High-risk Hematologic Malignancies Research Articles

Azacitidine and gemtuzumab ozogamicin as post-transplant maintenance therapy for high-risk hematologic malignancies.

Disease recurrence remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Post-transplant maintenance therapy with azacitidine (AZA) is promising to prevent relapse but the outcomes are unsatisfactory in patients at high risk of recurrence. Herein, we evaluated the outcome in patients who received AZA and gemtuzumab ozogamicin (GO), anti-CD33 antibody-calicheamicin conjugate, as post-transplant maintenance therapy. Twenty-eight patients with high-risk hematologic malignancies harboring CD33-positive leukemic blasts received the maintenance therapy. AZA (30 mg/m2) was administered for 7 days, followed by GO (3 mg/m2) on day 8. The maximum number of cycles was 4. At transplant, 21 patients (75.0%) had active disease. Their 2-year overall survival, disease-free survival, relapse, and non-relapse mortality rates were 53.6%, 39.3%, 50.0%, and 10.7%, respectively. Of these patients, those with minimal residual disease at the start of maintenance therapy (n = 9) had a higher recurrence rate (66.7% vs. 42.1% at 2 years, P = 0.069) and shorter disease-free survival (11.1% vs. 52.6% at 2 years, P = 0.003). Post-transplant maintenance therapy with AZA and GO was generally tolerable but more than half of the patients eventually relapsed. Further improvements are needed to prevent relapse after transplantation in patients with high-risk hematologic malignancies.

EHealth mindfulness-based music therapy for patients undergoing allogeneic hematopoietic stem cell transplantation: A pilot randomized controlled trial protocol

BackgroundAllogeneic stem cell transplantation (allo-SCT) is the preferred therapy for patients with high-risk or relapsed hematologic malignancies, but may be complicated by psychological distress (e.g., depression, anxiety) and symptom burden (e.g., fatigue, pain). Mindfulness-based music therapy (MBMT), a relatively novel integrative medicine intervention that draws from mindfulness and music therapy principles, has shown promise in improving psychosocial outcomes and symptom burden in cancer patients. We outline an eHealth-based MBMT (eMBMT) intervention protocol examining: (1) feasibility, acceptability, and intended effects of eMBMT in improving HRQOL, symptom burden, and clinical markers of disease activity (e.g., infections), and (2) the extent to which eMBMT music therapy component-associated improvements in HRQOL, symptom burden, and disease activity are mediated by improvements in psychosocial and physiological (e.g., systemic inflammation, immune recovery) adaptation. MethodsParticipants (n = 60) with a hematologic malignancy undergoing allo-SCT will be randomized to receive eMBMT or an eHealth-based mindfulness meditation (eMM) intervention. eMBMT includes eight 60-min sessions facilitated by a music therapist focusing on mindfulness and music therapy. eMM includes eight 60-min self-led MM practices. ResultsFeasibility, acceptability, HRQOL, symptom burden, disease activity, and mediation effects of psychosocial and physiological adaptation will be assessed at baseline, pre-infusion, and post-engraftment with blood collection at baseline and post-engraftment. ConclusionThe current pilot RCT is the first eMBMT intervention to address the HRQOL and symptom burden of patients who are undergoing allo-SCT. Results will inform a fully powered RCT to establish preliminary efficacy of eMBMT on improvements in HRQOL, symptom burden, and disease activity.

Neurologic Complications of the Central Nervous System after Allogeneic Stem Cell Transplantation: The Role of Transplantation-Associated Thrombotic Microangiopathy as a Potential Underreported Cause

Neurologic complications (NCs), especially those of the central nervous system (CNS), represent a severe complication after allogeneic stem cell transplantation (allo-HSCT) and are associated with relevant morbidity and mortality. We aimed to characterize the potential risk factors for the development of CNS-NC, with a special focus on the role of calcineurin inhibitors (CNIs) as a predisposing factor. For this purpose, we compared cyclosporin A (CsA) versus tacrolimus (TAC) with respect to their influence on the incidence and type of CNS-NC after allo-HSCT. We retrospectively analyzed the incidence, risk factors, and impact on outcomes of CNS-NC diagnosed during the post-transplantation follow-up in patients with different high-risk hematologic malignancies who underwent allo-HSCT at our institution over a 20-year period. All patients included in the analysis received CNI (CsA or TAC) as graft-versus-host disease (GVHD) prophylaxis. We evaluated a total of 739 consecutive patients who underwent transplantation between December 1999 and April 2019. During a median follow-up of 6.8 years, we observed a CNS-NC incidence of 17%. The development of CNS-NC was associated with decreased overall survival (OS) and increased transplantation-related mortality (TRM). The most frequent CNS-NCs were infections (30%) and neurologic adverse events related to the administration of CNI, TAC, or CsA as GVHD prophylaxis (42%). In the multivariable analysis, age, total body irradiation (TBI), and severe acute GVHD and chronic GVHD were significant risk factors in the development of CNS-NCs. TAC compared with CsA emerged as an independent predisposing factor for CNS-NCs. The TAC-associated risk of CNS-NCs was related mostly to the occurrence of transplantation-associated thrombotic microangiopathy (TA-TMA) with neurologic manifestations (neuro-TA-TMA), although the general TA-TMA incidence was comparable in the 2 CNI subgroups. CNS-NCs are associated with poor prognosis after allo-HSCT, with TAC emerging as a potential yet insufficiently characterized predisposing factor.

