stage was: 1A - 7.4%, IB - 2.1%, IIA – 39.4%, IIB - 51.1%; 61.9% PET2+ pts had stage IIB disease. Therapy was generally well tolerated. Grade > 3 neutropenia occurred in 86% of pts with 8% of PET2- and 10% of PET2+ with grade > 3 febrile neutropenia. 3-yr PFS estimates were 93.1% (95% CI: 87.4-99.1%) in PET2- pts, 89.7% (95% CI: 77.2-100.0%) in PET2+ pts (HR=1.01, 85% upper bound 2.32), and 92.3% (95% CI: 87.0-98.0%) for all pts. The protocol-defined primary endpoint was met as the PFS hazard ratio for PET2+ vs PET2- was less than 4.1 (one sided p=0.04). With a median follow-up of 5.5 yrs, 3 PET2- pts died (HL, anaplastic astrocytoma and COPD) and 1 PET2+ died of progressive disease. 3-yr overall survival (not a primary or secondary outcome of the study) estimates were 98.6% (95% CI: 95.9-100.0%) in PET2- pts, 94.4% (95% CI: 85.4-100.0%) in PET2+ pts (HR: 1.2, 95% CI: 0.12, 11.60), and 97.7% (95% CI: 94.7-100.0%) for all pts. Conclusions: Excellent PFS outcomes were observed in all pts using a PET-adapted approach that allowed omission of RT in 78% of pts. In addition, PET2+ pts treated with escalation to BEACOPP and consolidative RT did not have inferior outcomes. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org ; ClinicalTrials.gov Identifier: NCT01118026. Clinical trial information: NCT01118026.

INTRODUCTION: The Alliance A041202/ CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies. METHODS: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy. RESULTS: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; p

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient’s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60–92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival. Preliminary results from the Beat AML umbrella trial demonstrates the feasibility and efficacy of applying prospective genomic profiling for matching newly diagnosed patients with AML with targeted therapies.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.

Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n = 123), FR plus lenalidomide consolidation (FR+L; n = 109), or FR plus cyclophosphamide (FCR; n = 110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n = 27) or were reassigned to FCR+L (n = 31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L (P = .04) and FCR (P < .001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points (P = .01), but not significantly different from FCR (P = .21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.

ispartof: NEW ENGLAND JOURNAL OF MEDICINE vol:380 issue:17 pages:1679-1680 ispartof: location:United States status: published

Background The phase 3 trial A041202 solidified the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib as a standard of care for older patients with previously untreated CLL by showing superior progression-free survival (PFS) as compared with bendamustine plus rituximab. While ibrutinib is highly effective in previously untreated CLL, there do remain disadvantages to this therapy, specifically the low rate of complete response (CR) and therefore need for continuous administration, which increases cost and toxicity. In older patients especially, toxicities with ibrutinib are common; with median duration of ibrutinib treatment of 32 months, 17% of patients had atrial fibrillation and 29% had grade 3 or higher hypertension on the A041202 study. Thus, strategies to decrease the exposure time to ibrutinib are of interest. Venetoclax is an inhibitor of BCL2 which has shown efficacy as a single agent and in combination with monoclonal antibodies, specifically the anti-CD20 monoclonal antibody obinutuzumab for patients with previously untreated CLL. One significant advantage to venetoclax is the ability to produce CRs and minimal residual disease negative (MRD-) responses. In this study, we compare ibrutinib plus obinutuzumab (IO) to ibrutinib plus venetoclax plus obinutuzumab (IVO) with a response-dependent discontinuation. Study Design and Methods A041702 (NCT03737981) is a randomized phase 3 study led by the Alliance for Clinical Trials in Oncology that is currently enrolling through the national clinical trials network (NCTN). Eligible patients are those patients with CLL or SLL age 70 or older who are previously untreated and in need of therapy. Patients with del17p on FISH must be age 65 or older. Previous treatment of autoimmune complications with steroids or rituximab are allowed. Patients must have intermediate or high risk Rai stage, ECOG performance status 0-2, ANC ≥ 1000/mm 3 unless due to marrow involvement and plt ≥ 30,000/mm 3. CrCl must be ≥ 40 mL/min and AST/ALT ≤ 2.5x upper limit of normal. Patients with hepatitis B must have undetectable viral load, and patients must not have an intercurrent illness which is expected to limit survival to < 5 years. Warfarin and strong inhibitors or inducers of CYP3A4/5 are not permitted. Patients are initially pre-registered to the study and submit a peripheral blood sample for central FISH analysis of del(17p). Patients who are registered are randomized 1:1 to Arm 1 (IO) or Arm 2 (IVO), stratified upon Rai stage and presence of del(17p). IO consists of I daily starting cycle 1 day 1, and O dosed as standard starting cycle 1 day 1 and continuing to cycle 6 day 1. IVO consists of IO as in Arm 1, with V starting cycle 3 day 1 with standard 5-week ramp-up and continuing until cycle 14 day 28. At the end of 14 cycles, both arms undergo response evaluation with central peripheral blood and bone marrow MRD testing. Patients on IO then continue I indefinitely. Patients on IVO who are in a bone marrow MRD- CR discontinue all therapy, and those who are not continue I indefinitely. The primary objective of the study is to compare PFS between IO and IVO using the strategy of response-dependent discontinuation. There is 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes two interim analyses for superiority when 50% and 75% of the expected number of events have been observed and three interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed. Conclusions A041702 is an ongoing phase 3 clinical trial using a novel response-dependent discontinuation method. Results of this study have the potential to change the standard of care for older patients with previously untreated CLL. The study is expected to accrue until third quarter 2022, and we welcome participation from sites throughout the NCTN. Disclosures Woyach: AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee. Ruppert: Telios Pharma: Consultancy. Hill: AstraZenica: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding. Ding: DTRM: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Stone: Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Jazz: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; GlaxoSmithKline: Consultancy; Innate: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria.

