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The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

Hepatic veno-occlusive disease (VOD/sinusoidal obstructive syndrome) represents a constellation of clinical findings including right upper quadrant pain, jaundice, hepatomegaly, and ascites. In the post-hematopoietic stem cell transplant (SCT) setting, the reported incidence has been 10-15%, with severe VOD historically resulting in high mortality rates. Novel agents including calicheamicin conjugated with CD33 (gemtuzumab ozogamicin; GO) and CD22 (inotuzumab ozogamicin; InO) are increasingly used for the treatment of acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Both GO and InO are highly active, but also have unique hepatotoxicity profiles, including a higher risk of VOD in recipients of SCT. Introduction of GO and InO into pre-SCT leukemia management adds additional complexity to SCT patient selection and toxicity monitoring. In this article, we describe and review the risks and management associated with VOD in SCT recipients exposed to GO and InO.

BACKGROUND: Measurable residual disease (MRD) is associated with increased risk of relapse and death in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). Recently, next-generation sequencing (NGS) has emerged as a sensitive and specific method to detect MRD from both bone marrow and peripheral blood. NGS methods are particularly useful for detecting internal tandem duplication mutations of the FMS-like tyrosine kinase 3 gene (FLT3-ITD), which define a subgroup of AML patients who may be at higher risk for relapse and who often undergo consolidative allogeneic HCT. The SORMAIN trial recently reported a highly significant relapse-free survival benefit for the first generation FLT3 inhibitor sorafenib as post-HCT maintenance, particularly among patients with detectable MRD following HCT. In 2019 our program initiated prospective FLT3-ITD monitoring by NGS using a commercially available assay (Invivoscribe, Inc., San Diego, CA) of the peripheral blood or bone marrow throughout the first three months following HCT for all patients with FLT3-ITD mutated AML undergoing HCT. We encouraged but did not mandate FLT3 inhibitor use, regardless of MRD status. In this study, we describe the clinical impact of sensitive FLT3 MRD testing early after HCT, maintenance FLT3 inhibitor use in a non-clinical trial setting, and the ability of early post-HCT FLT3 inhibitor therapy to modify transplant outcomes. RESULTS: Thirty-six adults with FLT3-ITD mutated AML underwent HCT at Stanford University between April 2019 and August 2020 and were included in this observational study (Table 1). These patients were not enrolled in clinical trials evaluating FLT3 inhibitor therapy after HCT. Twenty-nine (81%) received pre-HCT FLT3 inhibitors, and 78% were in first complete remission (CR1) at HCT. Median follow up after HCT was 14.0 months (range 4.6-25.7). Two patients were excluded from subsequent analyses due to early graft failure and receipt of azacitadine/enasidenib maintenance, respectively. Of the evaluable cohort, 9 (26%) experienced clinical relapse at a median of 4.2 months after HCT (range 1.8-6.1), and 10 (29%) died, 5 from transplant-related mortality and 5 from AML (Figure 1A and B). Of the 34 patients evaluable for post-HCT MRD analysis, 10 (29%) had detectable MRD within the first three months while 24 (71%) remained MRD-negative (Figure 2A and B). Although there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD (p = 0.13, Figure 3A), OS was not significantly impacted by MRD (p = 0.35, Figure 3B). Among the four patients with early post-HCT MRD negativity who ultimately relapsed, only one was FLT3-negative at time of relapse. Twenty-four patients (71%) received FLT3 inhibitor maintenance, initiated a median of 2.8 months after transplant (range 0.7-17.1), and the median duration was 10.6 months (range 1.7-23.7). The most common FLT3 inhibitor used was gilteritinib (n = 15), followed by midostaurin (n = 9), and sorafenib (n = 5). Among the 10 patients (29%) who did not receive post-transplant maintenance, reasons included graft-versus-host disease (GVHD) (n = 4), clinician decision (n = 3), cytopenias (n = 2), and thrombotic microangiopathy (n = 1). The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS (Figure 3C and D). Interestingly, the use of early FLT3 inhibitors post-HCT augmented PFS and OS in both MRD-negative and MRD-positive patients (Figure 3E and F), and effectively prevented clinical relapse in four patients with post-HCT MRD positivity (Figure 2A). CONCLUSION: In this cohort study, we evaluated the clinical utility of sensitive post-transplant MRD monitoring and maintenance FLT3 inhibitors on transplant outcomes. We demonstrate that clinical relapse can be prevented even in patients with post-HCT MRD through the incorporation of early FLT3 inhibitors. This finding is in keeping with the results from the SORMAIN trial. We also found that real-time sensitive MRD results allowed clinicians to begin early initiation of FLT3 inhibitor therapy, which positively affected outcomes. Figure 1 Figure 1. Disclosures Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Muffly: Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy.

Acute myeloid leukemia (AML) patients refractory to induction therapy or relapsed within 1 year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in preclinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single-cell RNA sequencing using prospectively acquired patient specimens identified IFN response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well tolerated, with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies. Significance: This study demonstrates a favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML, thus supporting further investigation of this combination in a randomized trial. It also shows the utility of a novel application using multiplexed single-cell analyses to detect on-target activity and identify biomarkers of response. This article is highlighted in the In This Issue feature, p. 403

Context: In 2019, our transplant program initiated prospective FLT3-ITD measurable residual disease (MRD) monitoring by next-generation sequencing (NGS) of the peripheral blood or bone marrow throughout the first three months following HCT for all patients with FLT3-ITD-mutated AML undergoing HCT. We encouraged FLT3 inhibitor use as post-HCT maintenance. Objective: To evaluate the impact of post-HCT FLT3 MRD testing and FLT3 inhibitor use in a non-clinical trial setting. Design: Observational study of adults with FLT3-ITD-mutated AML who underwent allogeneic HCT at Stanford University between April 2019 and August 2020. Setting: Tertiary referral center. Patients or Other Participants: Thirty-six adults with FLT3-ITD-mutated AML are included in this study. Two patients were excluded from analyses due to early graft failure and receipt of azacitidine/enasidenib maintenance therapy. Interventions: Twenty-four patients (71%) received an FLT3 inhibitor after HCT, initiated a median of 2.8 months after transplant (range: 0.7–17.1). The median duration was 6.8 months (range: 1.1–18.8). Main Outcome Measures: Progression-free survival (PFS) and overall survival (OS). Results: Ten patients (29%) had detectable MRD within the first three months following HCT, while 24 (71%) patients remained MRD-negative. Although there was a trend toward inferior PFS for patients with early post-HCT MRD (p = 0.12), OS was not significantly impacted by MRD (p = 0.66). FLT3 inhibitor therapy improved PFS and OS, particularly in MRD-negative patients (maintenance vs no maintenance: PFS not reached vs 5.52 months, p = 0.002; OS not reached vs 5.85 months, p = 0.006). Conclusions: Clinical relapse can be prevented, even in patients with post-HCT MRD, by using early FLT3 inhibitor maintenance therapy, in keeping with the results from the SORMAIN trial. Real-time sensitive MRD testing allows clinicians to begin early initiation of FLT3 inhibitor therapy. This work was partially supported by the National Institutes of Health Grant UL1-TR003142 and Grant P30-CA124435.

Background Patients with lymphoproliferative disorders following hematopoietic stem cell transplant (HSCT) most commonly present with fever and lymphadenopathy within the first 5 months of transplant. Pulmonary post-transplant lymphoproliferative disorder (PTLD) is a particularly aggressive and rapidly progressive disease, with high morbidity and mortality. There are a very limited number of reported pulmonary PTLD cases following HSCT in patients with acute myeloid leukemia (AML). Early diagnosis and detection of pulmonary PTLD is critical given its high lethality. However, variable clinical presentations and nonspecific radiographic findings make pulmonary PTLD difficult to distinguish from other more common causes of pulmonary disease in AML patients. Case presentation Here, we describe a 68-year-old Caucasian man who presented for salvage induction therapy following relapse of his AML after a haploidentical allogeneic HSCT 10 months earlier. He developed recurrent fevers, dry cough, and hypoxemia, with chest computed tomography (CT) showing bibasilar consolidations and increased nodularity without increased lymphadenopathy. His symptoms initially improved with antibiotic and antifungal therapy, but his follow-up chest CT showed progression of disease despite symptomatic improvement. Epstein–Barr virus (EBV) was detected in his blood by polymerase chain reaction (PCR), and a lung biopsy revealed monomorphic PTLD with B cells positive for EBV. Unfortunately, the patient’s condition rapidly deteriorated, and he passed away prior to treatment initiation. Conclusions To our knowledge, this is the first reported case of an AML patient developing pulmonary PTLD relatively late in his post-transplant course in the setting of relapsed disease and salvage therapy. Pulmonary PTLD, a rare but highly lethal disorder, can imitate the symptoms and radiographic findings of pneumonia, a common diagnosis in immunocompromised AML patients. This case illustrates the importance of considering pulmonary PTLD in the differential diagnosis for pulmonary disease in AML patients with a history of HSCT, especially in the setting of progressive radiographic findings despite broad antibacterial and antifungal therapy. Further, our case demonstrates the importance of biopsy and uninterrupted EBV DNA monitoring in the definitive diagnosis of PTLD, given nonspecific symptomatology and radiographic findings.

Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

Objectives We sought to examine the natural history of geriatric assessment (GA) and quality of life (QOL) domains among adults age ≥ 50 years undergoing autologous hematopoietic cell transplantation (autoHCT). Materials and Methods A QOL tool and cancer-specific GA were completed before autoHCT in patients ≥50 years, and at 100 days, six months, and one year post-transplant. Results One hundred eighty-four patients completed the pre-transplant QOL/GA assessment, 169 (92%) completed the 100-day assessment, 162 (88%) completed the six-month assessment, and 145 (79%) completed the twelve-month assessment. Functional status, as measured by instrumental activities of daily living (IADL), decreased from baseline to day 101 (mean change −0.42 points, 95% CI, −0.75 to −0.09, p = 0.01) but returned to baseline by one year. Physical function as measured by Medical Outcomes Study-Physical Health (MOS-PH) increased by mean of 3.27 points (95% CI, −0.02 to 6.56, p = 0.05) by one year. Physician-rated KPS improved by one year, but patient-rated KPS did not. No QOL metric deteriorated from baseline. Baseline factors predictive of IADL and MOS-PH as measured over time included comorbidities and disease status at transplant. IADL and MOS-PH as measured over time were not significantly associated with age. Conclusions AutoHCT for adults age ≥ 50 years resulted in an initial decrease in functional status, with subsequent improvement back to baseline by one year. Physical health and QOL measures were improved or unchanged over time. AutoHCT is well tolerated in well selected older patients, using patient reported geriatric metrics as outcomes.

Allogeneic hematopoietic cell transplantation (alloHCT) has been increasingly offered to older adults with hematologic malignancies. However, optimal methods to determine fitness for alloHCT have yet to be defined. We evaluated the ability of a comprehensive geriatric assessment (CGA) to predict post-alloHCT outcomes in a single-center prospective cohort study of patients age 50 years and older. Outcomes included overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM). A total of 148 patients were included, with a median age of 62 years (range, 50 to 76 years). In multivariate regression analysis, several CGA measures of functional status were predictive of post-alloHCT outcomes, after adjusting for traditional prognostic factors. Any deficit in instrumental activities of daily living (IADL) was associated with inferior OS (hazard ratio [HR], 1.81, 95% confidence interval [CI], 1.07 to 3.08; P = .03) and PFS (HR, 1.85; 95% CI, 1.15 to 2.99; P = .01). A Medical Outcomes Study Physical Health scale (MOS-PH) score

Long-term disease-free survival in adults with T-cell acute lymphoblastic leukemia (T-ALL) remains poor, particularly after relapse, with few available salvage options. Preclinical data suggest that inhibition of the antiapoptotic protein BCL-2 (B-cell lymphoma 2) either alone or in combination with other agents, may be a unique therapeutic approach for the treatment of T-ALL. We present a case of a young male with T-ALL, relapsed after allogeneic hematopoietic stem cell transplant, who achieved a second complete remission following salvage therapy with combined venetoclax and decitabine. Assessment of measurable residual disease by next generation sequencing showed no evidence of residual disease of a sensitivity of 1 × 10−6. While the combination of venetoclax and hypomethylating agents has shown promise in the treatment of relapsed/refractory AML, and to our knowledge, this is the first report of this combination demonstrating clinical activity in relapsed/refractory T-ALL.

Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1.We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up.Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment.In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Introduction: The combination of a DNA methyltransferase inhibitor (DNMTi; parenteral azacitidine or decitabine) with the BCL2 inhibitor venetoclax is a newly established standard-of-care regimen for patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive induction chemotherapy (DiNardo et al, 2020). Replacing the parenteral DNMTi with an oral DNMTi with equivalent exposure may provide the benefit of reducing patient and caregiver burden of chronic parenteral therapy, and may help responding patients stay on treatment longer. ASTX727 (a fixed-dose combination of decitabine 35 mg and cedazuridine 100 mg) is an oral DNMTi that provides equivalent exposure to its parenteral DNMTi at standard dosing (Savona et al, 2020) and is under evaluation in combination with venetoclax as an all-oral regimen. Methods: This is an ongoing Phase 1 study being conducted at 7 US medical centers (ClinicalTrials.gov NCT04657081). Newly diagnosed AML patients 75 years or older, or with comorbidities that preclude use of intensive induction chemotherapy are eligible. The primary objective is to evaluate the effect of ASTX727 on the PK of venetoclax. Key secondary objectives are to evaluate the effect of venetoclax on the PK of ASTX727, and to determine the safety and efficacy profile for the combination. For Cycle 2 and beyond, ASTX727 is administered orally daily on days 1-5 and venetoclax 400 mg is administered orally daily on days 1-28 of 28-day cycles. For Cycle 1, ASTX727 is given in the same dose schedule while venetoclax is given as a ramp-up on days 1 and 2 according to the venetoclax US prescribing information (USPI); therefore, the PK studies are conducted during Cycle 2. Delay of subsequent cycles and venetoclax dose modifications for hematologic toxicities and anti-fungal concomitant medications follow the venetoclax USPI. Response assessments are evaluated using the 2017 ELN criteria (Döhner et al, 2017) and the CRh criterion (complete response [CR] with partial hematologic recovery) defined as those patients achieving marrow CR criteria but not peripheral blood count criteria and demonstrating an absolute neutrophil count >500/μL and platelet >50,000/μL (Kantarjian et al, 2017). Results: At the data cut-off date of August 1, 2021, 15 AML patients have enrolled and received study treatment. Median age is 78 years (range 66 - 84) and 9 (60%) are males. Of the 12 patients with data, 2 (17%), 6 (50%), and 4 (33%) patients are in the favorable, intermediate, and adverse risk ELN categories, respectively. Of the 15 dosed patients, 6 (40%) are diagnosed with AML with myelodysplasia-related changes. The median duration of exposure is 2 cycles (range 1-5) and 1.7 months (range 0.8-5.6). The most common adverse events (AEs) of Grade 2 or higher occurring in ≥10% of patients include neutropenia (5, 33%), febrile neutropenia (2, 13%), anemia (2, 13%), thrombocytopenia (2, 13%), vomiting (2, 13%), pneumonia (2, 13%), peripheral edema (2, 13%), hypertension (2, 13%) and vascular access complication (2, 13%). There are 17 serious AEs experienced in 7 patients; a grade 3 pneumonia and a grade 3 dysphagia are the only serious AEs assessed as related to ASTX727 and/or venetoclax and both events occurred in the same patient. Both AEs were part of the patient's medical history. Two deaths have occurred to date: one patient due to rapidly progressive disease during Cycle 2 and one patient who achieved a best response of CRh transitioned to hospice due to progressive multiple myeloma. Of 9 patients with response assessments and evaluable data, 3 (33%) achieved CR and 4 (44%) achieved CRh as the best response for a composite CR+CRh rate of 78%. Preliminary PK data available from 9 patients show venetoclax exposures are not affected by coadministration of ASTX727and are similar to historical data. Exposures of decitabine and cedazuridine are consistent with the range seen in previous studies. Updated PK, safety, and efficacy data will be provided in December 2021. Conclusions: A preliminary analysis of ASTX727 and venetoclax combination therapy in patients with newly diagnosed AML unfit for intensive induction chemotherapy demonstrate expected PK data, and a similar safety and efficacy profile to the approved combination therapy of a DNMTi and venetoclax. These preliminary data suggest that an all-oral regimen of a DNMTi in combination with venetoclax is feasible and should be investigated further. Disclosures Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Griffiths: Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Genentech: Research Funding; Abbvie: Consultancy, Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: 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; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Roboz: MEI Pharma - IDMC Chair: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Agios: Consultancy; Janssen: Consultancy; Astex: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Research Funding; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Mesoblast: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Dillingham: Astex Pharmaceuticals, Inc.: Current Employment. Wason: Astex Pharmaceuticals, Inc.: Current Employment. Zhu: Astex Pharmaceuticals, Inc.: Current Employment. Chan: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Oganesian: Astex Pharmaceuticals, Inc.: Current Employment. Dao: Astex Pharmaceuticals, Inc.: Current Employment. DiNardo: AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. OffLabel Disclosure: 1. Inqovi (35 mg decitabine and 100 mg cedazuridine) is a prescription medicine approved in the United States to treat adults with myelodysplastic syndromes and chronic myelomonocytic leukemia. In this study, Inqovi is referred as ASTX727 due to the off-label investigational use in combination with venetoclax in adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. 2. Venclexta is a prescription medicine approved in the United States for: 1) adults with chronic lymphocytic leukemia or small lymphocytic lymphoma; 2) adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine, or low-dose cytarabine. In this study, Venclexta is referred as venetoclax due to the off-label investigational use in combination with ASTX727 in adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Introduction: CPX-351 (United States: Vyxeos ®; Europe: Vyxeos ® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults and pediatric patients aged ≥1 year in the United States and in adults in the European Union. In a phase 3 study in adults aged 60 to 75 years with newly diagnosed high-risk/secondary AML, after 5 years of follow-up CPX-351 significantly improved median overall survival and remission rates versus conventional 7+3 cytarabine/daunorubicin, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the BCL-2 inhibitor venetoclax (VEN). Interim results from the V-FAST (Vyxeos - First Phase Assessment with Targeted Agents) study have demonstrated the safety and preliminary efficacy of CPX-351 in combination with VEN or midostaurin. Herein, we report the preliminary results of a subgroup analysis of adults with newly diagnosed AML treated with CPX-351 + VEN, based on age, to provide insights into the tolerability of this novel combination in younger versus older adults with AML. Methods: V-FAST is an ongoing, open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (venetoclax, midostaurin, enasidenib). Each combination arm had a dose-exploration phase (3+3 design; n ≤12) and a subsequent expansion phase (n = 20) to determine the recommended phase 2 dose (RP2D), safety, and initial efficacy of that treatment combination. Eligible patients included adults aged 18 to ≤75 years with newly diagnosed AML who were deemed fit for intensive chemotherapy and had an ECOG performance status of 0 to 2. Patients assigned to treatment with CPX-351 + VEN were to have wild type FLT3 and IDH2 based on molecular testing. The RP2D of this treatment arm was determined to be dose level 1, in which patients received CPX-351 100 units/m 2 (daunorubicin 44 mg/m 2 + cytarabine 100 mg/m 2) on Days 1, 3, and 5 + VEN 400 mg on Days 1 to 14 of the first induction. At this dose level, 1 of 6 patients in the dose-exploration phase experienced 2 dose-limiting toxicities (grade 4 neutropenia [Day 16] and grade 4 thrombocytopenia [Day 18]) that extended beyond 49 days; no dose adjustments were required and the study enrolled an additional 21 patients at this dose level. For this subgroup analysis, patients were grouped by age: 18 to ≤59 years (younger) and 60 to ≤75 years (older). Results: A total of 21 patients received CPX-351 + VEN and had sufficient data to be included in the analysis, comprising 14 patients aged 18 to ≤59 years and 7 patients aged 60 to ≤75 years. Patient baseline characteristics are shown in Table 1. The most common TEAEs of any grade in younger adults were neutropenia, febrile neutropenia, and constipation; the most common TEAEs in older adults were febrile neutropenia, thrombocytopenia, and nausea (Table 2). The most common grade ≥3 TEAEs in both age groups included febrile neutropenia, thrombocytopenia, neutropenia, and leukopenia (Table 2). TEAEs categorized as serious events included febrile neutropenia (n = 3 [younger]; n = 1 [older]), sepsis (n = 2 [younger]), ischemic stroke (n = 1 [older]), skin infection (n = 1 [older]), and AML (n = 1 [younger]). Six evaluable patients in the younger age group and 1 in the older age group died during the study due to primary causes of relapse/progression (n = 4), adverse event (n = 2), and other (n = 1; sepsis and multiorgan failure after early termination from treatment). Median platelet and neutrophil recovery times were similar between age groups (Table 3) and consistent with the previously reported safety profile of CPX-351 monotherapy. Complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) evaluable younger adults and 4/6 (67%) evaluable older adults, including 5/14 (36%) and 3/6 (50%) who achieved CR. Conclusions: This analysis of preliminary results by age group from the V-FAST study supports the conclusion that the combination of CPX-351 + VEN is equally feasible with a manageable safety profile in both younger and older adult patients with newly diagnosed AML. Promising remission rates were also reported for both age groups. Figure 1 Figure 1. Disclosures Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Levis: Astellas and FujiFilm: Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Strickland: Sunesis: Research Funding; AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Faderl: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chakravarthy: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chandrasekaran: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Erba: AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, and PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Covance (AbbVie): Other: Independent Review Committee . OffLabel Disclosure: combination of CPX-351 [Vyxeos] and venetoclax in adults with previously untreated AML