Allogeneic hematopoietic stem cell transplantation: A single-center experience, 2017 to 2021

IntroductionHematopoietic stem cell transplantation (HSCT) remains a critical treatment for advanced or high-risk hematological malignancies, posing challenges such as finding suitable donors and managing of graft-versus-host disease (GvHD). This study estimates 3-year overall survival in patients who underwent HSCT at our referral service in the state of Minas Gerais, Brazil. Material and methodsThis retrospective observational cohort study involved 41 patients who received HSCT between 2017 and 2021 at the Felício Rocho Hospital. Recipients received HSCT from either haploidentical donor (Haplo), matched unrelated donor (MUD), or HLA-matched sibling donor (MSD). The study evaluated parameters that included 3-year overall survival (OS), treatment-related mortality (TRM), GvHD incidence, post-transplant relapse rate, and engraftment. ANOVA, Kruskal-Wallis, and chi-square tests were used for statistical analysis. Survival curves were calculated using the Kaplan-Meier method and the Log-rank test compared the curves. ResultsOur study found that the engraftment time differed among groups: Haplo recipients engrafted earlier within a median of 16 days (ranging between 10 and 20 days) than MSD recipients with 18 days (ranging between 11 and 28 days), and MUD recipients with 19 days (ranging between 11 and 24 days; p = 0.019). Mild acute GvHD (grade I-II) was observed in 13 patients, progressing to chronic GvHD in 5 patients. Three-year OS rates were as follows: MSD group - 67.7%, Haplo group - 42.2%, and MUD group - 44.4% (MSD vs Haplo, p = 0.039). Three-year cumulative treatment-related mortality (TRM) rates were 17.8% for MSD group, 22.9% for Haplo group, and 22.1% for MUD group (pairwise comparisons p > 0.05). Infection-related mortality was reported in eight patients, while relapse rates at 3 years were similar across MSD, Haplo, and MUD groups (p = 0.891). Donor age influenced OS rates, showing better outcomes with donors under 45 years old, and significant differences were found in pairwise comparisons (p = 0.015). ConclusionDonor type and donor age significantly impacted HSCT outcomes in our analysis, thus emphasizing the importance of rigorous donor selection in risk stratification and suggesting potential benefits for younger donors.

Clinical research in the community.

Most patients with high-risk hematologic malignancies are treated in community oncology practices near their residence. This is partly due to patients' ardent desire to be closer to home and trust in local caregivers. Treatments are increasingly complex, even as initial therapy, and more so upon relapse. Improved outcomes in the past decade are largely available through clinical trials primarily offered through academic medical centers. Limited availability of clinical trials at community oncology practices is a major contributor to outcome disparities among minorities, rural, and elderly patients, all of whom are underrepresented in clinical trials. Between 2003 and 2023, the National Cancer Institute (NCI) established programs to address these challenges: the Community Clinical Oncology Program, Minority- Based Community Clinical Oncology Program, NCI Community Cancer Centers Program, and NCI Community Oncology Research Program. However, disparities have persisted, particularly for pharmaceutical-directed clinical research. Lack of representation in clinical research results in data absenteeism, data chauvinism and hallucination, and a delay in treatment availability for high-risk hematologic malignancies in community practice. To address this, the US Congress enacted the Food and Drug Administration Omnibus Act in 2022 to help establish diversity plans that would broaden clinical trial patient enrollment in the United States. We recommend using these initiatives in community oncology practices, including the adoption of the DRIVE strategy in collaboration with pharmaceutical companies, as well as using the NCI-established programs to promote clinical trial availability for patients with high-risk malignancies treated in community oncology practices.

Simultaneous Determination of Prednisone and Prednisolone in Serum by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic treatment for patients with high-risk hematologic malignancies and bone marrow failure syndromes. While allo-HCT can be highly effective, it is met with significant regimen-related toxicities and complications such as graft-versus-host disease (GVHD), poor immune reconstitution, and infections. Prednisone is the preferred treatment for patients with both acute and chronic GVHD. While effective, high-dose prednisone can cause many complications, including weight gain, skin fragility, muscle weakness, bone demineralization, hyperglycemia, insomnia, and psychosis. Optimizing prednisone (and prednisolone) dosing by measuring their concentrations and calculating their pharmacokinetic parameters will allow for personalized treatments for patients, producing more effective and safer treatments for GVHD. This chapter describes a method to measure both compounds simultaneously. Prednisone and prednisolone are extracted from serum by the addition of methanol containing deuterated internal standards. Chromatographic separation is achieved using a reversed-phase HPLC column followed by tandem mass spectrometry performed in the positive ion mode. This assay is fast, accurate, sensitive and allows for rapid drug measurements and timely dose modifications.

Abstract B134: Targeting Philadelphia chromosome-like acute lymphoblastic leukemia with a novel CRLF2 antibody fragment-drug conjugate

Abstract Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk hematological malignancy with poor outcome, and new treatments are urgently required. We address this challenge by targeting cytokine receptor-like factor 2 (CRLF2), which is overexpressed in ~50% of Ph-like ALL cases conferring chemoresistance and survival of Ph-like ALL cells through JAK/STAT signaling. CRLF2 is an ideal target due to its role in leukemogenesis, limiting the likelihood of relapse associated with antigen loss, and its minimal expression in healthy tissue. Here, we developed a novel CRLF2-targeting antibody fragment-drug conjugate (CRLF2-FDC) and evaluated its efficacy in preclinical models. Methods: A single-chain anti-CRLF2 variable monoclonal antibody fragment (scFv-Fc) was engineered by conventional hybridoma technology, PCR and expression in HEK293T cells. The scFv-Fc was conjugated to the anti-microtubule drug DM1 via a non-cleavable linker. The selective association and internalization of the CRLF2-FDC was determined in vitrousing Ph-like ALL cell lines and their CRLF2-knockdown counterparts, and ex vivo using patient-derived xenograft (PDX) cells. The in vivo efficacy of the CRLF2-FDC (equivalent to 10 mg/kg scFv-Fc, 0.4 mg/kg DM1, once weekly x 4 weeks via intravenous injection) was tested against pediatric ALL PDX models in immune-deficient (NSG) mice, in comparison to scFv-Fc or DM1 alone. The efficacy of the CRLF2-FDC was further evaluated following two weeks of standard-of-care induction chemotherapy [vincristine (0.15 mg/kg, once weekly), dexamethasone (5 mg/kg) and L-asparaginase (1,000 U/kg) both 5 days on 2 days off (VXL)]. Treatment efficiency was calculated by subtracting the median event-free survival (EFS) of the control and treated groups (T-C) and stringent objective response criteria (progressive disease, PD; partial response, PR; complete response, CR; maintained CR, MCR) and leukemia infiltration in major organs at day 28 post treatment initiation. Results: CRLF2-dependent association (P≤0.01) and internalization of the CRLF2-FDC was confirmed both in vitro and in vivo in Ph-like ALL cells. While the scFv-Fc alone or free DM1 elicited PDs in a Ph-like ALL PDX in vivo (T-C 6 and 1.6 days, respectively, P=0.0013 for both), the CRLF2-FDC achieved a PR (T-C 32 days, P=0.0088). Besides targeted drug delivery, the CRLF2-FDC also demonstrated a significant antagonistic impact on STAT5 signaling in vivo 8 h after administration, suggesting a two-pronged therapeutic approach. Notably, the CRLF2-FDC achieved an MCR when administered after VXL (T-C 53.9 days, P <0.0001) compared to a CR (T-C 25.2 days, P <0.0001) by VXL alone. Furthermore, the CRLF2-FDC significantly decreased leukemic burden in major organs at 28 days post treatment initiation. Conclusions: This study describes the selective potency and promising preclinical activity of a novel CRLF2-FDC for the treatment of Ph-like ALL when administered either as a single agent or following standard-of-care induction therapy. Citation Format: Richard B Lock, Sara M.A. Mohamed, Peter Schofield, Karl-Heinz Friedrich, Daniel Christ, Maria Kavallaris, Narges Bayat. Targeting Philadelphia chromosome-like acute lymphoblastic leukemia with a novel CRLF2 antibody fragment-drug conjugate [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B134.

