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Purpose: Marginal zone lymphoma (MZL) is an uncommon non–Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients and Methods: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111–214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Results: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Conclusions: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, was evaluated as monotherapy in CITADEL-202 (NCT02998476), an open-label, multicenter, phase 2 study in patients with relapsed or refractory diffuse large B-cell lymphoma. Patients enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve, n = 55; B, BTK inhibitor experienced, n = 5) received oral parsaclisib 20 mg once daily for 8 weeks, then 20 mg once weekly while deriving benefit. The futility boundary was crossed at the interim analysis of Group A, resulting in a negative study. Parsaclisib monotherapy demonstrated an objective response rate (ORR) of 25.5% (8 complete metabolic responses/6 partial metabolic responses) and a median duration of response of 6.2 months. ORR in Group B was 20.0% (1 complete metabolic response). Parsaclisib monotherapy demonstrated manageable toxicities with no new safety signals reported. Further evaluation of parsaclisib in combination with standard therapies and active investigational agents is underway. ispartof: LEUKEMIA & LYMPHOMA vol:62 issue:2 pages:368-376 ispartof: location:United States status: published

Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car-BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy-two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car-BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow-up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car-BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.

Background: Marginal zone lymphoma (MZL) is rare and heterogeneous and it has been difficult to define optimal therapeutic strategies. Like other indolent non-Hodgkin lymphomas, advanced stage disease is considered incurable, with most patients experiencing a continuing pattern of relapse and remission. MZL is typically dependent on B-cell receptor (BCR) signaling suggesting a role for BCR pathway targeting via inhibition of Bruton's tyrosine kinase (BTK). The utility of this approach was confirmed by the pivotal phase 2 study demonstrating a 48% objective response rate (ORR) to ibrutinib in patients with relapsed/refractory (R/R) MZL (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib (BGB-3111) is a potent, highly specific, and irreversible next-generation BTK inhibitor. It was specifically designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, which are thought to be related to atrial fibrillation, thrombocytopenia, and bleeding events. In an early-phase study (BGB-3111-AU-003) of 20 patients with R/R MZL treated with zanubrutinib, at a median follow-up of 27.1 months, the ORR was 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Presented here are initial efficacy and safety data in patients with R/R MZL enrolled in the MAGNOLIA trial (BGB-3111-214). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adult patients requiring systemic treatment for R/R MZL who had previously received one or more lines of therapy including at least one CD20-directed regimen. All patients were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR as determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Results: In total, 68 patients were enrolled and treated. The median age was 70 years (range, 37-95), with 28% aged ≥75 years. MZL subtypes included extranodal (mucosa-associated lymphoid tissue) in 38%, nodal in 38%, splenic in 18%, and unknown in 6% of patients. The median number of prior therapies was 2 (range, 1-6), and 35% of patients had disease refractory to last therapy. At a median follow-up of 6.8 months (range, 1.6-12.8), 67 patients were evaluable for efficacy. Investigator-assessed ORR (CR + PR) was 60% (CR 15%, PR 45%, stable disease 27%). Responses were observed in all MZL subtypes, with an ORR of 58%, 64%, 58%, and 50% in extranodal, nodal, splenic, and unknown subtypes, respectively. CR rate was 23% for extranodal MZL, 12% for nodal, and 50% for unknown subtype. CR was not observed in patients with splenic MZL. The median DOR and median PFS were not reached. Twenty-one (30.9%) patients discontinued study treatment. Treatment discontinuation was mainly due to disease progression (16 patients; 23.5%); 1 withdrew consent, 2 required prohibited medications, and 2 due to adverse events (AEs) - 1 from pyrexia (later attributed to disease transformation) and 1 from myocardial infarction. The most common treatment-emergent AEs reported in ≥10% of patients were diarrhea (19.1%), bruising (17.6%), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%). Most AEs were low grade. Neutropenia was the most common grade ≥3 AE (7.3%). Treatment-related serious AEs included atrial flutter, pyrexia, pneumonia, and thrombocytopenia (1 patient each). One patient with pre-existing coronary artery disease died from myocardial infarction, which was assessed as unrelated to zanubrutinib. All-grade AEs of interest included neutropenia (10.3%), thrombocytopenia (10.3%), and atrial flutter (1.5%). To date, no major hemorrhage, serious opportunistic infection, or tumor lysis syndrome have been reported. Conclusion: Preliminary results of this phase 2 study suggest that zanubrutinib is active in R/R MZL, with a favorable safety profile. (NCT03846427) Disclosures Opat: Beigene: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: 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; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Epizyme: Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tedeschi:AstraZeneca: 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy. Linton:The Christie NHS Foundation Trust and The University of Manchester: Current Employment; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria. McKay:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Beatson West of Scotland Cancer Centre: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Gilead, Takeda, and Janssen: Other: For lectures etc. Hu:Kite: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectar: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Beigene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chan:Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Browett:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; University of Auckland: Current Employment; BeiGene: Research Funding. Coleman:BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding. Sobieraj-Teague:Flinders Medical Centre: Current Employment; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ke:Peking University Third Hospital: Current Employment. Sun:Institute of Hematology and Blood Disease Hospital,Chinese Academy of Medical Sciences and Peking Union of Medical College: Current Employment. Marcus:Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding. Zhou:Henan Cancer Hospital: Current Employment. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Co:BeiGene: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Wang:BeiGene: Current Employment. Tankersley:Clovis Oncology, Inc: Ended employment in the past 24 months; BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zhou:BeiGene: Current Employment, Current equity holder in publicly-traded company; Beth Israel Deaconess Medical Center: Ended employment in the past 24 months. Cappellini:BeiGene Ltd.: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; BeiGene Aus Pty. Ltd.: Current Employment. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Trotman:BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for MZL in the US

7549 Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n = 37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n = 2; transformation to diffuse large B-cell lymphoma after stopping treatment, n = 1; adverse event [AE], n = 1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n = 3 each), fatigue, thrombocytopenia, and neutropenia (n = 2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Conclusions: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala. Clinical trial information: NCT02180711.

© The Author(s) 2021., Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.

Introduction Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Patients and Methods Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell–specific marker, and Ki-67. Myeloma cells (CD138 + ) were counted as proliferating if coexpressing Ki-67. Retrospective analysis was performed on 151 newly diagnosed, treatment-naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Results Median overall survival (OS) was not reached versus 78.9 months ( P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high-risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty-three (36%) of the 64 patients with low-risk disease (ISS stage 1, without high-risk cytogenetics) were uniquely reidentified as high risk by PCPI. Conclusion PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification.

