ALBERT

Description: Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and approximately 3-4% of MDS pts. Olutasidenib is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors on releasing differentiation block in IDHm leukemia models in vitro. Methods: The Phase 1 study (NCT02719574) assessed the safety, PK/PD, and clinical activity of olutasidenib in patients with IDH1m AML or MDS. Eligibility criteria included: IDH1m AML or MDS [relapsed/refractory (R/R) or treatment naïve (TN) pts not eligible for or refusing standard therapy], adequate liver and renal function. There were no restrictions for concomitant non-anticancer medications. IDH1m variant allele frequency (VAF) and co-mutations were measured at baseline and during treatment. Available safety data are presented for all pts (AML/MDS); efficacy data are presented for AML pts only. Results: As of April 12, 2019, 32 pts had been treated with single agent (SA) olutasidenib and 46 pts with olutasidenib in combination (COMBO) with AZA; median time on treatment was 4.2 mo for SA (range: 27 mo); disease control (SD 〉13 mo) was observed in pts without an IWG-defined response. Of the 59 AML pts (23 SA; 36 COMBO) who were transfusion-dependent at baseline, 26 (11 [48%] SA; 15 [42%] COMBO) and 21 (9 [39%] SA; 12 [33%] COMBO) became transfusion-independent (seen in all response categories) during 28 and 56 days on treatment, respectively. For R/R AML pts, median survival was 8.7 mo for SA and 12.1 mo for COMBO; for TN AML pts, median survival was 8.8 mo for SA (n=4) and not reached for COMBO. For R/R and TN AML patients with available pre- and on-treatment samples, IDH1m clearance or significant reduction (VAF

Description: Abstract 634 FLT3, a transmembrane receptor tyrosine kinase constitutively activated via mutation in blasts of patients (pts) with AML, is an important therapeutic target. Blasts from approximately 25% of pts have a length or internal tandem duplication (ITD) mutation in the juxtamembrane region or tyrosine kinase domain (TKD1) of FLT3, which is associated with reduced disease-free survival and overall survival (OS), particularly in pts with normal cytogenetics. Blasts from 5–10% of pts have a point mutation (typically D835Y) in the tyrosine kinase domain (TKD); the effect of this mutation on prognosis is uncertain. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with demonstrated clinical activity in FLT3-mutant (FLT3–mut) and FLT3-wild-type (FLT3–wt) AML (peripheral blood blast reduction in 70% and 30% of pts, respectively) but rarely produces complete remissions). Preclinical studies demonstrated synergy between FLT3 inhibitors and chemotherapy. We conducted a Phase 1b trial to investigate the feasibility of administering daunorubicin (60 mg/m2 IV, days 1–3) and cytarabine (100 mg/m2 IVCI, days 1–7) induction and high-dose cytarabine post-remission therapy (3 gm/m2 over 3h every 12h, days 1, 3, and 5 for 3 cycles) plus oral midostaurin at 100 mg or 50 mg each twice daily on days 8–21 (sequentially) or days 1–7, 15–21 (concomitantly) with all chemo cycles in newly diagnosed pts under age 61 with de novo AML. Whereas 100 mg of midostaurin plus induction chemotherapy was poorly tolerated due to nausea and vomiting, the 40 pts who received 50 mg of midostaurin orally twice daily ( 20 each on the sequential and concomitant schedules; 27 FLT3–wt; 13 FLT3–mut [9 with an ITD]), tolerated the combination well. Median midostaurin exposure was 133 days (range 21–975) for the FLT3–mut pts and 90 days (range 7–1016) for FLT3–wt pts. Maintenance therapy with midostaurin was allowed with investigator discretion and was received by 5 pts (3 FLT3–mut, 2 FLT–wt). The median ages for the FLT3–wt and FLT3–mut pts were 50 years (range 25–60) and 46 years (range 20–65), respectively. 