Quantification of Clofarabine and Fludarabine in Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic treatment for many patients with high-risk hematologic malignancies and bone marrow failure syndromes. While allo-HCT can be highly effective, it is met with significant bone marrow conditioning regimen-related toxicities and complications such as infections related to poor immune reconstitution. This chapter describes the measurement of clofarabine and fludarabine concentrations to support clinical trials whose goal is to determine the optimal therapeutic ranges in order to maximize effectiveness while minimizing variability and regimen-related adverse events and toxicities. Moreover, the same holds true for patients receiving fludarabine as part of their lymphodepleting chemotherapy for chimeric antigen receptor T-cells (CAR T-cells). It is believed that one of the causes of variable outcomes after CAR T-cell therapy is lymphodepletion due to the variable fludarabine concentrations.This chapter describes a HPLC-MS/MS method to measure both compounds simultaneously. Clofarabine and fludarabine are extracted with solvent from plasma by the addition of deuterated internal standards prepared in methanol. Chromatographic separation is attained using a reversed-phase column followed by mass spectrometry which is performed in the positive ion mode. Herein, the described method to quantify both compounds in plasma is fast, accurate, and sensitive and allows for rapid drug concentration monitoring and timely dose adjustments.

Lymphocyte Reconstitution after Naïve T Cell-Depleted Hematopoietic Cell Transplantation

Background: Allogeneic hematopoietic cell transplantation (HCT) is curative for many high-risk hematological malignancies. However, graft-versus-host disease (GVHD) causes morbidity, mortality, and reduced quality of life after HCT. Removal of all T cells from hematopoietic cell grafts (pan-T cell depletion; pan-TCD) significantly reduces GVHD but is associated with impaired immune reconstitution and increased non-relapse mortality due partly to opportunistic infections. We developed a novel strategy to remove CD45RA + naïve T cells (T N) from peripheral blood stem cell grafts (PBSC) that is associated with a low incidence of serious acute GVHD (aGVHD) and an exceptionally low incidence of chronic GVHD (cGVHD) (Bleakley, JCO 2022). Although CD45RA-depletion removes T N and other CD45RA-expressing effector T cell populations from PBSC along with most NK and B cells, T N-depletion (T ND) does not appear to increase infections or have a major negative impact on immune reconstitution. Understanding subtle differences in lymphocyte population dynamics after T ND compared to T cell-replete (TR) HCT will enable further graft engineering advances and may provide broader insights into human HCT immunobiology. Objective: To evaluate lymphocyte reconstitution after T ND HCT. Methods and Results: We compared blood lymphocyte populations in T ND HCT recipients (n=47) to those in TR HCT controls (n=19) at days 28, 56, 90, 180, and 360 post-HCT using multiparametric flow cytometry. To complement standard Boolean analysis, we employed a metaclustering approach to simultaneously evaluate ~20 cell surface markers for each class of lymphocytes (CD8 + and CD4 + T cells, NK cells, and B cells) over scores of batches of recipient and control samples. Absolute numbers of total CD8 + T cells were similar in T ND compared to TR at all timepoints, whereas total CD4 + T cell numbers were consistently lower in T ND until 1 year post-HCT. Using conventional gating and high-dimensional clustering analyses, we identified several key differences in T cells after T ND. CD45RA-expressing populations (T N and effector memory re-expressing CD45RA [T EMRA]) in CD8 + and CD4 + T cells were rare in CD45RA-depleted PBSC and remained decreased in T ND HCT recipients until around 1 year (CD8 +, Fig. 1). Activated CD8 + and CD4 + central and effector memory (T CM, T EM) T cells were increased proportionally and in absolute numbers in T ND early post-HCT (CD8 +, Fig. 1). Absolute numbers of regulatory T cells (Treg) were decreased in T ND; consequently, ratios of activated CD8 + and CD4 + to Treg were both markedly increased early post-HCT, despite a similar incidence of aGVHD in T ND and TR recipients. Although most NK cell populations were removed from CD45RA-depleted PBSC, absolute numbers of NK cells in all compartments, including both activated and inhibited, were increased in T ND recipients early post-HCT compared to TR. Like NK cells, most B cells except for plasmablasts and plasma cells were removed by CD45RA-depletion of PBSC. Immature, naïve, and memory B cells were reduced very early post-T ND HCT, but substantial B cell recovery occurred within the first 2-3 months. Conclusions: We present the first detailed description of lymphocyte reconstitution after T ND HCT. Despite the major effect CD45RA-depletion has on graft composition-removing all T N and T EMRA from the T cell compartment and most NK and B cells-NK and B cell recovery occurred early, and by 1 year post-HCT there was little difference in lymphocyte populations between T ND and TR. This is consistent with hematopoietic progenitors, not mature lymphocytes, as the source of B and NK cell reconstitution. Among T cells, the most striking findings were an increase in activated T CM and T EM CD4 + and CD8 + T cells early after T ND HCT, and increased ratios of activated T cells to Treg. Although elevated blood T effector/Treg ratios have been associated with cGVHD, cGVHD was uncommon and steroid-responsive after T ND HCT. Whether increased activated T cells reflect a reduction in Treg-mediated suppression after HCT, bystander T cell activation, activation by antigen (e.g., alloantigen, latent herpes viruses, microbiota), or multiple factors are questions we are now investigating. We are also exploring associations between lymphocyte populations early post-T ND HCT and clinical outcomes; these could serve as biomarkers to facilitate early intervention to prevent or treat GVHD, relapse, or infection.