INTRODUCTION: Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma, is characterized by recurrent mutations affecting epigenetic regulators. Azacitidine, a DNA demethylating agent, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the mature findings, including survival outcome and biomarker analysis, of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). METHODS: This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Oral azacitidine (aza) priming at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was CR per 2014 IWG criteria. Secondary endpoints included ORR, safety and survival. Correlative biomarker studies assessed mutation profile by whole exome NGS with germline control, genome-wide DNA methylation sequencing by RRBS, and gene expression by RNA-sequencing of paired tumor samples before and after aza priming prior to C1D1 chemotherapy. Survivals were estimated by Kaplan-Meier analysis, and log-rank tests were performed to correlate biomarkers to survival outcomes. RESULTS: A total of 21 subjects with previously untreated PTCL, including 17 with PTCL-TFH (81%), 3 with PTCL-NOS (14%), were enrolled and received treatment at 4 centers. The median age was 66 years (range 22-77), 19 (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (35%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment-emergent grade 3-4 hematologic toxicities included neutropenia (71%), thrombocytopenia (10%) and anemia (14%), with febrile neutropenia uncommon (14%). Grade 3-4 non-hematologic toxicities included fatigue (14%), hyponatremia (14%), diarrhea (5%), anorexia (5%), vomiting (5%), rash (5%), and elevated ALT (4.8%). There was no treatment-related mortality on study. As of July 2021 at a median follow-up of 21 months (range 16-30 months), 20 subjects were evaluable for primary endpoint, with one withdrawal after cycle 1. The end-of-treatment responses were all CRs, including CR at 75% (90%CI of 54.4 - 89.6%) for all evaluable patients (n=20) and 88.2% for PTCL-TFH (n=17). The 2-yr PFS was 65.8% (95%CI of 43.4-88.1%) for all patients, and 69.2% (95%CI of 46.7-91.7%) for PTCL-TFH. The 2-yr OS was 68% (95%CI of 46.7-89.2%) for all patients, and 75.6% (95%CI of 54.8-96.5%) for PTCL-TFH. The median PFS was estimated at 36 months (95%CI: 8 months - not reached). Consolidative stem cell transplant was performed in 10 subjects (9 auto and 1 allo), which did not impact PFS or OS. Mutational status was determined in 17 patients. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with RHOA and IDH2 mutations occurring in the hotspot positions (RHOA G17V, IDH2 R172G/T). For all patients, TET2 mutations were significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), while DNMT3A mutations were associated with adverse PFS (p=0.016). Within the PTCL-TFH subgroup, TET2 mutations were associated with favorable PFS (p=0.014). RNAseq and RRBS assays were performed in 5 paired tumor samples before and after aza priming. Differentially upregulated genes revealed enrichment of gene sets related to apoptosis (p CONCLUSIONS: This study demonstrates that priming with oral azacitidine (CC486) in combination with CHOP as initial therapy is safe, effective, and produces sustained remission in PTCL-TFH subtype. Epigenetic priming with azacitidine appears to inhibit the proliferation of TFH lymphoma cells, providing potential synergistic mechanism of action with chemotherapy. This active combination will be further evaluated in the upcoming ALLIANCE/ US Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P vs duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL. Figure 1 Figure 1. Disclosures Ruan: Pharmacyclics: Research Funding; Seagen: Consultancy; Kite Pharma: Consultancy; AstraZeneca: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Moskowitz: Janpix Ltd.: Consultancy; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Miragen: Research Funding; Bristol-Myers Squibb: Research Funding; Beigene: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Mehta-Shah: C4 Therapeutics: Consultancy; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding; Kiowa Hakko Kirin: Consultancy; Verastem: Research Funding. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Coleman: Merck: Research Funding; Innocare: Research Funding; BeiGene: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Bristol Myers: Research Funding; Abbvie: Research Funding; immunomedics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Pfizer: Research Funding; Roche: Research Funding. Melnick: Constellation: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees. Elemento: AstraZeneca: Research Funding; Eli Lilly: Research Funding; One Three Biotech: Consultancy, Other: Current equity holder; Freenome: Consultancy, Other: Current equity holder in a privately-held company; Champions Oncology: Consultancy; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Johnson and Johnson: Research Funding; Janssen: Research Funding; Owkin: Consultancy, Other: Current equity holder. 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. Martin: ADCT: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Oral azacitidine for treatment of peripheral T-cell lymphoma

Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R 2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE : N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1-21 of a 28-day cycle + rituximab IV at 375 mg/m 2/week cycle 1 and then every 8 weeks starting with cycle 3 (R 2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R 2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1-3a or MZL (FL grade 3b, tFL, and MCL not included). The focus of this interim analysis was overall response rate (ORR) by 1999 IWG criteria in the induction intention-to-treat population. Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R 2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo-NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5-NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade AEs were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue. Conclusions: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R 2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients. Figure 1 Figure 1. Disclosures Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Coleman: immunomedics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Abbvie: Research Funding; Bristol Myers: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Innocare: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning: Sanofi: Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Nowakowski: Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Curis: Consultancy; Selvita: Consultancy; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Karyopharm Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kyte Pharma: Consultancy; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy. Gharibo: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ahn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; ADC therapeutics: Current equity holder in publicly-traded company. Li: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman: BeiGene: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; AbbVie: Consultancy.

Background: Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with indolent non-Hodgkin lymphoma. Patients with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on patients aged ≥ 70 years from the MAGNIFY study. Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg on days 1-21 of a 28-day cycle + rituximab 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 vs rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable FL grade 1-3a and MZL patients (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Post-hoc analyses were performed by analyzing data from patients aged ≥ 70 years at time of study entry. Results: As of November 30, 2019, 393 patients have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of patients ≥ 70 and the overall population are shown in the table. Median PFS in the ≥ 70 subgroup was 36.0 months (95% CI, 28.3-NR). Overall response rate and CR/CRu were 75% and 38%, with a median duration of response that was not reached (95% CI, 27.1-NR). Efficacy results for the overall population are shown in the table. In patients ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in > 10% of patients (febrile neutropenia occurred in 3 patients [2%]). TEAEs led to lenalidomide dose reduction in 69 patients (46%) and discontinuation in 40 patients (26%). Seventy-eight patients ≥ 70 (51%) completed all 12 cycles of induction treatment, and 72 (47%) have entered the maintenance phase. Sixty-one patients ≥ 70 (40%), compared to 35% of patients in overall population, prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 26; 17%), progressive disease (n = 15; 10%), patient withdrawal (n = 12; 8%), death (n = 5; 3%), and other reasons (n = 3; 2%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 patients (n = 10; 7%). Conclusions: Similar to findings in the overall population, R2 treatment in advanced-age patients with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. Table Disclosures Lansigan: BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Andorsky:AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding. Coleman:Novartis Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Incyte Corporation: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding. Yacoub:Novartis: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning:Prisma Health: Current Employment; Abbvie: Consultancy; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi Aventis: Speakers Bureau. Kolibaba:Compass Oncology: Ended employment in the past 24 months; Atara Biotech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; AbbVie: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria; Janssen: Research Funding; Novartix: Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding. Gharibo:Bayer: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Amgen GmbH: Honoraria; Roche: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.

