HCT Outcomes Research Articles

Complex Restrictive Lung Disease Patterns Affecting Survival and Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant: A Single-Institution Retrospective Analysis

Background: Allogeneic stem cell transplant is the only curative therapy for some patients with hematologic malignancies. While pulmonary function impairment related to diffusion capacity and air flow obstruction is part of the predictive Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), restrictive changes are poorly reflected. A new entity known as complex restrictive lung disease (CRLD) refers to a discrepancy between Forced Vital Capacity percent predicted (FVCpp) and Total Lung Capacity percent predicted (TLCpp). FVCpp being disproportionately lower than TLCpp occurs due to impaired lung emptying from neuromuscular disease, obesity, bronchiectasis, occult obstruction, pulmonary hypertension and chest wall limitations. In simple restrictive lung disease (SRLD) such as pulmonary fibrosis, FVCpp is proportionately decreased compared to TLCpp. Methods: Over three years, 124 patients received myeloablative (MA) or reduced intensity conditioning (RIC) followed by matched unrelated donor (MUD) or matched related donor (MRD) grafts. Patients had complete pulmonary function tests (PFT) within 60 days prior to transplant and 6 months post-transplant. Simple Restriction was defined as TLCpp - FVCpp <10%. Complex Restriction was defined as TLCpp - FVCpp >10%. Our primary outcome in this study was Median Overall Survival (mOS). Median follow up was 14 months. Results: For the 124 enrolled patients, demographics included median age of 55 years (range: 18-70), 60% male, MUD status (73%) with male donor (75%); half received RIC (52%) with fludarabine melphalan (62%) vs fludarabine/busulfan (FLU/BU2) (32%) compared to MA (40%) with FLU/BU4 conditioning (77%). The demographics of diagnosis include Acute Myeloid Leukemia (40%), Lymphoma (17%) and Acute Lymphoblastic Lymphoma (16%) and Myelodysplastic Syndrome (16%). The median HCT-CI/Age score was 4 (0-11). Half (62) developed acute graft-versus-host disease (aGVHD) with 80% as Grade 1-2. One patient was lost to follow up, 65 patients were still alive and 22 had relapse of their initial disease with 17 deaths related to relapse. Out of 58 deaths in this study, 41 deaths (71%) were attributed to non-relapse mortality (NRM) with NRM at 33% and relapse mortality rate at 14%. Out of 124 patients, 10 patients had complex restriction prior to transplant and 9 patients developed complex restriction at 6 months post-transplant. The mOS was 7 months for patients with CRLD prior to transplant (1-14 months) compared to 13 months for patients without CRLD (1- 36 months) (p=0.0026). Eight patients with CRLD before transplant were deceased at follow-up of 14 months, with four (50%) out of those eight deaths related to acute respiratory distress syndrome (25%) and hypoxic respiratory failure (25%). The non-relapse mortality rate for this population was 60% and relapse mortality rate was 10%. For all patients with aGVHD, mOS was greater than 30 months for aGVHD Grades 0-1, 16 months for Grade 2, 6 months for Grade 3 and 5 months for Grade 4 (p=0.0048). Six out of six patients with GVHD and CRLD prior to transplant died from acute respiratory distress syndrome (ARDS) hypoxia, or other cause. Out of the 4 patients with CRLD without GVHD, one patient developed respiratory failure as cause of death. There was no statistical difference in mOS due to BMI (p=0.2895). Nonsmokers and past smokers had a m0S of 22 months, with current smokers at 10 months m0S (p=0.13). We found no statistical difference in survival for the 9 patients who developed CRLD after transplant (p=0.45), the 10 patients with simple restriction prior to transplant (p=0.55), the 21 patients who developed Bronchiolitis Obliterans Syndrome (B0S) after transplant (p=0.25), or the 26 patients with Chronic Obstructive Pulmonary Disease (COPD) prior to transplant compared to normal PFT (p=0.14). The mOS for these groups was 12 months. Conclusion: Patients with complex restrictive lung disease prior to allogeneic stem cell transplant are at high risk for poor outcomes from respiratory and non-respiratory disease when compared to the overall population. As complex restriction is not included in the current HCT-CI, patients with this lung disease should have closer monitoring and scrutiny prior to allogeneic stem cell transplantation. Based on the results of this study, addition of complex restrictive lung disease to the HCT-CI to improve predictability of HCT outcomes warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Incidence and Impact of Clostridioides Difficile Infection (CDI) on Outcomes after Allogeneic Hematopoietic Cell Transplant (alloHCT) - a CIBMTR Study

