Cell Transplantation For Hematologic Malignancies Research Articles

Complications and the impact of hematological parameters in donors involved in allogenic peripheral blood stem cell transplantation for hematological malignancies

Hematopoietic stem cell transplantation (HSCT) is a vital treatment option for many hematological malignancies, offering a more convenient alternative to bone marrow transplantation. In allogeneic HSCT, donors provide hematopoietic stem cells for transplantation into patients, necessitating careful consideration of the donor's health and hematological parameters to ensure successful engraftment and treatment outcomes. In a study involving 20 adult donors at Apeksha Hospital, Sri Lanka key hematological parameters, comorbidities, clinical histories, and medications were analyzed. Diabetes mellitus and hypertension were the most prevalent comorbidities among donors, while anemia, primarily linked to iron and vitamin B12 deficiencies, was common. Although baseline coagulation abnormalities were rare and no significant complications occurred during transplantation, early clinical issues such as pain and paresthesia correlated with abnormal peripheral blood smear findings. Notably, a 4-day single daily G-CSF dosing schedule was favored over a 5-day twice daily regimen due to fewer reported problems. While anemia and thrombocytopenia were infrequent, these findings underscore the critical importance of meticulous donor selection and vigilant monitoring throughout the transplantation process to optimize outcomes.

Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies

AbstractThe introduction of posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy–based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

Optimal Rabbit Antithymocyte Pharmacokinetics (PK) Is Associated with Improved Disease-Free Survival (DFS) in TCR-Αβ/CD19-Depleted Pediatric Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

Optimal Rabbit Antithymocyte Pharmacokinetics (PK) Is Associated with Improved Disease-Free Survival (DFS) in TCR-Αβ/CD19-Depleted Pediatric Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

Second line extracorporeal photopheresis for cortico-resistant acute and chronic GVHD after allogeneic hematopoietic cell transplantation for hematological malignancies: Long-term results from a real-life study

Background & ObjectivesThe primary objective of this observational study was to perform an exhaustive description concerning patients receiving extracorporeal photopheresis (ECP) as second line treatment after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes. Study designA total of 106 patients were included, 65 (61%) males and 41 (39%) females with a median age at transplantation of 52 years (range: 20–67). ECP was initiated after transplantation either for acute GVHD [N = 25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N = 5), gut alone (N = 12), gut and liver (N = 8), or chronic GVHD [N = 81 (76%), 15 (14%) limited and 66 (62%) extensive]. ResultsAmong the 25 patients treated for acute GHVD, 67% were responders and among the 81 patients with chronic GVHD, 78% were responders.Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14–56]. Patients with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56–78]. There was a significant difference in terms of survival for patients responding to ECP compared to non-responders in both acute and chronic GVHD forms. Acute GVHD grade III-IV, negatively impacted on OS (HR=7.77, 95%CI: 1.7–34), p = 0.007 and on disease relapse HR= 5.88, 95%CI: 1.7–20, p = 0.005. ConclusionWe demonstrated that ECP is an effective treatment for GVHD in a good proportion of patients with high overall response rate.

Identification and surveillance of rare relapse-initiating stem cells during complete remission after transplantation

AbstractRelapse after complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and, therefore, improved biomarkers for early prediction of relapse remains a critical goal toward development and assessment of preemptive relapse treatment. Because the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse prediction after transplantation. In a retrospective study of patients who relapsed and patients who achieved continuous-CR with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in the bone marrow at multiple CR time points after transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric-sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean, 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by >2 years. In contrast, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean, 8-fold). In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD screening for their persistence consistently enhances MRD sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation.