Multiple myeloma (MM) is a plasma cell malignancy diagnosed in approximately 30 thousand patients per year and accounts for nearly 12 thousand deaths in the US representing 2% of all cancer-related mortality. Novel agents have increased the survival of MM patients; however, patients with high-risk features and/or relapsed/refractory disease exhibit poor outcomes and remain an unmet, therapeutic challenge. Most patients develop refractory disease through a lack of successful mechanism-based therapies and progressive, genetic instability with copy number abnormalities. Aurora-kinase B (AURKB) is a key component of the chromosomal passenger complex (CPC), a key regulator of mitosis. The CPC ensures correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly as well as orderly cytokinesis. AURKB is a therapeutic target for many cancers but targeting attempts have been fraught with specificity and toxicity issues warranting further work to improve small molecule inhibitors. Thus, we sought to characterize the potential of MK7, a novel AURKB inhibitor, as a therapeutic approach in MM. MK7 is the first orally bioavailable AURKB inhibitor with favorable pharmacokinetic properties. Histone phosphorylation plays a direct role in major cell events, such as mitosis, cell death, repair, replication and recombination. MK7 activity can be assessed by a decrease in the levels of phosphorylation of histone H3(p-H3). First, we measured the expression of mRNA of AURKB in MM cell lines (i.e., MM1S, MM1R, U266, SKO-007, U266 lenalidomide resistant (U266-LR), AMO1, AMO1 bortezomib resistant (AMO1-BZ) and AMO1 carfilzomib resistant (AMO1-CZ) and primary CD138+ BM samples from patients with MM. In addition, we determined protein levels of AURKB and its substrate H3 (as phospho-H3) and found that all cell lines and primary samples showed detectable levels of AURKB and p-H3, including cell lines resistant to lenalidomide, bortezomib, and carfilzomib. Next, we evaluated the in vitro dose response to MK7 (5 to 0.015uM) and found a significant decrease in viability at concentrations below 125nM as early as 24 hours post-treatment in all cell lines tested (less than 50%). Furthermore, we observed dramatic changes in size and morphology as early as 6 hours post treatment. Response to MK7 was also assessed in vivo using U266-GFP/Luciferase xenografts. Mice were treated with 30 mg/kg P.O. MK7 three times a week (total 14 doses) and compared to vehicle. We observed an increase in overall survival in mice receiving MK7. Given the favorable results, additional in vivostudies are being performed and will be presented at the meeting. In summary, MK7 is a novel, orally bioavailable AURKB inhibitor with potent activity in MM. With this promising orally active chemical platform, we believe that AURKB inhibitors with favorable pharmacokinetics and a lower toxicity profile should be developed for the treatment of patients with MM. Citation Format: Jorge Contreras, Eloisi Caldas Lopes, Jorge Monge, David Jayabalan, Naresh Gunaganti, Brendan Frett, Hong-yu Li, Morton Coleman, Ruben Niesvizky, Monica L. Guzman. Orally bioavailable aurora-kinase B inhibitor (MK7) as a potential therapeutic approach in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5155.

8046 Background: Patients (pts) with relapsed iNHL have limited standard treatment options. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported 39.4-mo median PFS in R/R iNHL pts (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in pts with R/R FL gr1-3a, MZL, or MCL (NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and then q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in pts with SD, PR, or CR to R2 vs rituximab maintenance for 18 mo. Data presented here focus on induction R2 in efficacy-evaluable FL and MZL pts (MCL not included) receiving ≥ 1 treatment with baseline/post-baseline assessments to analyze the primary end point of ORR by 1999 IWG criteria. Results: As of June 16, 2019, 393 pts (81% FL gr1-3a; 19% MZL) were enrolled with a median follow up of 23.7 mo (range, 0.6-57.8) for censored pts (n = 335). Median age was 66 y (range, 35-91), 83% had stage III/IV disease, with a median of 2 prior therapies (95% prior rituximab-containing). ORR was 69% with 40% CR/CRu (Table). Median DOR was 39.0 mo, and median PFS was 40.1 mo. 199 pts (51%) have completed 12c of R2, and 188 (48%) have been randomized and entered maintenance. 139 pts (35%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n = 52, 13%) or PD (n = 45, 11%). Most common all-grade AEs were 48% fatigue, 43% neutropenia, 36% diarrhea, 31% nausea, and 30% constipation. Grade 3/4 AE neutropenia was 36% (9 pts [2%] had febrile neutropenia); all other grade 3/4 AEs occurred in < 7% of pts. Conclusions: R2 is active with a tolerable safety profile in pts with R/R FL and MZL, including rituximab-refractory, double-refractory, and early relapse pts. Clinical trial information: NCT01996865 . [Table: see text]

Carfilzomib and dexamethasone (Kd) has significant activity in relapsed and refractory multiple myeloma. Kd has not previously been evaluated in newly diagnosed multiple myeloma (NDMM). We report a single-arm phase 2 study of 72 patients with NDMM to evaluate the efficacy and tolerability of Kd induction. Carfilzomib was administered in two dosing cohorts with dosing of 20/45 mg/m2 in the first 25 patients and 20/56 mg/m2 in the subsequent 47 patients. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, dexamethasone 20 mg was administered orally on days 1, 2, 8, 9, 15, 16, 22 and 23. Treatment was continued to maximum response, progression of disease, or regimen intolerability. Endpoints included overall response rate (ORR), regimen toxicity and impact of carfilzomib on CD34+ stem cell collection yield. Sixty-five pts achieved at least a partial response (PR) for an ORR of 90%. The maximum response achieved was complete response or better in 5 (7%), very good partial response (VGPR) in 42 (58%), PR in 18 (25%) and stable disease in 7 pts (10%). Toxicities were predominantly low grade with 547 grade 1/2 adverse events and 44 grade ≥3 events. The rate of grade ≥3 cardiovascular adverse events was 11.1% with eight observed events. The activity of Kd described represents the highest rate of overall response and ≥VGPR for any 2-agent combination in NDMM reported to date. Kd demonstrated a safety profile consistent with previously reported carfilzomib studies.

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44–1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30–0.76; P

e19038 Background: Parsaclisib, a potent, highly selective, next-generation PI3Kδ inhibitor, showed preliminary efficacy as monotherapy for relapsed or refractory non-Hodgkin lymphoma, including DLBCL (Abstract 410, ASH 2017), in a phase 1/2 study. This phase 2 study further assessed parsaclisib in patients (pts) with relapsed or refractory DLBCL (NCT02998476). Methods: Pts enrolled into 2 groups (A, Bruton tyrosine kinase [BTK] inhibitor naïve; B, BTK inhibitor experienced) and received oral parsaclisib 20 mg QD for 8 wks, then 20 mg QW. In a planned interim futility analysis conducted in the first 40 pts treated in Group A, if ≤13 (≤32.5%) responded by IRC assessment, Group A was to be terminated. Results: At data cutoff (22 Jun 2018), 60 pts (Group A, n = 55; Group B, n = 5) were treated (median age, 71 y [range, 36—94]; men, 63.3%; ≥3 prior systemic therapies, 60%). At the planned interim analysis in Group A, ORR (by PET) was 25% (10/40 pts; 5 CMR, 5 PMR); the futility boundary was crossed. At data cutoff, ORR in Group A was 25.5% (14/55 pts; 8 CMR, 6 PMR); median PFS was 2.2 mo (95% CI: 2.0‒4.1); median DOR was 4.5 mo (95% CI: 2.1‒5.1). ORs were observed in germinal center B-cell (GCB) and non-GCB subtypes. ORR in Group B was 20% (1/5 pts; 1 CMR). The most common non-hematologic treatment-emergent adverse events (TEAEs) occurring in > 10% of all pts (all grade [Gr]; Gr 3/4) were rash events (21.7%; 1.7%), colitis/diarrhea events (16.7%; 5%), nausea (16.7%; 0%), cough (15%; 0%), and pyrexia (15%; 8.3%). Gr 3/4 AST and ALT elevations occurred in 5% and 1.7% of pts, respectively; Gr 3/4 neutropenia and anemia occurred in 5% of pts each. The most frequent ( > 5%) serious TEAEs were pyrexia (8.3%), general physical health deterioration (6.7%), and hypercalcemia (6.7%). TEAEs led to therapy discontinuation in 7 pts (2 treatment-related), dose interruption in 20 pts (10 treatment-related), and dose reduction in 3 pts (all treatment-related). Median duration of therapy was 57.5 d (range, 11–318). Conclusions: Parsaclisib monotherapy using a QD followed by QW dosing regimen was well tolerated with no new safety signals reported. Further evaluation of parsaclisib in all subtypes of DLBCL is ongoing in a combination study Clinical trial information: NCT02998476.