UM171 Expanded Cord Blood Transplantation Outcomes Compare Favorably to All Different Stem Cell Sources: An EBMT Registry Case-Control Analysis

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources, such as permissive human leucocyte antigen (HLA) mismatches, and low risk of chronic graft-versus-host disease (GVHD) and relapse. However, CBT has fallen into disfavor because of its high risk of non-relapse mortality (NRM) and prolonged hospitalization due to its low cell dose. Furthermore, the need for the rare large cord bloods (CBs) leads to selection of poorly HLA-matched CBs, known to further increase NRM. UM171 is a small molecule that expands hematopoietic stem cells. A phase I-II study of a single UM171-expanded, myeloablative and reduced intensity CBT for patients with high-risk hematologic malignancies who lacked a donor, demonstrated prompt neutrophil engraftment, the ability to use smaller, better HLA-matched CBs, and a low NRM of 5% (Cohen S et al. Lancet Haematol 2020). The aim of the current analysis was to compare outcomes after a UM171 CBT to real-world cohorts of 6 other stem cell sources identified in the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods: This is a retrospective study comparing 22 adults who received a single UM171-expanded CBT in the phase I-II study between 2016-2018, to 6 cohorts of patients allografted from different stem cell sources and reported to the EBMT registry. Control patients were eligible if they had received a myeloablative or reduced intensity allogeneic transplant for a hematologic malignancy in Europe during 2010-2021, were between the ages of 18-65 years, and had a Karnofsky performance status (KPS) score ≥70. The different donor control cohorts were: 1) CB, single or double units, with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) for GVHD prophylaxis, 2) 10/10 HLA-matched unrelated donor (MUD) peripheral blood stem cells (PBSC) with a CNI and MMF or methotrexate (MTX), 3) 10/10 MUD bone marrow (BM) with a CNI and MMF or MTX, 4) 9/10 HLA-MUD BM or PBSC (9/10 UD), 5) T cell replete haploidentical donor (haplo) BM or PBSC, and 6) matched sibling donor (MSD) BM or PBSC. Exclusion criteria included in vitro manipulated grafts and CBT recipients who received anti-thymocyte globulin or alemtuzumab. Patients were directly matched for disease and status at transplant and propensity score matching was used for prior allograft, age, KPS, and conditioning regimen. Endpoints included engraftment, GVHD, NRM, relapse, progression-free survival (PFS), overall survival (OS), and GVHD-free relapse-free survival (GRFS). The EBMT attempted to identify 3 controls for each patient. If no control was identified for a UM171 patient, the latter was excluded from the analysis. Results: Between 17 and 21 UM171 CB patients were compared to 36 to 62 controls depending on the donor group as 1-3 controls could not be identified for each patient (Table 1). Median follow-up for the UM171 group was 36 months and generally longer for the controls. Neutrophil engraftment with UM171 CB was similar to all donor groups except slower for CB and MUD BM. Platelet engraftment was consistently slower for UM171 CB except when compared to conventional CB. The incidence of severe acute GVHD was similar across all donor groups. As there was no severe chronic GVHD in the UM171 group, the latter was associated with less extensive/severe chronic GVHD compared to MUD (PBSC and BM) and MSD. There was a trend towards lower NRM for UM171 CB compared to haplo and 9/10 UD but it did not reach statistical significance. PFS, OS and GRFS were all better with UM171 CB compared to haplo. Finally, GRFS was improved with UM171 CB when compared to MUD PBSC (Figue 1), 9/10 UD, and MSD. Conclusions: This registry matched case-control analysis demonstrated real-word evidence suggesting UM171-expanded CBT recipients have improved outcomes compared to other donor types. More specifically and due to the absence of severe chronic GVHD with UM171 CB, GRFS was better with UM171 CB when compared to other graft sources except for CB and MUD BM. Also, OS and PFS were superior with UM171 CB compared to haplo donors. Limitations of this study included the small number of UM171 patients, the inability to identify controls for each case, and certain missing data for the controls. UM171 expansion of CB appeared to achieve the desired outcome of maintaining benefits of CB while removing its disadvantages. Thus, prospective randomized studies are warranted to confirm these results.

Safety and Efficacy of Orca-Q with Haploidentical Donors for the Treatment of Advanced Hematologic Malignancies without the Use of Post-Transplant Cyclophosphamide

Srour, Salhotra, Lowsky and Abedi contributed equally as authors BACKGROUND Allogeneic stem cell transplantation (SCT) can be curative for several high-risk hematologic malignancies, but access was previously limited to patients with a fully matched donor. The introduction of post-transplant cyclophosphamide (PTCy) GvHD prophylaxis has increased the use of haploidentical donors (haplo) for patients who lack an HLA-matched donor. However, clinical outcomes associated with PTCy-based regimens remain challenging due to increased relapse rates (particularly in the setting of reduced intensity conditioning) and the adverse event profile including higher incidence of mucositis, cytokine release syndrome (CRS), delayed engraftment & T cell reconstitution, infections, early cardiotoxicity events and death from organ failure (Dulery 2021, Abboud 2021, Nagler 2022, Hoover 2022, Bolaños-Meade 2023). Additionally, the incidence of chronic GvHD after haplo SCT with PTCy is 24 - 33% at 1 year in various historical cohorts. Orca-Q -an investigational precision engineered cell therapy biologic- represents an alternative strategy which may be administered with single agent prophylaxis and does not require PTCy. The cellular composition of Orca-Q includes enriched CD34+ stem cells, combined with specific T-cell subsets, and is intended to reconstitute the blood and immune systems. METHODS Adult patients with high-risk hematologic malignancies eligible for MAC SCT were enrolled on the haplo donor dose expansion arm of a multicenter phase1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA-A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received MAC conditioning and single agent GVHD prophylaxis with tacrolimus (starting on day -1 and taper day +60). Orca-Q was manufactured centrally at Orca Bio Manufacturing Site in Sacramento, CA from G-CSF mobilized peripheral blood apheresis. RESULTS Orca-Q was successfully manufactured and delivered to all subjects with a vein-to-vein time (time between end of donor apheresis to start of recipient's Orca-T infusion) of < 72 hours. A total of 33 patients (21 AML, 10 ALL, 2 CML) were included. Median age was 43 (range, 21 - 63) years, 73% were male. Median follow-up was 375 (range, 73 - 1384) days. Sixteen patients received TBI-based MAC; 17 received busulfan-based MAC (Table). All patients engrafted with median time of 12.0 (range, 8 - 25) and 15.5 (range, 8 - 79) days for neutrophil and platelet engraftment, respectively. Two patients had secondary graft failure. Two patients had Grade 1 CRS; 1 patient had Grade 2 CRS. Grade 2+ aGvHD through Day 180+ occurred in 15% of patients. Grade 3-4 acute GvHD (aGvHD) was rare with only 1 event of grade 3 aGvHD and no grade 4 aGvHD. No patients had moderate-to-severe cGvHD. Estimated incidence of CTCAE grade 2 and > grade 3 infections were 9% and 15% at 1 year, respectively. 5 patients died (2 from relapsed disease) during the study period. NRM was 9% at 1 year. The 1-year relapse-free survival, GvHD-and-relapse free survival (Figure), and overall survival at 1 year was 82%. CONCLUSIONS Our findings reveal promising safety and efficacy outcomes using Orca-Q cell therapy for haplo-SCT despite the use of MAC with only single-agent tacrolimus, and without PTCy. With median follow-up of approximately 1 year, no patients experienced moderate or severe cGvHD, the low AE profile in the haplo setting remains favorable, and 1 year GvHD-free, relapse-free survival of 83% is very encouraging. This phase 1 study continues to enroll patients across the US. REFERENCES Abboud R, Wan F, Mariotti J, et al. Bone Marrow Transplant. 2021;56(11):2763-2770. Bolaños-Meade GM, Hamadani M, Wu J. N Engl J Med. 2023; 388(25):2338-2348. Duléry R, Mohty R, Labopin M, et al. JACC CardioOncol. 2021; 3(2):250-259. Hoover A, O'Leary D, Cao Q, et al. Blood. 2022; 140 (Supplement 1):282-283 Nagler A, Tsirigotis P. Bone Marrow Transplant. 2022; 57(11):1640-1641.

