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Background Newly diagnosed patients with acute myeloid leukemia (AML) who receive induction with a hypomethylating agent (HMA) are often neutropenic with an increased risk for invasive fungal infections (IFIs). This study analyzed the incidence and risk factors for IFIs in these patients, evaluated clinical patterns in antifungal prophylaxis, and assessed the diagnostic utility of tests in this setting. Patients and Methods We studied 117 newly diagnosed patients with AML treated with HMAs at our center, divided into groups based on concern for IFI (cIFI: all possible, probable, and proven IFIs) versus no concern for IFI. The Fisher exact test compared patients with cIFI versus without, and a multivariable logistic regression model estimated odds for cIFI. Results Sixty-seven (57%) patients had cIFI, with 48 possible IFIs, 17 probable, and 2 proven cases. There was no difference in incidence based on home zip code, but the presence of chronic obstructive pulmonary disease was highly associated with cIFI (P = .001), as was male gender (P = .01). Neutropenia at treatment initiation was borderline in significance (P = .08). In diagnostics, 9% of patients had positive serum fungal markers, and 30 patients underwent bronchoscopy, with only 27% of cases yielding positive results. There was a difference in treatment regimens between patients receiving antifungal prophylaxis with mold coverage versus without mold coverage with respect to cIFI (P = .04). Conclusions cIFI in patients with AML treated with HMAs remains significant, especially in males and those with chronic obstructive pulmonary disease, who were found to be at higher risk. This may prompt clinicians to consider anti-mold prophylaxis in this setting.

Initial therapy for acute myeloid leukemia (AML) remained stagnant for approximately four decades despite advances in improved understanding of pathogenesis and prognostication of the disease. Treatment has typically consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the “7 + 3” regimen. Attempts have been made to improve on this regimen with modest improvements in response rates but no change in overalll survival, until the recent introduction of mutation-specific agents. However, the re-vamping of the delivery of both daunorubicin and cytarabine in a liposomal encapsulation, known as CPX-351, did show improvements of overall survival compared to traditional 7 + 3 in newly diagnosed secondary and therapy-related AML in patients aged 60–75. This led to the Food and Drug Administration (FDA) approval of the agent for both of these subtypes of AML in August of 2017. Herein we will review the rationale and preclinical development of CPX-351 and discuss the pivotal studies that led to its FDA approval.

Background: Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy following HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, current clinical outcomes of IDH1 - and IDH2 -mutated AML patients following HCT have not been well-described. Methods: In this multicenter retrospective analysis, 112 adult patients with either IDH1 - or IDH2 -mutated AML who underwent HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their outcomes — including progression-free survival (PFS), overall survival (OS), relapse, and non-relapse mortality — were analyzed. Findings: The median patient age was 64·1 years. 78·5% of patients had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Commonly detected co-mutations were DNMT3A (35·7%), NPM1 (33·1%), and FLT3-ITD (13·4%). The median follow-up was 27·5 months. For IDH1- mutated patients, the 1- and 2-year PFS was 75% and 58%, respectively, and the 1- and 2-year OS was 78% and 74%, respectively. For IDH2- mutated patients, the 1- and 2-year PFS was 64% and 58%, respectively, and the 1- and 2-year OS was 75% and 68%, respectively. Interpretation: Our analysis provides important benchmarks for analysis and interpretation of results emerging from ongoing clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients following HCT. Funding: This project has no funding source to report. Declaration of Interests: Dr. Eisfeld reports other from Karyopharm, personal fees from Vigeo, outside the submitted work. Dr. E Chen has nothing to disclose. Dr. Li has nothing to disclose. Dr. Luskin has nothing to disclose. Dr. Mims reports other from Jazz, other from Syndax, other from Abbvie, other from Kura