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has produced remarkable clinical response in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. We previously reported the identification of BTK(C481S) mutation in a CLL patient who progressed following 21-month ibrutinib therapy. Initial characterization at structural and biochemical levels revealed that the mutation disrupts the covalent binding of ibrutinib to BTK, reduces its binding affinity and diminishes its ability to inhibit the BTK enzymatic activity. Herein, we further characterized the functional consequences of BTK(C481S) in terms of molecular signaling, gene expression and cellular behavior in the patient, as well as in lymphoma cells transfected with either the wild-type or the mutant BTK constructs. Further, using an in vitro CLL proliferation model, alternative kinase inhibitors that have the potential to overcome ibrutinib resistance were explored.

Radioimmunotherapy (RIT) is effective treatment for indolent non-Hodgkin lymphomas (NHLs), but response durations are usually limited, especially in aggressive NHL. We hypothesized that administration of bortezomib as a radiosensitizer with RIT would be tolerable and improve efficacy in NHL. This phase 1 dose-escalation study evaluated escalating doses of bortezomib combined with 131I-tositumomab in patients with relapsed/refractory NHL. Twenty-five patients were treated. Treatment was well tolerated, with primarily hematologic toxicity. The maximum tolerated dose (MTD) was determined to be 0.9 mg/m2 bortezomib, in combination with a standard dose of 75 cGy 131I-tositumomab. Sixteen patients responded (64%), including 44% complete responses (CRs), with 82% CR in patients with follicular lymphoma (FL). At a median follow-up of 7 months, median progression-free survival was 7 months, and seven of 11 patients with FL remained in remission at a median of 22 months. In conclusion, bortezomib can be safely administered in combination with 131I-tositumomab with promising response rates.

Despite the evolution of effective frontline treatment strategies, many patients with myeloma inevitably relapse. Treatment can be complicated by the interplay of disease-, treatment-, and patient-related factors. Unfortunately, many patients eventually develop disease that is refractory to lenalidomide and bortezomib and have few treatment options. Pomalidomide is a distinct IMiD ® agent recently approved in the US and Europe. We review the pomalidomide mechanism of action, summarizing its direct antimyeloma, immunomodulatory, and stromal-support inhibitory activities. We also detail its clinical development, including establishment of the approved dose/schedule, phase 2 and 3 trials in relapsed and refractory patients, and novel pomalidomide-based combinations.

Background Emerging evidence indicates that MCL has increased angiogenesis within the tumor microenvironment. We initiated a phase II trial to determine if the addition of bevacizumab to the standard R-CHOP regimen could enhance antitumor effects in patients with previously untreated MCL. Patients and Methods Eleven patients with previously untreated MCL received bevacizumab at 15 mg/kg on day 1, and standard CHOP-21 (CHOP given every 21 days per cycle) with rituximab (375 mg/m 2 per cycle) on day 3 of each cycle for a total of 6 cycles. Planned study end points included safety and efficacy assessment, and exploratory analysis of angiogenic profiles. The study was suspended in August of 2010 based on safety findings in DLBCL (diffuse large B-cell lymphoma) of increased cardiovascular events with the regimen. Results Beyond the standard R-CHOP safety profile, Grade 3 left ventricular dysfunction developed in 2 patients (18%), Grade 1/2 hypertension, proteinuria, and bleeding each developed in 1 patient (9%). The overall response rate was 82% with 36% complete response (CR)/complete response unconfirmed (CRu). The median progression-free survival (n = 11) was 18 months (95% confidence interval, 3-not reached), and 3-year overall survival rate was 82%. Correlative studies showed increased vascular endothelial growth factor receptor 1 expression in tumor cells at baseline, and elevated levels of plasma vascular endothelial growth factor (VEGF) throughout treatment. Conclusion The addition of bevacizumab to the standard R-CHOP regimen did not appear to significantly improve efficacy beyond that observed from previous studies using R-CHOP alone. Therapeutic strategies that provide sustained inhibition on VEGF-related and VEGF-independent targets within the tumor microenvironment might further improve antiangiogenic effects and warrant further exploration in MCL.

Summary Background Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. Methods In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Findings Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. Interpretation The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. Funding Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

Background: Multiple myeloma (MM) remains incurable with eventual relapse and death occurring despite multiple lines of chemotherapy. Standard frontline therapy for MM has traditionally consisted of combinations of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and dexamethasone followed by consolidation with high-dose melphalan and autologous stem cell transplantation (ASCT). A randomized trial using IMiD and PI-based induction demonstrated significant progression-free survival (PFS) benefit with upfront ASCT in consolidation compared to ASCT in second-line at relapse, but no OS benefit (Attal et al, NEJM, 2017). Delay of ASCT to second-line or beyond may in part be due to the aforementioned lack of OS benefit shown with upfront ASCT and increase of sustained deep responses, including MRD negativity, to novel frontline 3 and 4-drug regimens and continuation of therapy in the frontline. We performed a chart review comparing PFS1, PFS2, and overall survival (OS) of patients who underwent upfront ASCT as consolidation to those who received ASCT in the second-line after one relapse ('delayed ASCT'). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: 124 MM patients who underwent ASCT either as consolidation in first-line or delayed ASCT after relapsing on one prior treatment between 2010-2016 were included. Demographics and clinical parameters were extracted from the electronic medical record. PFS1, PFS2, and OS were calculated from date of diagnosis to first relapse, second relapse, and death, respectively. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS1, PFS2, and OS of patients receiving upfront ASCT were compared to those of patients receiving delayed ASCT. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using upfront ASCT as the reference treatment. Results: Among the 124 patients, 93 underwent upfront ASCT as consolidation and 31 underwent delayed ASCT after relapsing on one prior line of therapy (Table 1). Induction regimens and pre-transplant therapies received are detailed in Table 1. Of the delayed group patients, 6 underwent ASCT directly without second-line induction and 25 as consolidation after second-line therapy. Patients receiving upfront ASCT had significantly longer median PFS1 compared to patients who received delayed ASCT (6.45 vs 1.25 years; P Conclusions: In this cohort of 124 MM patients undergoing ASCT as consolidation in the upfront setting or delayed ASCT in second-line after relapse, upfront ASCT was associated with significantly improved PFS1 and PFS2, similar to findings by Attal et al. However, in that study, no difference in OS was seen between upfront and delayed groups, while our data, with longer follow-up, showed median OS trending towards significance. This has important implications as with use of novel induction regimens and maintenance therapy, ASCT is more commonly being delayed to early relapse in second-line or beyond. If transplant is intended to be used in the first few lines of therapy, our data show that delaying ASCT even to second-line has a significant negative impact on PFS. In addition, a shorter OS with delayed transplant was suggested although did not reach statistical significance, possibly due to small numbers or more patients with high-risk MM in the delayed group. It is also important to note the lack of daratumumab-based regimens which may have improved PFS/OS in either or both arms. Thus, our findings should be prospectively validated in a larger trial of ASCT as consolidation in first-line vs second-line or beyond using novel, monoclonal antibody-based regimens. Disclosures Rosenbaum: Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Coleman:Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau. Van Besien:Miltenyi Biotec: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