Introduction: CDI is common after alloHCT mainly due to the frequent use of antibiotics before and during transplant. CDI is reported in 13 to 18% of recipients after alloHCT and in 6 to 8% after autologous HCT, mainly in the first-month post HCT. The determination of incidence and impact of CDI on HCT outcomes will help further our understanding towards the prevention and management of CDI post HCT.Methods: Using the CIBMTR dataset, we examined all patients aged two years and older who received first alloHCT for acute myeloid leukemia (AML), Acute Lymphocytic leukemia (ALL), or myelodysplastic syndrome (MDS) from related or unrelated donors between 2013 and 2018 at US centers. Stem cell sources included HLA-matched marrow, peripheral blood (PBSC), and umbilical cord blood (UCB) (4/6 or higher). The objective was to study the impact of CDI by day 100 on transplant outcomes by one year compared to the control cohort (without documented CDI from the same centers). Multivariable analyses were performed using Cox proportional hazard model for overall survival (OS), disease-free survival (DFS), Transplant related mortality (TRM), Infection-related mortality (IRM), chronic GVHD, and relapse. Both aGVHD preceding CDI and CDI preceding aGVHD were analyzed. Due to overlap in the onset of CDI and aGVHD, an interaction of these time-dependent events in some models were noted necessitating incorporation of a composite variable (CV - CDI+aGVHD) for OS, TRM, IRM, and cGVHD models.Results: A total of 826 patients with CDI and 6723 controls from 127 centers were analyzed. The cumulative incidence of CDI by day 100 following alloHCT was 18.7% (99% CI: 15% - 22.7%) and 10.2% (99% CI: 9.2% - 11.1%) in pediatric and adult patients, respectively [Figure 1]. The median time to diagnosis of CDI was 13 days (0 - 100). Recurrent CDI by 1 year occurred in 15% of patients. Myeloablative conditioning with total body irradiation (compared to Reduced-intensity/non-myeloablative (RIC/NMA) conditioning) and lower gastrointestinal GVHD preceding the diagnosis of CDI were risk factors for CDI. A diagnosis of MDS was associated with a lower risk of CDI. There was significant overlap in the onset of aGVHD and CDI [Figure 2] such that for patients with both CDI and aGVHD [n=378], 115 (30%) had aGVHD prior to CDI, and 70% were diagnosed with CDI first.CV - CDI + aGVHD was associated with a statistically significant increase in IRM and TRM and a decrease in OS. Specifically, CDI was associated with a 2.58-fold [99% CI: 1.43 - 4.66; p<0.001] increase in IRM which increased to >4 fold when CV-CDI + aGVHD was considered, irrespective of whether aGVHD preceded CDI or vice versa [CDI first: 4.88 (99% CI: 2.38 - 9.97), p<0.001; aGVHD first 4.15 (99% CI: 1.46 - 11.80), p = 0.0005]. CDI alone was not associated with increased risk of cGVHD [0.85 (99%CI: 0.66-1.09), p=0.0921], and the CV - CDI+aGVHD had similar risk of cGVHD as aGVHD without CDI. CDI had no impact on relapse or DFS.Conclusion: CDI tightly overlaps with aGVHD. Not surprisingly, the combination of CDI and aGVHD is associated with decreased overall survival and increased TRM. More concerning is that patients having both aGVHD and CDI had a >4-fold increased risk of death due to any infection. Our results highlight the burden and impact of CDI after alloHCT and the critical need to develop new/improved strategies for prevention in alloHCT recipients. [Display omitted] DisclosuresChemaly: Other: Other: Compensation: I am a consultant and advisor on companies who are developing new agents such as Merck, Ansun, and Janssen. Dandoy: Omeros: Other: Consulted and received Honorarium. Perales: Bristol-Myers Squibb: Honoraria; Sellas Life Sciences: Honoraria; Celgene: Honoraria; Cidara: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Merck: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Nektar Therapeutics: Honoraria, Other; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Servier: Honoraria; Takeda: Honoraria. Riches: BioIntelect: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Payment; ATARA Biotherapeutics: Other: Payment. Ustun: novartis: Honoraria; Blueprint: Honoraria.

Impact of Center Experience with Donor Type and Treatment Platform on Outcomes: A Secondary Analysis BMT CTN 1101

BACKGROUND: Our group recently reported on the results of Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 1101 a randomized comparison between double umbilical cord blood (dUCB) and haploidentical bone marrow (haplo) with post-transplant cyclophosphamide (ptCy) in the nonmyeloablative setting that showed similar progression free survival (PFS) between the two treatment groups, but lower non-relapse mortality (NRM) and better of overall survival (OS) in the haplo arm. In this secondary analysis we sought to investigate if transplant center experience with haplo and or cord blood HCT had an impact on outcomes.PATIENTS AND METHODS: All patient randomized in BMT CTN 1101 were included. In order to determine the transplant center experience with either haplo or dUCB we queried the Center for International Blood and Marrow Transplant Research (CIBMTR) for number of transplants with each platform in the year prior to initiation of the study. Centers were then grouped as dUCB center (> 10 dUCB, n=117, 10 centers), Haplo center (>10 haplo and ≤10 dUCB, n=110, 2 centers), and ≤10 haplo and ≤10 dUCB HCTs (other center, n=140, 21 centers). Further analysis considered the alternative cut-off for haplo (> 5 vs ≤ 5) experience, and considered the outcomes based on the donor experience vs. others (e.g. dUCB > 10 vs. ≤ 10; haplo > 5 vs. ≤ 5).RESULTS: The effect of center experience on HCT outcomes shown in Figure, below . After adjusting for age, Karnofsky performance score and, disease risk index we found that there was no difference in outcomes between haplo and dUCB for centers that were experienced with dUCB or had limited to no experience with either dUCB or haplo. In contrast, in centers that were primarily experienced with haplo had better outcomes with this donor type, as compared to dUCB. The higher risk of treatment failure (relapse or death) and overall mortality in dUCB in haplo experienced centers was driven by significantly higher risk of relapse. We then considered the transplant experience with each of the donor types separately. In transplant centers that had performed > 10 dUCB, there were similar outcomes for recipients of both dUCB and haplo. Similarly, centers that had ≤ 5 haplo HCTs had no difference in outcomes between donor types suggesting an overlap with centers that had performed > 10 dUCB HCTs. Overall mortality was higher among dUCB recipients in centers that had performed ≤ 10 dUCB. Notably, the hazard ratio of non-relapse mortality favored haplo in all four donor experience type of transplant center, albeit not statistically significant.CONCLUSION: Except for dUCB recipients in centers with < 10 dUCB/year had worse overall mortality, primarily driven by relapse, the transplant center experience in the year prior to the initiation of BMT CTN 1101 had limited impact on the outcomes of this randomized clinical trial. [Display omitted] DisclosuresBrunstein: NANT: Research Funding; FATE: Research Funding; GamidaCell: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria. Cutler: Deciphera: Consultancy; Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Jazz: Consultancy. Horowitz: Sobi: Research Funding; Regeneron: Research Funding; Orca Biosystems: Research Funding; Tscan: Research Funding; Xenikos: Research Funding; Miltenyi Biotech: Research Funding; Stemcyte: Research Funding; Medac: Research Funding; Vor Biopharma: Research Funding; Kite/Gilead: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Kiadis: Research Funding; Seattle Genetics: Research Funding; Mesoblast: Research Funding; GlaxoSmithKline: Research Funding; Sanofi: Research Funding; Pfizer, Inc: Research Funding; Omeros: Research Funding; Magenta: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; Vertex: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Shire: Research Funding; Gamida Cell: Research Funding; Daiicho Sankyo: Research Funding; CSL Behring: Research Funding; Chimerix: Research Funding; Bristol-Myers Squibb: Research Funding; bluebird bio: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Allovir: Consultancy; Actinium: Research Funding. Horwitz: Gamida Cell: Research Funding. McGuirk: Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Rybka: Spark Therapeutics: Consultancy; Merck: Consultancy. Vasu: Kiadis, Inc.: Research Funding; Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees.