77% of the FLT3–mut pts displayed normal, 15% adverse and 8% other intermediate cytogenetics compared with 18.5%, 26%, and 26%, respectively, for FLT3-wt (also 18.5% favorable; 11% unknown). Complete response occurred in 32/40 (80%) of all pts (20/27 [74%] of FLT3–wt patients, 12/13 [92%] of FLT3–mut pts). Patients were censored at the last date they were known to be alive with a median post treatment follow-up for FLT3-mut pts of 1059 days and 1086 days for FLT3-wt. Even accounting for their differing cytogenetics and ages, the OS of the FLT3–mut subgroup was expected to be inferior to that of the FLT3–wt subgroup. However, we report that the 1 and 2 year OS for the pts with FLT3–mut AML was 85% and 62%, respectively, and was comparable to that of the FLT3–wt subgroup (81% and 59%, respectively). Although based on small numbers and not stratified for type of FLT3 mutation (TKD, ITD, ITD length, location, or allelic ratio), these long-term results suggest that combination therapy with a FLT3 inhibitor and chemotherapy might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3–mut AML pts in first complete remission. Moreover, these data support the rationale for the ongoing international phase 3 study of induction, post-remission intensification, and maintenance with midostaurin (50 mg po bid) or placebo. Disclosures: Stone: Novartis: Research Funding, ad hoc consultancy; Cephalon: ad hoc consultancy. Off Label Use: midostaurin with chemothereapy for AML. Paquette:Novartis: Honoraria, Research Funding, Speakers Bureau. Schiller:Novartis: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Genzyme: Research Funding; Vion: Research Funding; Centocor: Research Funding; Eli Lilly: Research Funding; Celgene: Research Funding. Schiffer:Novartis: Consultancy, Research Funding; Genzyme: Consultancy. Ehninger:Novartis: Honoraria, Research Funding. Cortes:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Wyeth: Research Funding. Kantarjian:Novartis: Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon: Speakers Bureau; Novartis: Speakers Bureau. Huntsman-Labed:Novartis: Employment, Equity Ownership. Dutreix:Novartis: Employment, Equity Ownership. Rai:Novartis: Employment, Equity Ownership. Giles:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Vion: Research Funding.

Description: Autologous stem cell transplantation has become an important therapy in multiple myeloma (MM). To develop adequate autograft purging methods, it is necessary to determine whether antigens expressed on early hematopoietic progenitors exist on malignant cells. The Ig heavy chain produced by the MM cells shows evidence of prior somatic mutation without intraclonal diversity. As a result, this sequence can be used as a specific marker to detect all members of the malignant clone. The Ig heavy chain sequence expressed by the MM cells was obtained in five patients with advanced disease. Patient specific oligonucleotide primers were designed based on the complementarity determining regions (CDR) of each MM Ig sequence and used to amplify DNA by polymerase chain reaction for the detection of malignant cells. A highly purified collection of CD34+ cells was obtained after passage of the initial bone marrow cells through an immunoadsorption column and fluorescence- activated cell sorting. Despite an assay sensitivity of 1 tumor cell in 2,500 to 44,000 normal cells, none of the CD34+ samples showed product with the myeloma-specific CDR primers. Therefore, positive selection for cells bearing this antigen should yield a tumor-free autograft capable of providing hematopoietic recovery after myeloablative chemotherapy.