Background: Autologous stem cell transplantation (ASCT) performed early in the disease course or at first relapse leads to improved progression-free and overall survival in transplant-eligible patients with multiple myeloma (MM). Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF), when used after ASCT has been shown to accelerate time to neutrophil engraftment (TNE), and in some studies, it has been associated with reduced length of hospitalization, infectious complications, and antibiotic use. Strategies that reserve G-CSF administration to when neutrophil recovery is delayed, have attempted to show that there is no difference in infectious complications, length of hospitalization or TNE when compared to early administration of G-CSF on the day after stem cell infusion (DOT). However, the optimal timing for administering G-CSF has not yet been determined in patients with MM undergoing ASCT. Methods: This is a retrospective, single-center analysis of patients with MM undergoing ASCT from mobilized peripheral blood stem cells. Patients enrolled in a clinical trial of high-dose lenalidomide and melphalan as conditioning therapy which mandated the administration of filgrastim from day +1 after DOT (Lenalidomide Plus Melphalan as a Preparative Regimen for Autologous Stem Cell Transplantation in Relapsed Multiple Myeloma, NCT01054196) were assigned to the early strategy group (ES). Patients receiving filgrastim as per our institutional guideline (starting on day +12 if ANC < 1000 cells/uL, or at the physician's discretion) were included in the delayed strategy group (DS). Patients were excluded from the analysis if their conditioning regimen included a different agent other than melphalan or lenalidomide. DOT was defined as the day of stem cell infusion. Date of neutrophil engraftment was defined as the first of three consecutive days with an ANC ≥ 500 cells/uL. TNE was calculated as the time from DOT to the date neutrophil engraftment. Total duration of neutropenia was defined as the time from onset of neutropenia (ANC < 500 cells/uL) to date of neutrophil engraftment. Length of hospitalization was defined as the time from DOT to the day of discharge. Results: We identified 59 patients in the ES group and 39 patients in the DS group from 08-16-2010 to 05-22-2019, for a total of 98 included in this analysis. Median age was 60 and 65 years in the ES and DS groups, respectively. Patients received a comparable dose of CD34+ cells, 5.05x106/kg in the ES group vs 4.66x106/kg in the DS group (p = 0.48). The ES group started filgrastim administration earlier (day +1 vs +9, p < 0.001) and received a greater median number of doses (10 vs 4, p < 0.001) as compared to patients in the DS group. Median time to neutrophil engraftment was shorter in the ES group compared to the DS group (10 vs 12 days, p < 0.001), as was the total duration of neutropenia (5 vs 6 days, p < 0.001). Documented infections were just as likely in both groups, 37% in the ES group and 39% in the DS group (p = 1). Length of hospitalization was shorter in the ES group as compared to the DS group (15 vs 17 days, p = 0.01). Discussion: Filgrastim use guided by an ES decreased the time to neutrophil engraftment, the duration of neutropenia and the length of hospitalization compared to a DS. Further analyses to identify predictive factors associated with a reduction in infectious complications and length of stay are underway, with the aim of developing a risk-adapted strategy for the use of filgrastim in patients with MM undergoing ASCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

Background: Light chain (AL) amyloidosis is characterized by deposition of misfolded monoclonal immunoglobulin light chains leading to organ dysfunction. AL amyloidosis has traditionally been treated with agents used in multiple myeloma, primarily alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and high-dose melphalan/autologous stem cell transplantation (ASCT). A retrospective study comparing patients with AL amyloidosis who underwent ASCT as frontline therapy ('upfront ASCT') to those undergoing ASCT following induction ('deferred ASCT') revealed that deferred ASCT was associated with prolonged overall survival (OS) compared to upfront ASCT (Afrough et al, Biol Blood Marrow Transplant, 2018). Given the number of effective new therapies for AL amyloidosis, the potential to delay ASCT after one or more lines of therapy ('salvage ASCT') is feasible. To our knowledge, transplant outcomes of AL amyloidosis patients undergoing deferred vs salvage ASCT following at least one relapse have not been reported. A retrospective chart review was conducted to compare AL amyloidosis patients receiving deferred vs salvage ASCT for progression-free survival (PFS) and overall survival (OS). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: Twenty-four patients with AL amyloidosis who underwent deferred or salvage ASCT between 2000-2018 were included in the analysis. Patients who underwent upfront ASCT without induction chemotherapy were excluded. Demographics and clinical parameters were extracted from the electronic medical record. PFS was calculated from date of ASCT to first relapse and OS was calculated both from date of diagnosis and date of ASCT to death. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS as well as OS of patients who underwent deferred vs salvage ASCT were compared. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using deferred ASCT as the reference treatment. Results: Among the 24 patients included in this analysis, 13 underwent deferred ASCT with 1 prior line of chemotherapy (e.g., induction), and 11 underwent salvage ASCT with a median of 3 prior lines (Table 1). Ten patients had cardiac amyloidosis, 15 had renal amyloidosis, and 6 had multi-organ involvement. Induction regimens received in the deferred group are included in Table 1. Neither PFS nor OS was significantly different between patients receiving deferred vs salvage ASCT. After median follow-up of 2.9 years, median PFS in patients who received deferred ASCT was 6.5 years and not reached in those who received salvage ASCT (P=0.47), with a HR of 1.74 (95% CI, 0.38-7.85) (Figure 1A). Median OS from date of ASCT was not reached in either group after a median follow-up of 2.8 years (P=0.52), with a HR of 2.16 (95% CI, 0.19-24.04) (Figure 1B). Similarly, median OS calculated from date of diagnosis was not significantly different between deferred vs salvage ASCT (P=0.79) (Figure 1C). Conclusions: In this cohort of 24 AL amyloidosis patients, no significant differences in PFS or OS were seen between patients undergoing deferred ASCT following induction vs salvage ASCT following multiple lines of therapy. Unlike the superior OS seen with deferred vs upfront ASCT, our findings show that either deferred or salvage ASCT may be associated with comparable outcomes and suggest similar OS despite timing of transplant. However, it is important to note the small sample size and that none of our patients received daratumumab-based regimens which may have improved PFS/OS in either or both groups. There were also small differences between groups in use of maintenance (1 vs 3 patients in the deferred and salvage groups, respectively) and proportion of patients receiving higher doses of melphalan 200mg/m2 vs 140 mg/m2 (69% vs 55% in deferred and salvage groups, respectively). Nevertheless, the lack of difference seen in PFS and OS between the two groups suggests that eventual hematologic relapse and organ progression with death occur at similar time intervals despite timing of ASCT. This speaks to the point that in newly diagnosed AL amyloidosis as well as later in the disease, achieving deep responses to prevent organ progression and death regardless of timing of ASCT remains an important treatment goal. Disclosures Van Besien: Miltenyi Biotec: Research Funding. Coleman:Kite Pharmaceuticals: Equity Ownership; Pharmacyclics: Speakers Bureau; Merck: Research Funding; Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding. Rosenbaum:Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health.