Identification of Novel Prognostic Biomarkers DDX11 and CHD1 of Allogeneic Hematopoietic Cell Transplantation Outcomes for Patients with MDS: A CIBMTR Comprehensive Genomic Screening

BACKGROUNDMyelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid malignancies characterized by cytopenia and increased risk of progression to acute myeloid leukemia (AML) driven by accumulated somatic mutations in hematopoietic stem cells (HSCs). While recurrent mutations are known to associate with adverse outcomes in myelodysplastic syndrome (MDS), 10% of MDS cases have no known genetic indicators for survival prognosis. Whole genome sequencing (WGS) detects comprehensive mutations on coding and non-coding regions that empowers discovery of novel genetic biomarkers.METHODSWe conducted WGS at 60x read depth on 494 MDS patient subjects and scanned genome-wide for novel somatic biomarkers associated with MDS post allogeneic hematopoietic cell transplantation (allo-HCT) outcomes. Forward and backward stepwise variable selection was performed, and important clinical covariables were integrated into multivariate Cox proportional hazard models for survival outcome association tests. To test for associations with overall survival (OS), we conducted burden tests of somatic variants by summing the number of somatic nonsynonymous (missense, nonsense, splice) mutations per gene and testing for association with OS. For non-coding regions, we applied a sliding window approach, summing somatic mutations within each 10kb window and testing for association with OS. Furthermore, to distinguish potentially novel biomarkers from mutations in known MDS prognostic genes, we re-ran our association analyses considering only those MDS subjects with no known mutations in previously-identified prognostic genes for post allo-HCT survival(including TP53, RAS, JAK2, TET2, EZH2, ETV6, RUNX1, DNMT3A and ASXL1).RESULTSGenome-wide analyses of somatic coding variants on OS identified two statistically significant associations (Figure 1A I); one at TP53 (hazard ratio [HR], 2.19; 95% confidence intervals [CI] 1.48-2.75; P = 1.51e-06) and the other at HCN2 (HR, 5.84; 95% CI 2.38-14.34; P=1.18E-04). When we restricted our analyses to those patients with no mutations in known prognostic genes (N=301), we found one statistically significant candidate at DDX11 (HR, 3.74; 95% CI 1.87-7.47; P=1.83E-04). When we expanded our analyses to include non-coding somatic variants, we observed five additional significant genes (Figure 1A II, IV) including CHD1 (HR, 7.31; 95% CI 3.33-16.08; P=7.45E-07) that was significantly associated with post allo-HCT OS in the patient subset with no known mutations. Meta-analyses of OS using TCGA lymphoma and AML/MDS data provided validation that DDX11 and CHD1 mutations are associated with poor overall survival in hematopoietic malignancies (data not shown).Interestingly, many of the candidates from these analyses (e.g., DDX11, CHD1, RASGRF1 and ARHGEF7) are involved in DNA repair pathways. Gene set enrichment analyses confirmed that our association results are enriched a TP53-centered networks (p value: 0.0042, Figure 1B).Besides the novel candidates, a known MDS prognostic gene TP53 was replicated by our nonbiased screening approach. Co-occurrence of TP53 mutation and complex karyotypes, as well as high VAF of TP53 mutations in our MDS cohort were highly associated with poor post allo-HCT OS (data not shown). MDS patients with TP53, DDX11 and CHD1 mutations were overrepresented in samples with complex karyotypes.CONCLUSIONSOverall, through WGS of samples obtained at the time of allo-HCT, we identified two novel genetic prognostic biomarkers, DDX11 and CHD1 mutations, which were associated with inferior post allo-HCT OS. These results once validated could contribute to personalized risk assessments of post HCT outcomes for MDS patients. [Display omitted] DisclosuresSaber: Govt. COI: Other.

Racial and Socioeconomic Disparities in Long-Term Outcomes in ≥ 1 Year Allogeneic Hematopoietic Cell Transplantation Survivors: A CIBMTR Analysis