Background CLL International Prognostic Index (CLL-IPI) is a weighted scoring system combining five prognostic factors that was developed for risk stratification of TN CLL in the era of chemoimmunotherapy [CLL-IPI Working Group. Lancet Oncol 2016]. Recently, the four-factor model (CLL4) was validated in patients (pts) receiving ibrutinib, primarily for the treatment of relapsed or refractory CLL [Ahn et al. J Clin Oncol 2021]. Data on model performance are limited when ibrutinib is used as first-line therapy. Here we evaluated CLL4 and CLL-IPI in TN CLL pts aged 65 years or older in the Alliance A041202 trial (NCT01886872) [Woyach et al. N Engl J Med 2018]. Methods Pts were randomized to bendamustine plus rituximab (BR group) or ibrutinib-based therapy with or without rituximab (I/IR group). The CLL4 score was determined for individual pts by assigning 1 point each to the presence of TP53 aberration, β-2 microglobulin (B2M) ≥5 mg/L, elevated lactate dehydrogenase (LDH), and prior treatment, and summing over points; risk categories were low (0-1), intermediate (2), and high (3-4). We utilized the first three factors of CLL4 since all pts were previously untreated. The CLL-IPI score was determined based on the presence of TP53 aberration (4 points), B2M >3.5 mg/L (2 points), unmutated IGHV (2 points), age >65 years (1 point), and Rai stage I-IV (1 point), and summing over points; risk categories were low (0-1), intermediate (2-3), high (4-6), and very high (7-10). Two of five CLL-IPI risk factors contributed little information since all pts had Rai stage I-IV and nearly all had age >65 years. The primary endpoint for risk stratification was progression-free survival (PFS). We used Kaplan-Meier estimates and Cox proportional hazards models for analyses. Results Of 547 pts randomized, 472 pts had a complete set of data required for the calculation of CLL4 scores. The median age was 71 years, and 92% were older than 65 years. 12% had TP53 aberration including deletion 17p and TP53 mutation. Of 334 pts with known IGHV status, 61% had unmutated IGHV. The median follow-up for PFS was 4.5 years. In these 472 pts, 359 (76%) were low risk, 99 (21%) intermediate risk, and 14 (3%) high risk. In the BR group, PFS was significantly shorter for intermediate/high risk CLL4 than low risk (HR 2.43, 95% CI 1.55-3.79, p=0.0001). However, differences in PFS were less apparent for the I/IR group (HR 1.60, 95% CI 1.00-2.56, p=0.05). In 334 pts in whom CLL-IPI scores could be calculated, 6 (2%) were low risk, 38 (11%) intermediate risk, 262 (78%) high risk, and 28 (8%) very high risk. In the BR group, PFS was significantly shorter for high risk CLL-IPI than intermediate risk (HR 3.73, 95% CI 1.16-12.04, p=0.03) and for very high risk CLL-IPI than high risk (HR 6.05, 95% CI 2.80-13.08, p We next assessed individual components of the prognostic models in the 334 pt subset including both BR and I/IR groups (Table). Variables significantly associated with PFS were B2M, elevated LDH, and unmutated IGHV when controlling for the treatment group. In contrast, TP53 aberration conferred a poor prognosis in the BR group, but not in the I/IR group (interaction test, p=0.008), indicating first-line therapy with ibrutinib can improve the outcome of TP53 aberrant CLL to levels seen in pts without the aberration. In a multivariable model, the interaction between TP53 aberration and the treatment group remained significant. All adverse risk factors except elevated LDH maintained their independent prognostic value. Conclusions Neither CLL4 nor CLL-IPI effectively discriminated PFS of older adults receiving ibrutinib-based therapy for TN CLL. When given as a first-line treatment, ibrutinib can overcome the poor prognostic impact of TP53 aberration. IGHV mutation status and B2M had independent prognostic value in our dataset. Support: U10CA180821, U10CA180882, U24CA196171; Pharmacyclics, An AbbVie Company Clinicaltrials.gov identifier: NCT01886872 Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Wiestner: Merck: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Nurix: Research Funding; Genmab: Research Funding. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Stone: AbbVie: Consultancy; Jazz: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Janssen: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Novartis: Consultancy, Research Funding; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Boston Pharmaceuticals: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Introduction: It is well established that genetic prognostication using fluorescence in situ hybridization (FISH) for the common recurrent abnormalities deletion 13q, trisomy 12, deletion 11q, and deletion 17p hierarchically stratifies time to first treatment (TTFT) and overall survival (OS) for chronic lymphocytic leukemia (CLL) patients (pts). Approximately 20% of CLL pts are negative for each of these abnormalities (normal 12/13/11/17), which is considered a favorable prognostic finding. Although favorable, outcomes within this group are heterogeneous, with limited information as to the importance of other simultaneous factors. Limited studies have shown a subset of these pts have complex karyotypes, suggesting standard CLL FISH may be insufficient for prognostication of this group, prompting a need for studies focusing specifically on this subset of pts (Haferlach et. al. Leukemia 2007; Baliakas et. al. Blood 2019). Here, we investigated the normal 12/13/11/17 pts to interrogate the utility of additional genetic testing and identify prognostically important variables. Methods: We conducted a retrospective analysis of