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Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.

Limited treatment options exist for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Venetoclax (VEN) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) has been recently approved for treatment-naïve patients unfit for intensive induction. Limited data are available to characterize the efficacy of VEN combinations in R/R AML. We retrospectively analyzed 77 patients with a median of 1 prior therapy (range 0-5) treated with VEN combinations for R/R AML or AML secondary to myelodysplastic syndrome (MDS) progressing after HMA monotherapy. The median overall survival (OS) was 13.1 months (95% CI 9.2-15.1). The median progression-free survival (PFS) was 12 months (95% CI 8.2-15.4) with a median duration of response of 8.9 months (95% CI 5.7-13.9). Overall response rate (ORR) was 68% with a composite complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 53%. VEN combination therapy is efficacious in R/R AML and further prospective studies are warranted.

Introduction Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. Methods We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017–2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. Results Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19–32) with day + 4 initiation vs. 24 days (21–30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. Conclusion Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.

Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014-0.71

Introduction Hemorrhagic cystitis can commonly occur following an allogeneic hematopoietic cell transplant and treatment options are currently limited. Pentosan polysulfate, a heparin-like, sulfated polysaccharide, is used to relieve bladder pain and discomfort associated with interstitial cystitis. Initial reports in patients with hemorrhagic cystitis demonstrate that pentosan polysulfate may hasten hemorrhagic cystitis resolution and control symptoms. Methods and results This report includes a retrospective case series of six patients who received pentosan polysulfate for the treatment of hemorrhagic cystitis following an allogeneic hematopoietic cell transplant. Pentosan polysulfate was initiated at a median of 4.5 days (range: 3–18) following hemorrhagic cystitis onset and continued for a median duration of 17.5 days (range: 7–64). Four patients were tested for BK virus and all were found to have BK viremia and viruria around the time of pentosan polysulfate initiation. The median number of red blood cell transfusions seemed to decrease in the patients initiated on pentosan polysulfate. All patients received a multi-agent treatment regimen, which included pentosan polysulfate, and half the patients had symptom resolution. The median time to symptom resolution from pentosan polysulfate initiation was 9 days (range: 7–10). Conclusion Pentosan polysulfate was well-tolerated and seemed to assist with symptom resolution. Future studies are needed to confirm the impact of pentosan polysulfate on the treatment of hemorrhagic cystitis.

Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.

Advances in conditioning, graft-versus-host disease (GVHD) prophylaxis and antimicrobial prophylaxis have improved the safety of allogeneic hematopoietic cell transplantation (HCT), leading to a substantial increase in the number of patients transplanted each year. This influx of patients along with progress in remission-inducing and posttransplant maintenance strategies for hematologic malignancies has led to new GVHD risk factors and high-risk groups: HLA-mismatched related (haplo) and unrelated (MMUD) donors; older recipient age; posttransplant maintenance; prior checkpoint inhibitor and autologous HCT exposure; and patients with benign hematologic disorders. Along with the changing transplant population, the field of HCT has dramatically shifted in the past decade because of the widespread adoption of posttransplantation cyclophosphamide (PTCy), which has increased the use of HLA-mismatched related donors to levels comparable to HLA-matched related donors. Its success has led investigators to explore PTCy’s utility for HLA-matched HCT, where we predict it will be embraced as well. Additionally, combinations of promising new agents for GVHD prophylaxis such as abatacept and JAK inhibitors with PTCy inspire hope for an even safer transplant platform. Using 3 illustrative cases, we review our current approach to transplantation of patients at high risk of GVHD using our modern armamentarium.

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence, and survival after haploidentical donor transplantation with posttransplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1 mismatching with HLA-DQB1 matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-nonpermissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1, and -DPB1 predicted disease-free survival, as did patient and donor cytomegalovirus serostatus, patient age, and comorbidity index. A web-based tool was developed to facilitate selection of the best haploidentical-related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.

The key immunologic signatures associated with clinical outcomes after posttransplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major posttransplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival (OS) due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly used GVHD prophylaxis platforms. Specimens collected on NCT0079656226 and NCT0080927627 https://clinicaltrials.gov/.