Impact of stem cell selection between bone marrow and peripheral blood stem cells for unrelated hematopoietic stem cell transplantation for hematologic malignancies: on behalf of the Donor/Source Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background aimsThis study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. MethodsA retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0–70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. ResultsAmong 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0–24 years, indicating that both sources are viable choices for young patients. ConclusionsThis real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

Immunological aspects of hematopoietic stem cell transplantation for hematologic malignancies and some immunological peculiarities of cancer radioimmunotherapy

This literature review provides basic information about the role of hematopoietic stem cell transplantation in the treatment of myelodysplastic syndromes, acute myeloid leukemia, acute lymphoblastic leukemia. The recommendations for the use of stem cell transplantation are indicated. Conditioning regimens (myeloablative, non-myeloablative, reduced intensity), their advantages and disadvantages are considered. The issues of prevention and treatment of graft-versus-host disease, including graft preparation (T-cell depletion), extracorporeal photopheresis and mechanisms of graft-versus-tumor (-leukemia) reaction are highlighted. The historical milestones of theimmunotherapy development, the creation of therapeutic monoclonal antibodies, the development of targeted therapy, for example, conjugates of monoclonal antibodies with cytostatic drugs and radionuclides (targeted radionuclide therapy) are reported. Information about radioimmunotherapy as a method used for treatment of solid tumors and non-Hodgkin’s lymphoma, and information on the use of mesenchymal stem cells for the treatment and prevention of the graft-versus-host reaction are presented.

Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy.

Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on "active" rATG population PK (popPK) analysis, while "total" rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5-3mg/kg) within 3days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), CD4+ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest.

A Case Report of Lung Transplantation After Hematopoietic Stem Cell Transplantation and Literature Review

Pulmonary complications may occur after hematopoietic stem cell transplantation for hematologic malignancies. Lung transplantation is the only treatment option for end-stage lung failure. We presented a case of acute myeloid leukemia who received a hematopoietic stem cell transplantation and underwent bilateral lung transplantation with end-stage usual interstitial pneumonia and chronic obstructive lung disease. This case showed that lung transplantation could be successfully applied in properly selected hematologic malignancy patients with long disease-free survival, like lung transplantations performed for other indications.

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies.

Total body irradiation (TBI) has been an essential component of the conditioning regimen in hematopoietic cell transplantation for many years. However, higher doses of TBI reduce disease relapse at the expense of more significant toxicities. Therefore, total marrow irradiation and total marrow and lymphoid irradiation have been developed to deliver organ-sparing targeted radiotherapy. Data from different studies show that TMI and TMLI can be safely administered in escalating doses in association with different chemotherapy conditioning regimen protocols, in situations with unmet needs, such as multiple myeloma, high-risk hematologic malignancies, relapsed or refractory leukemias, and elderly or frail patients, with low rates of transplant-related mortality. We reviewed the literature on applying TMI and TMLI techniques in autologous and allogeneic hematopoietic stem cell transplantation in different clinical situations.

Outcomes of Busulfan, Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience

Reduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine-total body irradiation (TBI) with fludarabine among patients with hematologic diseases. This retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d×2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years. The donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P=.06, and 5-year OS rate 53% vs 39%, P=.13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P=.003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P=.001) in both groups. A high disease risk index was possibly associated with inferior OS (P=.07) in both groups. The FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.

GVHD relapse-free survival after peripheral blood hematopoietic cell transplantation for hematologic malignancies.