Immunosuppression Free at One-Year Post Haploidentical Hematopoietic Cell Transplantation (Haplo) with Post-Transplant Cyclophosphamide (PTCY)

Haploidentical related donor transplantation with PTCY has expanded the donor availability and made it feasible for most patients with high risk hematologic malignancies to receive a curative transplantation. Haplo with PTCY carries similar disease control and lower incidences of GVHD compared to matched donors using calcineurin inhibitor based GVHD prophylaxis. Chronic GVHD among transplant patients who are one-year survivors after matched related or unrelated allogeneic transplantation was shown to be associated with higher non relapse mortality and worse overall survival 1 . The impact of clinically significant chronic GVHD requiring immunosuppression (IS) on haplo recipients with PTCY who have survived one-year post-transplant has not been studied and is being assessed in this analysis. A total of 322 consecutive adult patients who received haplo transplant with PTCY at our center were included in this study. Two hundred and forty-nine survived first year post-transplant and were included in the primary analysis for predictors of being immunosuppression (IS) free at one year. Two hundred and twenty-one patients were free of relapse at 1-year post haplo and were included in the analyzing the effect of IS free status on non-relapse mortality (NRM), progression free survival (PFS), Relapse and overall survival (OS). Median follow up for survivors was 63.9 months (18.3-165). Patient, disease, and transplant related characteristics were retrieved from our database where they have been prospectively entered. All patient received standard GVHD prophylaxis of PTCY, Mycophenolate (stop day +35) and Tacrolimus through day 180. A total of 163 patients (65%) were IS free at one-year post haplo. Patients' characteristics were as follows: median age 48 (19,80) years, male sex 56%, Race (white 61%, black 34%), most common diagnosis ( AML/MDS 55%), comorbidity index HCT-CI ≥3 52%, cell source (PBSC 81%), and myeloablative intensity (49%). Both groups IS free and still on IS had similar baseline characteristics except for higher female-male donor (28% vs 15 %, P=0.03) and female donors (48% vs 30%, p=0.008) for patients on IS at 1-year. Logistic regression to identify patients more likely to be on IS at 1-year post Haplo showed that female donor sex to be a significant risk (OR 2.11, CI 1.21-3.69, p=0.009). In a Cox analysis on the effects of IS on transplant outcomes, being on IS at 1-year had no impact on OS (HR 1.44, CI 0.90-2.31, p=0.13) or relapse (HR 0.77, CI 0.37-1.61, p=0.49) but a significantly higher NRM ( HR 4.18, CI 1.80-6.72, p<0.001) and a trend towards worse PFS (HR 1.59, CI .95-2.66, p=0.08). These results indicate that female donors are significant risk factor for requiring IS at one-year post haplo with PTCY. Additionally, clinically significant chronic GVHD requiring IS at one-year post haplo with PTCY has no significant effect on relapse but is associated with higher NRM and a trend towards worse PFS. These results can be used to inform appropriate donor selection to avoid late complications among haplo recipients.

The Composite Health Risk Assessment Model (CHARM) to Predict 1-Year Non-Relapse Mortality (NRM) Among Older Recipients of Allogeneic Transplantation: A Prospective BMT-CTN Study 1704

