Indication For Hematopoietic Cell Transplantation Research Articles

Epidemiology of Diffuse Alveolar Hemorrhage in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk factors and outcomes are not well understood owing to a sparsity of cases spread across multiple centers. The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplantation-related risk factors and comorbid critical care diagnoses associated with post-HCT DAH. Retrospective analysis was performed in a multicenter cohort of 6995 patients age ≤21 years who underwent allogeneic HCT between 2008 and 2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox regression, with DAH as a time-varying covariate. DAH occurred in 81 patients at a median of 54 days post-HCT (interquartile range, 23 to 160 days), with a 1-year post-transplantation cumulative incidence probability of 1.0% (95% confidence interval [CI], .81% to 1.3%) and was noted in 7.6% of all pediatric intensive care unit patients. Risk factors included receipt of transplantation for nonmalignant hematologic disease (reference: malignant hematologic disease; hazard ratio [HR], 1.98; 95% CI, 1.22 to 3.22; P = .006), use of a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis (referent: CNI plus methotrexate; HR, 1.89; 95% CI, 1.07 to 3.34; P = .029), and grade III-IV acute GVHD (HR, 2.67; 95% CI, 1.53-4.66; P < .001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (P < .05) than those without DAH. From the time of DAH, median survival was 2.2 months, and 1-year overall survival was 26% (95% CI, 17% to 36%). Among all HCT recipients, the development of DAH when considered was associated with a 7-fold increase in unadjusted all-cause post-HCT mortality (HR, 6.96; 95% CI, 5.42 to 8.94; P < .001). In a landmark analysis of patients alive at 2 months post-HCT, patients who developed DAH had a 1-year overall survival of 33% (95% CI, 18% to 49%), compared to 82% (95% CI, 81% to 83%) for patients without DAH (P < .001). Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of nonmalignant hematologic indication for HCT, use of CNI + MMF as GVHD prophylaxis, and severe acute GVHD. Further investigations and validation of modifiable risk factors are warranted given poor outcomes.

International recommendations for screening and preventative practices for long-term survivors of transplantation and cellular therapy: a 2023 update.

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.

Incidence and risk factors of pain crisis after hematopoietic cell transplantation for sickle cell disease

AbstractVaso-occlusive episodes (VOC) or pain crises are the most common indications for hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). Elimination of pain crisis after HCT is an important patient-centered outcome and may improve understanding of the natural history of pain syndromes in SCD. We examined deidentified records of 763 patients followed-up for a median of 36.7 months (range, 0.3-168.6 months), with 69.6% patient's age <18 years at HCT, 83.3% patient's Karnofsky-Lansky performance score (KPS) ≥90, overall survival 92.9%, event-free survival 72.4%, graft failure (GF) 22.4%, AGVHD 21.4%, CGVHD 27%, and pain crisis 8.65%. On unadjusted logistic regression, increased risk of pain crisis after HCT was observed in patient's aged >10 years at HCT (range, 11-17 years; OR, 9.43; 95% CI, 3.20-27.79; P < .0001), in age ≥18 years (OR, 16.62; 95% CI, 5.85-47.16; P < .0001), in those with history of pain crisis 2 years before HCT (OR, 13.16; 95% CI, 4.08-42.42; P < .0001), alternate donors (haploidentical [OR, 4.80; 95% CI, 2.48-9.31; P < .0001], unrelated matched [OR, 2.71; 95% CI, 1.23-5.97; P = .0132], and mismatched unrelated [OR, 3.19; 95% CI, 1.44-7.05; P = .0041], and those with GF (n = 41 [5.37%]; OR, 7.15; 95% CI, 4.20-12.18; P < .0001). Pain crisis was less frequent with KPS of ≥90 (OR, 0.31; 95% CI, 0.18-0.55; P < .0001). Multivariable logistic regression models confirmed age at HCT, KPS, graft type, donor type, history of VOC 2 years before HCT, and GF as independent predictors of pain crisis after HCT and generated predictive models and nomograms for pain crisis after HCT for SCD, which can support shared decision making.