Background: The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML. Methods: Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression. Results: 82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS. There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10). Conclusions: Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. Figure 1 Figure 1. Disclosures Mannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

Context: Magrolimab, an anti-CD47 antibody, induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing prophagocytic “eat me” signals. Magrolimab + AZA is clinically effective in acute myeloid leukemia (AML) and myelodysplastic syndrome. Objective: To report Phase 1b data of magrolimab + AZA in untreated AML. Design: This is an open-label, nonrandomized, Phase 1b, interventional study. Interventions: Patients received a magrolimab priming/intrapatient dose-escalation regimen (1–30 mg/kg intravenous weekly followed by 30 mg/kg every 2 weeks in cycle 3 and beyond) and AZA (75 mg/m2 on days 1–7 on a 28-day cycle). Patients or Other Participants: Treatment-naive AML patients unfit for intensive chemotherapy. Main Outcomes Measures: Outcome measures included the percentage of patients with adverse events (AEs), objective response (OR), time to response, and duration of response. Results: Fifty-two patients were treated with magrolimab + AZA. Overall, 64% had poor-risk cytogenetics, and 65% had TP53 mutations. Magrolimab + AZA was well tolerated with a safety profile similar to AZA monotherapy. Treatment-related AEs (≥15% of patients) were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%). On-target anemia was generally transient and reversible, and no immune-related AEs associated with magrolimab were observed. Of 34 patients evaluable for efficacy, 22 (65%) achieved an OR, 15 (44%) achieved complete response (CR), 4 (12%) with CR with incomplete count recovery (CRi), 1 (3%) with partial response, 2 (6%) with morphological leukemia-free state (MLFS), 11 (32%) with stable disease (SD), and 1 (3%) with progressive disease (PD). Time to response was 2.04 months. In TP53-mutant patients, 15/21 (71%) achieved an OR, 10 (48%) achieved a CR, 4 (19%) with CRi, 1 (5%) with MLFS, 5 (24%) with SD, and 1 (5%) with PD. The median overall survival for TP53-mutant patients (n=34) and TP53–wild-type patients (n=16) was 12.9 and 18.9 months, respectively, with a median follow-up of 4 and 12 months, respectively. Conclusions: Magrolimab + AZA was well tolerated, with efficacy in both TP53-mutant and TP53–wild-type AML patients. A Phase 3 trial evaluating magrolimab + AZA in untreated TP53-mutant AML patients is planned (NCT04778397).

A 33-year-old woman with a 2-year history of documented human immunodeficiency virus (HIV) infection presented to the emergency room at San Francisco General Hospital with a new-onset seizure disor...

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT02074839","term_id":"NCT02074839"}}NCT02074839.

Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.

e19005 Background: CALGB 10403 is a pediatric-inspired ALL regimen that has recently been shown to have improved survival rates in adolescents and young adults with ALL when compared to historical outcomes with traditional adult ALL regimens (Stock et. al, 2019). Methods: This is a retrospective cohort study of ALL patients who received induction CALGB 10403 at Stanford University (both on and off trial), achieved CR1, and subsequently relapsed. Primary outcome of interest was event free survival from time of diagnosis. Events were defined as relapse or death. Secondary outcomes were overall survival and event free survival from first relapse. Patients were censored at time of last clinical follow up. Results: 25 patients met inclusion criteria and received front-line CALGB 10403 from April 2010 to September 2018. At the time of initial diagnosis median age was 30 years (range 18 – 39 years). 68% of patients were male. 48% of patients were overweight and 40% were obese. 76% of patients had precursor B cell ALL while 24% had T cell ALL. 12% had CNS disease at diagnosis. 36% of patients had WBC greater than 30k. 12% of patients had CRLF2 rearrangement. 12% of patients were MRD positive after first induction. 20% of patients received rituximab. Median event free survival time from diagnosis was 20 months (range 3 – 79 months) and median overall survival time was 53 months. Blinatumomab was the most common salvage therapy after 1st relapse, followed by inotuzumab. 15 patients (60%) achieved CR2, of which 4 (27%) were MRD positive after 2nd induction. 15 patients (60%) went to HSCT. Of the patients who achieved CR2, 8 relapsed for a second time. Median event free survival time after first relapse was 23 months. Survival 1 year after relapse was 60%. 11 of the 25 patients were alive at last follow up. Median follow up time of survivors was 6 years. Conclusions: This is a descriptive retrospective cohort study of adult patients in a real world setting who received CALGB 10403 induction and subsequently relapsed. Compared to other studies of relapsed ALL patients who were induced with traditional chemotherapy (Fielding et. al, 2007), survival 1 year after relapse was much higher (60% vs. 22%). As CALGB 10403 becomes an increasingly common induction regimen for AYA and adults with ALL, further outcomes study is required.[Table: see text]