all treatment-naïve CLL pts with cytogenetics performed at The Ohio State University Cytogenetics Laboratory from 2008 to 2018 for whom standard 12/13/11/17 CLL FISH were normal on their first cytogenetic analysis at our institution. Chromosome banding analysis was performed on cells stimulated with CpG oligonucleotides, phorbol-12-myristate-13-acetate, and pokeweed mitogen and analyzed according to standard laboratory procedures. FISH using probes for the standard CLL panel, D13S319, D12Z3 , ATM, TP53, and an expanded panel including BCL6, MYC, REL, SEC63/MYB, CDKN2A, and IGH were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. TTFT and OS were both measured from diagnosis; pts not starting treatment were censored at death or last follow-up for TTFT, and pts who were alive were censored at last follow-up for OS. Cox regression models were used to evaluate TTFT and OS. A multiple imputation procedure was used to impute missing data and obtain regression estimates from combining results across 30 imputed datasets. Results: We analyzed 280 pts with a median follow up of 6.1 years among survivors since diagnosis. Median age at diagnosis was 58, and 63% were men. 95% of pts had low to intermediate Rai stage at diagnosis, 49% were IGHV unmutated, and 6% expressed IGHV3-21. 35% of pts showed an abnormal karyotype, with 8% being complex (3 or more abnormalities). Additional FISH testing showed 7% had deletion of IGH, 5% had BCL6 gain/rearrangement, 5% had deletion 6q, 4% had gain/rearrangement of MYC, 4% had gain of REL (limited subset tested, n=180), and 3% had IGH rearrangement. None of the tested pts (limited subset tested, n=115) had CDKN2A deletion. 144 pts (51%) progressed to requiring treatment, with a median TTFT of 6.5 years (95% CI 5-7.6). On univariable analysis, male sex, advanced Rai stage, increasing Beta-2-microglobulin (B2M), unmutated IGHV, increasing karyotypic complexity, gain of REL, and deletion 6q by FISH were significant predictors of shorter TTFT. However, only increasing B2M (p=0.03, HR 1.15 (95% CI 1.01-1.32)) and unmutated IGHV (p Conclusions: Additional cytogenetic testing demonstrates alternative genetic alterations are common in normal 12/13/11/17 CLL pts, however, our data do not show that these alterations are significant independent predictors of TTFT or OS. While normal FISH CLL is a relatively heterogeneous group, pts with mutated IGHV represent a subset of pts with very low risk disease. Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Bhat: Beigene: Consultancy; Aptitude Health: Honoraria; Onclive: Honoraria; AstraZeneca: Consultancy. Kittai: Janssen: Consultancy; Abbvie: Consultancy; Bristol-Meyers Squibb: Consultancy. Rogers: Acerta Pharma: Consultancy; Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Janssen Pharmaceuticals, Inc: Research Funding; AbbVie Inc.: Consultancy, Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Woyach: AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety.

Background: High grade B-cell Lymphoma with rearrangements of MYC and BCL2 and/or BCL6, also known as double hit lymphoma (DHL), and double expressing lymphomas (DEL; DLBCL with IHC expression of MYC and BCL2, but without double hit cytogenetics) are highly aggressive B cell non-Hodgkin lymphomas and patients (pts) often develop relapsed/refractory disease following standard first-line chemoimmunotherapy. DA-EPOCH-R is widely used in patients with DHL, and a phase 1 trial of venetoclax + DA-EPOCH-R established the dose of 600 mg for 5 days with each cycle as the recommended phase 2 dose (Rutherford, et al. Proc ASCO 2020). A051701 is a phase II/III randomized trial evaluating chemoimmunotherapy +/- the BCL2 inhibitor venetoclax in a DHL cohort (pts with DHL with BCL2 rearrangement and/or expression), and a DEL cohort. Here we report the initial results from the DHL cohort of A051701. Methods: Pts age ≥ 18 years with newly diagnosed DHL were stratified on International Prognostic Index (IPI) score and receipt of a single cycle of chemotherapy prior to registration, which was permitted, and randomized 1:1 to receive DA-EPOCH-R (Arm 1) or DA-EPOCH-R with venetoclax (Arm 2). Enrollment was based on local pathology results which were centrally confirmed. DA-EPOCH-R was administered as previously published. Venetoclax was dosed at 600 mg po daily on days 4-8 of cycle 1 and on days 1-5 of subsequent cycles for up to 6 total cycles. All cycles were supported by GCSF or peg-GCSF. For the interim analysis at the end of phase II, 53 events ensured 90% power to detect an improvement in 24-month progression-free survival (PFS) from 40% in Arm 1 to 60% in Arm 2 (HR=0.557) using a one-sided stratified log-rank test with type I error rate of 20%. The Alliance Data and Safety Monitoring Board approved the data release after accrual was stopped early due to excess toxicity in Arm 2. These data were frozen July 8, 2021. Results: 73 pts were registered (36 in Arm 1 and 37 in Arm 2) between 8/7/19 and 9/18/20. Analyses were performed for the modified intent-to-treat (mITT) population, defined as eligible pts with DHL histology confirmed (n=66; 30 Arm 1, 36 Arm 2). Median age was 65 years in both arms (range 37-80) and baseline demographic factors were well balanced. An allowed pre-protocol chemoimmunotherapy cycle was administered in 60% and 56% of Arm 1 and Arm 2 pts, respectively. The majority of pts had advanced stage disease (Arm 1 87%, Arm 2 86%), GCB immunophenotype (Arm 1 100%, Arm 2 88%), ECOG PS 0-1 (Arm 1 90%, Arm 2 86%), and high-intermediate/high risk IPI score (Arm 1 63%, Arm 2 64%). Therapy was completed per protocol in 70% and 