Introduction Rhizobium radiobacter is a gram-negative, opportunistic phytopathogen that rarely causes human infections. We report two cases of Rhizobium radiobacter central line-associated bloodstream infection (CLABSI) in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We review previous reports and common microbiological characteristics associated with this organism. Case reports Two adult males developed R. radiobacter CLABSIs at day +81 and day +77 post-alloHCT. Patient one was asymptomatic on presentation while patient two was febrile. One patient had a polymicrobial infection, which has not been previously described. The presence of high-level ceftazidime resistance in both patients suggests third-generation cephalosporin resistance may be more common than previously recognized. Management and outcome For both patients, microbiologic clearance was achieved through peripherally inserted central catheter removal and initiation of intravenous cefepime. Antibiotic therapy was narrowed to oral levofloxacin for a total 14-day course from the time of first negative blood culture. There has been no subsequent recurrence of R. radiobacter infection at 12 and 5 months of follow-up for patients one and two, respectively. Discussion These two cases add to the scant literature characterizing R. radiobacter infection following alloHCT. Immunosuppressive agents for graft-versus-host disease prophylaxis may have predisposed these patients to R. radiobacter infection. Our reports, and previously reported cases, suggest R. radiobacter exhibits low virulence, mild symptom burden, and does not confer a high mortality risk. In the alloHCT setting, further accumulation of cases is needed to aid in understanding clinical features and characteristics of R. radiobacter infection.

Background HLA-haploidentical (haplo) blood or marrow transplantation (BMT) with post-transplantation cyclophosphamide (PTCy) is widely used, but few factors that inform donor selection have been identified. Based on prior observations for HLA-B leader (EW Petersdorf et al. Lancet Haematol 2020), HLA-DRB1 (YL Kasamon et al. BBMT 2010), and HLA-DPB1 (SR Solomon et al. BBMT 2018), we hypothesized that mismatching at individual HLA loci may influence BMT outcomes, but single and additive HLA gene effects have not been evaluated systematically in the context of haploBMT with PTCy. Methods The Center for International Blood and Marrow Transplant Research (CIBMTR) identified 1,434 patients who underwent T-cell-replete haploBMT with PTCy for acute leukemia or myelodysplastic syndrome (MDS) between 2008-2017. Multivariable models assessed transplant outcomes associated with 3 HLA-factors: (1) B-leader dimorphism (MM, MT, TT) matching; (2) HLA-DRB1 mismatching in the graft-versus-host (GVH) direction; and (3) nonpermissive HLA-DPB1 mismatching in the GVH direction using the T-cell epitope-3 model, which classifies HLA-DPB1 mismatches into permissive or non-permissive. All final models contained the HLA factors and adjusted for other significant clinical covariates at p Results Diagnoses were 58% AML, 23% ALL, 19% MDS. 22% of AML patients were in advanced disease stage (relevant analyses were stratified for disease stage for both acute leukemia and MDS). Median recipient age was 54 (range 1-78) years. Median follow up among survivors was 12 (range 2-119) months. Marrow was the graft source in 43% of recipients. Myeloablative conditioning was used in 45% of recipients. Fifty percent of recipients had hematopoietic cell transplantation-comorbidity index (HCT-CI) scores of ≥3. HLA-DP typing was missing in 52% of cases and thus all models had a "missing" category for HLA-DP. Mismatching in the GVH direction at HLA-A, HLA-C, or HLA-DQ was not associated with study outcomes [overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), or grade II-IV acute, grade III-IV acute, or chronic graft-versus-host disease (gr2-4a or cGVHD)]. When compared to leader-matched patients, HLA-B leader-mismatching was associated with worse OS and DFS (hazard ratio [HR] 1.25 [95% CI, 1.09 to 1.44]; P=.002, and HR 1.18 [95% CI, 1.03 to 1.34]; P=.01, respectively), and higher risk of NRM (HR 1.38 [95% CI, 1.10 to 1.74]; P=.005), but was not associated gr2-4a or cGVHD, or relapse. In contrast, when compared to matching at HLA-DRB1, the presence of any GVH direction mismatch at HLA-DRB1 was associated with improved DFS (HR 0.80 [95% CI, 0.68 to 0.94]; P=.007) and lower risk of relapse (HR 0.69 [95% CI, 0.56 to 0.86]; P=.0008), but with no effect on OS, gr2-4a or cGVHD, or NRM. Similarly, any nonpermissive GVH mismatching at HLA-DPB1 was also associated with improved DFS (HR 0.72 [95% CI, 0.55-0.94], p=.015) and OS (HR 0.59 [95% CI, 0.43-0.82], p=.002), with a tendency towards lower relapse (HR 0.75 [95% CI, 0.54-1.05], p=.09), but with no effect on gr2-4a or cGVHD, or NRM. When combining the effects of leader matching at HLA-B and mismatching at HLA-DRB1 there was an additive improvement in both DFS and OS (Figure 1 A and B) with significantly lower NRM (p=0.03) and relapse (p=0.008) when compared to other groups. Within this unselected large cohort, favorable haplo donors based on B-leader matching and HLA-DRB1 mismatching were used for 48.5% of recipients and had improved DFS (HR 0.68 [95% CI, 0.52 to 0.88], p=.004) when compared to B-leader mismatched and HLA-DRB1 matched pairs, suggesting that with intentional selection of donors based on these factors, even more could receive a favorable combination. Conclusion HLA-B leader mismatching is a risk factor for NRM and worse OS and DFS, whereas either HLA-DRB1 or nonpermissive HLA-DPB1 mismatch is associated with reduced relapse and improved DFS, after haploBMT with PTCy. PTCy dissociates the graft-versus-leukemia effect of HLA-DRB1 and nonpermissive HLA-DPB1 mismatching from GVHD. The best outcomes after haploBMT with PTCy are seen when a donor is HLA-B leader matched and HLA-DRB1 mismatched. When there is more than one potential haplo donor for an acute leukemia or MDS patient, selection based on HLA considerations may improve DFS and OS. Figure Disclosures Shaw: Orca Bio: Consultancy. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding.

