For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL‐2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off‐label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia‐free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post‐HCT AML relapse has an exceedingly poor outcome, and venetoclax‐based therapy is a potent therapy option that should be studied prospectively in this setting.

Introduction: AML pts who relapse after allogeneic hematopoietic cell transplantation (HCT) face poor clinical outcomes and short overall survival (OS) (Schmid et al, Blood2012). The delivery of optimal salvage therapy is challenging as some pts do not tolerate high intensity regimens, and lower intensity therapies may not yield sufficient disease control. Favorable responses in older, treatment naïve AML pts with venetoclax (VEN) in combination with low-dose cytarabine (LDAC) or DNA methyltransferase inhibitor (DNMTi) led to its approval. Off-label use in relapsed/refractory AML is increasing (DiNardo et al, Am J Hematol2018; Aldoss et al, Haematologica2018). We retrospectively evaluated the overall response rate (ORR = CR+CRi+PR+MLFS) and report our clinical experience with VEN-based salvage in post-HCT relapsed AML. Methods: After IRB approval, consecutive pts with post-HCT relapsed AML treated with VEN+LDAC or VEN+DNMTi from May 2018 to July 2019 were retrospectively analyzed. Selection of VEN partner and dosing were at the discretion of the treating physician based on institutional guidelines and published prescribing information. Responses were assigned based on the AML IWG criteria. The Kaplan-Meier method was used to describe OS. ORR and treatment complications were summarized via descriptive statistics. Results: 18 pts with post-HCT relapsed AML who received at least 1 cycle of VEN-based salvage chemotherapy were included. Median age at HCT was 64.5 years (range 34.5-73.7 years). Most pts were poor risk: 6/18 pts had an antecedent hematologic malignancy, 12/18 had an abnormal or complex karyotype (CK) prior to HCT, and 4/12 pts with CK also were TP53mut. 15/18 (83.3%) received reduced intensity conditioning and MUD was the predominant graft type (50%). All pts received PBSCs. Additional disease and response characteristics are reported in Fig 1A. Median time from HCT to relapse was 5.5 mos (range: 0.9 to 44.9 mos); 27.8% of pts relapsed within 100 days and 55.6% relapsed within 6 mos of HCT. At relapse, 1 patient had grade 2 aGVHD and 1 had severe, extensive cGVHD. No pts experienced a GVHD flare or progression during treatment. 14/18 (77.8%) of pts were receiving immunosuppressive therapy (IST) at relapse and received VEN concurrently with IST. VEN-based salvage chemotherapy began shortly after confirmed relapse (range: 4-46 days); 4/18 pts received VEN with LDAC and 14/18 were treated with a DNMTi partner. 15/18 pts were evaluable for response. IWG responses were seen in 8 pts with an ORR of 53%. There were 0 CR, 6 CRi, 0 PR, 2 MLFS, 7 pts had progressive disease (4 by BM, 3 by PB, Fig 1B). 3/18 additional pts had a ≥50% reduction in circulating blasts indicating treatment effect but were non-evaluable given lack of surveillance BM biopsy. Pts received a median of 2.5 cycles (range 1-9). 15/18 pts had treatment held or delayed due to fever/infection (7), PB cytopenias (4), combination (3), or non-hematologic toxicity (1). 6/8 pts who achieved a CRi/MLFS had VEN dosing reduced or administered as a single-agent. One patient achieved CRi with dose interruptions lasting ≥3 mos, maintained this response, and subsequently cleared a TP53 mutation. The majority of pts 13/18 (72.2%) experienced infectious complications during treatment: 7 developed bacterial pneumonia (4 associated with sepsis), 4 fungal penumonia, and 2 oral infections (both associated with sepsis). 8/18 pts had active infections at the time of death. Time from HCT or IST status did not appear to impact the frequency or severity of infectious complications. After a median of 2.7 mos of follow up (range 0.6-8.9 mos), the mOS after the start of VEN was 130 days. Consolidation with donor lymphocyte infusion or second HCT is planned for several pts. Conclusions: Transplant related- and disease related-mortality are difficult to disentangle in post-HCT AML relapse making it challenging to ascertain the benefit of therapy. In this cohort, the majority of pts relapsed within 6 mos of HCT and were receving IST at the start of salvage therapy. In spite of this, VEN-based salvage induced meaningful responses. To convert these responses to long term survival benefit, as VEN-based salvage is more widely used in this setting, consideration of immunosuppression and previous marrow injury should inform alternative dosing regimens, careful monitoring for infectious complications in close follow-up, and broad spectrum antimicrobial prophylaxis. Disclosures Byrne: Karyopharm: Research Funding. Dholaria:Celgene: Honoraria. Ferrell:Incyte: Research Funding; Agios: Consultancy; Forma Therapeutics: Research Funding; Astex Pharmaceuticals: Research Funding. Jagasia:Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Savona:Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Venetoclax use in relapsed/refractory AML