Background Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the polyomavirus John Cunningham (JCV) in the setting of immunosuppression. It has been described in patients with hematologic malignancies including multiple myeloma (MM), solid organ malignancies, granulomatous and inflammatory diseases, transplant recipients, lymphopenic patients (including patients with HIV) and with the use of certain drugs (rituximab, natalizumab). We present the first report to our knowledge of a patient with MM developing PML in association with daratumumab and pomalidomide therapy. Case Report A 63yo woman with relapsed/refractory IgA-Lambda MM on daratumumab and pomalidomide, presented to the emergency department after noticing difficulty putting her hair up in a ponytail. Her MM was diagnosed in 2003 and treated with steroids, high-dose melphalan and autologous stem cell transplant, maintenance therapy with thalidomide, switched to lenalidomide; upon relapse in 2010, she was treated with bortezomib, doxorubicin and dexamethasone, followed by bortezomib maintenance. Ten months prior to presentation, she relapsed and was started on daratumumab and pomalidomide, achieving an unconfirmed complete response (uCR), complicated by acquired hypogammaglobulinemia for the prior 8 months without infections. She developed progressive left arm weakness and gait instability; she denied any fevers, dysarthria, vision changes, headaches or seizures. On exam, she was alert and oriented; no cranial nerve abnormality; calculation, concentration and recall were intact; 4/5 strength in left upper extremity and 5/5 strength in all other extremities with preserved sensation and reflexes; coordination intact but a hemiparetic gait; rest of the exam was unremarkable. A brain MRI showed patchy and confluent areas of T2 hyperintense signal in the right greater than left cerebral hemispheres. She underwent a lumbar puncture which was positive for JCV by PCR (98 copies/mL) in her CSF and negative for neoplastic involvement by flow cytometry. The rest of her work-up was unremarkable. A diagnosis of PML was made and daratumumab and pomalidomide were discontinued. On follow-up brain MRIs four and eight weeks later, she had persistent extensive asymmetric patchy T2 hyperintense signal. Repeat LP revealed stable JCV in the CSF (95 copies/mL). Despite the lack of radiologic improvement, she had a remarkable clinical response with near resolution of neurologic symptoms and remains in an uCR. Discussion PML has been reported in association with multiple drugs used in the management of MM including corticosteroids, alkylating agents (cyclophosphamide, melphalan), immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, ixazomib), however, an association with pomalidomide or daratumumab has not yet been reported. In a clinical trial of daratumumab and pomalidomide for MM, a case of PML was reported, however, it was not considered to be related to these agents given that the patient received only one dose of daratumumab (Chari A. Blood 2017). PML has been reported in patients with primary hypogammaglobulinemia, however, it is not known whether acquired hypogammaglobulinemia - either due to MM or its therapy - is a risk factor for PML. Furthermore, the role for IVIG in the primary prevention or treatment of PML has not been clearly defined and warrants further study. The current treatment approach of PML remains the restoration of the host's adaptive immune response, including the discontinuation of immunosuppressive agents, unfortunately, evidence is lacking for any specific pharmacologic treatment. Recently, immune checkpoint inhibitors have shown clinical improvement or stabilization in small cohorts of patients with PML (NEJM 2019;380), however, given the safety concerns regarding their use in MM (KEYNOTE-183,-185) and the rapid clinical response seen in this case, no further therapy was instituted. This is the first report of pomalidomide and daratumumab as potential drugs associated with PML. Although it is not possible to ascertain their direct role in the reactivation of JCV, it should help clinicians recognize this potentially fatal complication in patients receiving either immunomodulatory drugs or anti-CD38 monoclonal antibodies, since prompt discontinuation may be life-saving. Disclosures Perry: Celgene: Speakers Bureau. Coleman:Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

7513 Background: Standard treatment is lacking for patients with relapsed indolent NHL (iNHL). PI3K inhibitors reported a median PFS of < 1 y in R/R iNHL. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported a 39.4-mo median PFS in R/R iNHL patients (AUGMENT; Leonard. ASH 2018:445). Methods: MAGNIFY is a multicenter, non-registrational phase IIIb trial in patients with R/R FL grade 1-3a and MZL designed to determine the optimal duration of lenalidomide. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in patients with stable disease or better to continued R2 vs rituximab maintenance. These analyses evaluate the primary endpoint of ORR by 1999 IWG criteria for induction R2 in efficacy-evaluable patients receiving ≥ 1 treatment with baseline/post-baseline assessments. Results: At a median 16.7 mo follow-up, 370 patients (80% FL grade 1-3a; 20% MZL) were enrolled with a median age of 66 y, 83% stage III/IV disease, and a median of 2 prior therapies (95% prior rituximab-containing). Efficacy-evaluable patients showed a 73% ORR and 45% CR (Table). Median TTR was 2.7 mo, median DOR was 36.8 mo, and median PFS was 36.0 mo. 142 of 370 patients have been randomized and entered maintenance. The most common all-grade AEs were 48% fatigue, 40% neutropenia, 35% diarrhea, 30% nausea, and 29% constipation. Grade 3/4 AE neutropenia was 34%; all other grade 3/4 AEs were < 6%. Conclusions: R2 therapy is active with a tolerable safety profile in patients with R/R FL and MZL, and in patients refractory to rituximab. Clinical trial information: NCT01996865. [Table: see text]

7530 Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range

Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200 mg/m2. Twenty-five subjects were enrolled into 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225 mg/m2 + melphalan 200 mg/m2 was expanded to further evaluate safety. Overall, there was no transplant related mortality and only one grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment were 11 (range, 9 to 14) and 13 (range, 10 to 21), respectively. Disease responses at day +100 posttransplantation were progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with pre-existing high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after autologous stem cell transplant. Bendamustine up to a dose of 225 mg/m2 added to autologous stem cell transplantation conditioning with high-dose melphalan in patients with multiple myeloma did not exacerbate expected toxicities.

Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. Results: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand–foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. Conclusion: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield. Clin Cancer Res; 19(6); 1534–46. ©2013 AACR.

Diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma (NHL), is the most-common subtype of NHL. DLBCL can be classified into at least 3 major immunologically distinct types, which contributes to considerable variation in disease prognosis and response to treatment. DLBCL potentially is curable, even when diagnosed at advanced stages. The current standard of care for most patients with untreated or relapsed/refractory DLBCL is chemoimmunotherapy containing rituximab, an anti-CD20 monoclonal antibody. With advanced understanding of the molecular mechanisms involved in the pathogenesis of DLBCL and specific signaling pathways that are activated in different subtypes, potential new therapeutic targets have been identified, some of which are at the late stages of clinical development. This review summarizes the critical role of rituximab in the current standard of care treatment for DLBCL and discusses why rituximab is likely to remain an important component of treatment options for DLBCL in the foreseeable future. In addition, current and emerging therapeutic agents, including potential benefits of rituximab biosimilars, for patients with DLBCL are discussed. The advent of rituximab biosimilars may facilitate accessibility of rituximab-based chemotherapies to patients with DLBCL and has potential cost-saving benefits for healthcare systems globally.

Purpose: The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67+ malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. Experimental Design: The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. Results: MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms. Conclusions: These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms. Clin Cancer Res; 17(13); 4309–19. ©2011 AACR.