The preferred choice for hematopoietic cell transplantation (HCT) donors in India is a matched related donor (MRD) followed by a haploidentical (haplo) donor for patients with hematological malignancies. International data in the haplo-HCT setting is mainly using bone marrow as a source. Almost all HCTs in India use peripheral blood stem cells (PBSC), which increases the risk of graft-versus-host disease (GVHD). In this single-center prospective study from 2017 to 2021, we sought to compare these outcomes prospectively in adult patients with hematological malignancies. Patient, disease, donor, and HCT details were prospectively recorded. GVHD prophylaxis included cyclosporine + methotrexate in MRD-HCT and post-transplant cyclophosphamide (PTCy) based in haplo-HCT. The primary endpoint GVHD relapse-free survival (GRFS) was defined as the time post-HCT without any of the following events: grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause. A total of 41 MRD and 33 haplo-HCT recipients were included in the study. Both cohorts were matched for age, sex, diagnosis, disease risk index, donor age, sex and CMV mismatches, and CD34 counts. A lower proportion of MRD-HCT recipients than haplo-HCT received myeloablative conditioning (39% vs. 76%, p = 0.002). There was no difference in the cumulative incidence of grade III-IV acute GVHD (16% vs. 27%, p = 0.2) or moderate-to-severe chronic GVHD (58% vs. 71%, p = 0.5). The one-year GRFS was not significantly different (53% vs. 38%, p = 0.2), with median GRFS of 420 and 274 days. The relapse incidence (22% vs. 19%, p = 0.6) and non-relapse mortality (25% vs. 35%, p = 0.4) did not differ. There was no difference in overall survival at one year (60% vs. 52%, p = 0.3). Despite a higher proportion of myeloablative conditioning in the haplo-HCT cohort, all outcomes, including GRFS, were comparable to those of the MRD-HCT cohort. This should encourage patients without an MRD to undergo haplo-HCT.

Impact of total marrow/lymphoid irradiation dose to the intestine on graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for hematologic malignancies.

Graft-versus-host disease (GvHD) is a leading cause of non-relapse mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The Perugia Bone Marrow Transplantation Unit designed a new conditioning regimen with total marrow/lymphoid irradiation (TMLI) and adaptive immunotherapy. The present study investigated the impact of radiotherapy (RT) doses on the intestine on the incidence of acute GvHD (aGvHD) in transplant recipients, analyzing the main dosimetric parameters. Between August 2015 and April 2021, 50 patients with hematologic malignancies were enrolled. All patients underwent conditioning with TMLI. Dosimetric parameters (for the whole intestine and its segments) were assessed as risk factors for aGvHD. The RT dose that was received by each intestinal area with aGvHD was extrapolated from the treatment plan for each patient. Doses were compared with those of the whole intestine minus the affected area. Eighteen patients (36%) developed grade ≥2 aGvHD (G2 in 5, G3 in 11, and G4 in 2). Median time to onset was 41 days (range 23-69 days). The skin was involved in 11 patients, the intestine in 16, and the liver in 5. In all 50 TMLI patients, the mean dose to the whole intestine was 7.1 Gy (range 5.07-10.92 Gy). No patient developed chronic GvHD (cGvHD). No dosimetric variable emerged as a significant risk factor for aGvHD. No dosimetric parameter of the intestinal areas with aGvHD was associated with the disease. In our clinical setting and data sample, we have found no clear evidence that current TMLI dosages to the intestine were linked to the development of aGvHD. However, due to some study limitations, this investigation should be considered as a preliminary assessment. Findings need to be confirmed in a larger cohort and in preclinical models.

Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation

AbstractAdministration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients’ samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.

396 - A Two-Part, Single- and Two-Arm Randomized, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of KRP203 in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

396 - A Two-Part, Single- and Two-Arm Randomized, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of KRP203 in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Antithymocyte globulin plus post-transplant cyclophosphamide combination as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation for hematological malignancies.

Post-transplant cyclophosphamide (PT-Cy) and calcineurin inhibitors used in peripheral blood haplo-identical stem cell transplantation (haploSCT) increase the risk of acute/chronic graft-versus-host disease (GVHD). Whether ATG/PT-Cy is feasible for Asian patients undergoing haploSCT is unclear, and an optimal strategy for GVHD prophylaxis is needed. We retrospectively analyzed 61 hematologic malignancy patients who underwent peripheral blood haploSCT using ATG/PT-Cy from January 2013 to December 2018. We also compared the effects of ATG/PT-Cy (ATG group; n = 61) with historical data from patients who underwent haploSCT using sirolimus/PT-Cy (non-ATG group; n = 22). Cumulative incidences of grades II-IV acute GVHD and moderate to severe chronic GVHD did not differ significantly. The ATG group had higher incidence of Epstein-Barr virus (EBV) reactivation, but neither group had post-transplant lymphoproliferative disorders. The ATG group also had a higher OS rate (2-year OS in ATG group vs. non-ATG group: 43.4% vs. 27.3%, respectively; P = 0.071). ATG/PT-Cy is an acceptable strategy for GVHD prophylaxis in Asian patients undergoing haploSCT.