47% of pts, respectively, for Arm 1 and 2, and disease progression on therapy occurred in 10% and 3%. Treatment was discontinued due to adverse events in 7% of pts in Arm 1 and 11% of pts in Arm 2. Consent was withdrawn after beginning treatment in 3% and 11% in Arm 1 and 2, respectively. Death on treatment occurred in 1 patient (3%; PJP pneumonia) in Arm 1 and 6 pts (17%; sepsis (n=4), cardiac arrest (n=2)) in Arm 2. The observation of excess deaths on Arm 2 prompted suspension of accrual to the DHL cohort. Treatment was discontinued for other reasons in 3 (10%) and 4 (11%) pts in Arms 1 and 2, respectively. Venetoclax was dose-reduced and/or omitted in 15 (42%) pts. Grade 4 neutropenia was not significantly different between arms (Arm 1 67%, Arm 2 71%), nor was grade ≥3 neutropenic fever (Arm 1 36%, Arm 2 40%). Sepsis occurred more frequently in Arm 2 (14% vs. 23%). The end of treatment overall and complete response rates in the mITT population were 73% and 67% in Arm 1, and 58% and 50% in Arm 2. The end of treatment overall and complete response rates among only pts evaluated for response (n=52) were 79% and 71% in Arm 1, and 88% and 75% in Arm 2. With a median follow-up of 7.4 months, the median PFS was not reached (NR) in Arm 1 (95% CI 6.1-NR) and was 6.7 months in Arm 2 (95% CI 4.5-NR) (two-sided p=0.13). The median OS was NR in Arm 1 and was 8.5 months in Arm 2 (95% CI 5.2-NR) (two-sided p=0.004). Conclusions: DA-EPOCH-R plus venetoclax in DHL pts resulted in excess treatment-related mortality compared to DA-EPOCH-R alone, prompting early discontinuation of accrual and venetoclax treatment for the study cohort. Based on these data, we recommend against combining venetoclax with DA-EPOCH-R in DHL. Robust accrual to this study shows that prospective trials are feasible in DHL, and the favorable outcome thus far in the DA-EPOCH-R arm may serve as a benchmark for future trials Figure 1 Figure 1. Disclosures Abramson: Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Ruppert: Telios Pharma: Consultancy. Hsi: Seattle Genetics: Honoraria; Cytomx: Honoraria; Eli Lilly: Research Funding; AbbVie: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Friedberg: Acerta: Other: DSMC ; Novartis: Other: DSMC ; Bayer: Other: DSMC . Bartlett: Millennium: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Bristol Myers Squibb: Research Funding; Roche/Genentech: Consultancy; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. OffLabel Disclosure: venetoclax in double hit lymphoma

Background: IVO is an oral potent inhibitor of mutated IDH1 (IDH1m) enzyme, recently approved for the treatment (Tx) of ND adult patients (pts) with IDH1m AML ≥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. In this Phase 2 sub-study of the Beat AML Master Trial, we evaluated the efficacy of IVO + AZA combination Tx in ND pts aged ≥60 years with IDH1m AML (ClinicalTrials.gov: NCT03013998) Methods: This open-label multicenter (16 sites / 9 enrolling) combination Tx study enrolled ND pts with R132 mIDH1 AML, utilizing the modified minimax Simon's 2-stage Phase 2 design. Pts received IVO + AZA for 6 cycles in the absence of disease progression (PD), unacceptable toxicity or stem cell transplant. Pts who achieved complete remission (CR)/complete remission with hematologic improvement (CRh)/complete remission with incomplete hematologic recovery (CRi) continued IVO + AZA for a total of 12 cycles, then IVO monotherapy until PD. Pts without CR/CRh/CRi after 6 cycles continued IVO + AZA if they demonstrated Tx benefit, as defined in Figure 1. Key eligibility included ND IDH1 R132 mutated AML pts aged ≥60 years and ECOG performance status 0 - 2 (Karnofsky ≥60). All pts received IVO 500 mg/day orally in continuous 28-day cycles + AZA 75 mg/m2 IV or SC on days 1-7 every 28 days. The primary endpoint was CR+CRh+CRi rate after 6 cycles of Tx. Response was assessed using modified 2017 ELN AML criteria. The modified minimax Simon's 2-stage design required 40 pts and tested the null hypothesis that the CR/CRh/CRi rate equaled 25% vs the alternative of 50% (one-sided alpha = 0.025, power 90%). Stage 1 required >5/16 responses for continued enrollment. Even though these criteria were met, the sponsor decided to discontinue the trial on 12/12/2019. Here we report the final primary endpoint results. Data were frozen 02/03/2021. Results: Between 07/2018 and 11/2019, 19 patients were enrolled with IDH1m AML; 18 started IVO + AZA Tx and are included in the analyses. At data freeze, 5 pts had died and 7 pts still on Tx were offered standard of care IVO. Median age of the pts was 75 years, 50% were ≥75 years, 61% were female and 89% were White (Table 1). The most common reasons for Tx discontinuation were trial discontinued by sponsor (7 or 39%), stem cell transplant (4 or 22%), and PD (3 or 17%). A total of 13 pts achieved CR/CRh/CRi (72%) by up to 6 cycles of Tx (Table 2 & Figure 2). Over the entire study period, 14 pts achieved CR/CRh/CRi (78%) with 8 CR (44%), 3 CRh (17%) and 3 CRi (17%). No deaths occurred within the first 60 days of Tx. After a median follow up of 19.8 months (mos), Page 2 median response duration was not reached, with 12-mos disease-free survival rate of 69%; also, median OS was not reached, with 12- and 18-mos OS rates of 100% and 73%, respectively. The median (range) time on Tx was 12 mos ( Conclusions: In ND pts with IDH1m AML and ≥60 years of age, IVO + AZA Tx was associated with a high CR/CRh/CRi rate, no early deaths (60 days) and a 1-year OS of 100%. IVO + AZA was acceptably tolerated and no unexpected toxicities occurred. Most common unique toxicities of IVO observed