Purpose The proteasome inhibitor bortezomib may enhance activity of chemoimmunotherapy in lymphoma. We evaluated dose-escalated bortezomib plus standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (R) in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Patients and Methods Seventy-six subjects with untreated DLBCL (n = 40) and MCL (n = 36) received standard CHOP every 21 days (CHOP-21) with R plus bortezomib at 0.7 mg/m2 (n = 4), 1.0 mg/m2 (n = 9), or 1.3 mg/m2 (n = 63) on days 1 and 4 for six cycles. Results Median age was 63 years (range, 20 to 87), and International Prognostic Index (IPI) scores were generally unfavorable (39% with IPI of 2, and 49% with IPI of 3 to 5), as were Mantle Cell Lymphoma International Prognostic Index scores in patients with MCL (28% intermediate risk and 39% high risk). Toxicity was manageable, including neuropathy in 49 subjects (8% grade 2 and 4% grade 3) and grade 3/4 anemia (13%), neutropenia (41%), and thrombocytopenia (25%). For DLBCL, the evaluable overall response rate (ORR) was 100% with 86% complete response (CR)/CR unconfirmed (CRu; n = 35). Intent-to-treat (ITT, n = 40) ORR was 88% with 75% CR/CRu, 2-year progression-free survival (PFS) of 64% (95% CI, 47% to 77%) and 2-year overall survival (OS) of 70% (95% CI, 53% to 82%). For MCL, the evaluable ORR was 91% with 72% CR/CRu (n = 32). The ITT (n = 36) ORR was 81% with 64% CR/CRu, 2-year PFS 44% (95% CI, 27% to 60%) and 2-year OS 86% (95% CI, 70% to 94%). IPI and MIPI correlated with survival in DLBCL and MCL, respectively. Unlike in DLBCL treated with R-CHOP alone, nongerminal center B cell (non-GCB) and GCB subtypes had similar outcomes. Conclusion Bortezomib with R-CHOP-21 can be safely administered and may enhance outcomes, particularly in non-GCB DLBCL, justifying randomized studies.

Background: MCL is a subtype of NHL that remains largely incurable with conventional therapies; BR is standard first-line therapy. Acalabrutinib is a potent, highly selective, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. Acalabrutinib was approved by the FDA in October 2017 for patients with R/R MCL and ≥1 prior therapy. This ongoing, multicenter, open-label Phase 1b study assessed the safety and efficacy of acalabrutinib + BR in patients with TN or R/R MCL. Methods: Patients aged ≥18 y with ECOG PS ≤2 and adequate organ function were eligible; R/R patients had received ≥1 prior therapy. Patients received oral acalabrutinib 100 mg twice daily, plus B 90 mg/m2 intravenously (IV) on days 1 and 2 and R 375 mg/m2 IV on day 1 in each 28-day cycle. Acalabrutinib was given until disease progression (PD) or intolerance; BR was repeated every 28 days for up to 6 cycles. Patients with TN MCL who achieved partial or complete response (CR) received rituximab maintenance therapy (375 mg/m2 every other cycle for up to 12 doses starting on cycle 8). Dose-limiting toxicity (DLT) was evaluated in the first 6 patients per cohort (TN or R/R) after completing 1 cycle. If Results: A total of 38 patients enrolled (TN, n=18; R/R, n=20); 63% were men; 55% were ≥65 y. At baseline, 100% of TN and 95% of R/R patients had ECOG PS ≤1; 89% and 95% had Ann Arbor stage IV disease, 44% and 60% had intermediate-risk and 11% and 15% had high-risk simplified MCL International Prognostic Index scores, respectively. The median number of prior therapies in the R/R cohort was 2 (range 1-4) and 45% were refractory (stable disease or PD) to most recent prior treatment. As of 4 May 2018, median time on study was 17.6 mo (range 0.6-23.1) for TN and 14.2 mo (range 1.2-23.6) for R/R patients; 78% of TN and 50% of R/R patients completed 6 cycles of BR with acalabrutinib. Across both cohorts, no DLTs were observed. Adverse events (AEs) of any grade in ≥30% of patients in any cohort are in Table 1. In the TN cohort, Grade ≥3 AEs in ≥10% of patients were neutropenia (33%) and pneumonia (11%). Serious AEs (SAEs) occuring in ≥2 patients included pneumonia (Grade 3, n=2 [11%]) and pyrexia (Grade 1, n=2 [11%]). One patient had pulmonary alveolar hemorrhage (Grade 4, investigator assessed as related to acalabrutinib) leading to discontinuation of study treatment (acalabrutinib + BR). There were 3 deaths: 1 patient had Grade 5 pneumonitis (investigator assessed as related to acalabrutinib; 24 days after last dose), 1 died of unascertained cause, and 1 died of unknown cause. In the R/R cohort, Grade ≥3 AEs (in ≥10%) were neutropenia (50%); diarrhea, leukopenia, decreased neutrophil count, pneumonia and thrombocytopenia (10% each). Pneumonia was the only SAE to occur in ≥2 patients (n=3; 1 Grade 1, 2 Grade 3). Three patients had major hemorrhage; all were Grade 3 AEs and investigator assessed as unrelated to study treatment (subdural hematoma [after a traumatic fall], large intestinal ulcer hemorrhage [on study day 2], gastrointestinal hemorrhage [duodenal tumor found on endoscopy]). One patient had Grade 3 angina pectoris (unrelated) leading to discontinuation of study treatment (acalabrutinib + BR). There were 4 deaths: 1 patient had Grade 5 AE cerebrospinal meningitis (investigator assessed as unrelated to acalabrutinib; 123 days after last dose), 1 died of unascertained cause, and 2 had PD. No patients had cytomegalovirus infection, pneumocystis jiroveci pneumonia, or atrial fibrillation during the study. In the TN cohort, the ORR was 94%, with a CR rate of 72% (Table 2); median DOR and median PFS were not reached (NR). In the R/R cohort, ORR was 80% and CR rate was 65%; median DOR was 15.0 mo (95% CI: 12.2, NR) and median PFS was 16.6 mo (95% CI: 14.2, NR). There were no clinically meaningful differences in steady-state acalabrutinib exposure when administered with or without BR (n=12 [TN, n=6; R/R, n=6]). Conclusion: Combination therapy with acalabrutinib + BR showed an acceptable safety profile, with no meaningful changes in acalabrutinib exposure. The high CR rate with acalabrutinib + BR in both TN and R/R MCL further supports a phase 3 randomized study of acalabrutinib + BR versus BR in TN MCL (NCT02972840). Disclosures Phillips: Bayer: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Consultancy; Gilead: Consultancy. Smith:Portola: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding. Jurczak:Afimed: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy; Janssen: Consultancy; Sandoz-Nowartis: Consultancy; AstraZeneca/Acerta: Consultancy, Research Funding; European Medicines Agency: Consultancy. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Acerta: Research Funding; Pharmacyclics: Research Funding; Genentech: Honoraria, Research Funding, Speakers Bureau; Charles M. Farber, MD, PhD, LLC-Medical legal consulting: Consultancy; ummit Medical Group-MD Anderson Cancer Center: Employment; Gilead: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Maddocks:Merck: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Pharmacyclics/Janssen: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria; BMS: Research Funding. Flinn:Janssen: Research Funding; Trillium: Research Funding; Calithera: Research Funding; Celgene: Research Funding; Forma: Research Funding; Verastem: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; BeiGene: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Genentech: Research Funding; Agios: Research Funding; Infinity: Research Funding; Merck: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Research Funding; Portola: Research Funding; Gilead: Research Funding; Kite: Research Funding; Incyte: Research Funding; ArQule: Research Funding; Curis: Research Funding. Jedrzejczak:BMS: Research Funding; Astellas: Research Funding; Onconova: Research Funding; Amgen: Research Funding; Polish Ministry of Higher Education and Science: Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria; Polish Parliament: Consultancy; Polish Ministry of Health: Consultancy; Medical University Warsaw, Central Hospital Warsaw: Employment; Astex: Research Funding; AstraZeneca: Research Funding. Goy:Seattle Genetics: Research Funding; Genentech: Research Funding; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics/J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hackensack University Medical Center: Employment; COTA: Membership on an entity's Board of Directors or advisory committees. Zinzani:MSD: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zaucha:Celgene: Honoraria; Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria. Coleman:Gilead: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Celgene: Consultancy, Research Funding, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy, Research Funding, Speakers Bureau; Incyte: Research Funding. Chen:Acerta Pharma: Employment; AstraZeneca: Equity Ownership; Merck: Equity Ownership. Lee:Acerta Pharma: Employment. Liang:Acerta Pharma: Employment. Seto:Acerta Pharma: Employment. Wang:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Dava Oncology: Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding.