Introduction: It has been shown that racial/ethnic minorities have worse survival after matched unrelated donor allogeneic hematopoietic cell transplantation(allo-HCT) compared to Whites. Whether the racial disparity in allo-HCT outcomes persists in long-term survivors, and possibly may even be exacerbated in this population that frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study we sought to compare long-term outcomes among one-year survivors, by race/ethnicity and socioeconomic status (SES), after allo-HCT reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).Methods: The CIBMTR database was used to identify 5,473 patients with Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML), or Myelodysplastic Syndrome (MDS) who received HCT between 2007-2017, who were alive and in remission for at least 1 year after allo-HCT. Study was restricted to patients transplanted in the United States. Cox regression model was used to determine association of ethnicity/race and SES with overall survival (OS), relapse, and treatment related mortality (TRM). Standardized mortality ratio (SMR) was calculated to compare mortality rates of the study patients to their general population peers matched on race/ethnicity, age and sex.Results: Patients were reported to be Non-Hispanic White (W) (n=4385), Non-Hispanic Black (B) (n=338), Hispanic (H) (n=516), and Asian (A) (n=234). Median follow up after 1 year allo-HCT (months): 69 W, 50 B, 59 H and 57 A (Table 1). Patient neighborhood poverty level was estimated from residential ZIP code at the time of allo-HCT. A ZIP code with ≥20% of persons below the federal poverty level was considered high poverty area. In multivariable analysis, we observed no significant differences in OS, relapse or TRM based on race or poverty level when adjusted for patient-, disease- and transplant-related covariates (Table 2).Conclusions: Our study highlights that among those who survived at least 1-year in remission after allo-HCT, previously reported disparities in post HCT outcomes based on racial/ethnic factors, are not evident in contemporary practice. This might suggest that previously recognized disparity in outcomes could be due to factors that mostly affect patients in their first year post HCT. Future studies are needed to identify these early adverse factors and implement strategies to mitigate them. [Display omitted] DisclosuresBlue: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; WebMD: Consultancy. Wood: Pfizer: Research Funding; Teladoc: Consultancy; Koneksa Health: Consultancy, Current equity holder in publicly-traded company. Majhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Saber: Govt. COI: Other.

A Guidance for Concomitant Drug Reconciliation Prior to Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults.

Pediatric diseases treated by allogeneic hematopoietic stem cell transplantation (alloHCT) are complex and associated with significant comorbidities and medication requirements that can complicate the transplant process. It is critical to reconcile pre-transplant concomitant medications (pcon-meds) in the weeks prior to alloHCT and to consider the potential for pcon-meds to cause harmful drug-drug interactions (DDIs) or overlapping toxicities with conditioning agents. In this perspective, we describe a systematic process to review pcon-meds and determine the drug modifications needed to avoid DDIs with conditioning regimens. We provide an extensive appendix with timelines for discontinuation or modification of common pcon-meds that patients are taking when presenting to the HCT medical team. The timelines are based on the pharmacokinetic (PK) properties of both the pcon-meds and the planned conditioning medications, as well as anticipated DDIs. They also account for the ages seen at pediatric transplant centers (0–30 years old). Common scenarios, such as when pcon-med discontinuation is not an option, are discussed. Since alloHCT patients are often dependent upon psychiatric medications with problematic DDIs, a table of alternative, non-interacting psychiatric medications is also presented. The appendix provides details regarding how to adjust pcon-meds prior to the start of chemotherapy for children and young adults undergoing alloHCT, however patient-specific circumstances always need to be taken into account. Careful attentiveness to pcon-meds at the time the decision is made to pursue transplant will result in more consistent HCT outcomes, with lower toxicity and increased efficacy of conditioning agents.

Alemtuzumab/Low Dose TBI Conditioning Facilitates Stable Long-Term Donor Hematopoietic Cell Engraftment from Sibling Donors in Children with Sickle Cell Disease

BackgroundHematopoietic stem cell transplant (HCT) is the only established curative approach for sickle cell disease (SCD). Due to the high toxicity profile of myeloablative regimens, some adult patients with severe sickle cell anemia are not eligible for such therapy. However, a new adult nonmyeloablative protocol (National Institutes of Health, NIH protocol) described by Hsieh et al. (2014) was able to achieve a curative degree of mixed donor chimerisms with minimal transplant-related complications. The NIH protocol includes alemtuzumab, low dose total-body irradiation (TBI) of 300 cGy, and prolonged sirolimus for graft-versus-host disease (GVHD) prophylaxis for those recipients with a matched-sibling donor (MSD).The Alberta Children's Hospital has adopted this published regimen for MSD HCT in adolescents and younger children with SCD since the NIH data was presented in 2013.To our knowledge, there is no published literature describing the application of the NIH protocol in a pediatric population; the youngest subject in the referenced adult study was 16 years of age.MethodsThis retrospective cohort describes outcomes of nonmyeloablative allogeneic MSD HCT in children and adolescents with SCD who underwent HCT between 2013-2017. Fourteen patients with SCD under 18 years of age at the time of HCT received the NIH conditioning regimen. HLA-matched siblings had either normal hemoglobin or sickle cell trait and of the appropriate weight/height to donate peripheral blood stem cells (PBSCs) without blood priming of the apheresis circuit.The conditioning regimen consisted of alemtuzumab 1.0 mg/kg administered subcutaneously daily divided over five days (Days -7 to Day -3). Patients received a single TBI dose of 300 cGy on day -2, with testicular shielding for male recipients. GVHD prophylaxis consisted of a sirolimus loading dose of 3mg/m2/dose (PO) on day -1, followed by 1mg/m2/dose once daily starting on Day 0. PBSCs were typically collected on Day -3 to allow for cancellation of the HCT before TBI in the event of failed mobilization. Unmanipulated PBSCs were infused fresh on Day 0. Patients were eligible for early discharge post-transplant even prior to neutrophil engraftment. Weaning of sirolimus was initiated no earlier than 1-year post-HCT and if donor T-cell chimerisms were greater than 50%. Treatment failure was defined as clinical manifestation of SCD, failure to start weaning sirolimus by 2-years post-HSCT, or a failure to complete a sirolimus wean by 2.5 years post-HCT.ResultsFourteen patients (3 M,11 F) are included on this retrospective study. Median age at HCT was 11 years. Post-HCT follow-up ranges from 1 to 48 months (median 17). There were no failed donor stem cell mobilizations. Patients received a median of 11.4x106 CD34 cells per kilogram of body weight.All patients were discharged home prior to neutrophil engraftment with a median hospital stay of 7 days (range 5-19). All patients had donor neutrophil engraftment at a median of 21 days (mean= 22, SD= 4) and platelet engraftment at median of 14 days (mean= 12, SD= 14). Six patients never required platelet transfusion. Readmission after initial discharge was required in 9/14 patients with an average of 1 readmission/patient (range 1-4), typically for fever or CMV pre-emptive therapy. One patient developed septic shock with Acinetobacter ursingii related to poor central line care at home.All patients are currently alive. Post-HCT, there have been no cases of graft failure, sickling crises, veno-occlusive disease, idiopathic pneumonia syndrome, cerebral hemorrhage, PRES, or PTLD. Although 6/14 patients had CMV reactivation, only 3 patients required pre-emptive therapy. None had CMV/EBV disease.There were no treatment failures as defined by protocol. Currently, 8 patients are off sirolimus, 1 is currently weaning, with no secondary graft failure events. Only 2 patients over 1-year post-HCT have not initiated sirolimus weaning. There have been no cases of acute or chronic graft-versus-host disease.ConclusionsNonmyeloablative conditioning regimen is safe and effective as curative therapy for children with SCD. Outpatient management pre-engraftment was feasible in this population. In contrast to adult data, sirolimus weaning was possible in most patients by one-year post-HCT. Graft integrity was maintained after discontinuation of sirolimus in all eligible patients. [Display omitted] DisclosuresGuilcher:Patient Access Solutions: Consultancy; Canada Market Research: Consultancy; Jazz pharmaceuticals: Consultancy. Bruce:Bristol-Meyers-Squibb - consultant 2016-2017: Consultancy; ovartis consult and ad board 2015-2016: Consultancy; Apopharma 2015: Consultancy.