Introduction Older adults with AML are often ineligible for high intensity chemotherapy and potentially curative allogeneic hematopoietic cell transplantation (HCT) due to poor performance status at presentation, comorbidities, and/or adverse genetic features associated with refractory disease and chemoresistance. Recently, the lower intensity combination of a hypomethylating agent and venetoclax (HMA/Ven) was shown to achieve durable responses in patients with AML. Despite this combination having been studied primarily in older, transplant-ineligible adults, a small subset of patients on the Phase 1b trial were successfully bridged to HCT (Pratz et al, 2019). We conducted a multi-center analysis assessing patient characteristics and clinical outcomes of patients treated with HMA/Ven who subsequently proceeded to HCT. Methods We retrospectively identified 51 adults who received HMA/Ven in either the front-line or relapsed/refractory (R/R) setting and underwent subsequent HCT between 2017 - 2019 at Stanford University, the University of California, San Francisco, and the University of California, Los Angeles. Patients received either azacitidine or decitabine in combination with venetoclax. Patients were evaluated for efficacy endpoints including: best response prior to HCT (complete remission [CR], CR with incomplete hematologic recovery [CRi], morphologic leukemia-free state [MLFS]), measurable residual disease (MRD) prior to HCT by flow cytometry (sensitivity threshold ≤1x10-4), and post-HCT relapse and survival. Results The median age at HCT was 65.5 years (24 - 76). Fifty-three percent of patients had a KPS of ≤ 80, and 29% had an HCT-CI of ³ 3. Fifty-seven percent had adverse-risk disease by 2017 European Leukemia Net criteria. The majority (63%) received decitabine; 23 (45%) received HMA/Ven as front-line induction and 28 (55%) for R/R disease. Compared to patients with R/R disease, patients who received front-line HMA/Ven were more likely to be older (67 vs 54 years, p = 0.003) and have a KPS ≤ 80 (65% vs 47%, p = 0.03). Patients with R/R disease had a median of 2 (1 - 4) lines of therapy prior to receiving HMA/Ven and 2 patients had undergone prior HCT. The number of HMA/Ven cycles prior to HCT varied considerably, with a median of 3 (1 - 11). The majority (78%) of patients achieved a complete remission prior to HCT. Of the patients who received front-line HMA/Ven, 83% achieved CR, 13% CRi, and 4% MLFS; 17 (74%) patients had a pre-HCT MRD assessment, of which 71% were MRD-negative. Of the patients who received HMA/Ven for R/R disease, 41% achieved CR, 22% CRi, 33% MLFS, and 4% had refractory disease; 24 (86%) of patients had a pre-HCT MRD assessment, of which 54% were MRD-negative. Across the full cohort, 49% of patients received non-myeloablative, 35% myeloablative, and 16% reduced intensity conditioning. The majority (94%) of patients received peripheral blood stem cell grafts; donor sources were 35% HLA-matched related, 43% HLA-matched unrelated, and 22% haploidentical. Following HCT, 100-day non-relapse mortality was 4%, 6-month overall survival (OS) was 85% and 6-month relapse-free survival (RFS) was 63%. Among patients who received front-line HMA/Ven, 6-month OS was 88% and 6-month RFS was 80%; among patients with R/R disease, 6-month OS was 81% and 6-month RFS was 51%. Patients who were MRD-negative had a 6-month OS of 87% and RFS of 75%; MRD-positive patients had 6-month OS of 73% and RFS of 46%. Among the 27 patients transplanted prior to July 1, 2019, 1-year OS and RFS were 78% and 59% for the entire cohort, 90% and 80% for the 10 patients receiving frontline HMA/Ven, and 71% and 47% for the 17 patients with R/R disease. Conclusion In patients with AML, an HMA in combination with venetoclax can achieve complete remissions-MRD-negative in many cases-thus providing a viable pathway to potentially curative HCT. This treatment pathway is especially important in older/unfit patients receiving front-line HMA/Ven due to ineligibility for high intensity induction chemotherapy, as well as those with relapsed/refractory and previously chemoresistant disease. Following HCT, patients treated in both settings had low NRM and favorable rates of disease response. Prospective studies are warranted to further explore the optimal use of HMA/Ven therapy as a bridge to successful transplant outcomes. Disclosures Muffly: Amgen: Consultancy; Adaptive: Research Funding; Servier: Research Funding. Logan:Abbvie: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Amphivena: Research Funding; Autolus: Research Funding; Jazz: Research Funding; Kadmon: Research Funding; Kite: Research Funding; Pharmacyclics: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post-transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1.

Although the use of geriatric assessment (GA) in the allogeneic hematopoietic cell transplantation (HCT) setting has been reported, few studies have evaluated the impact of patient-reported function on autologous HCT (autoHCT) outcomes. In this study, GA, including the administration of Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) quality of life tool, was performed in 184 patients age ≥50 years (median age, 61 years; range, 50 to 75 years) before autoHCT. Associations among GA findings, quality of life metrics, and post-transplantation outcomes were evaluated using Cox regression. Indications for autoHCT included multiple myeloma (73%), non-Hodgkin lymphoma (20%), and other disorders (7%). The median progression-free survival (PFS) was 28 months, whereas the median overall survival (OS) was not reached. In unadjusted analysis, both PFS and OS were significantly associated with 5 GA components: limitation in instrumental activities of daily living, patient-reported Karnofsky Performance Status (KPS), and the Physical, Functional, and BMT subscale scores of the FACT-BMT. In multivariate analysis, 3 components—limitation in instrumental activities of daily living, patient-reported KPS, and FACT-BMT Physical subscale—remained predictive of both PFS and OS when adjusted for age, provider-reported KPS, disease status, and HCT comorbidity index. In older adults undergoing autoHCT, limitation in any 1 of 3 patient-reported measures of functional status was independently associated with inferior PFS and OS, even after adjusting for known prognostic factors.

Background. The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention. Methods. To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX). Results. We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 Conclusion. Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

We report here the largest study to date of adult patients with acute myeloid leukemia (AML) tested for measurable residual disease (MRD) at the time of autologous hematopoietic cell transplantation (auto-HCT). Seventy-two adult patients who underwent transplantation between 2004 and 2013 at a single academic medical center (University of California San Francisco) were eligible for this retrospective study based on availability of cryopreserved granulocyte colony–stimulating factor (GCSF)–mobilized autologous peripheral blood progenitor cell (PBPC) leukapheresis specimens ("autografts"). Autograft MRD was assessed by molecular methods (real-time quantitative PCR [RQ-PCR] for Wilms tumor 1 (WT1) alone or a multigene panel) and by multiparameter flow cytometry (MPFC). WT1 RQ-PCR testing of the autograft had low sensitivity for relapse prediction (14%) and a negative predictive value of 51%. MPFC failed to identify MRD in any of 34 autografts tested. Combinations of molecular MRD assays, however, improved prediction of post–auto-HCT relapse. In multivariate analysis of clinical variables, including age, gender, race, cytogenetic risk category, and CD34+ cell dose, only autograft multigene MRD as assessed by RQ-PCR was statistically significantly associated with relapse. One year after transplantation, only 28% patients with detectable autograft MRD were relapse free, compared with 67% in the MRD-negative cohort. Multigene MRD, while an improvement on other methods tested, was however suboptimal for relapse prediction in unselected patients, with specificity of 83% and sensitivity of 46%. In patients with known chromosomal abnormalities or mutations, however, better predictive value was observed with no relapses observed in MRD-negative patients in the first year after auto-HCT compared with 83% incidence of relapse in the MRD-positive patients (hazard ratio, 12.45; P = .0016). In summary, increased personalization of MRD monitoring by use of a multigene panel improved the ability to risk stratify patients for post–auto-HCT relapse. WT1 RQ-PCR and flow cytometric assessment for AML MRD in autograft samples had limited value for predicting relapse after auto-HCT. We demonstrate that cryopreserved autograft material presents unique challenges for AML MRD testing because of the masking effects of previous GCSF exposure on gene expression and flow cytometry signatures. In the absence of information regarding diagnostic characteristics, sources other than GCSF-stimulated PBSC leukapheresis specimens should be considered as alternatives for MRD testing in AML patients undergoing auto-HCT.

Intensification of therapy for adults with ALL using pediatric regimens with intensive asparagine depletion is feasible. Targeted therapies are improving outcomes. We hypothesized that the UCSF 8707 regimen (Linker et al.JCO 2002;20:2462) could be safely intensified with the addition of pegylated asparaginase (peg asp), cyclophosphamide, rituximab, dasatinib, and intrathecal liposomal cytarabine. Methods: Patients (pts) enrolled at 4 centers. The primary objective was 3-year (yr) EFS (goal >55%). Eligible pts were age 18-60 yrs with untreated ALL or LBL. Treatment consisted of induction Course 1A (C1A): daunorubicin 60 mg/m2 IV d1-3, vincristine (VCR) 1.4 mg/m2 (2 mg if age >50 yrs) IV day 1,8,15,22, prednisone 60 mg/m2 orally (PO) d1-28, peg-asp 2,000 IU/m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d15, cyclophosphamide 750 mg/m2 IV d1,15 (or 500 mg/m2 IV q12h d15,16 if d14 marrow M2 or M3). ALL pts in CR/CRi and LBL pts in CR or PR proceeded to post-remission Course 1B (C1B): methotrexate (MTX) 220 mg/m2 IV bolus then 60 mg/m2/hr CIV for 36 hrs d1,15 with leucovorin rescue, 6-mercaptopurine (6-MP) 60 mg/m2 PO d1-7, 15-21, peg-asp 2,000 IU/ m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d16. Course 1C (C1C) consisted of cytarabine 2,000 mg/m2 IV d1-4 and etoposide 500 mg/m2 IV d1-4. Courses A-C repeated once then a third course B given. Maintenance POMP (6-MP 60 mg/m2 PO daily, VCR 1.4 mg/m2 (2 mg age >50 yrs) IV monthly, MTX 20 mg/m2 PO weekly, prednisone 60 mg/m2 PO d1-5) repeated monthly for 12 months then POMP with every other month VCR and prednisone for 12 months. Peg asp was given d16 of maintenance month 1. If B-ALL (+/- CD20 expression), rituximab 375 mg/m2 IV was given every 2 weeks for 8 doses starting day 1 of C1A. If Ph+ ALL, dasatinib 140 mg PO daily was given but held during high-dose MTX then restarted when serum [MTX] was Results: Between 4/2014 and 2/2017, 31 pts enrolled and 29 were eligible. Median age was 28 yrs (20-54), 62% were male, 52% were Hispanic, and 86% had ALL. The end induction ORR (CR + PR) was 90% (2 ALL with PR, 1 early death). ORR for LBL was 100% (n= 4). The CR rate for ALL was 88%. For Ph- B-ALL (n=16), the CR rate was 86% with MRD 0.1%. Five pts underwent allogeneic HCT in first CR to study therapy. With a median follow up of 32 months (16-44), the 2- and 3-yr EFS were 59%. EFS was similar for B-ALL, T- ALL, LBL, Ph- B-ALL, and Ph+ B-ALL. Five pts relapsed. The 2- and 3-yr RFS were 66%. Concomitant marrow and CNS relapse occurred in 1 pt. No isolated CNS relapses occurred. Transplant-censored 2- and 3-yr OS were 80% and 72%. Uncensored 2- and 3-yr OS were 75% and 70%. Among eligible pts, 8 died: 4 after relapse, 1 in induction from infection, 2 in CR from infection, and 1 from allogeneic HCT complications. Three reversible grade 3-4 events were attributed to liposomal cytarabine, all grade 3: syncope, pseudotumor cerebri, and headache. Grade 3-5 possible peg asp toxicities were transaminitis (58%), hyperbilirubinemia (42%), hyperglycemia (29%), hypertriglyceridemia (26%), elevated GGT/alkaline phosphatase (19%), thrombosis (19%, 1 cerebral venous), hypoalbuminemia (10%), hypersensitivity (6.5%), elevated lipase (6.5%), pancreatitis (3.2%), encephalopathy (3.2%), and avascular necrosis (3.2%). One pt died from encephalopathy. Conclusions: Intensification of UCSF 8707 is feasible and effective. Post-induction remissions were deep with high MRD-negativity rates. EFS, RFS, and OS are favorable with follow up and accrual ongoing (NCT02043587). Strategies to limit peg asp toxicity are needed. Disclosures Wieduwilt: Amgen: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Leadiant: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees. Curtin:Amgen: Research Funding; Onconova: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Andreadis:Genentech: Consultancy, Employment; Bayer: Consultancy; Astellas: Consultancy; Gilead: Consultancy; Juno: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Damon:Actelion: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Novartis: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company.