during the study were differentiation syndrome and QTc prolongation; these led to Tx discontinuation in only 1 pt. CR/CRh/CRi rate obtained with IVO +AZA is higher than that previously reported in studies with the individual agents or intensive chemotherapy approaches, suggesting a synergistic effect. Our overall response rate is similar to that reported recently for IVO + AZA in older ND IDH1 mutant AML pts, despite not including pts with morphologic leukemia-free state and partial remission. Based on these results, a global Phase 3 evaluation of IVO or placebo plus AZA is ongoing (NCT03173248). Figure 1 Figure 1. Disclosures Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Peerview: Honoraria. Ruppert: Telios Pharma: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Leukemia and Lymphoma Society: Research Funding; Nkarta: Research Funding; Celyad Oncology: Research Funding; Syndax: Honoraria; Xencor: Research Funding; Abbvie: Honoraria; Forma Therapeutics: Research Funding; AmerisourceBergen: Honoraria. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Sangamo: Research Funding; Takeda: Research Funding; Ono-UK: Consultancy, Research Funding; Gamida Cell Ltd.: Research Funding; Tolero: Research Funding; Samus: Research Funding; Karyopharm: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Mateon: Research Funding; Genentech-Roche: Research Funding; FujiFilm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Celator: Research Funding; Forma: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Elevate: Research Funding; Deciphera: Research Funding; Actuate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding; Onconova: Research Funding; Geron: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Actinium: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Daiichi Sankyo: Research Funding; Astellas: Honoraria, Research Funding. Foran: pfizer: Honoraria; gamida: Honoraria; servier: Honoraria; kura: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; bms: Honoraria; syros: Honoraria; taiho: Honoraria; OncLive: Honoraria; actinium: Research Funding; aptose: Research Funding; boehringer ingelheim: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Pluristem: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Foster: Agios: Consultancy; Daiichi Sankyo: Consultancy; Macrogenics: Consultancy; Rafael Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Bellicum Pharmaceuticals: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Vergilio: Roche: Current equity holder in publicly-traded company; Foundation Medicine: Current Employment. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; EnLiven: Consultancy, Research Funding; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Nemucore Medical Innovations, Inc.: Consultancy; Merck & Co: Patents & Royalties; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bristol-Myers Squibb: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: QIAGEN: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Celgene: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Incyte: Consultancy; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Gilead: Honoraria; Amgen: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees. Mims: Leukemia and Lymphoma Society: Consultancy; Kura Oncology: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Aptevo: Research Funding; Xencor: Research Funding; Glycomemetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Daiichi-Saynko: Consultancy. OffLabel Disclosure: IVO is an oral potent inhibitor of mutated IDH1 enzyme, recently approved for the treatment of ND adult patients with IDH1m AML âââ,¬Â°Ã,Â¥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. The combination of AZA, a hypomethylating agent, and venetoclax, an oral BCL-2 inhibitor, is also FDA approved for newly diagnosed AML in adults 75 years or older, or who have comorbidities precluding intensive chemotherapy. This presentation will discuss the combination of IVO and AZA.

Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl > 40 mL/min, bilirubin < 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, 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, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Background: In vitro studies and emerging clinical data suggest that inhibition of spleen tyrosine kinase may have an antileukemic effect in human AML. Pts with AML and TP53 mutations (TP53m) are commonly associated with older age (≥60 years) and complex karyotype (CK) and respond poorly to standard 7 + 3 induction (IND) chemotherapy with Methods: This multicenter (13 sites), open-label, Phase 2 combination Tx study utilized Simon's 2-stage Phase 2 design and enrolled AML pts with TP53m (identified molecularly) ± CK (Cohort A) or CK (≥3 metaphase abnormalities) without TP53m (Cohort B). Pts initially received 5 days of ENTO lead-in (which was later discontinued), followed by ENTO + DEC and those who achieved CR/CRh/CRi/MLFS with up to 3 cycles of IND proceeded to consolidation (CON) Tx for up to 11 cycles (Figure 1). Pts with CRi/MLFS after IND were allowed up to 6 cycles (IND + CON) to achieve CR/CRh or stayed on Tx if they got clinical benefit or went off Tx. CON was followed by maintenance (MTN) Tx for up to 2 years from start of study Tx. Pts were eligible if aged ≥60 years, ND, and had ECOG performance status 0 - 2. Pts received ENTO 400 mg orally twice daily for 5 days during ENTO lead-in, and then every 28 days during IND, CON, and MTN + DEC 20 mg/m 2 IV days 1-10 (IND) or days 1-5 (CON) every 28 days. Response was assessed using modified 2017 ELN AML criteria. The primary endpoint was composite