High-dose cyclophosphamide given post-transplant (PTCy) successfully enables tolerance induction in HLA-mismatched related blood or marrow transplantation (haploBMT) manifested by low rates of graft failure, severe acute graft-versus-host disease (GVHD), and chronic GVHD. When proceeded by nonmyeloablative conditioning, PTCy has also been associated with a low incidence of nonrelapse mortality. The safety of this platform has garnered interest in expanding its use to non-malignant indications for allogeneic blood or marrow transplantation (alloBMT). After success in a preliminary Phase I/II trial, use of a PTCy-based haploBMT platform is now being explored in a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study for sickle cell disease. These emerging data in patients with hemoglobinopathies provided the rationale for exploring the use of PTCy in combined solid organ and BM transplantation as a means of tolerance induction through donor hematopoietic chimerism with a goal to obviate the need for a lifetime of immunosuppression. Several case reports, series, and small clinical trials have now been published of combined solid organ and alloBMT in patients with hematologic malignancies who had organ failure that would have been preclusive of alloBMT in the absence of solid organ transplantation. Here we will review the pre-clinical and clinical studies supporting the use of PTCy for chimerism-based tolerance induction.

Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P.001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting “irreversible” fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children ; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections ; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes ; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

INTRODUCTION PARAGRAPHMultiple large COVID-19 genome-wide association studies (GWAS) have identified reproducible genetic associations indicating that some infection susceptibility and severity risk is heritable.1-5 Most of these studies ascertained COVID-19 cases in medical clinics and hospitals, which can lead to an overrepresentation of cases with severe outcomes, such as hospitalization, intensive care unit admission, or ventilation. Here, we demonstrate the utility and validity of deep phenotyping with self-reported outcomes in a population with a large proportion of mild and subclinical cases. Using these data, we defined eight different phenotypes related to COVID-19 outcomes: four that align with previously studied COVID-19 definitions and four novel definitions that focus on susceptibility given exposure, mild clinical manifestations, and an aggregate score of symptom severity. We assessed replication of 13 previously identified COVID-19 genetic associations with all eight phenotypes and found distinct patterns of association, most notably related to the chr3/SLC6A20/LZTFL1 and chr9/ABO regions. We then performed a discovery GWAS, which suggested some novel phenotypes may better capture protective associations and also identified a novel association in chr11/GALNT18 that reproduced in two fully independent populations.