Inhibition of CDK4/6 has emerged as an effective therapy in human cancer. Palbociclib, the first selective CDK4/6 inhibitor (CDK4/6i), is FDA-approved for treatment of metastatic breast cancer, and abemaciclib has been fast tracked for approval as a front line breast cancer treatment. Recent evidence in mouse models of breast cancer further indicates that CDK4/6 inhibition triggers anti-tumor immunity, but the precise tumor intrinsic mechanism that mediates CDK4/6 inhibition for a clinical response remains to be defined. To address this, we inhibited CDK4/6 with palbociclib in sequential combination with immunomodulary drugs (IMiD)s in primary bone marrow myeloma cells (BMMCs), using normal bone marrow plasma cells as a control. IMiDs, lenalidomide (Len) and pomalidomide (Pom), are standard of care for multiple myeloma (MM) and lymphoma. Each rarely achieves complete remission despite a high overall response rate and durability. However, each markedly potentiates the clinical efficacy of diverse partners by unknown mechanisms. Cereblon (CRBN), a substrate receptor of the CUL4-ROC1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, is requited for IMiD's anti-tumor activity. Binding of Len or Pom to CRBN accelerates the recruitment of transcription factors IKZF1/3 to CRL4CRBN for ubiquitination and degradation in MM cells. One of the targets of IKZF1/3 is IRF4, which is required for survival of MM cells and reduced after exposure to Len or Pom. Moreover, MEIS2, a homeobox transcription factor was identified to be an substrate of CRBN in crystal structure and by biochemical screen, implicating a role for MEIS2 in modulates IMiD's anti-tumor activity. However, evidence for MEIS2 expression in myeloma cells is lacking. Previously, we have shown that prolonged early G1 arrest (pG1) induced by sustained CDK4/6 inhibition reprogrammed cancer cells for vulnerability to diverse clinically relevant agents ex vivo and in animal models. To address if CDK4 inhibition reprograms MM cells for IMiD vulnerability, first we show that the intrinsic IMiD sensitivity in primary BMMCs ex vivo is a major determinant for the clinical response to IMiD therapy in myeloma patients. Second, we discovered that MEIS2 is aberrantly expressed and associated with CRBN in BMMCs. Third, MEIS2 is regulated by the cell cycle in primary MM cells and required for the survival of MM cells in part by maintaining IRF4 expression. Finally, CDK4/6 inhibition liberates CRBN from association with MEIS2 in pG1. This rapidly accelerates Len-mediated ubiquitination and degradation of IKZF1/3, loss of IRF4, de-repression of IRF7 and induction of interferon (IFN) responsive genes that culminated in TRAIL-mediated apoptosis. Dissociation of MEIS2 from CRBN thus represents a noel mechanism by which CDK4/6 inhibition reprograms myeloma for vulnerability to IMiDs through induction anti-tumor IFN response. Citation Format: Xiangao Huang, David Jayabalan, Maurizio Di Liberto, Zhengming Chen, Anna Schinzel, Scott A. Ely, Adriana Rossi, Morton Coleman, Joseph M. Lane, William C. Hahn, Tomer M. Mark, Ruben Niesvizky, Selina Chen-Kiang. CDK4/6 inhibition triggers dissociation of MEIS2 from CRL4CRBN E3 ligase to induce interferon response and reprogram myeloma for IMiD vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2300.

BACKGROUND: Bortezomib has preclinical and clinical in B-cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). METHODS: Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29-84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R-CHOP was administered on a 21-day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m2 [n = 4 patients], 1.0 mg/m2 [n = 9 patients], or 1.3 mg/m2 [n = 7 patients]) administered on Days 1 and 4 of each cycle. RESULTS: The maximum tolerated dose of bortezomib with R-CHOP was not reached, and the 1.3-mg/m2 dose level had acceptable tolerability. A dose-limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m2 of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow-up of 56 months, overall survival at 4 years was 75% and progression-free survival was 58%. CONCLUSIONS: Bortezomib at a dose of 1.3 mg/m2 twice per cycle can be added to R-CHOP chemotherapy with acceptable toxicity. Multi-institutional and cooperative group follow-up studies of this regimen are currently ongoing. Cancer 2010. © 2010 American Cancer Society.

Purpose The efficacy and safety of cyclophosphamide, vincristine, and prednisone (CVP) followed by tositumomab and iodine-131 (131I) –tositumomab therapy were evaluated in a multicenter phase II study in patients with untreated low-grade follicular lymphoma. Patients and Methods Patients received six cycles of CVP followed by one cycle of tositumomab and 131I-tositumomab (one dosimetric dose and one therapeutic dose). The treatment was evaluated for efficacy and safety. Results All 30 patients enrolled completed CVP as well as tositumomab and 131I-tositumomab therapy. The overall response rate after completion of therapy was 100%, with 28 patients (93%) achieving a complete response (CR) and two patients achieving a partial response. Of the 17 patients with bone marrow involvement at enrollment, 15 achieved a confirmed CR. Fourteen of 15 patients with bulky disease (≥ 5 cm) had a CR after treatment completion. After a median follow-up of 8.4 years, the median response duration had not been reached (range, 3 to 111+ months). Five-year progression-free and overall survival rates were 56% and 83%, respectively. The most common grade ≥ 3 hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Nineteen patients received growth factor support, and three required blood product transfusions. No patients developed human antimurine antibodies. Two patients developed myelodysplastic syndrome/acute myeloid leukemia. Conclusion These mature data demonstrate that sequential therapy with a non-anthracycline–containing regimen comprising CVP followed by one cycle of tositumomab and 131I-tositumomab produced high response rates with adequate safety and durable remissions and that this regimen represents a highly active treatment for first-line therapy of follicular non-Hodgkin's lymphoma.

7549Background: Bruton tyrosine kinase (BTK) inhibition has shown clinical benefit in FL. Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK. We evaluated acalabrutinib ± R in a...

7516Background: In the relapsed/refractory (R/R) setting for indolent non-Hodgkin lymphoma (iNHL), duration of response (DOR) to and types of prior therapy are important factors in predicting outco...