Introduction Decitabine and hypomethylating agents are considered non-curative treatments for patients with acute myeloid leukemia (AML) and are a standard approach for those patients not fit for intensive induction chemotherapy, usually due to age and multiple comorbidities. A phase 2 study reported a better overall response rate of 64% with a 10-day schedule of decitabine (Blum, Garzon et al. 2010). A second study reported on a higher rate of response among patients with TP53 mutations (Welch, Petti et al. 2016). However, these responses were not considered durable with median duration of response of about 11 months. We herein describe four patients with longer than expected response duration to decitabine, two of which were able to discontinue therapy with sustained multi-year remission and an apparent cure of their AML. Methods We sought to evaluate the clinical and pathological characteristics of patients with a particular long-term response to decitabine. We screened patients at two institutions who have been in complete remission (CR) for greater than 2 years with single-agent decitabine therapy. Current efforts are on-going to identify patients from five other institutions that also meet these criteria and will be added for the final presentation of this data. Results Four patients have been identified who have experienced CR for over 2 years with average age at diagnosis of 70 years (range 60-76). Three patients had cytogenetically normal (CN) AML and one had core-binding factor (CBF) with t(8;21). Time to treatment response for CR was as follows: 2 patients required 2 cycles, 1 required 1 cycle, and 1 required 4 cycles of decitabine. Two CN patients received 27 cycles of decitabine in total before therapy discontinuation because of trial termination [1]. One patient has remained in CR for 4 years while the second CR lasted for 8 years after cessation of therapy. Both patients were lost to follow-up after those time periods. The other CN patient remains in CR and continues on therapy (30 cycles). The CBF patient relapsed after 28 cycles of therapy and unfortunately succumbed to complications of relapsed AML. Molecular testing was performed on 2 of 4 patients as listed in Table 1 with no clear correlation to outcomes with this limited number of patients. Discussion Currently, the only acceptable long-term cure for patients with AML is intensive induction followed by consolidation with high-dose chemotherapy or allogeneic stem cell transplant. Elderly patients and patients with multiple comorbid conditions are not candidates for this aggressive approach. Here we present 4 patients with prolonged responses to 10-day decitabine induction therapy with 2 patients who appear to be cured of their AML with this approach. Further study is warranted to better characterize these super-responders and determine if there is a particular subpopulation of patients with AML that can achieve long-term survival without the perils of intensive chemotherapy or stem-cell transplantation. Disclosures Mannis: NKarta: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mims:Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations are seen in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for mIDH1 AML. Ivosidenib suppresses production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To determine the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in the first-in-human, phase 1, dose escalation and expansion study of patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Enrollment completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. MTD was not reached; 500 mg QD was selected as the dose for expansion cohorts. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present data for all patients with untreated AML whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 34 patients with untreated AML (9 from dose escalation, 25 from expansion) who received ivosidenib 500 mg QD. Baseline characteristics for these 34 patients were: 19 male/15 female with median age 76.5 years (range 64-87); 56% were ≥75 years of age; 79% had secondary AML and 53% had prior MDS; 41% had ≥1 hypomethylating agent for antecedent hematologic disorder. As of 10Nov2017, 9 of 34 (26.5%) patients remained on treatment. Three (8.8%) patients discontinued treatment for allogeneic stem cell transplantation. Median duration of exposure to ivosidenib was 4.3 months (range 0.3-29.1). Treatment was well tolerated; the most common adverse events (AEs) (n=34) of any grade, irrespective of causality, occurring in ≥20% of patients were diarrhea (50.0%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), peripheral edema (26.5%), dyspnea (23.5%), thrombocytopenia (23.5%), hypomagnesemia (23.5%), constipation (20.6%), dizziness (20.6%), and insomnia (20.6%). The majority of AEs were grade 1-2 and reported as unrelated to treatment. IDH differentiation syndrome (IDH-DS) was seen in 6 of 34 (17.6%) patients, and was grade ≥3 in 3 (8.8%); ivosidenib was held due to IDH-DS in 3 patients (8.8%), but IDH-DS did not lead to permanent treatment discontinuation or death. CR rate was 26.5% (95% CI 12.9%, 44.4%), CR+CRh rate was 41.2% (95% CI 24.6%, 59.3%), and ORR 58.8% (95% CI 40.7%, 75.4%; 20/34 patients). Median durations of CR, CR+CRh, and overall response were not estimable (lower bound of 95% CI 4.2, 6.5, and 4.2 months, respectively); 12-month durations of response were 75.0%, 56.4%, and 54.3%, respectively. Of patients who were transfusion dependent at baseline, 38.1% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 23 patients with untreated AML in expansion: IDH1 mutation clearance was seen in 6 of 11 patients who achieved CR+CRh, including 3 of 7 patients with CR and 3 of 4 with CRh. The relationship between baseline co-occurring mutations and response will be presented. CONCLUSION: Ivosidenib monotherapy was well tolerated in patients with untreated mIDH1 AML, and induced durable remissions and transfusion independence in a molecularly defined, poor prognosis, elderly patient population with high rates of secondary AML, and prior hypomethylating agent exposure. These results support the role of ivosidenib as an effective, oral, targeted treatment for patients with untreated mIDH1 AML who are not eligible for intensive chemotherapy. Disclosures Roboz: Argenx: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Stein:Agios: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Mims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Altman:Pfizer: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; FujiFilm: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celator: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work. Arellano:Cephalon: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Pollyea:Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Tallman:AbbVie: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding. Choe:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership. Stone:Merck: Consultancy; Cornerstone: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Ono: Consultancy; Fujifilm: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Jazz: Consultancy; Astellas: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Sumitomo: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; Pfizer: Consultancy.

Introduction The challenges posed by the increasing incidence of hematologic malignancies in older patients are significant and while during the past 20 years there has been a dramatic expansion in the therapeutic armamentarium against hematologic malignancies, there is a need for data to guide treatment decisions for older adults, particularly with respect to the use of novel targeted or immunotherapeutic agents. To a large extent, this is a consequence of the under-representation of this growing demographic in cancer-related clinical trials. Management of primary CNS lymphoma (PCNSL) in patients age ≥ 70 years represents a significant problem. While it is established that older PCNSL patients benefit from high-dose methotrexate-based induction regimens, whole brain irradiation consolidation is not a favored option because of excessive neurotoxicity. While there is evidence that high‐dose chemotherapy improves outcomes in patients age < 70, dose‐intensive chemotherapy is not an option for most older PCNSL patients. Given that the median age of PCNSL at diagnosis is ~ 60 years, determination of the optimal consolidative approach for older patients is an important question. This problem is particularly significant given that the incidence of PCNSL continues to rise in this older age group. While PCNSL increasingly appears to be a curable brain tumor, outcomes for patients age > 60 remain poor, with 1-year progression-free survival (PFS) of ~ 40% and median overall survival of 14-30 months. Population-based registry data suggests a median overall survival for PCNSL patients age > 70 of approximately 7 months over the past decade. New therapeutic approaches are needed for the particularly vulnerable older PCNSL patient population. Given the evidence for activity of low-dose lenalidomide in relapsed primary and secondary CNS lymphoma, in 2011, we began using low-dose lenalidomide as maintenance in consecutive older PCNSL patients (age ≥ 70 years, HIV negative) following standard methotrexate/rituximab-based induction, in lieu of surveillance, whole brain irradiation or high-dose chemotherapeutic consolidation. Here we report on the characteristics, outcomes, toxicities, progression-free and overall survival of the first 11 PCNSL patients, age ≥ 70, to receive lenalidomide maintenance after high-dose methotrexate-based induction at our institution. Results Eleven patients age > 70 received low-dose lenalidomide maintenance 5-10 mg/d on a 21-d cycle after induction therapy for PCNSL.Median age of the cohort is 77 years (range 70-86). Median Karnofsky performance status (KPS) is 60 (range 50-80); median IELSG prognostic risk score is 4 (range 3-5). The median methotrexate dose administered was 2.5 grams/m2 (range 0.5 - 8). With overall median follow-up of 30 months, median time on lenalidomide maintenance is 14.8 months (range 0.9 - 65.2). Two patients received lenalidomide plus maintenance rituximab, every 6 months. Median PFS is 48 months (range 16.8 - 84.8). Median OS has not been reached, and there have been no deaths (Figure 1). Four patients experienced disease progression on lenalidomide; 3 of them continued maintenance lenalidomide after salvage and 1 received maintenance pomalidomide. Lenalidomide maintenance has generally been well-tolerated. However, 5 toxicities potentially related to therapy have mandated cessation of lenalidomide: 1 grade 2 arthralgia, 1 subdural hematoma, 1 pneumonia, 1 grade 3 fatigue, 1 deep vein thrombosis. Conclusions These encouraging preliminary results of prolonged PFS and OS with low-dose lenalidomide illustrate the feasibility and challenges, as well as suggest a potential benefit of maintenance therapy with low-dose lenalidomide in older patients with PCNSL. Nine of 11 patients were able to complete at least 8 months of lenalidomide maintenance after induction therapy. Toxicities were manageable and strikingly, there have been no deaths. Recently, lenalidomide has been shown to enhance the proliferation, survival, and chemotactic responses in T-cells isolated from older subjects. This suggests a potential mechanistic basis by which low-dose lenalidomide may improve immunity in the elderly and potentiate response to chemotherapy. Future studies are needed to prospectively test the benefit and mechanisms of lenalidomide maintenance in older patients with PCNSL. Figure 1. Figure 1. Disclosures Rubenstein: Genentech: Research Funding; Celgene: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees.