Multiple COVID-19 genome-wide association studies (GWASs) have identified reproducible genetic associations indicating that there is a genetic component to susceptibility and severity risk. To complement these studies, we collected deep coronavirus disease 2019 (COVID-19) phenotype data from a survey of 736,723 AncestryDNA research participants. With these data, we defined eight phenotypes related to COVID-19 outcomes: four phenotypes that align with previously studied COVID-19 definitions and four 'expanded' phenotypes that focus on susceptibility given exposure, mild clinical manifestations and an aggregate score of symptom severity. We performed a replication analysis of 12 previously reported COVID-19 genetic associations with all eight phenotypes in a trans-ancestry meta-analysis of AncestryDNA research participants. In this analysis, we show distinct patterns of association at the 12 loci with the eight outcomes that we assessed. We also performed a genome-wide discovery analysis of all eight phenotypes, which did not yield new genome-wide significant loci but did suggest that three of the four ' expanded' COVID-19 phenotypes have enhanced power to capture protective genetic associations relative to the previously studied phenotypes. Thus, we conclude that continued large-scale ascertainment of deep COVID-19 phenotype data would likely represent a boon for COVID-19 therapeutic target identification.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Oropharyngeal mucositis (OPM) is common following conditioning for allogeneic hematopoietic cell transplantation (alloHCT) and results in pain, functional status decline, need for nutritional support, infections, and prolonged length of stay (LOS). Methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis exacerbates OPM and slows hematopoietic engraftment, which may prolong LOS. Previous studies have demonstrated reduced OPM and more rapid engraftment when leucovorin (LCV) is added following MTX GVHD prophylaxis, yet this practice is controversial. The primary objective of this study was to determine if the routine addition of LCV to MTX GVHD prophylaxis impacted the duration of grade 2 to 4 OPM. Secondary objectives included determination of the incidence of grade 2 to 4 and grade 3 to 4 OPM, time to engraftment, ability to receive all four planned MTX doses, use of total parenteral nutrition (TPN), use of patient-controlled analgesia (PCA), LOS, incidence of acute or chronic GVHD, relapse-free survival (RFS), and overall survival (OS). This single-center, retrospective cohort study compared alloHCT outcomes for 46 adult patients who received MTX 15 mg/m2 day +1; MTX 10 mg/m2 days +3, +6, and +11 (15-10-10-10); and LCV following days +3, +6, and +11 MTX compared to historical controls who did not. Patients who received myeloablative conditioning (MAC) and matched related donor (MRD) or matched unrelated donor (MUD) alloHCT were included. The addition of LCV resulted in significant reductions in the duration of grade 2 to 4 OPM (median, 6 days versus 10.5 days; P = .0004), duration of TPN (7 days versus 16 days; P = .001), PCA use (16% versus 39%; P = .0001), time to neutrophil engraftment (median, 18 versus 20 days; P = .008), and LOS (median, 27.5 versus 31 days; P = .017) compared to historical controls. Patients who received routine LCV had similar incidences of grade 2 to 4 acute GVHD (30% versus 28%; relative risk [RR], 1.08; 95% confidence interval [CI], .57 to 2.03; P = 1.0), grade 3 or 4 acute GVHD (2% versus 7%; RR, .33; 95% CI, .04 to 3.09; P = .62) and chronic GVHD (37% versus 30%; RR, 1.21; 95% CI, .67 to 2.16; P = .66) compared to historical controls. Graft failure occurred in 2% of patients in each group. In a multivariable logistic regression analysis, RFS was similar in the LCV group compared to historical controls (HR, .86; 95% CI, .24 to 1.2; P = .13); however, OS was improved in patients who received LCV (HR, .33; 95% CI, .13 to .83; P = .01). In patients undergoing MAC MRD/MUD alloHCT with four planned doses of MTX GVHD prophylaxis (15-10-10-10), LCV was associated with reduced duration of grade 2 to 4 OPM, faster neutrophil engraftment, reduced utilization of TPN and PCA, and shortened LOS compared to historical controls not receiving routine LCV. These benefits were apparent without an increased risk of acute or chronic GVHD or adverse effect on RFS. LCV improved OS; however, it is unclear if this was due to the intervention or an unmeasured confounder. A randomized, prospective trial of LCV prophylaxis in patients receiving MAC alloHCT and MTX 15-10-10-10 GVHD prophylaxis is warranted to confirm our findings.

BackgroundThe enormous toll of the COVID-19 pandemic has heightened the urgency of collecting and analyzing population-scale datasets in real time to monitor and better understand the evolving pandemic.MethodsThe AncestryDNA COVID-19 Study collected self-reported survey data on symptoms, outcomes, risk factors, and exposures for over 563,000 adult individuals in the U.S. in just under four months, including over 4,700 COVID-19 cases as measured by a self-reported positive test.ResultsWe replicated previously reported associations between several risk factors and COVID-19 susceptibility and severity outcomes, and additionally found that differences in known exposures accounted for many of the susceptibility associations. A notable exception was elevated susceptibility for males even after adjusting for known exposures and age (adjusted odds ratio [aOR]=1.36, 95% confidence interval [CI] = (1.19, 1.55)). We also demonstrated that self-reported data can be used to build accurate risk models to predict individualized COVID-19 susceptibility (area under the curve [AUC]=0.84) and severity outcomes including hospitalization and critical illness (AUC=0.87 and 0.90, respectively). The risk models achieved robust discriminative performance across different age, sex, and genetic ancestry groups within the study.ConclusionThe results highlight the value of self-reported epidemiological data to rapidly provide public health insights into the evolving COVID-19 pandemic.THUMBNAILWhat is already known on this subjectThe COVID-19 pandemic has exacted a historic toll on human lives, healthcare systems and global economies, with over 83 million cases and over 1.8 million deaths worldwide as of January 2021.COVID-19 risk factors for susceptibility and severity have been extensively investigated by clinical and public health researchers.Several groups have developed risk models to predict COVID-19 illness outcomes based on known risk factors.What this study addsWe performed association analyses for COVID-19 susceptibility and severity in a large, at-home survey and replicated much of the previous clinical literature.Associations were further adjusted for known COVID-19 exposures, and we observed elevated positive test odds for males even after adjustment for these known exposures.We developed risk models and evaluated them across different age, sex, and genetic ancestry cohorts, and showed robust performance across all cohorts in a holdout dataset.Our results establish large-scale, self-reported surveys as a potential framework for investigating and monitoring rapidly evolving pandemics.