Introduction: Allogeneic hematopoietic cell transplantation (HCT) remains the only therapy for long-term disease control for many high-risk hematologic malignancies (HM). HCT use in older HM patients (pts) continues to increase. However, concerns of excessive transplant-related morbidity and non-relapse mortality (NRM) limit referrals and broader application of curative intent HCT. The HCT-comorbidity index (HCT-CI) was initially developed to improve risk-stratification of NRM. More recently, geriatric assessment (GA) and biomarkers have emerged as promising additional tools that may refine estimates of these risks. We hypothesized that a combination of health assessments by GA and biomarkers would constitute a robust and valid model, CHARM, for accurate personalized estimation of one-year (1-yr) NRM. Here, we report the results of the largest, first of its kind, prospective study of older recipients of HCT through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1704 study (NCT03992352). Patients and Methods: Adults aged ≥60 years (yrs) with HM institutionally eligible for HCT were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. Within 21 days of conditioning, 13 prospectively identified older pt.-specific health variables, informed from prior studies, were collected: age, HCT-CI, % of weight loss over the past yr, pt reported Karnofsky performance status, PROMIS physical function scale, instrumental activities of daily living (IADL), number of falls, PROMIS depression scale, number of prescribed medications, 4-meter walk speed, cognition by the Montreal Cognitive Assessment (MoCA), C-reactive protein (CRP) and albumin. The CHARM score to predict NRM within 1 yr was built using a multivariable (MVA) Fine-Gray model, with multiple imputation to handle modest missingness in covariates and grouped penalized variable selection using SCAD to identify variables to retain in the model. Final variables were used as continuous. The model further considered adjustment for conditioning intensity, CMV serostatus, and donor type. Area under the ROC curve (AUC) was calculated to validate the CHARM and compare to HCT-CI alone, with bootstrap sampling to correct for optimism in the within-sample AUC. MVA of overall survival (OS) within 1 yr used the CHARM score and adjusted for other significant variables derived from stepwise regression. Results: The primary analysis included 1105 pts who were confirmed eligible and proceeded to transplant. Median age was 67 (range 60-82) and 32% were ≥ 70 yrs. AML (45%) and MDS (30%) were the most common indications and matched donors the most frequent donor type at 72%. Reduced intensity conditioning with fludarabine (flu)-melphalan (38%) and flu-busulfan (20%) were the most common regimens. Baseline geriatric vulnerabilities among evaluable pts were frequent including slow walk speed (<0.8 meter/second) in 22%, any IADL limitation in 37%, and cognitive impairment (MoCA < 23) in 12%. 1-yr NRM was lower than expected at 14.4% with 1-yr OS of 72%. In the MVA model, albumin, CRP, HCT-CI, and weight loss were independently associated with NRM (Table) and comprised the CHARM. Of note, increasing age did not significantly affect NRM. The CHARM had within sample and bootstrap corrected AUC of 0.641 and 0.607 whereas the HCT-CI alone achieved corresponding AUC values of 0.601 and 0.598. NRM by tertiles is shown in Figure. Each point increase in the CHARM (median -2.2504, range -3.6327 to 0.1381), was associated with a hazard ratio (HR) of 2.83 (95% CI 2.12 - 3.78, p < 0.0001) for NRM. The CHARM also predicted overall mortality within 1-yr with a HR of 2.04 (1.65- 2.53, p <0.0001) per one point increase, independent of the disease risk index, which had a HR of 1.5 (95% CI 1.12 - 1.99, p =0.0059) for high/very high vs low/intermediate categories. Conclusions: We report on the first prospectively established tool, CHARM, to risk-stratify older adult HCT comprised of simple and readily available parameters in transplant and oncology clinics. Adopting CHARM in practice may promote HCT referrals and access for older pts, given low risks of NRM among CHARM lower 2/3 rd tertiles. Identifying high-risk CHARM pts pre-HCT will promote developing novel strategies to reduce NRM. Further analysis of the impacts of the 13 health assessment variables on geriatric morbidity such as disability trajectories is in-process.

Optimized Double-Unit Cord Blood Transplantation Mitigates Transplant-Related Mortality Resulting in High Progression-Free Survival in Adults with Hematologic Malignancies

Background : Double-unit cord blood transplantation (dCBT) with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400cGy) and cyclosporine-A (CSA)/ mycophenolate mofetil (MMF) graft-versus-host disease (GVHD) prophylaxis has been associated with high progression-free survival (PFS) in adult patients (pts) with hematologic malignancies ( Barker JN et al, Blood Advances 2020). Now, our Center has investigated multiple refinements to further mitigate transplant-related mortality (TRM). Herein, we have analyzed transplant outcomes in these adult dCBT pts to establish an optimized dCBT platform. Methods : Consecutive adult first allograft pts with high-risk hematologic malignancies who underwent first allografts with intermediate intensity dCBT between 3/2018-8/2022 were analyzed. Optimizations involved further refined unit selection placing highest priority on unit quality (i.e. optimized banking practices) & CD34+ cell dose over HLA-match, ensuring therapeutic (CSA) levels (> 250 ng/mL) by day 0, prompt treatment of pre-engraftment syndrome (PES) & letermovir prophylaxis in CMV seropositive pts from day +7. Also, we have investigated 2 strategies to mitigate acute graft-versus-host disease (aGVHD): pts early in the study period received CSA, MMF & tocilizumab (8 mg/kg on day -1) prophylaxis ( Toci Group), whereas recent pts ( Recent Group) received CSA/ MMF with prompt therapy of clinically diagnosed aGVHD. Results : Of 74 patients (Table), 49 were in the Toci Group, & 25 in the Recent Group. Most pts were transplanted for acute leukemia (n = 55, 74%) & over half (n = 39, 53%) had non-European ancestry. Distribution of diagnoses, CMV serostatus, HCT-CI & graft characteristics were similar between the groups but Recent Group pts tended to be younger (38 vs. 47 years, p = 0.071). Toci Group pts had delayed neutrophil recovery [engraftment incidence 94% (95%CI: 87-99) at a median of 25 days (range 16-40), one graft failure], but low rates of PES (n = 19, 39%). The day-100 incidence of grade II-IV & III-IV aGVHD were 69% (95%CI: 56-82) & 10% (95%CI: 2-19), respectively. One pt (false negative CMV-serostatus) who did not receive letermovir had CMV infection. One-year TRM was 16% (95%CI: 6-27) with a 1-year relapse rate of 6% (95%CI: 3-13). TRM was due to infection (n = 3), aGVHD (n = 3, 1 with concurrent COVID-19 infection), multiorgan failure (n = 2) & graft failure (n = 1). With a median follow-up of 47 months (range 28-62), the 1-year OS was 84% (95%CI: 73-94) & 1-year PFS was 78% (95%CI: 66-89). By contrast, the engraftment incidence in Recent Group pts was 100% with a faster median neutrophil recovery of 19 days (range 11-36, p = 0.002) & all engrafted platelets at a median of 36 days (range 24-92). However, most Recent group pts developed PES [n = 20 (80%), p < 0.001] although this responded promptly to short course corticosteroids. Day 100 grade II-IV aGVHD was also higher [92% (95%CI: 81-99), p = 0.009], although grade III-IV aGVHD was low [8% (95%CI: <1-19)] & similar to tocilizumab pts. Day 100 incidence of CMV was 0%. With a median follow-up of 17 months (range 6-50), the 1-year TRM in Recent Group pts is 0% with a 1-year relapse incidence of 13% (95%CI: 7-27). Consequently, the 1-year OS & PFS are high at 96% (95%: 89-99) & 87% (95%CI: 74-99), respectively (Figure). Conclusions: Optimized dCBT with intermediate intensity conditioning, graft selection that prioritizes unit quality & CD34+ dose, CSA/ MMF prophylaxis with prompt therapy of PES & aGVHD, & letermovir CMV prophylaxis mitigates TRM in young & middle-aged adults. Thus, combined with relatively low relapse rates, the PFS & OS are high. Tocilizumab has been abandoned due to its notable association with delayed neutrophil engraftment & lack of survival advantage. Letermovir is highly effective completely preventing CMV infections & may contribute to the reduced aGVHD-related mortality recently (as compared to the pre-tocilizumab era), since avoidance of CMV antiviral therapy toxicities greatly facilitates aGVHD prevention & therapy. Given the rapid availability of cryopreserved unmanipulated CB grafts & frequent limitations of URD availability for minority populations, optimized dCBT is a highly attractive curative therapy for acute leukemias & other high-risk myeloid malignancies warranting prospective multi-center investigation.