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) has historically been reserved for younger, fit patients with hematologic malignancies. With the introduction of non-myeloablative conditioning regimens and improved supportive care, alloHCT has been increasingly offered to older adults. Objectives: To determine the association between functional status as measured by a cancer-specific comprehensive geriatric assessment (CGA) and post-transplant outcomes in an older alloHCT patient population. Methods: We conducted a prospective cohort study of patients aged 50 or older who underwent alloHCT at the University of California San Francisco between October 2011 and September 2017. A cancer-specific CGA (1) was administered prior to alloHCT, which included measures of functional status such as Lawton Instrumental Activities of Daily Living (IADL), Medical Outcomes Study (MOS) Physical Health scale, and patient-reported Karnofsky Performance Status (KPS). Post-transplant outcomes included length of hospital stay (LOS), non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). Results: A total of 148 patients were included in the analysis. The median age at transplant was 62 (range 50-76). Disease types included acute myeloid leukemia (43%), myelodysplastic syndrome (26%), myeloproliferative neoplasm (12%), acute lymphoblastic leukemia (10%), non-Hodgkin lymphoma (5%), multiple myeloma (1%), and other (3%); 68% received non-myeloablative conditioning. Median follow-up was 16.3 months (range 0.9-72.7 months). Median PFS and OS were 22.9 months and 47.6 months, respectively. At baseline, 39% had at least one IADL deficit, and 88% had at least one MOS Physical Health scale deficit. The mean patient-KPS was 82.4 and mean provider-KPS was 91.6; these were weakly correlated (Spearman's r=0.39, p In univariate analysis, the presence of any IADL deficit was associated with inferior PFS (HR 1.78, p=0.01) and OS (HR 1.68, p=0.04) (Figure). MOS Physical Health score was associated with increased NRM (HR 1.06 per 1-point change in 20-point scale, p=0.04), inferior OS (HR 1.05, p=0.04), increased LOS (difference 0.63 days, p=0.007), but not with PFS (HR 1.04, p=0.06). Neither patient- nor provider-KPS was associated with NRM, PFS, or OS, but lower patient-KPS was associated with increased LOS (difference 1.94 days, p=0.01). In this study, the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), disease risk by American Society for Blood and Marrow Transplantation (ASBMT) classification, and conditioning intensity were not associated with NRM, PFS, or OS. Notably, chronologic age was not associated with NRM, PFS, or OS (Figure). In addition, age was not associated with baseline IADL score (r=-0.02, p=0.26) or MOS Physical Health score (r=-0.13, p=0.06). Conclusion: IADL impairment was associated with inferior PFS and OS, supporting previous studies (2, 3) identifying IADL as an important predictor for alloHCT. In univariate analysis, IADL was a stronger predictor of post-transplant outcomes than traditional prognostication tools such as age, HCT-CI, and provider-KPS. MOS Physical Health score was associated with multiple poor outcomes including NRM and LOS, suggesting a primary impact on alloHCT toxicity. Multivariate analyses, as well as examination of other CGA variables, are ongoing. References:J Clin Oncol. 2011 Apr 1;29(10):1290-6.Haematologica. 2014 Aug;99(8):1373-9.Bone Marrow Transplant. 2018 May;53(5):565-575. Figure. Figure. Disclosures Andreadis: Genentech: Consultancy, Employment; Gilead: Consultancy; Juno: Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Logan:Napajen: Consultancy; Adaptive Biotech: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Smith:Astellas Pharma: Research Funding. Martin:Roche: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Damon:Novartis: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Actelion: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company. Olin:Synapse: Honoraria; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding.

10030Background: The optimal means of assessing fitness for AutoHCT in older adults with hematologic malignancies is unknown. Few studies have evaluated the impact of patient reported function on A...

Since the incorporation of tyrosine kinase inhibitors into the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), the notion that all patients with "high-risk" ALL uniformly require allogeneic (allo) hematopoietic cell transplantation (HCT) has received increasing scrutiny. Although multiple studies have shown superiority of alloHCT over autologous (auto) hematopoietic cell transplantation for high-risk patients, these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. We retrospectively evaluated minimal residual disease (MRD) using next-generation sequencing (NGS) in the PBPC leukapheresis product of 32 ALL patients who underwent autoHCT. Twenty-eight patients (88%) had diagnostic samples with quantifiable immunoreceptor rearrangements to follow for MRD. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Philadelphia chromosome–negative (Ph−) B-ALL, and 4 (14%) had T cell ALL. With a median follow-up of 41 months (range, 3 to 217), median relapse-free survival (RFS) and overall survival for the entire cohort were 3.2 and 4.2 years, respectively; at 5 years after transplantation, 42% of patients remain alive and relapse free. Using MRD detection at a threshold of ≥ 1 × 10−6, median RFS for patients with detectable MRD was 6.5 months and was not reached for patients without detectable disease (P = .0005). In multivariate analysis, the only factor significantly associated with relapse was the presence of MRD ≥1 × 10−6 (odds ratio, 23.8; confidence interval, 1.8 to 312.9; P = .0158). Our findings suggest that NGS for MRD detection can predict long-term RFS in patients undergoing autoHCT for high-risk ALL.

Background Despite recent advances, treatment of relapsed refractory multiple myeloma (RRMM) remains a challenge. Venetoclax, a BH3 mimetic, is an oral, specific, and potent small molecule inhibitor of BCL-2 that has been approved for treatment of 17p-deleted CLL and in combination with azacitidine or decitabine in AML patients >/= 75 years of age.Pre-clinical and clinical studies suggest that bcl-2 inhibition can induce MM cell death and may synergize with bortezomib and dexamethasone. Based on this, several prospective clinical trials of venetoclax in RRMM have been performed. However, clinical use of this targeted therapeutic for salvage therapy in RRMM has not been well described. Methods We performed a single-center, retrospective chart review of all patients with RRMM diagnosed after January 1, 2009 who were treated with off-label use of venetoclax. The goal of this study was to describe the clinical characteristics of these patients, assess the response to salvage treatment with venetoclax as determined by the International Myeloma Working Group (IMWG) criteria, and assess the toxicities during salvage treatment with venetoclax in an academic practice setting. Results 43 patients were identified. Median number of lines of prior therapy was 7 (range 2-13). 12 patients had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), t(14;20), t(4,14), gain (1q), or nonhyperdiploidy. Of the 36 patients with cytogenetics/FISH available, 8 had t(11;14). 34 patients were refractory to bortezomib. 40 patients had progressed after carfilzomib, 36 after pomalidomide, and 41 after anti-CD38 antibody therapy. 39 patients were treated with venetoclax in combination with a proteasome inhibitor (bortezomib (n=36); carfilzomib (n=3)). 23 patients were treated with venetoclax, proteasome inhibitor, and dexamethasone. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily (11 received 800 mg/daily as final dose). Overall patients were on treatment for a median of 67 days (range 2-855). 2 patients received intermittent venetoclax therapy, defined as being off venetoclax for at least 3 months before restarting. Best response by IMWG criteria include; CR 5%( 2/43), VGPR 12% (5/43) and PR 16% (7/43) for an overall response rate of 33% (14/43). In addition, MR was seen in 5% (2/43) and stable disease in 9% (4/43). Fifty-one percent (22/43) had progressive disease (PD). Out of the 8 patients who had t(11;14), best responses were: 2 VGPR, 2 PR, 1 SD, and 3 PD for a response rate of 50% (4/8) in this subgroup. Median time to best response for all responding patients was 90 days (range 15-305) and median duration of response was 206 days (range 28-820). At time of data collection, median follow-up time from venetoclax treatment initiation was 192 days (range 8-1058). Four patients have not progressed and remain on therapy, 23 patients remain alive, and 4 patients have been lost to follow-up for over 6 months. The most common treatment related AEs were cytopenias including leukopenia in 26 /43 (60%) patients, neutropenia in 19/43 (44%) patients, and thrombocytopenia in 22/43 (51%) patients. Non-hematologic toxicities included diarrhea in 12/43 (30%) patients, nausea/vomiting in 15/43 (35%) patients, infections in 11/43 (26%) patients, and fatigue in 23/43 (53%) patients. 8/43 (19%) patients required dose reduction, 7/43 (16%) patients required temporary discontinuation of treatment, and 4/43 (9%) patients required permanent discontinuation due to treatment related AEs. 38/43 (88%) patients had any grade treatment related AEs, 27/43 (63%) patients had grade >/= 3 AEs and 2/43 (5%) patients had treatment related SAEs. One patient had a treatment related death from an infectious complication (CMV pneumonitis). Conclusions Venetoclax is an active and well-tolerated agent in relapsed multiple myeloma. Furthermore, it is easily administered in the outpatient setting. Additional areas of research with this therapy include understanding the importance of t(11:14) for response and selecting the best anti-MM partner for combination therapy. Disclosures Ledergor: Venetoclax: Other: off-label use; Immunai: Consultancy. Martin: Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Wolf: Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Wong: Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Shah: Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This study is looking at the safety and efficacy of venetoclax in relapsed refractory myeloma patients who are treated off-label since venetoclax is not currently approved for multiple myeloma