Human infection with SARS-CoV-2, the causative agent of COVID-19, leads to a remarkably diverse spectrum of outcomes, ranging from asymptomatic to fatal. Recent reports suggest that both clinical and genetic risk factors may contribute to COVID-19 susceptibility and severity. To investigate genetic risk factors, we collected over 500,000 COVID-19 survey responses between April and May 2020 with accompanying genetic data from the AncestryDNA database. We conducted sex-stratified and meta-analyzed genome-wide association studies (GWAS) for COVID-19 susceptibility (positive nasopharyngeal swab test,ncases=2,407) and severity (hospitalization,ncases=250). The severity GWAS replicated associations with severe COVID-19 nearABOandSLC6A20(PP−8. The strongest association was nearIVNS1ABP, a gene involved in influenza virus replication1, and was associated only in males. The other two novel loci harbor genes with established roles in viral replication or immunity:SRRM1and the immunoglobulin lambda locus. We thus present new evidence that host genetic variation likely contributes to COVID-19 outcomes and demonstrate the value of large-scale, self-reported data as a mechanism to rapidly address a health crisis.

Objectives: The purpose of this study was to investigate the occurrence and develop a risk score for heart failure (HF) in acute leukemia. Background: Knowledge is scarce regarding the incidence and risk factors of symptomatic HF in patients with acute leukemia. Methods: Baseline clinical and echocardiographic parameters, including indices of cardiac function (left ventricular ejection fraction and myocardial strain [global longitudinal strain; GLS]), were obtained in 450 patients with acute leukemia treated with anthracyclines, before chemotherapy initiation. Potential risk factors for HF were evaluated using Fine and Gray’s regression analysis, and from this, a 21-point risk score was generated. Results: Forty patients (8.9%) developed HF. The HF risk score included a baseline GLS >−15% (indicative of greater impairment) (6 points), baseline left ventricular ejection fraction 60 years (1 point). Patients were stratified into low (score 0 to 6), moderate (score 7 to 13), and high risk (score 14 to 21). The estimated 1-year cumulative incidence of HF for low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively (p < 0.001). The HF risk score was also predictive of all-cause mortality (p < 0.001). After adjustment for age and leukemia type, however, only GLS was significantly associated with all-cause mortality (hazard ratio: 1.73; 95% confidence interval: 1.30 to 2.31; p < 0.001). Conclusions: We developed a baseline risk score to determine risk of HF in patients with acute leukemia. Additional studies are needed to determine the external validity of these findings.

We studied the association between non-HLA donor characteristics (age, sex, donor-recipient relationship, blood group [ABO] match, and cytomegalovirus [CMV] serostatus) and transplant outcomes after T-cell-replete HLA-haploidentical transplantation using posttransplantation cyclophosphamide (PT-Cy) in 928 adults with hematologic malignancy transplanted between 2008 and 2015. Siblings (n = 358) and offspring (n = 450) were the predominant donors, with only 120 patients having received grafts from parents. Although mortality risks were higher with donors aged 30 years or older (hazard ratio, 1.39; P < .0001), the introduction of patient age to the Cox regression model negated the effect of donor age. Two-year survival adjusted for CMV seropositivity, disease, and disease risk index was lower in patients aged 55 to 78 years after transplantation of grafts from donors younger than 30 years (53%) or aged at least 30 years (46%) compared with younger patients who received grafts from donors younger than 30 years (61%) and at least 30 years (60%; P < .0001). Similarly, 2-year survival in patients aged 55 to 78 years was lower after transplantation of grafts from siblings (45%) or offspring (48%) compared with patients aged 18 to 54 years after transplantation of grafts from siblings (62%), offspring (58%), and parents (61%; P < .0001). Graft failure was higher after transplantation of grafts from parents (14%) compared with siblings (6%) or offspring (7%; P = .02). Other non-HLA donor characteristics were not associated with survival or graft failure. The current analyses suggest patient and disease, rather than non-HLA donor characteristics, predominantly influence survival in adults.