Description: Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures 〉5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed. In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3). Severe (≥Grade 3) AEs occurring in 〉5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation. Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment. Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. Disclosures Lee: LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Description: Introduction: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (MM). The recommended phase 2 dose (RP2D) of twice-weekly combination of selinexor, carfilzomib, and dexamethasone (SKd) was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg (NCT02199665). The ORR of this regimen in patients with MM refractory to carfilzomib in last line of therapy (n=13) was 62% and clinical benefit response was 77% (Jakubowiak et al. Br J Haematol 2019). This is consistent with data from the combination of selinexor, bortezomib and dexamethasone where a 43% ORR was observed in bortezomib refractory disease. We conducted the STOMP study to assess the safety and preliminary efficacy of SKd combination using once weekly (QW) dosing in patients with relapsed/refractory MM. Methods: STOMP is a multicenter, open-label study. Patients with relapsed/refractory MM that was not refractory to carfilzomib, and who may have had prior proteasome inhibitor exposure were enrolled. Oral Selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (excluding day 22 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose, RP2D and evaluate the efficacy and safety of SKd in patients with relapsed/refractory MM. Results: As of July 01 2019, 12 patients were enrolled in the study. Of these, 5 were male and 7 were female. The median age was 70 years (range: 50-76 years). The median number of prior treatments was 4 (range: 2 - 8). Nine of 12 patients received prior autologous stem cell transplantation. All 12 patients were carfilzomib naïve. Nine of 12 patients had MM refractory to bortezomib; 11 patients had MM refractory to lenalidomide and/or pomalidomide including 5 patients with MM refractory to both; and 7 patients with MM refractory to daratumumab. Four dose limiting toxicities (DLTs) were observed across 3 dose cohorts (Table 1). Common treatment related adverse events (Grade 1/2 , Grade ≥3) included anemia (42%, 17%), thrombocytopenia (17%, 58%), leukopenia (17%, 17%), nausea (67%, 0%), decreased appetite (33%, 0%), insomnia (33%, 0%), hyperglycemia (25%, 17%), fatigue (25%, 8%), vomiting (25%, 8%), and pneumonia (0%, 17%). The ORR was 75% including 3 complete responses, 5 very good partial responses and 1 partial response. Two patients had stable disease and 1 patient had minimal response. As of July 01, 8 patients remain on treatment. Conclusions: The once weekly SKd combination demonstrated encouraging preliminary activity with an ORR of 75% including complete responses and very good partial responses. Most DLTs were thrombocytopenia and all the DLT events occurred in patients with baseline Grade 1/2 thrombocytopenia. This activity and manageable side effect profile with QW selinexor in combination with carfilzomib and dexamethasone is promising. Disclosures Gasparetto: Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Constellation Pharmaceutical: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Tuchman:Roche: Research Funding; Alnylam: Honoraria, Research Funding; Karyopharm: Honoraria; Prothena: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding. Bahlis:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chen:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Other: Internal Review Committee participant. Kotb:Takeda: Honoraria; Amgen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Karyopharm: Equity Ownership. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sebag:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Research Funding; J&J: Research Funding; Sanofi: Honoraria; Takeda: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding.

Description: Tumor lysis syndrome (TLS) is a potentially lethal metabolic complication of chemotherapy or cytolytic antibody therapy usually seen in patients with hematologic malignancies, especially those malignancies with a high proliferative rate, large cellular burden and/or sensitivity to chemotherapy. The prevention and management of TLS includes hydration and reduction of serum uric acid (SUA) levels. Although Allopurinol (ALLO) has had longstanding use for TLS prophylaxis, its efficacy in controlling SUA is limited, especially due of its lack of action on pre-existing hyperuricemia. Rasburicase (RAS), a recombinant urate oxidase, effectively reduces SUA due to conversion of UA into allantoin, a readily excretable and soluble substance. RAS has significant activity in the initial management of TLS-associated acute hyperuricemia in pediatric populations, and is currently indicated in the US for this condition in children and adolescents. A prospective, randomized, controlled phase III study was conducted in adult pts to compare the efficacy in SUA control of RAS (0.20 mg/kg/d, IV) days 1–5, versus RAS+ALLO (RAS 0.20 mg/kg/d, IV days 1–3 plus oral ALLO 300 mg/day days 3–5) versus ALLO alone (300 mg/d) days 1–5. 280 pts (275 evaluable) with hematological malignancies at high or potential risk for TLS were enrolled. 92 pts received RAS, 92 pts received RAS+ALLO, and 91 received ALLO. Treatment arms were well balanced in terms of demographics, baseline characteristics, TLS risk, and percentage of pts with baseline hyperuricemia. The SUA response rate - defined as normalization of SUA (≤ 7.5mg/dl) at days 3–7 was 87.0% in the RAS arm, 78.3% in the RAS+ALLO arm and 65.9% in the ALLO arm. RAS was superior over ALLO (p=0.0009) in the overall study population as well as in pts at high risk TLS (89.0% vs. 62.8%, p=0.0012), and in pts with baseline hyperuricemia (89.5% vs. 52.9%, p=0.0151). The time to control SUA in hyperuricemic pts was 4.1 h in the RAS arm and 27 h in the ALLO arm. The mean SUA area under the curve (AUC) results indicated that there was an 8.4-fold increase in UA exposure in the ALLO arm compared to the RAS arm. There were no significant differences in the incidence or severity of adverse events, serious adverse events or deaths. The majority of RAS and/or ALLO-related adverse events were grade 1 and 2, and most of these events were hypersensitivity-related reactions. No cases of anaphylaxis, methemoglobinemia or hemolysis were observed with RAS treatment. In conclusion, RAS is superior to ALLO in normalization of SUA, with a faster effect, in adult pts at risk for TLS. RAS alone or followed by ALLO are two valid options for this patient population.