7040 Background: Pts with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum HGF level is an adverse prognostic factor in AML (Verstovsek, et al. 2001; Kim, et al. 2005). Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death (Kentsis, et al. 2012). Methods: We initiated a phase I study to assess the safety and tolerability of Fi combined with Cy in patients with AML who are refractory to 7+3 or have relapsed within 1 year of induction. Fi is given in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks, starting on day 0, and Cy at a fixed dose of 2g/m2 on days 2-7, using a 3x3 design. PBMCs, BM and serum are collected at defined time points to assess HGF levels and activation of the c-Met pathway. Results: Dose escalation is complete and there were no protocol-defined DLTs identified in 9 evaluable pts. All pts treated to date were refractory to induction. Four had de novo AML; 2 had undifferentiated leukemia; 2 prior MDS; 1 prior MPN. Most frequent grade 3/4 TEAEs were febrile neutropenia (56%), LFT abnormalities (11%), and electrolyte disturbance (11%). There was 1 death (11%) from sepsis and multi-organ failure on day 23, following ANC recovery. Of the 7 evaluable pts, 3 achieved a CR (43%), all in the 2nddose cohort. Two of the 3 CRs are long lasting 11 and 12 months following AlloHCT. All patients had detectable circulating HGF levels at baseline compared to control subjects without AML. HGF levels increased following exposure to Fi by an average of 193%. Baseline HGF levels or change from baseline were not associated with treatment response. Conclusions: Ficlatuzumab can be safely combined with HiDAC in this high-risk AML population and produce durable clinical responses. Circulating HGF levels were detectable at baseline and uniformly increased with treatment suggestive of a feedback response or immune complex stabilization. Dose expansion is ongoing. Clinical trial information: NCT02109627.

e19514 Background: Despite recent advances, treatment of relapsed multiple myeloma (MM) remains a challenge. Pre-clinical studies suggest that bcl-2 inhibition can lead to MM cell death and may synergize with bortezomib. Methods: We performed a single-center, retrospective chart review of patients with relapsed MM following autologous stem cell transplantation (auto-HCT) who were treated with venetoclax, a bcl-2 inhibitor, with bortezomib. Results: 11 patients were identified. Median number of lines of prior therapy was 9 (range 5-13). 1 patient had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), or t(14;20). In the 8 patients with cytogenetics/FISH available, no patients had t(11,14). 9/11 patients were refractory to bortezomib. 11/11 patients had progressed after carfilzomib, 9/11 after pomalidomide, and 11/11 after anti-CD38 antibody therapy. In all cases, patients were treated with venetoclax in combination with bortezomib. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily. Overall patients received a median of 14.24 weeks of treatment (range 3-25.5). IMWG criteria were utilized to assess responses, including: 0/11 CR, 1/11 VGPR and 3/11 PR for an overall response rate of 36% (4/11). 1/11 had a minor response (light chain decrease by greater than 25% but less than 50%), 1/11 achieved stable disease, 5/11 had progressive disease. Median time to best response was 35 days (range 21-37) and median duration of response was 45 days (with several patients remaining on drug). All patients who responded had bortezomib-refractory disease. With median follow-up of 57 days, 4/11 patients have not progressed and 9/11 remain alive. The most common adverse effect was GI upset (bloating, nausea, vomiting, diarrhea) in 4/11 patients with no patients discontinuing due to side effects. There was no evidence of tumor lysis and there were no treatment-related deaths. Conclusions: Venetoclax is an active agent in relapsed multiple myeloma. Further efforts to study this therapy include prospective phase II trials and combination therapy with proteasome inhibitors and steroids.

Background Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML. Patients and Methods In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) μmol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion. Results Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade ≥ 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 ( P = .08). Conclusion Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 μmol/min.

A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naive patients; P

Background: Isatuximab (ISA) is an anti-CD38 mAb with potent anti-myeloma (MM) activity given alone or in combination with lenalidomide (LEN) and dexamethasone in relapsed and refractory MM (RRMM). Carfilzomib (CFL) is a second generation proteasome inhibitor approved for the treatment of RRMM. This is an initial report of safety and efficacy data from an ongoing Phase Ib dose-escalation trial combining ISA and CFL in RRMM. (clinicaltrials.gov: NCT02332850) Objectives: The primary objective is to determine the maximum tolerated dose (MTD) of ISA with standard dose CFL in RRMM. Secondary objectives include characterization of pharmacokinetics, safety (including immunogenicity) and disease response (overall response rate [ORR]; IMWG criteria). Methods: ISA is given IV every 2 weeks (Q2W), or weekly (QW) for 4 doses then Q2W in combination with standard CFL (20®27 mg/m2: Day 1, 2, 8, 9, 15, 16, every 28 days). Three ISA dosing levels (DL) have been tested: 10 mg/kg Q2W, 10 mg/kg QW x 4 then Q2W and 20 mg/kg QW x 4 then Q2W using a classic 3+3 dose escalation design based on dose-limiting toxicities. Standard premedications (dex 20 mg IV/PO, acetaminophen 650 mg, diphenhydramine 25-50 mg IV/PO and famotidine 20mg IV) were given prior to each ISA infusion. Results: Eleven patients have been treated across the 3 DL (DL1=3, DL2=3, DL3=5). Treatment disposition: 4 patients have progressed, 7 remain on therapy. This was a heavily pretreated population with a median of 4.5 prior lines of therapy (range: 2-8). All subjects had received prior LEN, 10/11 had received prior BORT and 9/11 had received prior CFL. 10/11 were refractory (refr) to their previous regimen (4 quad refr and 7/11 refr to CFL). 10 patients are evaluable for response. The ORR is 80%: 2VGPR, 6 PR, and CBR is 90% (DL1: 2PR, 1SD; DL2: 3PR; DL3:2VGPR, 1PR, 1MR). The median # of cycles given is 6 (range 1-20). No DLT's or severe adverse drug reactions have been observed. No dose reduction for ISA or CFL have been needed. The most frequent occurring non-hematologic (NH) adverse events ( occurring in ≥ 15%) at all DLs are dyspnea (45%), fatigue (45%), nausea (45%), pain (back, chest wall and pelvis; 36%), peripheral neuropathy (36%), HTN (27%), cough (27%), anorexia (27%), GERD (18%), constipation (18%), diarrhea (18%), nasal congestion (18%) and hypokalemia (18%); Conclusion: Combining ISA and CFL appears to be well tolerated; no unexpected adverse drug reactions were noted. MTD has not been reached. Encouraging anti-MM activity is reported in heavily pretreated patients with RRMM. Expanded accrual is ongoing, additional safety, pharmacokinetics and response data will be presented. (Figure 1: spider plot of % change in serum m-protein over time) Figure 1. Figure 1. Disclosures Martin: Sanofi Aventis: Research Funding; Amgen: Research Funding. Chari:Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Campana:Sanofi Aventis: Employment. Hui:Sanofi Aventis: Employment. Wolf:Pharmacyclics: Honoraria; Telomere Diagnostics: Consultancy; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Background For women at potentially increased risk for ovarian cancer, data regarding screening and risk reduction are limited. Previous studies have reported on the behaviors of BRCA mutation carriers, but less is known about the behaviors of non- BRCA carriers. We surveyed a large cohort of women after BRCA testing to identify the prevalence and posttest predictors of risk-reducing and screening interventions. Methods A median of 3.7 years after BRCA testing, 1447 women who received genetic counseling and BRCA testing at 2 hospital sites were surveyed, with a 77.6% response rate. We analyzed data from 1077 survey respondents. We performed univariate and multivariate logistic regression analyses to identify predictors of risk-reducing salpingo-oophorectomy (RRSO), screening transvaginal ultrasonography (TVUS), and screening serum cancer antigen 125 (CA-125). Results Among the respondents, 201 women (18.7%) received positive test results for a deleterious mutation, 103 women (9.6%) received true-negative results, and 773 women (71.8%) received uninformative results. Overall, 19.1% of eligible women underwent RRSO and 39.6% used screening procedures. A positive BRCA result predicted RRSO (odds ratio [OR], 28.1; 95% CI, 16.2-48.6), TVUS (9.5 [4.3-21.0]), and serum CA-125 (13.0 [5.5-29.0]). Similarly, a true-negative BRCA result reduced the OR for RRSO (0.1 [0.0-0.6]), TVUS (0.2 [0.1-0.5]), and serum CA-125 (0.3 [0.1-0.7]). Of the 71.8% of women who received uninformative results after BRCA testing, 12.3% subsequently underwent RRSO, 33.8% reported ever having undergone screening serum CA-125 since BRCA testing, and 37.3% reported ever having undergone screening TVUS since BRCA testing. Conclusions Results of BRCA testing strongly predict RRSO and ovarian cancer screening. Use of RRSO and ovarian screening was reported in a sizable percentage of non- BRCA carriers despite insufficient data to determine the effectiveness of these interventions.