complete remission (CCR) rate (CR + CRh) with up to 3 cycles of IND, and CRi/MLFS that achieved CR/CRh by up to 6 cycles (IND + CON). Beyond stage 1, pt accrual to Cohort A was allowed based on pts with CRi and to Cohort B was stopped early for futility. Results: Between Oct 2017 and Feb 2020, of the 63 pts enrolled (Cohort A = 48; Cohort B = 15), pts with confirmed eligibility who started study Tx were included in the analyses (Cohort A = 45; Cohort B = 13). During lead-in, 27 pts in Cohort A and 6 pts in Cohort B received ENTOm for 5 days. All pts received ENTO + DEC except 1 pt in Cohort A who withdrew consent (WOC). Median ages of the pts were 70 years (range 60 - 84) in Cohort A and 74 years (range 65 - 86) in Cohort B. Median time (range) on Tx was 2.2 mos and 4.8 mos in Cohort A and B, respectively. Most common reasons for Tx discontinuation were adverse event (AE; 27%), Tx failure (TF; 27%) and WOC (18%) in Cohort A; TF (31%), disease progression and relapse (each 15%) in Cohort B. In each cohort, 1 pt discontinued Tx due to death from leukemia and 1 pt in Cohort A in CRh due to development of an additional genetic abnormality. Four pts (9%) in Cohort A and 1 pt (8%) in Cohort B proceeded to transplant. The CCR (CR + CRh) rates with up to 6 cycles of Tx for Cohort A and B were 13.3% and 30.8%, respectively; overall CR + CRh rates were 17.8% and 38.5% (Table 1). In Cohort A, with a median follow-up of 11.5 months, 0% were 1-year disease-free and median OS (mOS) was 6.5 months. In Cohort B, with a median follow-up of 15.1 months, 25% were 1-year disease-free and mOS was 11.5 months. Deaths within 7-, 30-, and 60-days of Tx were 0, 3 and 11 in Cohort A and 0, 0 and 2 in Cohort B. Most common treatment-related Grade ≥3 AEs in Cohort A and B were febrile neutropenia (31% and 39%) and anemia (22% and 31%) (Table 2). Overall, 83 serious AEs (SAEs) were reported in 33 pts in Cohort A and 12 SAEs in 6 pts in Cohort B; most common SAEs in Cohort A were pneumonia (18%) and respiratory failure (11%), and in Cohort B sepsis, dehydration and acute kidney injury (each 15%). Most common treatment-related grade ≥3 laboratory abnormalities in Cohort A and B were neutrophils decreased (27% and 31%), WBC count decreased (20% and 23%), and lymphocyte count decreased (18% and 15%). Conclusions: ENTO + DEC demonstrated activity in ND AML pts aged ≥60 years with TP53m ± CK and CK without TP53 but induced low CR/CRh rates and short OS consistent with previously published poor CR rates and OS in these pts. Our results differ from the high remission rate and longer OS previously reported for DEC monotherapy in AML pts with TP53m. ENTO + DEC was safe and acceptably tolerated. Novel Tx strategies that can benefit AML pts with these most adverse risk factors are urgently needed. Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Borate: Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Foghorn Therapeutics: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; Blueprint Medicines: Consultancy; PinotBio: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Amerisource Bergen; Abbvie, Syndax: Honoraria; Forma Therapeutics, Xencor; Celyad: Research Funding. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Actinium Pharmaceuticals, Inc: Research Funding; Gamida Cell Ltd.: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kaiser Permanente: Consultancy; Abbvie: Research Funding; AstraZeneca: Consultancy; Genentech-Roche: Research Funding; Delta-Fly: Research Funding; Cyclacel: Research Funding; Mateon: Research Funding; Actuate: Research Funding; Onconova: Research Funding; Geron: Research Funding; Sangamo: Research Funding; Arog: Research Funding; Ariad: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Trovagene: Research Funding; Ono-UK: Consultancy, Research Funding; Tolero: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Deciphera: Research Funding; FujiFilm: Research Funding; Samus: Research Funding; Regimmune: Research Funding; PrECOG: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomed Valley Discoveries: Research Funding; Ono: Consultancy; Eli Lilly: Research Funding; Sellas: Research Funding; ASH foundation: Other: Chair-unpaid; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Astellas: Honoraria, Research Funding; Actinium: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Foran: certara: Honoraria; pfizer: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; servier: Honoraria; revolution medicine: Honoraria; trillium: Research Funding; takeda: Research Funding; abbvie: Research Funding; novartis: Honoraria; bms: Honoraria; OncLive: Honoraria; gamida: Honoraria; sanofi aventis: Honoraria; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: AbbVie: Research Funding; Omeros: Other: Advisory Board; Astellas: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Actinium: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Cogle: Aptevo therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Vergilio: Foundation Medicine: Current Employment; Roche: Current equity holder in publicly-traded company. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; EnLiven: Consultancy, Research Funding; Merck & Co: Patents & Royalties; Pfizer: Research Funding; Nemucore Medical Innovations, Inc.: Consultancy; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Zentalis: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Prelude: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Consultancy; Celgene: Research Funding; Roche: Honoraria, Research Funding; Auron: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Off-label use of entospletinib and decitabine.