Description: Allogeneic hematopoietic transplantation following nonmyeloablative preparative conditioning (also know as “mini-dose transplantation”) is frequently applied to patients who, on the basis of prior therapy, organ dysfunction, or co-morbid conditions may be considered ineligible for full, dose-intenstive treatment. This approach assumes that early regimen-related toxicity can be averted by the nonmyeloablative approach. We present the results obtained in a group of consecutive, unselected older adults with advanced hematologic neoplasia who underwent allogeneic transplantation from fully histocompatible siblings or unrelated donors after dose-reduced preparative conditioning in a single center. Thirty-four patients, median age 57 years (range 26–66) underwent allogeneic transplantation from siblings (14 patients) or unrelated donors (20 patients) following preparative conditioning consisting of chemotherapy only (typically fludarabine, cytarabine, and cyclophosphamide) or those drugs plus antithymocyte globulin, respectively. One recipient of a related allograft and one recipient of an unrelated allograft received preparative fludarabine/melphalan and busulfan/fludarabine/ATG, respectively. Diagnoses prior to transplantation included advanced acute leukemia and myelodysplasia (17 patients), nonHodgkin’s or Hodgkin’s lymphoma (11 patients), and CLL or Multiple Myeloma (6 patients). Allogeneic transplantation followed previous autologous transplantation in 17 patients. Time from previous autologous transplantation to nonmyeloablative allogeneic transplantation varied. Prior autograft conferred a significant adverse risk on recipients of allogeneic transplants following nonmyeloablative conditioning. Only two of 17 patients with a history of prior autograft enjoyed long-term survival as opposed to seven of 17 who had not undergone prior autologous transplant. Mortality before day + 100, typically attributed to treatment-related toxicities, occurred in 11 patients; nine of these patients had had prior autologous transplantation. Prior autologous transplantation typically was done for acute myelogenous leukemia in first complete remission and referral for allotransplant may have been an indicator of more aggressive disease biology. In conclusion, allogeneic transplantation following a nonmyeloablative preparative regimen may be associated with significant risk of early mortality in patients who undergo this treatment after prior autologous transplantation, especially for acute leukemia, suggesting that criteria for allogeneic transplantation after nonmyeloablative condition should take this risk into account. Further studies from multiple centers will be required to confirm this observation.