Efficacy and safety of hematopoietic stem cell transplantation for hematologic malignancies

Abstract Introduction: Hematopoietic stem cell transplantation is an essential and often the sole treatment strategy for relapsed and refractory hematologic malignancies (HMs). More and more systematic reviews and meta-analysis of clinical trials have investigated the effects of hematopoietic stem cell transplantation in patients with HMs. In order to systematically appraise and synthesize these results, we will conduct an overview of systematic review and meta-analysis. Methods: This is a protocol for an overview of systematic reviews and meta-analysis. We will search eight databases: PubMed, Embase, Cochrane Library, Web of Science Core Collection, China Biology Medicine disc, Chinese National Knowledge Infrastructure, Chinese Scientific Journals Database and Wan Fang Data. The time is limited from the construction of the library to May 2021.Systematic reviews and meta-analysis of clinical trials evaluating the efficacy and safety of hematopoietic stem cells in patients with HMs will be included. Hematopoietic stem cells included bone marrow, peripheral blood stem cells and cord blood stem cells. Patients with HMs including leukemia, malignant lymphoma, myelodysplastic syndrome, etc. Two independent authors will screen titles and abstracts retrieved in the literature search and select studies meeting the eligibility criteria for full text review. The methodological quality of the included reviews will be assessed using A Measurement Tool to Assess Systematic Reviews-2. The efficacy and safety of different stem cell types in the treatment of the same hematological disease and the same stem cell type in the treatment of different HMs will be analyzed. Additionally, the quality of evidence will use the Grading of Recommendations Assessment, Development and Evaluation system. Our reviewers will conduct systematic reviews, qualification evaluation, data extraction, methodological quality and evidence quality screening in pairs. Results: The results will be published in a peer-reviewed journal. Conclusion: This overview will provide comprehensive evidence for hematopoietic stem cell transplantation in patients with HMs. Protocol Registration: INPLASY202150064.

Donor Socioeconomic Status As a Predictor of Altered Immune Function and Treatment Response Following Hematopoietic Cell Transplantation for Hematologic Malignancy