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries and is spelled by substantial genetic and clinical heterogeneity. During CLL transformation, loss or gain of genetic material appears to be a key determinant of disease phenotype and clinical outcome, with major chromosome aberrations observed in up to 80% of patients. Alternatively, balanced translocations, specifically those resulting in constitutive over-expression of various proto-oncogenes under the immunoglobulin heavy chain locus (IGH; 14q32), occur far less frequently. Despite their infrequence, molecular profiling of these rare rearrangements have revealed broad importance of un-recognized genes critical to the pathogenesis of CLL. Employing this strategy, we identified a young CLL patient with a previously undescribed t(X;14)(q28;q32) translocation, co-localization of the mature T cell proliferation 1 (MTCP1; Xq28) coding region with the IGH locus, triggering overexpression of MTCP1 in the CLL cells. Translocations involving MTCP1 are a driving factor in T-prolymphocytic leukemia; however, a role for MTCP1 in CLL has not been described. Inspired by this observation, we screened >1700 suspected CLL cases and evaluated gene expression data for further evidence of MCTP1 aberrations. This query identified seven additional Xq28 rearrangements, revealed MTCP1 mRNA was globally over-expressed in CLL cells compared to normal B-cells, and increased MTCP1 mRNA expression portends a poor response to chemoimmunotherapy. To establish a role for MTCP1 as an oncogene in B cell malignancies, we generated a mouse model with B cell-specific MTCP1 overexpression (Eµ-MTCP1). Longitudinal evaluation revealed a majority of Eµ-MTCP1 mice developed a lethal hematologic malignancy between 5-12 months of age, highlighted by the progressive emergence of clonally related CLL-like B lymphocytes (CD19+/CD5+ B cells) in the blood and accumulating in the spleen and lymph nodes. To support the use of the newly generated Eµ-MTCP1 mouse as a tool for pre-clinical evaluation of CLL therapeutics, we demonstrate that continuous ibrutinib administration in Eµ-MTCP1 mice was sufficient to delay the onset of the CLL-like disease and significantly prolonged survival. In summary, we report Xq28 translocations as rare genetic abnormalities in CLL, yet being one mechanism by which CLL cells amplify expression of MTCP1 compared to normal B cell subsets. Further, the Eµ-MTCP1 mouse model should be considered as an alternative tool for both biologic assessment of co-expressed genes and pre-clinical evaluation of novel CLL therapeutics. Lastly, relevant to all cancer types, successful application of a strategy pursuing the functional consequence of genes involved in rare translocations contributed to the understanding of this disease and identified a novel target for future therapeutic consideration. Citation Format: Janek S. Walker, Zachary A. Hing, Steven Sher, James Cronin, Katie Williams, Bonnie Harrington, Jordan N. Skinner, Casey B. Cempre, Charles T. Gregory, Max Yano, Larry P. Beaver, Brandi R. Walker, Jadwiga M. Labanowska, Nyla A. Heerema, Krzysztof Mrozek, Jennifer A. Woyach, Amy S. Ruppert, Amy Lehman, Hatice Gulcin Ozer, Vincenzo Coppola, John C. Byrd, James S. Blachly, Rosa Lapalombella. Evaluating a rare t(X;14)(q28;q32) translocation reveals MTCP1 as a driving factor in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2260.

Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 ( P = .03), deletion 17p ( P = .03), and complex karyotype ( P = .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation ( P P = .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P P = .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

Acute graft-versus-host disease (aGVHD) continues to be a frequent and devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT), posing as a significant barrier against the widespread use of HSCTs as a curative modality. Recent studies suggested serum/plasma microRNAs (miRs) may predict aGVHD onset. However, little is known about the functional role of circulating miRs in aGVHD. In this article, we show in two independent cohorts that miR-29a expression is significantly upregulated in the serum of allogeneic HSCT patients at aGVHD onset compared with non-aGVHD patients. Serum miR-29a is also elevated as early as 2 wk before time of diagnosis of aGVHD compared with time-matched control subjects. We demonstrate novel functional significance of serum miR-29a by showing that miR-29a binds and activates dendritic cells via TLR7 and TLR8, resulting in the activation of the NF-κB pathway and secretion of proinflammatory cytokines TNF-α and IL-6. Treatment with locked nucleic acid anti–miR-29a significantly improved survival in a mouse model of aGVHD while retaining graft-versus-leukemia effects, unveiling a novel therapeutic target in aGVHD treatment or prevention.

Introduction: Our group and others have previously shown that the presence of complex karyotype (>/= 3 cytogenetic abnormalities) is an important prognostic factor in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) patients treated with ibrutinib (Woyach JCO 2017, Thompson Cancer 2015, Maddocks JAMA Oncology 2015). It has been shown recently that increasing karyotypic complexity is a prognostic marker (Baliakis Blood 2019), but whether this is relevant for patients treated with novel therapies is unclear. Here, we aimed to determine whether the degree of karyotypic complexity beyond the dichotomy of complex versus not is a prognostic variable for patients with CLL treated with ibrutinib. Methods: We conducted a retrospective analysis of all patients with CLL treated with ibrutinib as a single agent or in combination with a monoclonal anti-CD20 antibody (MOAB) from 2010 through 2019 at The Ohio State University. We included patients with both treatment-naïve (TN) and RR disease. To determine karyotype, cells were stimulated with mitogen cocktail (PWM/PMA/CpG-ODN) and analyzed according to standard laboratory procedures. FISH using probes for D13S319, D12Z3, ATM, and TP53 were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. Cytogenetic testing was included in the analysis if done Results: We analyzed 561 patients with a median age of 65 (range 26-91). 86% were treated with ibrutinib monotherapy, 22% were TN, and median number of prior therapies was 2 (range 0-13). 96% had an ECOG performance status (PS) of 0 or 1. Median LDH, WBC, HgB and PLT were 213 U/L, 23.2 K/uL, 11.2 g/dL, and 115 K/uL respectively. With available data, del13q14, trisomy 12, del11q22, and del17p13 was present in 50%, 22%, 30%, and 29% of patients respectively; 74% of patients were IGHV unmutated. 63 patients were excluded from cytogenetic analyses as the test was not done during the specified time window. Of the 458 evaluable, 50% had >3 cytogenetic abnormalities including 30% with >5 abnormalities. After a median follow up of 55.5 months, for the entire cohort estimated median PFS was 61.6 months (95% CI 56.1-69.5), and estimated median OS was 95.4 months (95% CI 86.3-not reached). On univariable analysis, older age, RR status, higher ECOG PS and LDH, lower HgB and PLT, presence of del17p13 and increasing karyotypic complexity were found to be statistically significant predictors of worse PFS and OS. To illustrate the relationship between increasing karyotypic complexity and clinical outcome, Kaplan-Meier plots are provided grouping pts with 0-2, 3-4, and 5 or higher aberrations (Figure 1). Accounting for statistically and clinically important factors on multivariate analysis (MVA, Table 1), increasing karyotypic complexity continued to be a statistically significant predictor of both PFS (p=0.01, HR 1.08 (95% CI 1.02-1.15)) and OS (p=0.001, HR 1.14 (95% CI 1.05-1.23)). Del17p13 did not retain statistical significance independently of karyotypic complexity on MVA. The interaction effect between prior treatment status and karyotypic complexity term was not significant for OS (p=0.89) and PFS (p=0.46), suggesting the prognostic effect of karyotypic complexity is similar across TN and RR cohorts. Conclusions: In this single center retrospective analysis, we found that increasing karyotypic complexity predicts inferior survival for patients with CLL treated with ibrutinib. This highlights that it is not only important to dichotomize presence of complex karyotype as >3 abnormalities, but to describe the number of karyotypic abnormalities in subsequent studies. Disclosures Bond: Seattle Genetics: Honoraria. Byrd:Acerta Pharma: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Syndax: Research Funding. Rogers:AstraZeneca: Other: Travel; Abbvie, Acerta, AstraZeneca, Pharmacyclics: Consultancy; Abbvie, Genetech, Janssen: Research Funding. Woyach:Pharmacyclics: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding.