oncology, personal fees from Agios, other from Novartis, outside the submitted work. Dr. Jones reports personal fees from Pharmacyclics LLC, outside the submitted work. Dr. Antin has nothing to disclose. Dr. Cutler reports other from Incyte, other from Kadmon, other from Jazz, other from Medsenic, other from Generon, other from Mesoblast, outside the submitted work. Dr. Koreth reports personal fees from Equilium, personal fees from Amgen, personal fees from Moderna Therapeutics, personal fees from Biolojic Design, personal fees from EMD Serono, other from Therakos, other from Cugene, grants from Miltenyi, grants from BMS, grants from Reneron, other from Clinigen, outside the submitted work. Dr. Gooptu has nothing to disclose. Dr. Romee has nothing to disclose. Dr. El-Jawahri has nothing to disclose. Dr. McAfee has nothing to disclose. Dr. Defilipp reports grants from Incyte, grants from Regimmune, personal fees from Syndax, outside the submitted work. Dr. Soiffer reports other from Kiadis, other from Gilead, other from Rheos, other from Cugene, other from Precision Bioscience, other from Mana Therapeutics, other from VOR Biopharma, other from Novartis, other from Juno, other from Celgene, other from Alexion, other from National Marrow Donor Program, outside the submitted work. Dr. YB Chen reports personal fees from Incyte, personal fees from Takeda, personal fees from Magenta, personal fees from Kiadis, other from Actinium, other from Equilium, other from Abbvie, outside the submitted work. Dr. Fathi reports grants from Takeda, personal fees from Boston Biomedical, personal fees from PTC Therapeutics, personal fees from Amphivena, personal fees from Astellas, personal fees from Daiichi Sankyo, personal fees from Novartis, grants and personal fees from Celgene/BMS, personal fees from Trovagene, personal fees from Forty Seven , personal fees from NewLink Genetics , personal fees from Pfizer, personal fees from Abbvie, grants and personal fees from Seattle Genetics , grants and personal fees from Agios, personal fees from Amgen, personal fees from Trillium, personal fees from Kura Oncology, personal fees from Blueprint, personal fees from Genentech, outside the submitted work. Ethics Approval Statement: This study was approved by the Institutional Review Boards at the Dana-Farber Harvard Cancer Center and Ohio State University Comprehensive Cancer Center

Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy after HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, clinical outcomes of IDH1- and IDH2-mutated AML patients after HCT have not been well described. The primary objective of this study was to describe the clinical characteristics and post-HCT outcomes of IDH-mutated AML patients. Survival outcomes included progression-free survival (PFS), overall survival, and cumulative incidences of relapse and nonrelapse mortality. In this multicenter retrospective analysis, 112 adult patients with IDH1- or IDH2-mutated AML who underwent HCT and did not receive an IDH inhibitor as maintenance therapy after HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their survival outcomes were analyzed. Univariate and multivariate analyses were performed. The median patient age was 64.1 years. The median follow-up was 27.5 months. Among patients, 78.5% had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Fifty-eight percent of patients received intensive induction chemotherapy, 82% of patients underwent HCT during first complete remission (CR) or CR with incomplete hematologic recovery (CRi), and 34% of patients received myeloablative conditioning. Frequently detected co-mutations were DNMT3A (35.7%), NPM1 (33.1%), and FLT3-ITD (13.4%); TP53 mutations were detected in 3.6% of patients. For IDH1-mutated patients transplanted during first CR/CRi, the 1- and 2-year PFS was 75% and 58%, respectively. For IDH2-mutated patients transplanted in first CR/CRi, the 1- and 2-year PFS was 64% and 58%, respectively. The 2-year cumulative incidence of relapse was 31% and 25% for IDH1- and IDH2-mutated cohorts, respectively. Multivariable analysis suggested first CR/CRi and age ≤60 was associated with improved outcomes for IDH2-mutated patients. To date, this is the largest multicenter study of outcomes of IDH-mutated AML patients after HCT. Our analysis provides important benchmarks for analysis and interpretation of results emerging from clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients after HCT.