A Modified Busulfan/Cyclophosphamide Preconditioning Regimen Incorporating Selinexor for Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Hematologic Malignancies

Objective: To investigate the safety and efficacy of a modified busulfan (Bu)/cyclophosphamide (Cy) conditioning regimen incorporating Selinexor for allogeneic hematopoietic stem cell transplantation in relapsed/refractory hematologic malignancies. Methods: We retrospectively evaluated the clinical outcomes of patients with hematologic malignancies who had received allo-HSCT with conditioning incorporating Selinexor at the Institute of Hematology and Blood Disease Hospital. Results: Between September 2022 and June 2023, 13 adult patients with high-risk hematologic malignancies were enrolled including 6 males and 7 females with a median age of 49 (13-58) years. There were 7 patients with acute myeloid leukemia (AML), 4 with myelodysplastic syndromes (MDS)/AML, 1 with multiple myeloma (MM) and 1 with extramedullary plasmacytoma. Six patients were in complete remission (CR), four in CR1, two in ≥CR2, five in non-remission (NR), and two patients were in a progressive disease status (PD) prior to conditioning. Three patients received matched-sibling donors transplant, while ten received related haploid hematopoietic stem cell transplantation. All patients had received myeloablative conditioning regimen incorporating Selinexor. Eleven patients received the conditioning: Bu (3.2mg/kg/d*2d); Melphalan (Mel, 60mg/m 2/d*2d), Fludarabine(Flu 30mg/m 2/d*3d) or CLA (5mg/m 2/d*3d), Cy (40mg/kg/d*2d), Selinexor 60mg/d*2d. The other 2 patients received the conditioning: Decitabine (DAC, 20mg/m 2/d*5d), Bu (3.2mg/kg/d*3d), Cy (40mg/kg/d *2d), Flu 30mg/m2/d*3d, Selinexor 60mg/d*2d. The median amount of infused mononuclear cell and CD34 + stem cell were 11.72×10 8/kg(range, 9.66 to 14) and 2.92×10 6/kg(range, 2.35 to 9.61), respectively. All the 13 patients achieved neutrophil engraftment with a median time of 12 (range, 9 to 18) days and 9 patients achieved platelet engraftment with a median time of 13 (range, 11 to 30) days. Four patients were still experiencing prolonged isolated thrombocytopenia. All patients achieved complete donor chimerism and minimal residual disease (MRD) negative at 30 days post-transplantation.The cumulative incidence of cytomegalovirus (CMV) reactivation was 15.4%, while Epstein-Barr virus (EBV) reactivation was not observed. Six patients (46.2%) experienced mucosal barrier injury, comprising three cases of oral mucosal ulcer, one case of digestive tract hemorrhage, and two cases of hemorrhagic cystitis. The cumulative incidence of II-IV and III-IV acute GVHD was 23.1% and 15.4%. The median follow-up for all the participants was 93 (40-316) days after transplantation. Only one patient was dead due to Thrombotic Microangiopathy (TMA) 78 days after transplant. One patient experienced molecular relapse 156 days after transplant, and another patient experienced hematology relapse 20 days after transplant. The two relapsed patients had received donor lymphocyte infusions after chemotherapy. The other 10 patients were still in CR with complete donor chimerism and MRD negative. The cumulative transplant-related mortality (TRM) and relapse rates are 7.7% (1 case) and 15.4% (2 cases), respectively. Conclusions: Incorporating Selinexor into the modified BU/CY conditioning regimen for allogeneic HSCT in patients with relapsed/refractory hematologic malignancies demonstrated a favorable safety profile. Ongoing prospective trials will provide valuable insights into the potential benefits of Selinexor in patients undergoing HSCT.

Utilization and outcome disparities in allogeneic hematopoietic stem cell transplant in the United States.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is increasingly being used in the United States (US) and across the world as a curative therapeutic option for patients with certain high-risk hematologic malignancies and non-malignant diseases. However, racial and ethnic disparities in utilization of the procedure and in outcome following transplant remain major problems. Racial and ethnic minority patients are consistently under-represented in the proportion of patients who undergo allo-HSCT in the US. The transplant outcomes in these patients are also inferior. The interrelated driving forces responsible for the differences in the utilization and transplant outcome of the medical intervention are socioeconomic status, complexity of the procedure, geographical barriers, and the results of differences in the genetics and comorbidities across different races. Bridging the disparity gaps is important not only to provide equity and inclusion in the utilization of this potentially life-saving procedure but also in ensuring that minority groups are well represented for research studies about allo-HSCT. This is required to determine interventions that may be more efficacious in particular racial and ethnic groups. Various strategies at the Federal, State, and Program levels have been designed to bridge the disparity gaps with varying successes. In this review paper, we will examine the disparities and discuss the strategies currently available to address the utilization and outcome gaps between patients of different races in the US.

Telemedicine in Hematopoietic Cell Transplantation and Chimeric Antigen Receptor-T Cell Therapy.