Introduction: Hematopoietic cell transplantation (HCT) carries significant risks for mortality, which are not proportionally shared across individuals. Among HCT recipients, we have previously shown that low socioeconomic status (SES) is predictive of increased mortality following HCT, and the underlying mechanism for this outcome is not fully explained by race, insurance status or access to care. Furthermore, following HCT, the donor immune system replaces that of the recipient, leading to long-term engraftment with donor-derived immune cells. Previous work has not addressed the influence of donor socioeconomic factors on HCT recipient outcomes. Therefore, we hypothesized that SES would impact donor hematopoietic cells and this effect would be transferrable and associated with adverse recipient outcomes.Methods: Recipients of matched unrelated donor allogeneic peripheral blood stem cell HCT between 2000-2013 for hematologic malignancy, resided in the United States (US) with a documented ZIP code, and had a HCT donor with documented US ZIP code were identified from the Center for International Blood and Marrow Transplantation Research (CIBMTR). Using donor ZIP code, SES measures of household income, poverty, education, housing and employment were derived from the U.S. Census American Community Survey. A standardized donor SES composite score was computed as an equally weighted average of the 5 standardized SES variables (mean composite score = 0, standard deviation (SD) = 1). Multivariable models, adjusted for donor and recipient characteristics, were used to evaluate associations between donor SES composite score with HCT recipient disease free survival (DFS), overall survival (OS), treatment related mortality (TRM), relapse, and acute and chronic graft versus host disease (GVHD). Results were considered significant if P < 0.01.Results: Among 2,005 HCT recipients, median age at diagnosis was 51 years (range 1-77), 44% were female, and 55% had acute myeloid leukemia. Median post-HCT follow up was 120 months (range 4-219). Donors were 44% female and median age at hematopoietic cell donation was 34.7 years (range 18-62). The standardized donor composite scores ranged from -2.6 to 3.9, with a higher composite score indicative of greater socioeconomic disadvantage. Multivariable analyses identified significant associations between the standardized donor SES composite score and DFS (HR 1.07 per SD SES, 95% CI 1.02-1.13; p=0.0088), OS (HR 1.09 per SD SES, 95% CI 1.04-1.15; p=0.0007), and TRM (HR 1.10 per SD SES, 95% CI 1.03-1.17; p=0.0049). Significant associations were not identified between donor SES and relapse or GVHD. Quantitatively, recipients transplanted with cells from a donor of greater socioeconomic disadvantage (i.e. SES composite score 2 SD above the mean) experienced a 10% reduction in DFS and OS, and a 5% increase in TRM at 3 years compared with those transplanted with cells from a high-SES donor (SES composite score 2 SD below the mean) (Figure).Conclusions: For the first time, we have demonstrated that socioeconomic disadvantage among HCT donors results in adverse transplant outcomes in the HCT recipient. This novel finding suggests that SES has biologic impacts down to the stem cell level that persist even when transplanted into a new host during HCT. The implications of these findings are broad and suggest the need for public health interventions targeting socioeconomic support as a means for preventing social disparities in cancer treatment outcomes. [Display omitted] DisclosuresVerneris: Novartis: Other: advisory board; jazz: Other: advisory board; Fate Therapeutics: Consultancy.

Healthcare utilization and cost of cancer-related care prior to allogeneic hematopoietic cell transplantation for hematologic malignancies in the US: a retrospective real-world analysis

BackgroundHematopoietic cell transplantation (HCT) is a potentially curative therapy as well as a costly procedure. Published studies have examined the cost of HCT in the US and the complications that follow but little is known about the cancer-related healthcare costs and resource utilization prior to the procedure and none of the studies have examined the variability in cost based on the type of hematologic malignancy involved. The aim of this study was to estimate mean cancer-related costs and resources incurred before the HCT is performed from the time the hematologic malignancy first develops.MethodsThe IBM® MarketScan® Research Databases were used to identify adult patients ≥18 years of age with commercial or Medicare supplemental insurance who had undergone allogeneic HCT for hematologic malignancies from January 1, 2008 to December 31, 2017. Healthcare utilization and costs were assessed during the 6 months prior to diagnosis (pre-diagnostic period) and the follow-up period from diagnosis just prior to the HCT (pre-HCT period). Multivariable regression models were constructed to estimate total all-cause costs and cancer-related costs as well as healthcare utilization by type in each time period.ResultsA total of 2663 commercially insured patients and 266 with Medicare supplemental insurance were included in the study population. The mean-adjusted incremental cancer-related costs for commercially insured patients was $399,011 in the overall observation period including the pre-diagnostic and pre-HCT periods combined, 9% of which was incurred in the pre-diagnostic period. The corresponding mean-adjusted incremental cancer-related costs for Medicare supplemental patients was $195,575 for the same time period but the patterns of healthcare utilization were similar to the commercially insured population. Inpatient care accounted for approximately one-half the cost in both patient populations. By type of hematologic malignancy, costs were lowest for myeloproliferative disorders ($211,561) and highest for acute lymphocytic leukemia ($462,072) in the commercially insured population.ConclusionThis study demonstrates that overall patients with hematologic malignancies requiring HCT have considerable cancer-related healthcare resource utilization and costs leading up to HCT compared to the period of time prior to developing cancer.

Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice

AbstractGraft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II+ donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.