Introduction PML is a rare infection with JC virus affecting mostly oligodendrocytes and the white matter of the central nervous system. It affects patients with profound cellular immunodeficiency such as uncontrolled HIV or those receiving immunosuppression for neoplastic and autoimmune diseases. Prognosis is poor as there is no effective therapy except for immune recovery which is not feasible in all cases. Herein, we describe using Quadrivalent (CMV,EBV, Adenovirus and BK) VSTs in a recipient of an unrelated donor hematopoietic cell transplant (HCT) with PML. Methods A 64-year-old female with history of acute myeloid leukemia who underwent 10/10 HLA matched unrelated donor peripheral blood HCT complicated by acute mild skin graft vs host disease. She was off all immunosuppression by 7 months post transplant. At 15 months post HCT, she presented with mild confusion, left hemianopia and difficulty performing some routine tasks. Brain MRI showed demyelination involving the right parietal lobe, corpus callosum and bilateral dorsal periventricular areas. Cerebrospinal fluid (CSF) with JC virus DNA load of 389,773 copies/ml. Serum JC virus level was 1112 copies/ml and CD 4 218 (8.7%). Patient was referred to Cincinnati Children's Hospital for third-party VST infusion . A 3/10 HLA matched unit from their existing VST bank was infused 3 days after her PML diagnosis. She received a total of 6 VST infusions, each 28 days apart. Results Patient was monitored with monthly CSF JC virus and weekly serum JC virus levels. JC virus was cleared from serum and CSF after the fourth and fifth VST infusions, respectively (figure 1). T cell expansion analysis against BK was done by ELISpot (figure 2). Patient received a total of 6 VST infusions. Neuro symptoms stabilized after the second infusion. At 7.5 months from diagnosis (3 months since last VST infusion), she remained neurologically stable with no new deficits, GVHD or other toxicities. Conclusions VSTs with BK activity is a promising therapy for PML patients in whom immune reconstitution is unlikely to occur in a short time frame. More studies are warranted to evaluate the efficacy and long term outcomes of this method. Physicians should be aware of this novel therapy in selected PML cases given poor disease outcomes and lack of effective alternative therapies.

Background: Consolidation therapy with allogeneic hematopoietic stem cell transplant (HSCT) is recommended to prevent relapse and improve survival in patients with intermediate and poor risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Due to toxicity, older patients with comorbidities were historically not candidates for HSCT. The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to proceed to HSCT by reducing toxicities associated with myeloablative conditioning (MAC).The cornerstone of reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). This can be achieved by the use of patient-specific pharmacokinetic targets. Previous studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day x 4 days in a subset of patients to balance reduced toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. Methods: To compare the two regimens, a retrospective, IRB-approved cohort study was conducted. The inclusion criteria were as follows: age 18-89 years, HSCT for a diagnosis of AML or MDS, and fludarabine + busulfan conditioning regimen ± antithymocyte globulin. In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to neutrophil recovery; time to platelet recovery; incidence of acute and chronic graft vs host disease (GVHD); sinusoidal obstructive syndrome; febrile neutropenia; graft failure; and grade 3-5 mucositis, acute kidney injury, or hepatic dysfunction. The log-rank test was used to compare RFS and OS, and Cox proportional hazard regression model was used to estimate the hazard ratio. Gray's test was used for competing risks analysis of relapse, acute GVHD, and chronic GVHD. Fine and Gray regression models were used to estimate the hazard ratio. Results: Seventy-four patients who received conditioning from 2015-2018 with either AUC 4,000 or RIC were identified. Disease type was similar between groups with 61.8% AML in the AUC 4,000 group and 52.5% in the RIC group. There were no significant differences in disease risk status. In the AUC 4,000 group, 17.6% had either AML with myelodysplastic changes or therapy-related AML/MDS, compared to 17.5% in the RIC group. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different, at 66.9% with AUC 4,000 compared to 57.5% with RIC (p=0.37) (A). Eighteen-month overall survival was also not significantly different with 66.9% alive in the AUC 4,000 group and 60% in the RIC group (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not significantly different (p=0.82, p=0.18, respectively) (C,D). There was, however, a statistically significant difference in the cumulative incidence of relapse over 18 months in favor of the AUC 4,000 regimen (hazard ratio 4.08, 95% confidence interval 1.15-14.5) (E). Grade 2-4 mucositis was more common in the AUC 4,000 group (85.3% vs 30%, p Discussion: Though no significant difference existed in disease risk between the groups, choice of regimen was driven by physician judgement, perceived fitness, and ability to tolerate potential adverse effects. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower cumulative incidence of relapse. Adverse effects other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed. Figure Disclosures Brammer: Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. William:Guidepoint Global: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.