Telemedicine has played an important role in delivering healthcare for primary care, chronic disease patients, and those with solid organ malignancies. However, its application in subspecialties such as hematologic malignancies, hematopoietic cell transplantation (HCT), or chimeric antigen receptor-T cell (CAR-T) therapy is not widespread since physical examination is a vital component in delivering care. During the COVID-19 pandemic, we widely used telemedicine, since protecting our immunocompromised patients became our top priority. The employment of HCT and CAR-T therapies continues to grow for high-risk hematologic malignancies, particularly in older and frail patients who must visit specialty centers for treatment access. Generally, HCT and CAR-T therapy care is highly complex, necessitating commitment from patients, caregivers, and a multidisciplinary team at specialty academic centers. All healthcare systems adapted to the crisis and implemented rapid changes during the COVID-19 public health emergency (PHE). Telemedicine, a vital modality for delivering healthcare in underserved areas, experienced rapid expansion, regardless of the geographic region, during the COVID-19 PHE. The data emerging from practices implemented during the PHE are propelling the field of telemedicine forward, particularly for specialties with complex medical treatments such as HCT and CAR-T therapy. In this review, we examine the current data on telemedicine in HCT and cellular therapy care models for the acute and long-term care of our patients.

Predictors of SARS-CoV-2 Omicron breakthrough infection after receipt of AZD7442 (tixagevimab-cilgavimab) for pre-exposure prophylaxis among hematologic malignancy patients.

AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for pre-exposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or realworld experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 high-risk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher firsttime dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.

Etiology and outcomes of neutropenic fever in Malawi: A prospective, observational cohort.

e18831 Background: Neutropenic fever (NF) is a common, life-threatening complication of chemotherapy. Over 80% of high risk hematological malignancy cases will develop NF, with mortality rates reaching 10%. In high income countries (HIC), NF prevention guidelines including prophylaxis have decreased treatment-related mortality. In sub-Saharan Africa (SSA), little is known about the causes of NF as many deaths occur in facilities without blood culture availability. Pathogens in SSA may vary from those in HIC due to high burden of HIV infection as well as different antibiotic stewardship, endemic infections, and chemotherapy regimens. Unknown bacterial spectrum and resistance patterns prevent extrapolation of NF guidelines to SSA. Methods: Patients undergoing chemotherapy at Kamuzu Central Hospital (KCH) in Lilongwe, Malawi were eligible to participate in the study if they were starting a new chemotherapy regimen, lived within 200 kilometers, and (1) had a hematologic malignancy of any kind or (2) had a solid tumor and were HIV-infected. Enrolled patients were given a thermometer and if a temperature of 38º C or greater was recorded, they were instructed to return for management, including admission and antibiotics. Evaluation consisted of complete blood count with differential, urine and blood cultures, and other testing at the clinician’s discretion. All patients were followed through 90 days post fever event or completion of chemotherapy, whichever came later. Results: 106 patients were screened and 50 were enrolled. The primary reason for screen failure was household distance from KCH. Of the enrollees, 26 (52%) were men and 26 (52%) were HIV positive with an average ART treatment time of 7 years and CD4 count of 293 cells/mL. Diagnoses included: aggressive lymphoma (36%), Hodgkin lymphoma (22%), low-grade lymphoma (10%), multicentric Castleman disease (6%), non-Hodgkin lymphoma, NOS (4%), breast cancer (6%), cervical cancer (4%), and other solid tumors (12%). There were 23 febrile events recorded from 15 patients (10 HIV– and 5 HIV+), with no relationship between HIV status and febrile events (p = 0.08). Of the 23 events, a causative agent was isolated in 13 cases (E. coli (6), Malaria (3) and S. pneumonia (2), Pseudomonas (1) and C. freundii (1). Of the 6 E.coli isolates, 3 were found to be multidrug resistant (ie resistant to fluoroquinolones and cephalosporins) and treatment was escalated with a carbapenem. All patients but one survived; death was attributed to Pseudomonas bacteremia. Conclusions: This study demonstrates the initial laboratory trends of febrile events in cancer patients in Lilongwe, Malawi. GNRs, followed by malaria, were the most common source of infection and GNRs were associated with high rates of resistance. Endemic and resistant bacterial infections should be considered when treating NF. Larger studies are needed across the region to identify the pathogens most commonly associated with NF.

Impact of body mass index (BMI) and weight changes on hematopoietic stem cell transplant (HSCT) outcomes in the elderly population.

e19058 Background: HSCT remains the only curative treatment for high-risk hematologic malignancies. Reduced intensity conditioning (RIC) has increasingly allowed transplant of elderly patients. However, maximizing outcomes in this population remains a challenge. We examine the influence of BMI and weight changes on HSCT outcomes in the elderly. Methods: This was a retrospective review of 216 patients ≥60 years of age who underwent first HSCT at the Loyola University Medical Center between 8/30/2000-6/15/2017. Pearson Chi-square tests for independence evaluated the associations between categorical variables and timing of recurrence. Fisher’s exact test were used where expected frequencies were <5. Independent two-sample t-tests and ANOVA assessed differences in numerical variables. Results: BMI at time of transplant, defined as underweight (BMI<18), normal weight (BMI 18-25), overweight (BMI 25-30), and morbidly obese (BMI>30), did not impact incidence of cardiac dysfunction, pulmonary complications (Cx’s), renal Cx’s, graft versus host disease (GVHD), paraenteral nutrition (TPN) use, changes in albumin, or mortality. However, there was a trend towards increased disease relapse in those who were not normal weight (p=.08). Normal weight (BMI 18-25) at Day 100 was associated with decreased cardiac dysfunction (p=.02), days of hospitalization (p = .03), and mortality (p = .02) compared to non-normal BMI (BMI < 18 or BMI > 25). But there appeared no difference in rates of renal Cx's, GVHD, TPN use, or relapse. Having >10% weight change at discharge from transplant admission was associated with increased renal Cx’s (p = .007), infectious Cx’s (p = .03), use of TPN (p = .006), length of hospital stay (p = .0002), and mortality (p = .009). However, it was not associated with cardiac dysfunction, pulmonary Cx’s, readmissions by 6 months, GVHD, or relapse. Having >10% weight change at Day 100 was associated with increased risk of acute (p = .01) and chronic GVHD (p = .002) and readmissions by 6 months (p = .01), but not with other Cx’s, relapse, or mortality. Conclusions: Patients who were underweight or overweight at key timepoints may impact complications and HSCT outcomes. Furthermore, maintaining a stable weight during transplant admission and the first 100 days was associated with decreased rates of complications and adverse HSCT outcomes. These findings warrant further evaluation into age-related weight and nutritional targets to improve understanding and optimize HSCT outcomes in this vulnerable population. [Table: see text]