Introduction Increasingly clinicians face the choice between CPX-351 (NCT01696084) and venetoclax and azacitadine (ven/aza, NCT02993523) in front-line acute myeloid leukemia (AML), especially for frailer older adults with comorbidities. Given no prospective data, we examined retrospective observational survival outcomes for patients with newly diagnosed AML receiving either CPX-351 or ven/aza as initial therapy. Methods After local Institutional Review Board approval, we included patients from both the University of Pennsylvania ("HUP", n=111) and the Flatiron Health electronic health record (EHR) derived, de-identified database with a first incident AML diagnosed between January 2017 and 2021, and with documented receipt of CPX-351 or venetoclax and azacitadine as initial therapy (n=548). Given a total of 219 patients received CPX-351 and 440 received ven/aza, there was 90% power to detect a hazard ratio (HR) of 0.77 or smaller with alpha 0.05. Overall Survival (OS) was analyzed by the Kaplan-Meier method and compared between arms using the log-rank test. Pre-planned sensitivity analyses included restriction and multiple imputation (MI) to address missingness with inverse-probability of treatment weighting (IPTW) to balance baseline covariates with treatment effect estimates from each imputed dataset combined via Rubin's rules. Results For all patients, baseline covariates showed patients receiving ven/aza were older (75 vs 65 years old median age), more likely to have Medicare (29% vs 20%), have de-novo AML vs secondary or therapy-related disease (52% vs 29%) and be treated in the community rather than an academic center (66% vs 52%). All other baseline covariates-including ELN cytogenetic risk groups, high risk mutations (TP53, ASXL1, RUNX1), FLT3, IDH, HCT-comorbidity index-were not statistically significant different between groups (table 1). Missing values in the HUP dataset was Median OS (mOS) was 12 months for all patients and 13 months for CPX-351 versus 11 months for ven/aza (HR 0.87, 95% CI 0.70-1.07, p-value 0.184, Fig 1a). There was no clear subset with improved OS with CPX-351 vs ven/aza (Fig 1b); in multi-variate analysis controlling for all covariates with univariate p-value < 0.20 induction choice did not affect overall survival (limited to complete cases n=133, HR 0.63, p-value 0.73). Restricting to only the population eligible for CPX-351 pivotal trial, there was no significant difference in OS (CPX-351 n=160 mOS=10, ven/aza n=181 mOS=12 HR 0.86 p-value 0.33). After MI and IPTW, survival remained similar with HR 0.95 p-value 0.77 (Fig 1c). Adjusting further for variables with absolute standardized difference >10% after MI and IPTW (baseline HCT-comorbidity index, race and insurance status), multivariable Cox model gave similar results (HR 0.93, p-value 0.70). Regarding safety outcomes, early mortality was similar. However, documented diagnosed infections were higher in CPX-351 patients and within the HUP cohort, rates of febrile neutropenia and culture positive infection were also higher (Fig 1d). Length of stay, including any admission prior to next cycle of therapy, was more than twice as long for CPX-351 in the HUP cohort. Additional analyses, including detailed assessment of baseline covariates, multivariate analysis with transplant as a time-varying dependent covariate, event free survival, disease free survival also available for presentation. Conclusion In this multi-center real word dataset with over 600 patients, there was no statistically significant difference in overall survival between induction with CPX-351 and ven/aza. This large retrospective dataset is limited by missingness in covariates, risk of misclassification bias and lack of power for formal equivalence testing. However, a consistent lack of superiority for CPX-351 or ven/aza within a robust, manual chart-review of an academic institution, a large national real world database and combined analyses of these cohorts supports clinical equipoise. Given the apparent lack of a large survival benefit further work is needed. Prospective studies to confirm similar effectiveness with careful attention to side effects, quality of life and impact on transplant outcomes may help clinicians decide between these therapies. Figure 1 Figure 1. Disclosures Perl: Syndax: Consultancy; Loxo: Consultancy; Forma: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy; Actinium: Consultancy; Genentech: Consultancy; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Fujifilm: Research Funding; BMS/Celgene: Consultancy; Arog: Research Funding; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Frey: Kite Pharma: Consultancy; Novartis: Research Funding; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current Employment, Current equity holder in publicly-traded company; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Unity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Stadtmauer: Oncopeptides: Consultancy; Amgen: Consultancy; BMS Celgene: Consultancy; GSK: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Maillard: Regeneron: Research Funding. Margolis: Pfizer: Consultancy; Leo: Consultancy; Sanofi: Consultancy; National Eczema Association: Membership on an entity's Board of Directors or advisory committees. Pratz: Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding; University of Pennsylvania: Current Employment.