Background Haplo-HCT emerged as a reliable option for patients with high risk hematological malignancies with no HLA-matched related or unrelated donors available. Retrospective registry data suggest comparable outcomes to HLA-matched donors; however, relatively little is known regarding predictors of disease relapse following haplo-HCT. We hypothesize that attainment of full-donor CD3 and CD33 chimerism at day 30 (D30) and 100 (D100) is associated with lower incidence of relapse after haplo-HCT. Methods We undertook a retrospective analysis of 78 patients who underwent haplo-HCT at the Ohio State University James Cancer Hospital between January 2013 and December 2017. The associations between patient characteristics including CD3/CD33 donor chimerisms and the cumulative incidence rate (CIR) of relapse were evaluated using proportional sub-distribution hazards model, treating death without relapse as the competing risk. The models were built adopting a landmark analysis approach at D30 and D100. Progression-free survival (PFS) was estimated using the method of Kaplan-Meier. Results Median age at haplo-HCT was 56 (20-74) years and 68% were males. 50% had acute myeloid leukemia/myelodysplastic syndrome, and 54% had intermediate disease risk index (DRI). Most patients (85%) received reduced-intensity conditioning and 50% received bone marrow (BM) grafts. Complete (100%) CD3 donor chimerism was observed in 63 (84%) patients at D30, and subsequently 59 (95%) patients at D100. Complete CD33 donor chimerism was observed in 67 (89%) patients at D30, and subsequently 56 (88%) patients at D100. In univariable D30 landmark analysis, the CIR of relapse was significantly lower in patients who achieved complete CD3 (and CD33) chimerism compared with patients with less than complete chimerism (Figure 1A; p Conclusions Complete CD3 and CD33 donor chimerisms at D30 and D100 predict a patient's risk for relapse following haplo-HCT. We observed a strong association between CD3 chimeric status at D30 with DRI, as well suggestive that high risk disease may be associated with impaired immune reconstitution after transplant and perhaps a less robust graft vs disease effect.

Introduction Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Preventing GVHD without impairing the graft-versus-tumor effect remains an important goal for successful allo-HSCT. Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as aGVHD prophylaxis. The influence of TAC has proved effective for preventing aGVHD after allo-HSCT. There is also variability in the serum concentrations of TAC and very little is known on the impact of early (first 4 weeks) TAC levels on aGVHD incidence. Methods Data were analyzed for 707 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002- 2016. All patients received standard prophylaxis with TAC daily and methotrexate on days +1, +3, +6, and +11 post allo-HSCT. Tacrolimus dose was adjusted to achieve a target serum level of 5-12 ng/ml. Fine and Gray's proportional hazard models accounting for competing risks were used to evaluate the association between TAC levels and outcome of aGVHD, cGVHD, GVHD-free/relapse-free survival (GRFS),and relapse. Cox proportional hazard models were used for the association with OS. Results The mean weekly TAC concentrations at weeks 1, 2, 3 and 4 were 8.0, 9.7, 11.3 and 10.5 ng/mL, respectively. The cumulative incidence of grades II–IV aGVHD was 40% at day 100 and 45% at day 180 post HSCT. In univariable analysis, high TAC level at week 1 was associated with lower grade II-IV aGVHD (Hazard ratio (HR), 0.96; p = 0.006). We examined the effect of week 1 TAC levels categorized into tertiles ( 8.95 ng/ml). Higher level of TAC (>8.95 ng/ml) was associated with lower risk of aGVHD (Figure 1a). In multivariable analysis, week 1 TAC levels > 5.85 ng/ml remained associated with a lower risk of grade II-IV aGVHD. However, only levels of 5.85-8.95 ng/ml were associated with statistically significant lower risk with HR=0.75, p=0.04 compared to the lower group ( 7.2 ng/ml (HR: 0.78, p=0.03). The CI of cGVHD was 41% at 1 year post-allo-HSCT. Week 2 TAC level >10.6 ng/ml was associated with an increased risk of relapse (HR, 1.37, p=0.043) (Figure 1b). The cumulative incidence of relapse at 1, 3 and 5 year post allo-HSCT was 33%, 38% and 40%, respectively. TAC levels at weeks 1, 2, 3 and 4 were not associated with OS. The 1, 3 and 5 year GRFS was 21%, 14% and 12%.TAC levels at any week were not associated with GRFS. Conclusion Achieving mean whole-blood level of tacrolimus between 6.0-9.0 ng/ml within the first week post-allogenic bone marrow transplantation may reduce the risk of aGVHD.