Healthcare Reimbursement and Service Utilization for One Year of Post-Allogeneic Hematopoietic Cell Transplantation (alloHCT) Care for Medicare Beneficiaries Ages 65 and Older with Acute Myeloid Leukemia

Objective: Acute myeloid leukemia (AML) is the most common indication for alloHCT in the United States (US) for Medicare beneficiaries. An increasing number of older patients are now able to undergo alloHCT; however, there is a significant gap in knowledge about their healthcare costs. The primary objective of this study was to assess healthcare reimbursement, service utilization, and overall survival for designated time points up to 1-year post-alloHCT for Medicare beneficiaries ages 65 and older in the US with an AML diagnosis.Methods: Medicare claims data from 2010 - 2012 were merged with Center for International Blood & Marrow Transplant Research (CIBMTR) clinical outcomes data. Patients were excluded who underwent alloHCT before 3/1/10 or after 12/31/11 (to allow for 2 months prior and 1-year follow-up), had a prior autologous or alloHCT, or were not enrolled in both Parts A and B 60 days prior to and on date of HCT. The total amount of reimbursement for 1-year post-transplant included the Medicare payment, secondary payer payments, and coinsurance and out-of-pocket payments made by beneficiaries. Cumulative reimbursement for Part A facility inpatient services, outpatient services, home health and hospice services and Part B physician services were inflation-adjusted to 2017 dollars using Centers for Medicare and Medicaid Services (CMS) Market Baskets. Weighted generalized linear models were used to identify key drivers of total reimbursement adjusting for age, gender, transplant center region, year of transplant, Karnofsky score, disease status, donor type, graft type, Sorror comorbidity score, cytomegalovirus (CMV) serostatus, conditioning intensity, graft-versus-host disease (GVHD) prophylaxis, anti-thymocyte globulin (ATG)/Alemtuzumab (Campath) use, and 2-month total reimbursement prior to the index HCT hospitalization or outpatient HCT date. Service utilization was measured by counts of reported claims and total service days. The Kaplan-Meier method was used to estimate the probability of overall survival (OS) stratified by disease status and conditioning intensity.Results: A total of 250 patients met inclusion criteria. Mean age at HCT was 68.7 yrs. The total cumulative reimbursement for the entire cohort were $166,032 (95% confidence interval (CI): $153,931, $178,133) at 100-days and $230,815 (95% CI: $214,381, $247,249) at 1-year post-alloHCT with inpatient reimbursement accounting for more than 80% of the total at each designated time point (Figure 1). The cumulative total reimbursements were $148,684 (95% CI: $137,994, $159,375) for patients surviving 100 days and $186,254 (95% CI: $166,765, $205,744) for patients surviving 1-year post-alloHCT. Counts of claims and total service days by service component and time point post transplant are shown (Tables 1 and 2). In multivariate analysis, patients who received cord blood compared to peripheral blood stem cell had significantly higher adjusted reimbursement (p=0.006). Similarly, myeloablative (MA) conditioning was associated with significantly higher reimbursement compared to non-myeloablative (NMA) (P < 0.0001). The Northeast (p=0.0275) and West (p=0.0323) regions had significantly higher reimbursement compared to the Midwest region. OS at 1-year post-alloHCT was 52% (95% CI: 46%-59%). Patients undergoing alloHCT in CR1/CR2 had better survival (p=0.0030) as did those who received NMA conditioning (P=0.0067).Conclusions: This unique dataset facilitated an analysis of key drivers of Medicare reimbursement for AML by patient and HCT related variables and outcomes. It was not surprising that a cord blood graft was a driver of reimbursement, likely due to acquisition costs, prolonged time to engraftment and subsequent hospitalization. The variation in reimbursement by region may be partly due to geographic adjustment of Medicare payments or transplant center billing practices. Interestingly, NMA conditioning not only led to lower 1-year reimbursement but also improved survival and may inform clinical practice. Future research will stratify each component of post-transplant reimbursement into specific cost categories to evaluate Medicare reimbursement and effects of practice patterns. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Pretransplantation Renal Dysfunction on Outcomes after Allogeneic Hematopoietic Cell Transplantation

Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age ≥40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n=13,505; cohort selected given a very low incidence of renal dysfunction in individuals age <40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n=46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR ≥90 mL/min (n=7062), eGFR 60 to 89 mL/min (n=5264), eGFR 45 to 59 mL/min (n=897), and eGFR <45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR <60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR ≥90 group, the hazard ratio (HR) for NRM was 1.46 (P=.0001) for the eGFR 45 to 59 mL/min group and 1.74 (P=.004) for the eGFR <45 mL/min group. Compared with the eGFR ≥90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P < .0001) and the eGFR <45 mL/min group (HR, 3.09; P < .0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR <45 mL/min was associated with an increased overall mortality (HR, 1.63; P < .0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.