Background: Genetically modified T cells expressing an anti-CD19 murine chimeric antigen receptor (CAR) result in response rates of up to 90% in patients with relapsed or refractory (r/r) B cell acute lymphoblastic leukemia (ALL). Durable remissions are limited by relapses of both CD19+ disease, correlating with loss of persistence, and CD19- disease, due to target antigen loss. The use of humanized CAR T products with improved persistence and dual antigen targeting are strategies that may improve relapse free survival. Methods: Adult patients with r/r ALL were co-administered two humanized autologous CAR T cell products, one targeted to CD19 (huCART19) and the other to CD22 (CART22-65s) after fludarabine and cyclophosphamide lymphodepletion. A three day fractionated adaptive dosing scheme was used in which the second or third huCART19 and CART22-65s infusions could be held for early signs of cytokine release syndrome (CRS). Total planned dose was 2.0x10 6 CART22-65sf2 cells/kg and 2.0x10 6 huCART19 cells/kg. Safety of the novel combination was the primary endpoint of the study; feasibility and efficacy were key secondary endpoints. Results: Of 13 treated patients (median age 46 (range 28-71)), two had received prior murine CART19 cells, 8 had prior blinatumomab, 8 had prior inotuzumab and 10 had a prior allogeneic stem cell transplant (SCT). The two products had distinct peak expansions which correlated with two clinically distinct episodes of CRS in some patients. The median time to peak huCART19 expansion was 9 days versus 16 days for CART22-65s. Eleven patients experienced CRS, all Grade 1 or 2. Two patients had immune effector cell-associated neurotoxicity syndrome (ICANS), one of which was grade 4. Two patients died within 30 days of infusion, one from complications of treatment (Grade 4 ICANS and sepsis) and one from rapidly progressive disease. One patient developed hemophagocytic lymphohistiocytosis-like syndrome that was clinically and temporally distinct from a CRS event; this was characterized by delayed pancytopenia, transaminase elevation and hypofibrinogenemia, similar to events reported in other trials of CART22. This syndrome was refractory to IL6 and IL1beta inhibition but ultimately responded to ruxolitinib. Of the 11 patients evaluable for response, 100% achieved CR with unmeasurable residual disease (uMRD) one month after infusion. One of the 11 had molecular recurrence 9 months post infusion. The other 10 patients are alive and remain in an uMRD remission with a median follow up of 6.2 months (range 0.2 to 25 months) and none have proceeded to consolidative SCT. Three months after infusion, 9/11 patients had detectable huCART19 and 8/11 patients had detectable CART22-65s. At 6 months, 7/8 evaluable patients had detectable huCART19 cells and 4/8 patients had detectable CART22-65s. All three patients with 12 months follow-up had detectable huCART19 and CART22-65s. Conclusion: Co-administration and adaptive dosing of CART22-65s with huCART19 in adult patients with r/r ALL is feasible and effective. The two different products demonstrated differential expansion and persistence kinetics. Despite prior exposure to CD19- and/or CD22-specific immunotherapies, all evaluable patients achieved CR with uMRD; we continue to monitor CAR T cell persistence and its impact on durability of response. Disclosures Frey: Novartis: Research Funding; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy; Kite Pharma: Consultancy. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Pratz: Abbvie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; University of Pennsylvania: Current Employment; Agios: Consultancy; Cellgene: Consultancy, Honoraria; Millenium: Research Funding. Perl: AbbVie: Consultancy, Research Funding; Roche: Consultancy; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Fujifilm: Research Funding; Arog: Research Funding; BMS/Celgene: Consultancy; Genentech: Consultancy; Actinium: Consultancy; Forma: Consultancy; Syndax: Consultancy; Loxo: Consultancy; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Ruella: viTToria biotherapeutics: Research Funding; Tmunity: Patents & Royalties; AbClon: Consultancy, Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties. Brogdon: Novartis Institutes for Biomedical Research: Current Employment. Engels: Novartis: Current Employment, Current equity holder in publicly-traded company. Levine: In8bio: Membership on an entity's Board of Directors or advisory committees; Ori Biotech: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Immusoft: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Other: Co-Founder and equity holder; Immuneel: Membership on an entity's Board of Directors or advisory committees; Avectas: Membership on an entity's Board of Directors or advisory committees; Akron: Membership on an entity's Board of Directors or advisory committees. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; Novartis: Patents & Royalties; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; DeCart: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Hexner: Tmunity Therapeutics: Research Funding; Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This trial reports outcomes from investigational products delivered as part of a clinical trial.