Description: Introduction Venetoclax (VEN) is a selective BCL-2 inhibitor that has demonstrated activity against acute myeloid leukemia (AML) and has been shown to be effective when used in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for treatment-naïve, elderly AML patients unfit for intensive chemotherapy. Data on its use in the relapsed/refractory setting is limited. Methods A retrospective analysis was performed among 12 relapsed or refractory AML patients treated with VEN combination therapy at the University of California Los Angeles from 2018-2019. Seven patients received VEN in combination with azacitidine (75 mg/m2 x 7 days), 4 patients with decitabine (20 mg/m2 x 5 days), and 1 patient with low-dose cytarabine (20 mg/m2 x 10 days). Results The median patient age at time of VEN therapy was 58 years (range 41-79). Four patients (33.3%) had secondary AML. The majority (9 patients, 75.0%) had adverse cytogenetics. Three patients (25.0%) had received an allogeneic stem cell transplant prior to VEN therapy, and 5 patients (41.7%) had failed HMA therapy prior. Notable molecular mutations present were TP53 (4 patients, 33.3%), FLT3 (3 patients, 25.0%), and IDH2 (1 patient, 8.3%). Eight patients (66.7%) had grade 3 or greater neutropenia at time of VEN initiation, and 9 patients (75.0%) had grade 3 or greater thrombocytopenia. Four patients (33.3%) had a grade 3 or greater infection prior to VEN therapy. Dosing of VEN was by physician discretion with a median starting dose of 150 mg (range 100-800) and a median maintenance dose of 450 mg (range 200-800). The median number of cycles of VEN combination therapy was 2 (range 1-5). Seven patients (58.3%) had decreased VEN dosage due to concomitant azole for antifungal prophylaxis. Four patients (33.3%) were on an additional small molecular inhibitor while receiving VEN therapy (sorafenib in 3 patients, ruxolitinib in 1 patient). The majority (10 patients, 83.3%) had an interruption in VEN dosing for the following reasons: bone marrow functional delay (7 patients), inability to tolerate oral pills (4 patients), infection (3 patients), and bleeding (2 patients). The objective response rate (ORR) was 41.7% with 3 patients (25.0%) achieving complete remission with incomplete hematologic recovery (CRi) and 2 patients (16.7%) achieving partial remission (PR) (Table 1). Three patients (25.0%) experienced early death within 30 days due to the following: pneumonia (1 patient), multi-organ failure from infection and graft-versus-host disease (1 patient), and intracranial hemorrhage (1 patient). The median time to first and best response was 56 days (range 27-101) or after approximately 2 cycles of VEN combination therapy. During VEN therapy, all patients (100%) had grade 3 or greater neutropenia and thrombocytopenia, and 10 patients (83.3%) had grade 3 or greater anemia. The nadir of most cytopenias occurred during cycle 1. Six patients (50.0%) developed a grade 3 or greater infection following VEN therapy, and 2 patients (16.7%) developed a grade 3 or greater intracranial hemorrhage. The only other notable grade 3 or greater side effects noted during VEN therapy were dizziness (1 patient, 8.3%) and diarrhea (1 patient, 8.3%). After a median follow-up time of 3.14 months (range 1.22-13.48), 2 patients (16.7%) progressed, and the 1-year progression-free survival (PFS) rate was 71.11% (95% CI 43.40-100.00) (Figure 1). Eight out of 12 patients died as a result of infection (6 patients, 50.0%), disease progression (1 patient, 8.3%), and bleeding (1 patient, 8.3%). The median overall survival (OS) was 4.74 months (range 1.18-9.15), and the 1-year OS rate was 14.60% (95% CI 2.54-83.80) (Figure 2). VEN was discontinued in all patients because of no response (5 patients, 41.7%), adverse effects (4 patients, 33.3%), transition to donor lymphocyte infusion (1 patient, 8.3%), or transition to allogeneic stem cell transplant (2 patients, 16.7%). Conclusions We present our institutional experience with VEN combination therapy for the treatment of relapsed/refractory AML with a particularly high-risk patient cohort, predominantly characterized by adverse genetic features and grade 3 cytopenias prior to start of therapy. Overall, the response rate was modest, but not inferior to that with conventional salvage chemotherapy. Adverse events were primarily due to pre-existing bone marrow failure, likely exacerbated by treatment. Disclosures Schiller: Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. It does not currently have an approved use for the treatment of acute myeloid leukemia in the relapsed/refractory setting.

Description: In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.