521 - Outcomes of Bone Marrow Failure Syndromes Post-Allogeneic HCT Using Enhanced Data Back to Center (eDBtC) Platform: Experience from the Florida Pediatric Bone Marrow Transplant and Cell Therapy Consortium (FPBCC)

521 - Outcomes of Bone Marrow Failure Syndromes Post-Allogeneic HCT Using Enhanced Data Back to Center (eDBtC) Platform: Experience from the Florida Pediatric Bone Marrow Transplant and Cell Therapy Consortium (FPBCC)

Allogeneic Hematopoietic Cell Transplantation and Cellular Therapy.

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) generally require allogeneic hematopoietic cell transplantation (allo-HCT) for a cure, except for patients with favorable genetic genotypes such as those with core-binding factor AML. However, the use of intensive chemotherapy followed by prompt HCT does not fully prevent relapse or refractory disease. Despite improvements in transplant techniques and management of complications, further improvement of HCT outcomes is urgently needed. Moreover, careful patient counseling, donor selection, and choice of transplant type are essential to maximize the benefits of early allografting. Maintenance after HCT focusing on selective immunomodulation combined with targeted immunotherapies that control persisting or relapsed hematologic malignancies is currently under active investigation. To improve the balance between GVHD, relapse, and infection, the use of purified blood stem cell grafts in conjunction with ex vivo expanded T-cells from stem cell donors targeting common infectious and leukemic antigens has been explored. T cells against infectious agents might also be generated using partially HLA-matched third-party T cells from cryopreserved cell banks, and a series of studies confirmed the clinical value of donor-derived CMV- and EBV-specific T cells. This approach has also been applied to acute leukemia, and trials using donor-derived cytotoxic T-cells targeting multiple leukemic antigens such as WT1, PRAME, survivin, and NY-ESO, as well as donor-derived CAR19 T-cells after allo-HCT, are currently underway.

Economic and Clinical Burden of Virus-Associated Hemorrhagic Cystitis in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Hemorrhagic cystitis (HC) due to viral infections, such as BK virus, cytomegalovirus and/or adenovirus, after Allogeneic Hematopoietic Cell Transplantation (allo-HCT) causes morbidity and mortality, impacts quality of life, and poses a substantial burden to the health care system. Virus-associated HC (V-HC) occurs in up to 25% and 54% of pediatric and adult allo-HCT recipients respectively. V-HC is associated with incapacitating pain, life-disturbing urinary symptoms, and in severe forms, severe hematuria requiring transfusion support, bladder obstruction, renal impairment and increased mortality. At present, management is purely supportive as there are no approved or recommended anti-virals for V-HC. The impact of V-HC on health resource utilization (HRU) and HCT outcomes has not been studied at a national level. The objective of this study was to compare the economic burden, HRU and clinical outcomes among allo-HCT recipients with V-HC to those without V-HC using a large US claims database. Methods: A US claims database obtained from the Decision Resources Group Real World Evidence Data Repository was used to identify patients with first (index) allo-HCT procedure from 1/1/2012-12/31/2017. The 1-year period prior to the index allo-HCT was considered as the baseline period. Although, there are diagnosis codes in the International Classification of Diseases (ICD-9 or ICD-10) coding system for HC, there are no specific diagnosis codes to identify V-HC. Hence, an algorithm was developed through clinical guidance to identify these patients among those with HC diagnosis codes (Figure 1). Outcomes were examined in the 1-year post allo-HCT and included total healthcare reimbursements, HRU and clinical outcomes for allo-HCT patients with vs. without V-HC. Total reimbursements were estimated from submitted charges using a reimbursement-to-charge ratio of 0.425 and were reported in 2019 US dollars, adjusted using the medical care component of the US Consumer Price Index. Further, a generalized linear model was used to determine adjusted reimbursements stratified by the presence or absence of any acute or chronic graft-versus-host diseases (GVHD) after adjusting for age, health plan, underlying disease, stem cell source, number of comorbidities, baseline costs, and follow-up time. Results: Of 13,363 allo-HCT recipients, 759 (5.7%) patients met the criteria for V-HC. Total unadjusted mean reimbursement was $632,870 (SD=$640,815) for patients with V-HC and $340,469 (SD=$377,591) for patients without V-HC (Table 1). In multivariable model after adjusting for confounders, the adjusted reimbursements were significantly higher for V-HC patients with and without GVHD compared to patients without V-HC (p&amp;lt;.0001) (Figure 2). V-HC was associated with increased hospital length of stay (LOS) and readmission rates. Patients with V-HC had 7.9 additional days in the hospital (35.5 vs 27.6 days; p&amp;lt;.0001) and 6.1 additional days (34.3 vs. 28.2 days; p=0.0009) in the intensive care unit (ICU) for the index hospitalization, as compared to patients without V-HC (Table 1). The hospital readmission rate was higher for allo-HCT patients with V-HC compared to those without V-HC (3.5 vs. 1.9 per person yr; p&amp;lt;.0001), resulting in 12.9 more days in the hospital (50.0 days vs. 37.1 days; p&amp;lt;.0001) and 7.3 more days in the ICU (25.8 days vs. 18.5 days; p&amp;lt;.0001) after the index hospitalization (Table 1). V-HC was associated with increased mortality in patients with GVHD and increased risk of renal impairment in all allo-HCT patients. Among patients with GVHD, those with V-HC had significantly higher all-cause mortality as compared to those without V-HC (23.2% vs. 18.4%; p=0.0035) (Table 2). When stratified by GVHD, there were no significant differences in the baseline risk for renal impairment; while V-HC was associated with increased risk for renal impairment in the follow-up period in patients with or without GVHD (p&amp;lt;.0001 for both) (Table 2). Conclusions: Allo-HCT patients with V-HC have significantly higher healthcare reimbursements, health resource utilization, and worse clinical outcomes including renal impairment, irrespective of the presence of GVHD; with significantly higher all-cause mortality in the presence of GVHD. Our results highlight the unmet clinical need for effective strategies to prevent and treat V-HC in HCT recipients that may also reduce costs among these patients. Disclosures McGuirk: Pluristem Ltd: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding. Moon:AlloVir, Inc.: Current Employment, Current equity holder in publicly-traded company. Chandak:AlloVir, Inc.: Other: Independent contractor. Zhang:AlloVir, Inc.: Other: Independent contractor. Papanicolaou:Chimerix: Other: Consulting and other fees, Research Funding; Astellas Pharma: Other: Consulting and other fees, Research Funding; Merck &amp; Co.: Other: Consulting and other fees, Research Funding; Octapharma: Other: Consulting and other fees; Partner Therapeutics: Other: Consulting and other fees; ADMA Biologics: Other: Consulting and other fees; Shionogi: Other: Consulting and other fees; Cidara: Other: Consulting and other fees; Amplyx: Other: Consulting and other fees; Siemens: Other; Takeda: Research Funding.