Background Pharmacologic immunosuppression and incomplete immune reconstitution after allogeneic stem cell transplant (alloSCT) may impair a patient's ability to mount an immune response to vaccines, including currently available COVID-19 vaccines. Since immunocompromised patients are susceptible to severe COVID-19 and likely to respond poorly to vaccination, we sought to characterize SARS-CoV-2 antibody responses after vaccination in alloSCT patients to determine predictors of serologic response, which may inform timing of vaccine administration. Methods This retrospective analysis included adult patients who underwent alloSCT at the University of Pennsylvania between 1/1/2019 and 1/1/2021. Chart review identified patients who had received COVID-19 vaccines and had post-vaccination antibody titers drawn by July 2021 as part of routine care (n=63). Antibodies to SARS-CoV-2 spike protein receptor binding domain were detected using an assay developed at the Hospital of the University of Pennsylvania. Variables analyzed include interval between transplant date and initial vaccination, active GVHD, concurrent immunosuppressive therapy, absolute CD4 count greater than or equal to 200 cells/mm3 peri-vaccination, and total IgG greater than or equal to 400 mg/dL peri-vaccination. Immunosuppressive therapy was defined as tacrolimus, rituximab, ruxolitinib, prednisone 10 mg daily or greater, or extracorporeal photopheresis. Predictors of positive antibody response were assessed using a multivariate, binary logistic regression. Results Median transplant to vaccine interval was 458 days (range 125 to 813) for the 63 vaccinated patients with serologies available. GVHD was present in 23/63 (37%), and 19/63 (30%) were receiving immunosuppressive therapies at the time of vaccination. CD4 count greater than 200 cells/mm3 was observed in 49 patients (78%), and total IgG greater than 400 mg/dL was observed in 51 patients (81%). In total, 50/63 patients (79%) were positive for SARS-CoV-2 IgG antibodies. Positive serologies were observed in 41/49 (84%) with CD4 counts greater than 200 cells/mm3, compared to 9/14 (64%) with CD4 less than 200 cells/mm3. Our model found that peri-vaccination CD4 count greater than 200 cells/mm3 was a significant predictor of positive SARS-CoV-2 IgG serologies in this population (OR 2.14, 97.5% CI = 0.7 to 3.8, p= 0.005). Transplant to vaccine interval, total IgG levels, GVHD status, and immunosuppressive therapies were not significant predictors of serologic response. As of July 2021 no patients had developed COVID-19 after vaccination, regardless of serologic response. Conclusions This retrospective observational study demonstrates that the majority of alloSCT patients vaccinated against COVID-19 within 2 years of transplant, including those with active GVHD and on immunosuppressive therapies, can mount serologic responses. CD4 count greater than 200 cells/mm3 is a significant predictor of positive serologic response, though even among patients with CD4 counts under 200 cells/mm3 over 60% developed SARS-CoV-2 IgG antibodies. Disclosures Perry: Incyte: Consultancy, Speakers Bureau; Abbvie,: Speakers Bureau; Kadmon: Consultancy. Pratz: University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Novartis: Consultancy; BMS: Consultancy, Honoraria; Agios: Consultancy; Millenium: Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Perl: Astellas: Consultancy, Research Funding; Loxo: Consultancy; AbbVie: Consultancy, Research Funding; Syndax: Consultancy; BMS/Celgene: Consultancy; Roche: Consultancy; Fujifilm: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Forma: Consultancy; Arog: Research Funding; Genentech: Consultancy; Actinium: Consultancy; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Porter: ASH: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Research Funding. Frey: Sana Biotechnology: Consultancy; Kite Pharma: Consultancy; Syndax Pharmaceuticals: Consultancy; Novartis: Research Funding.

Recurrent cytogenetic abnormalities have provided the backbone for prognosticating acute myeloid leukemia and predicting response to consolidative therapies for decades. However, more than 45% of acute myeloid leukemia patients have normal cytogenetics on both karyotype and fluorescence in situ hybridization at diagnosis. Increasingly utilized next-generation sequencing has led to the discovery of numerous recurrent molecular mutations in acute myeloid leukemia, which can currently be identified in 97.3% of patients. Despite the prevalence of dozens of these recurrent lesions, only NMP1, CEBPA, KIT, FLT3-ITD, and TP53 have been incorporated into widely accepted risk-stratification schemas, such as the 2017 National Comprehensive Cancer Network guidelines. Here we review the most frequent molecular genetic abnormalities, their utility in predicting relapse and survival, and their function as markers of minimal residual disease. We also provide a summary of sixteen common recurrent molecular abnormalities about which sufficient data exists ( Table 1 ).

Purpose T-cell–replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.