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have poor treatment outcomes when treated with traditional chemoimmunotherapy. Superior outcomes have been observed with the 2 CAR-T cell products approved by the US FDA; tisagenlecleucel (CTL109) and axicabtagene ciloleucel (Axi-cel) with 12 months overall survival rates of 49% and 59% respectively. The 2 major acute toxicities of these therapies are cytokine release syndrome (CRS) and neurotoxicity. The incidence of grade 3 or higher neutropenia, anemia, and thrombocytopenia was 78%, 43%, and 38% in patients treated with axi-cel. Little is known regarding the patterns and outcomes of these cytopenias. Here we present our preliminary experience on the patterns and outcomes of cytopenias in 32 patients who received commercially-available CAR-T cell therapy at our institution. We retrospectively reviewed all DLBCL patients receiving either CTL109 or axi-cel between January and September 2018 at our institution. All patients received a conditioning regimen of low-dose cyclophosphamide and fludarabine, followed by CAR-T infusion. Persistent cytopenias were defined as incomplete absolute neutrophil count ( The median age of patients was 59 years (range, 23-80); 63% were male, 4 patients (13%) received CTL109 and 28 (87%) received axi-cel. Twenty-two patients (69%) had a 3 month follow up imaging for assessment of response, of whom 7 patients (32%) achieved complete response (CR), 6 patients (27%) achieved partial response (PR), and 9 patients (41%) had progressive disease (PD). Persistent neutropenia was observed in 3 patients (9%), while persistent thrombocytopenia was seen in 21 cases (65%) and persistent anemia was the most common with a frequency of 72% (23/32 cases). Median time to neutrophil, platelet and Hb recoveries were 11 days (range, 5-218 days), 59.5 days (range, 4-241 days), and 76 days (range, 0-218 days), respectively. Filgrastim was used in 15 (47%) patients to facilitate neutrophil recovery. Twenty-three patients (72%) experienced neurotoxicity, of whom 11 (34%) had grade 3-4 toxicity. The frequency of CRS was 94% (29 out of 32 patients), with grade 3-4 CRS observed in 4 cases (12.5%). We observed no significant association between CRS and persistent cytopenias. In our preliminary series of 32 patients, persistent anemia and thrombocytopenia were more common than neutropenia after CAR-T cell therapy. However, most of these patients required growth factor support for neutrophil recovery. Longer duration of follow up is necessary to determine the impact of persistent cytopenias on outcomes and survival after CAR-T cell therapy.

Introduction Autologous stem cell transplant patients (ASCT) are at risk for bacterial. Antibacterial prophylactic strategy is variable among centers. Fluoroquinolone prophylaxis in ASCT patients has not been found to add a survival benefit. We performed a retrospective review of patients undergoing ASCT with and without bacterial prophylaxis to compare endpoints of interest. Methods At our institution, patients undergoing ASCT for multiple myeloma (MM) receive levofloxacin 500 mg daily as prophylaxis, while lymphoma patients do not. We retrospectively examined MM or lymphoma patients undergoing ASCT between July of 2015 and 2018 for bacteremia episodes. MM patients received melphalan and lymphoma patients received BEAM. All patients received growth factor support. Clinical and microbial data was recorded and analyzed using SPSS. Results In total, 172 patients underwent ASCT for lymphoma and 343 for MM. Seventeen percent (30/172) of lymphoma patients and 5.5% (19/324) of MM patients had febrile neutropenic episodes associated with bacteremia. Relative risk was 3.1 [1.83 – 5.43, p Discussion Fluoroquinolone prophylaxis resulted in less blood stream infection episodes but more breakthrough infections with resistant isolates. There was no statistically significant difference between the rates of CDI infections despite a trend to lower incidence in the prophylaxis group. Bacteremia was more difficult to treat for the resistant isolates. There were two infection-related mortalities in the prophylaxis group. In the era of antimicrobial resistance, further reevaluation of the utility of fluoroquinolone prophylaxis should be carefully weighed against the risks.