CD19 is an attractive therapeutic target as it is highly expressed in CLL. Tafasitamab (Taf) is an Fc-engineered, humanized anti-CD19 monoclonal antibody with efficacy in CLL as a single agent. Compared to non-engineered antibodies, Taf shows significantly increased antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and direct cytotoxic effects (apoptosis) on tumor cells. With the addition of lenalidomide (Len), ADCC can be further augmented in vitro. Given the potential synergy of these agents, acceptable individual safety profiles, and efficacy as single agents, we conducted a study of Taf in combination with Len in patients (pts) with treatment-naïve (TN) and relapsed/refractory (RR) CLL, and included a pilot cohort of ibrutinib (IB)-treated pts with resistance mutations, but no clinical relapse, with Taf added to IB. We present the final results of this single institution phase II trial. In combination with Len, Taf was given at a dose of 1 mg/kg on cycle(C) 1 day(D) 1, 9 mg/kg on C1 D 2, 8, 15, and 22, and D1 of C2-12. Len 2.5 mg began daily on C1D8 and was given continuously. Len was escalated to 10 mg daily in pts without toxicity. After C12, Len could continue indefinitely in responding pts. In combination with IB, Taf was given at 1 mg/kg on C1D1, 12 mg/kg on C1 D2, 8, 15, and 22, weekly during C2-3, and every other week through C12. IB continued at 420 mg daily. The primary endpoint for Phase II was overall response rate (ORR) after C6. Based on previous studies with single agent Len, we tested whether the combination could improve ORR, from 50% to 80% in the TN cohort, and from 30% to 60% in the RR cohort. Using single stage designs, 19 pts per cohort provided at least 90% power to detect an increase in ORR (type I error rate 10%). By design, 13 and 9 responses were needed in the TN and RR cohorts, respectively, to warrant further study. A secondary endpoint was ORR after 12 cycles of therapy. Twelve pts were enrolled in the TN cohort; median age was 62 (range 44-75). Six pts were Rai stage III/IV, and 1 had both del(17p) and del(11q). Nine pts had ZAP 70-methylated disease. After C6, ORR was 67% [1 complete response (CR), 7 partial responses (PR); 90% confidence interval (CI): 39-88]; responses remained the same after C12. Three pts completed treatment per protocol, 3 discontinued treatment for progressive disease (PD) and 6 for AEs. Thirteen pts were enrolled in the RR cohort, median age was 70 (range 62-75). Eight pts were Rai stage III/IV, 4 had del(17p) and 2 had del(11q). Eleven pts had ZAP 70-methylated disease. After C6, ORR was 15% (all PRs - 90% CI: 3-41), and responses improved to 38% after C12 (90% CI: 17-65). Additional 1 pt had stable disease (SD). Five pts completed treatment per protocol, 6 discontinued treatment for PD, 1 for alternative therapy, and 1 continues on treatment. Nine pts with molecular progression on IB were enrolled; median age was 62 (range 45-87). Seven pts had del(17p) and 1 pt had del(11q). Eight pts had ZAP 70-methylated disease. After C6, only 1 pt (11%) responded with a PR; 3 additional pts had SD. Two pts completed treatment per protocol criteria, 3 discontinued treatment for AEs, 2 for alternative therapy and 1 pt each for PD and increased C481S allelic frequency. Figure shows Progression-free Survival (PFS) and Overall Survival (OS) for the 3 cohorts. Taf plus Len was well tolerated. Grade(gr)≥3 AEs included: infections [4: I each of lung infection, sinusitis, upper respiratory tract infection (URTI) and appendicitis], decreased neutrophil count (3) and infusion related reactions (2) in TN pts and decreased neutrophil count (10), infections [7: 2 catheter related urinary tract infections, 1 each with URTI, lung infection and soft tissue infection, 2 unspecified], diarrhea (3), hyponatremia (3) and hypophosphatemia (3) in RR pts. In the Taf plus IB cohort most common gr≥3 AEs included infections (4: 2 lung infections, 1 URTI and I unspecified), hyperglycemia (3) and hyponatremia (3). Gr≥3 atrial fibrillation was seen in 1 pt. In conclusion, although the trial did not fully accrue as planned, Taf in combination with Len appeared safe and demonstrated promising activity in TN CLL, warranting further investigation, and has similar efficacy to rituximab plus Len in RR CLL. Taf plus IB was less effective in pts with resistance to IB. Disclosures Blachly: AbbVie, AstraZeneca, KITE Pharma: Consultancy. Rogers:AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy, Other: Travel Funding. Lozanski:Genentech, Novartis, Beckman Coulter: Research Funding. Byrd:Syndax: Research Funding; Vincera: Research Funding; Acerta Pharma: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other. Woyach:Karyopharm: Research Funding; Morphosys: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Loxo: Research Funding. OffLabel Disclosure: Lenalidomide off label use for CLL