AML-262: Ivosidenib (IVO) Prior to Hematopoietic Cell Transplant (HCT) for Patients with IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) Who Cannot Tolerate Intensive Chemotherapy (IC)

Context Allogeneic HCT provides a potentially curative option for R/R AML. Disease status at transplant is a major determinant of prognosis, with patients typically receiving salvage chemotherapy prior to HCT to induce remission. IVO is an oral, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥ 75 years of age or ineligible for IC, and those with R/R AML. Objective To assess HCT outcomes in patients with mIDH1 R/R AML who proceeded to HCT after responding to IVO 500 mg once daily in a phase 1 study ( NCT02074839 ). Results 18 patients proceeded to HCT: median age, 61.5 years (range 36–68); 56% male; 16.7% secondary AML; 16.7% had ≥ 3 prior regimens; 11.1% had prior HCT. Median duration on IVO prior to HCT 3.9 months (range 2.1–15.2). Last responses prior to HCT were 50.0% CR, 22.2% CRi/CRp, 11.1% MLFS, 5.6% relapse, and 11.1% response not evaluable. Six- and 12-month post-HCT survival rates were 77.8% and 50.0%; median post-HCT relapse-free survival was 7.3 months (range 2.6–not estimable [NE]). Median OS from start of IVO was 16.8 months (95% CI 9.2, NE) for HCT patients vs 9.0 months (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time was 33.2 months (range 3.2–41.9). Eight HCT patients were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Among 43 patients who achieved CR as best response, median OS was NE (95% CI 9.1, NE) for the 12 CR patients who underwent HCT vs 20.5 months (95% CI 16.4, NE) for the 31 CR patients who did not undergo HCT. mIDH1 was undetectable in 1/18 (5.6%) patients (digital PCR; 0.02–0.04% mutation frequency detection limit); 6/18 (33.3%) patients had mIDH1 reduction ≤ 1%. Conclusion IVO monotherapy is a potential treatment option to induce remissions prior to HCT for patients with mIDH1 R/R AML who were not previously considered candidates for IC. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combinations prior to HCT. Funding Agios.

Outcome of Allogeneic Hematopoietic Cell Transplantation after Venetoclax and Hypomethylating Agent Therapy for Acute Myelogenous Leukemia

The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML.

Hematopoietic cell transplantation in pediatric patients with acute leukemias or myelodysplastic syndrome using unrelated adult or umbilical cord blood donors in Brazil.

The choice of alternative donors for HCT for patients without an HLA-matched related donor depends on several factors. We compared major HCT outcomes in 212 consecutive children transplanted at 11 centers in Brazil for acute leukemia or MDS from an HLA-matched unrelated donor (MUD, n=95), mismatched unrelated donor (MMUD, n=47) or unrelated umbilical cord blood (UCB, n=70). Most had ALL (61%), bone marrow (57%) as the graft source and 95% received a MAC regimen. The 3-year OS probability were 57, 55, and 37% after HCT from MUD, MMUD, and UCB, respectively (HR 1.68, 95%CI 1.07-2.63; P=.02). In comparison with MUD, OS was similar after transplantation of a≥6/8 HLA-matched or a high cell dose (>5×107 TNC/kg) CB unit (HR 1.41, 95%CI 0.88-2.27; P=.15). NRM was higher for UCB (HR 3.90, 95%CI 1.43-10.7; P=.01) but not for MMUD (HR 1.03, 95%CI 0.53-2.00; P>.20). Advanced disease (HR 2.05, 95%CI 1.26-3.33; P<.001) and UCB with high probability of being<6/8 HLA-matched (HR 5.34, 95%CI 2.0-13.9; P<.001) were associated with higher mortality. Relapse and acute GVHD were similar among groups, while PGF was higher among UCB transplants (P=.002) and chronic GVHD among MMUD group (HR 2.88, 95% CI 1.05-7.88; P=.04). Our results suggest that in Brazil HCT outcomes performed with MMUD and MUD donors were comparable, while with UCB units<6/8 HLA-matched were associated with higher NRM for children with acute leukemia or MDS.