Background: Bendamustine and rituximab (BR) is a commonly chosen frontline treatment for grade 1-2 (G 1-2) follicular lymphoma (FL). This regimen resulted in significantly longer progression-free survival (PFS) and less toxicity compared to R-CHOP in the STiL trial [Rummel et al., 2013] and similar results were observed when comparing BR vs. R-CHOP/R-CVP in the confirmatory BRIGHT trial [Flinn et al., 2014, updated ASCO 2017]. Importantly, patients (pts) with grade 3A (G 3A) FL were excluded from these studies, yet the conclusions are often extrapolated to the treatment of G 3A pts. Notably, G 3A pts were included in the GALLIUM trial which used both bendamustine as well as CHOP backbones. Several retrospective studies of FL pts treated with frontline R-CHOP have demonstrated equivalent or improved overall survival (OS) for G 3A relative to G 1-2 FL (Koch et al., 2016, Mustafa et al., 2017, Yuan et al., 2017, Maeshima et al., 2013). Early disease progression after diagnosis and treatment with frontline R-CHOP has been identified as a strong predictor of poor OS in FL pts [Casulo et al. 2015], but has not been assessed in pts treated with frontline BR. We retrospectively evaluated outcomes of a large cohort of FL pts treated with frontline BR and stratified the results based on histologic grade and early vs. late progression. Methods: We reviewed medical records of adult (age >18) pts with FL treated with frontline BR at 18 US cancer centers. There was no central pathology review; each academic institution confirmed the diagnosis and grade of FL. Pts with unknown grade, grade 3B, or cutaneous FL were excluded. Baseline characteristics between grades were evaluated with the Chi-Square test for categorical variables and the Mann-Whitney U for continuous variables. Outcomes were calculated from time of initiation of BR. Patients were grouped according to whether or not they had progression of disease within 24 months of BR initiation (POD24). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 687 pts were included (616 G 1-2, 71 G 3A). Median age at diagnosis was 60 years (range 21-94) with 53% men. The median time from diagnosis to treatment with BR was 1 month (range 0-139). The median duration of follow up for the entire cohort was 39 months. Characteristics including age, gender, ethnicity, ECOG, stage, LDH, and FLIPI are shown in the Table, and did not significantly differ between G 1-2 and G 3A pts. Rates of complete response (CR) and partial response (PR) to BR were similar between G 1-2 and G 3A (72%/22% vs. 66%/21%, respectively, p=0.114) but progressive disease (PD) was higher in G 3A pts (11.9%) relative to G 1-2 (4.8%, p=0.025). As shown in the Figure (A and B), 3-year PFS and OS was significantly longer for G 1-2 vs. G 3A pts (75% vs. 65%, log rank p= 0.035 and 90% vs. 86%, log rank p=0.007, respectively). Seventy-six (12.3%) of the 616 G 1-2 pts and 13 (18.3%) of the 71 G 3A pts experienced POD24 (p=0.19). For pts with both G 1-2 and G 3A FL, POD24 was associated with inferior OS (3-year OS 95% vs. 57% for G 1-2 pts, log rank p<0.0001 and 3-year OS 93% vs. 37% for G 3A pts, log rank p<0.0001) compared to patients without POD24. Conclusions: G 3A FL pts have an inferior OS and are significantly more likely to have PD to frontline BR compared to G 1-2, which differs from the published experience with R-CHOP. Similar to outcomes after frontline treatment with R-CHOP, POD24 after frontline BR for FL is associated with very poor OS. Future studies are needed to address optimal frontline management of pts with G3A as well as for pts with any grade FL with POD24 after frontline BR. Disclosures Nastoupil: Novartis: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Merck: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Juno: Honoraria. Cerhan:Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding; Nanostring: Research Funding. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Smith:Genentech: Research Funding; Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Seattle Genetics: Research Funding. Lossos:Affimed: Research Funding. Portell:TG therapeutics: Research Funding; Amgen: Consultancy; Kite: Research Funding; AbbVie: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Research Funding; Infinity: Research Funding. Calzada:Seattle Genetics: Research Funding. Cohen:Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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; Janssen: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy. Ghosh:Spectrum: Consultancy; SGN: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Celgene: Consultancy; Juno: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Genentech: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Forty seven Inc: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Caimi:Kite Pharma: Other: Advisory Board Participation; Genentech: Other: Advisory Board PArticipation, Research Funding; Celgene: Speakers Bureau; Kite Pharma: Other: Advisory Board Participation. Danilov:Gilead Sciences: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Genentech: Consultancy, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Martin:AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Kite: Consultancy; Gilead: Consultancy; Bayer: Consultancy. Kamdar:Seattle Genetics: Speakers Bureau; Genentech: Consultancy. Kahl:AstraZeneca: Consultancy; Acerta: Consultancy; Juno: Consultancy; CTI: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A significant barrier to advancing the standard of care for patients with hematologic malignancies undergoing stem cell transplantation is access and willingness to participate in clinical trials. The importance of clinical trial enrollment is magnified in an era of targeted therapies, accelerated drug discovery, and investment by the pharmaceutical industry. As disease targets are identified, novel therapies are being evaluated in efforts to reduce treatment-related toxicity and improve progression-free and overall survival. The enrollment of hematopoietic cell transplantation (HCT) patients on clinical studies is essential to promote the development of such therapies. Increasing clinical trial participation requires understanding of potential barriers to enrollment, including patient concerns, institutional and provider hurdles, and disease-specific characteristics.

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