While commonly used in other hematological malignancies, high dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) has not been widely adopted in acute myeloid leukemia (AML) due to concerns regarding high post-transplant relapse rates. These relapses may be due, in part, to autograft contamination with AML. High sensitivity methods to detect residual AML have demonstrated the ability to correctly identify patients in morphological complete remission (CR) at risk of relapse. We sought to determine if testing of the graft prior to transplantation could predict post auto-HCT relapse. Prior studies investigating the utility of measurable residual disease (MRD) in auto-HCT have been limited by small patient cohorts and/or by the use of a single biomarker to detect AML, a heterogeneous cancer. We report here the largest retrospective study to date of adult auto-HCT AML patients tested for measurable residual disease (MRD) by both molecular methods (RQ-PCR) and multi-parameter flow cytometry (MPFC). Seventy-two patients transplanted between 2004-2013 at a single academic medical center (UCSF) were eligible for this study based on availability of cryopreserved GCSF mobilized autologous peripheral blood progenitor cell (PBPCs) specimens. All samples were collected on IRB approved research protocols. The median age at time of transplant was 48 (24-69), 54% were female, cytogenetics were known in 94% (of which 24% were favorable, 69% intermediate, 7% poor), 99% were in CR at the time of HCT (64/72 in CR1, 6 in CR2, 1 in CR3). Following auto-HCT 1 year RFS was 50% (1 year relapse rate 43%) and 2 year RFS was 40% (2 year relapse rate 47%). Wilms tumor 1 (WT1) is expressed in up to 90% of AML, but sufficiently over-expressed in peripheral blood to have utility as a sensitive marker of MRD in less than 50% of cases. RQ-PCR detectable WT1 above the previously established European LeukemiaNet threshold was found in 9 patients, of whom 6 relapsed in the first year after auto-HCT (19% sensitivity, 93% specificity, PPV: 67%, NPV: 60%). We have previously reported that multi-gene testing can augment WT1 based MRD detection in AML. We were unable however to use one component of our previously reported AML MRD panel, PR3, due to increased baseline expression in these GCSF stimulated PBPC products. Increased PR3 expression following GCSF administration, correlating with neutrophilia, was also observed in an independent cohort of healthy donors. Testing for PRAME, MSLN, CCNA1, t(8,21), Inv16, t(15:17) and NPM1 mutations A, B and D, as a supplement for WT1, in pre-HCT PBPCs resulted in substantially improved ability to predict post auto-HCT relapse (52% sensitivity, 80% specificity, PPV: 67%, NPV: 69%). Addition of these extra genes allowed for correct identification of 10 additional MRD+ patients who relapsed within 1yr after transplant, and added 5 false positive patients (1 of whom suffered early non-relapse mortality, and another who did relapse but more than 1 year after HCT). Finally, in expert hands, flow cytometry can identify residual AML with high sensitivity. Forty PBPC samples from the above cohort were also assessed for MRD using MPFC. CD34 positive cells comprised 0.05-12.5% of autograft specimen mononuclear cells. Due to immunophenotypic changes likely attributable to GCSF mobilization, and without leukemia associated immunophenotypes from diagnosis available, MPFC was unable to identify MRD in any of 40 patients tested. In summary, no single MRD test on autografts could completely predict post-HCT AML relapse. Auto-HCT presents unique challenges for AML MRD testing due to masking effects of GCSF on MPFC and RQ-PCR gene expression signatures. Additionally, detection of any AML autograft contamination must be extremely sensitive to be useful for predicting relapse given the absence of any potentially protective graft versus leukemia effect following an auto-HCT. Here we show combinations of molecular MRD assays can overcome some, but not all, of these limitations (Figure). Figure 1. Figure 1. Disclosures Radich: Incyte: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Novartis: Other: Lab Contract. Andreadis:Cellerant: Consultancy; Novartis: Consultancy; McGraw Hill: Other: Publishers; Pharmacyclics: Honoraria. Damon:Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Atara: Consultancy; Sigms Tau: Research Funding. Logan:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy. Martin:Sanofi: Consultancy.

Background Although multiple studies have shown superiority of allogeneic hematopoietic cell transplantation (alloHCT) over autologous hematopoietic cell transplantation (autoHCT) for patients with "high-risk" acute lymphoblastic leukemia (ALL), these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. Methods We retrospectively evaluated minimal residual disease (MRD) via next-generation sequencing (NGS) (Adaptive Biotechnologies, S. San Francisco, CA) in the PBPC leukapheresis products from 32 ALL patients who underwent autoHCT. All patients had "high-risk" ALL, as defined by B-lineage disease with WBC at diagnosis >30,000/uL; high-risk cytogenetics including t(9;22), t(4;11), other 11q23 abnormalities, or monosomy 7; or primary refractory disease. Peripheral hematopoietic cell mobilization consisted of cytarabine 2000mg/m2 IV every 12 hours (16,000mg/m2 cumulative) concurrent with etoposide 40mg/kg cumulative by continuous IV infusion over 4 days. The autoHCT conditioning consisted of 1320cGy total body irradiation (TBI) given in 11 fractions from day -8 to -5, etoposide 60mg/kg IV on day -4, and cyclophosphamide 100mg/kg IV on day -2. Tyrosine kinase inhibitors (TKI) were allowed for patients with Philadelphia chromosome-positive (Ph+) B-ALL. Seven patients (22%) participated in a multi-institutional trial in which the PBPC graft underwent ex vivo complement-mediatedpurging using monoclonal antibodies against CD9/CD10/CD19/CD20 for patients with B-lineage disease, or against CD2/CD3/CD4/CD5/CD8 for patients with T-lineage disease. Kaplan-Meier curves were generated using GraphPad Prism (GraphPad Software, La Jolla, CA) and statistical differences assessed via Log-Rank and Wilcoxon analyses, with a p-value of Results Twenty-eight patients (88%) had diagnostic bone marrow samples with quantifiable immunoglobulin or T cell receptor (Ig/TCR) gene rearrangements suitable for MRD quantification in the PBPC collections. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Ph-neg B-ALL, and 4 (14%) had T-cell ALL. The majority of patients were male, in first complete remission, and autografted between 2000-2009, with a median age at autoHCT of 32 (range 19-55). With a median follow-up of 41 months (range 3-217), median relapse-free survival (RFS) and overall survival (OS) for the entire cohort are 3.2 and 4.2 years, respectively. At 5 years post-autoHCT, 42% of patients remain alive and relapse-free. Of the 28 diagnostic bone marrow specimens, 21 (75%) had rearrangements in more than 1 immunoreceptor locus (Figure 1A). A total of 73 rearrangements were identified across all patients. Clonal Ig heavy chain (IGH) sequences with complete VDJ rearrangement were the most commonly identified rearrangement, present in 17 of 28 patients (61%) and representing 30 of the 73 (41%) total rearrangements. When stratified by graft MRD burden, the median RFS for patients with MRD detectable at a level ≥10-6 (n=13) was 6.5 months, and has not been reached for patients without detectable MRD above this threshold (n=15; p=0.0005; Figure 1B). Ex vivo antibody-based purging failed to eradicate leukemia cells from the PBPC collections of 3 patients with detectable MRD who received a purged graft (Figure 1C), all of whom ultimately relapsed. Of the Ph+ cohort, 6 (50%) had detectable MRD in the PBPC graft. Two (33%) of these patients were not treated with a TKI; 1 relapsed at 4 months post-autoHCT and the other died from non-relapse mortality. Of the 4 Ph+ patients with detectable MRD who received a TKI, 2 (50%) remain long-term relapse-free survivors. Of the 6 patients without MRD who were treated with a post-autoHCT TKI, 5 (83%) remain relapse-free. Conclusion We demonstrate that the NGS-based immunosequencing platform identifies ALL MRD in leukapheresed PBPC collections. The presence of MRD in the autograft strongly predicts relapse, with only 15% RFS in patients harboring ≥10-6 MRD at stem cell collection versus 73% in patients with undetectable MRD. The absence of MRD in PBPC may thus identify a subset of "high-risk" patients likely to achieve long-term remissions without alloHCT. TKI therapy for patients with Ph+ B-ALL may also, in some cases, abrogate the need for alloHCT, even with quantifiable MRD prior to high-dose therapy. Disclosures Damon: Atara: Consultancy; Sunesis: Research Funding; Sigma-Tau: Research Funding; McGraw-Hill: Patents & Royalties: Book Chapter. Andreadis:McGraw Hill: Honoraria; Novartis: Consultancy; Cellerant: Consultancy; Pharmacyclics: Honoraria. Olin:Daiichi-Sankyo: Research Funding. Kong:Adaptive Biotechnologies: Employment, Equity Ownership. Faham:Adaptive Biotechnologies: Employment, Equity Ownership.