Healthcare retention and clinical outcomes among adolescents living with HIV after transition from pediatric to adult care: a systematic review

BackgroundAdolescents living with HIV (ALWH) who transition from pediatric to adult care face several challenges that increase their risk of experiencing treatment interruptions and being lost to HIV care with resultant increased morbidity and mortality. To date, few studies have examined their outcomes post-healthcare transition (HCT), precluding the development and dissemination of evidence-based interventions aimed at retaining ALWH in HIV care both during and after HCT. We conducted a systematic review to synthesize the outcomes of ALWH post-HCT to provide suggestions for future directions.MethodsWe systematically searched several electronic databases through October 2019 using keywords for HIV, HCT and ALWH. We categorized studies by target population, country (i.e., upper-high income and low-middle income), study design (i.e., descriptive, mixed methods, quantitative), outcomes measured, and follow-up period.ResultsA total of 24 studies met inclusion criteria. Studies were categorized according to the following HCT outcomes: retention in HIV care post-HCT (n = 13), changes in CD4+ count and viral load post-HCT (n = 16), and mortality among ALWH post-HCT (n = 7). Most studies (n = 11) examining retention in HIV care indicated that more than 70% of ALWH were retained in care 1–2 years post-HCT while the remaining studies (n = 2) reported retention rates less than 55%. While studies indicated that CD4+ counts and viral loads tended to worsen during the first few years post-HCT, these differences were often not statistically significant. Among all ALWH who transitioned to adult care, a small proportion died within their first seven years post-HCT. Among qualitative studies, common themes included transition readiness (n = 6), provider-patient relationship in the adult clinic setting (n = 6), and concern about the adult clinic setting (n = 4).ConclusionsTransition outcomes were poorest for ALWH with unsuppressed viremia pre-HCT, suggesting that this subgroup of ALWH may need greater support from their treatment teams and caregivers during and post-HCT to improve clinical outcomes.

Graft Cryopreservation Does Not Impact Overall Survival after Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis.

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P=.81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P=.62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P=.60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P=.12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P=.05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P=.27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P=.32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P=.09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P=.04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P=.04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.

The geriatric syndrome of sarcopenia impacts allogeneic hematopoietic cell transplantation outcomes in older lymphoma patients

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.

Development of the Renal Adjusted Hematopoietic Cell Transplant Comorbidity Index (RA-HCT-CI) Using Different Levels of Renal Dysfunction According to Estimated Glomerular Filtration Rate (eGFR)

Background Chronic kidney disease (CKD) is a known risk factor for post-HCT mortality. Currently, HCT-CI assigns a score of 2 for moderate-severe renal dysfunction based on serum creatinine (Cr), though Cr is not ideal marker of renal function and can be influenced by several factors. The aim of this study is to examine whether utilization of incremental degrees of renal dysfunction based on eGFR improves the utility of HCT-CI to predict allogeneic HCT outcomes. Method Patients age ≥40 years receiving HCT for malignancies from 2008 to 2016 were included. Estimated glomerular filtration rate (eGFR), calculated using CKD-epidemiology collaboration method, was used to categorize patients into 4 groups: eGFR ≥ 90ml/min (n=7062), eGFR 60-90 (n=5264), eGFR 45-59 (n=897) and eGFR Results eGFR groups were similar on disease risk index, graft and donor source, but patients with eGFR≥90 were younger and received a myeloablative regimen more frequently. Patients with eGFR Conclusion These findings provide support that degree of renal dysfunction is independent predictor of OS and TRM after allogeneic HCT. In addition, the newly developed RA-HCT-CI is valid in predicting both TRM and OS and performs similarly to original HCT-CI.

Development and content validation of the Healthcare Transition Outcomes Inventory for young adults with type 1 diabetes

BackgroundThe literature on the specification and measurement of the outcomes of the healthcare transition from pediatric to adult centered-care is scarce and methodologically weak. To address these gaps, we conducted a series of studies to develop a multidimensional, multi-informant (young adults, parents, and healthcare providers) measure of healthcare transition outcomes for young adults with type 1 diabetes (T1D), the Healthcare Transition Outcomes Inventory (HCTOI). The current study describes the development and refinement of the HCTOI item pool.MethodsFollowing Patient Reported Outcomes Measurement Information System (PROMIS) standards, the research team conducted qualitative interviews to define six content domains of healthcare transition outcomes from the perspectives of multiple stakeholders, developed an initial item pool of the HCTOI based on the six domains, analyzed expert item ratings and feedback for content validation, and conducted cognitive interviews with informants (patients, parents, and healthcare providers) for further item pool refinement.ResultsQualitative findings revealed six healthcare transition outcome domains: 1) Biomedical markers of T1D control; 2) Navigation of a new health care system; 3) Possession of T1D self-management skills and knowledge; 4) Integration of T1D care into emerging adult roles; 5) Balance of parental involvement with autonomy; and 6) Attainment of T1D “ownership.” An initial pool of 88 items focused on the extent to which a young adult with T1D is successful on each of the six domains. Experts rated all content domains and all but six items as relevant. In addition to suggesting additional items, experts were concerned about the length of the measure, response burden, and whether every informant type would have sufficient knowledge to rate items in particular content domains. Cognitive interviews resulted in retaining all six content domains, but dropping some items and yielded fewer items for the healthcare provider version (47 items versus 54 items for the young adult- and parent-versions).ConclusionsExpert review and cognitive interviews confirmed that all six domains of HCT outcomes were relevant and both procedures resulted in retaining a sufficient number of clear and representative items for each content domain. The HCTOI represents the first multi-informant, rigorously developed item pool that comprehensively measures the multiple components of the transition from pediatric to adult specialty healthcare.