Optimizing Vaccine Delivery Among Pediatric Allogeneic Hematopoietic Cell Transplant Recipients: A Quality Improvement Initiative

Abstract Background Pediatric allogeneic hematopoietic cell transplantation (HCT) recipients are at risk for vaccine-preventable infections (VPI). Although evidence-based guidelines recommend starting vaccination efforts between 3-6 months post-HCT, most children remain sub-optimally vaccinated and at-risk for VPI. Our prior work demonstrated that early vaccination starting at 4-6 months post HCT was safe and immunogenic. To reduce potential patient harm from vaccine-preventable infections (VPI), we created a quality improvement (QI) initiative to increase vaccination rates among eligible pediatric allo-HCT recipients, beginning early post-HCT by implementing a best practice immunization strategy at our institution. Methods This QI initiative applied a quasi-experimental design and multiple bundled interventions in Plan-Do-Study-Act (PDSA) cycles to implement and sustain an early immunization strategy among allogeneic HCT recipients in our ambulatory HCT clinic from November 2018-May 2022. The study aimed to increase vaccination rates in eligible patients by providing a core vaccine bundle (pneumococcal conjugate [PCV13], Haemophilus influenzae type b [Hib], inactivated polio [IPV], diphtheria, tetanus, acellular pertussis [DTaP], and hepatitis B vaccines [HBV]) beginning at 6 months [Day+168 to 180] post-HCT, allowing a 30-day grace period for clinic scheduling. The number of subjects who completed a full vaccine series (4 PCV13, 3 DTaP/HBV/IPV and Hib) within the expected time post HCT were recorded. Subjects were ineligible for early vaccination if the indication for HCT was a primary immunodeficiency, and if at screening or vaccination, subjects had relapsed primary disease, graft failure, died, received anti-CD20 therapies in the preceding 6 months and had no evidence of B cell recovery, or were receiving augmented immunosuppression (prednisone-equivalent of ≥ 2 mg/kg/day). The process measure was the proportion of patients screened for vaccine eligibility vs all eligible allo-HCT recipients at 4 months post-HCT. The outcome measure included the proportion of eligible allo-HCT recipients who received the first doses of core vaccines at 6 months (+30 days) among the total number of eligible patients dur for early vaccination. PDSA interventions included creating and implementing a standardized vaccine clinical practice guideline, stakeholder engagement and communication, pre-clinic screening at 4 months post-HCT, creation of a vaccine order set per time post-HCT, and patient-individualized vaccine decision support recommendations. Results Among 72 children who underwent allo-HCT, 37 (51%) were deemed eligible for early vaccination. Review of institutional baseline data revealed that only 43% of eligible allo-HCT received the core vaccines beginning at 6 mos post-HCT. After the first two PDSA cycles, the proportion of eligible patients receiving core vaccines beginning early post-HCT increased from a baseline of 43% to 62%. After implementation of a patient-individualized vaccine decision support recommendation, early immunization rates increased to 92% and were sustained for over 2 years. In total, 33 (90%) patients, predominantly males (55%) with a median age of 9 y [range 0.33-19], received core vaccines at a median of 175 days [range 168-210] post-HCT during the study period. Among children who received early vaccination post-HCT, 82% remained eligible to continue their recommended vaccine roadmap and completed the full vaccine series by the expected 14-16 months post-HCT. Conclusions A multidisciplinary approach applying QI methodology and individualized vaccine decision support allowed for improved and sustained early vaccination after pediatric allo-HCT and completion of vaccine series, thereby reducing potential VPI-associated patient harm. Figure 1. Statistical Process Control Chart (p-chart) of Quality Improvement Initiative to Improve Vaccination Delivery Starting at 6 months After Pediatric Allogeneic Hematopoietic Cell Transplantation (HCT)

Donor Hemoglobin Genotype Does Not Impact Outcomes Following Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Study

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes. Retrospective data was available for this analysis on 182 SCD patients ≥1 year post MRD HCT at 10 participating Sickle Transplant Advocacy and Research (STAR) Alliance centers. Summary statistics were presented as mean (standard deviation) for continuous variables and count (%) for categorical variables. Comparisons were made between Hb AA and Hb AS donor groups using both parametric and non-parametric tests for continuous variables and Chi-square test/exact test for categorical variables, with p-value &amp;lt;0.05 set as significant. Amongst 182 patients undergoing MRD HCT, 67% (n=122) had a Hb AS donor ( Table). In the overall cohort, median age at HCT was 8.7 (4.8) years and most patients had HbSS (n=174; 96%) with a severe clinical phenotype (n=97; 54%). HCT was performed using bone marrow (n=166; 92%) with myeloablative conditioning (n=156; 86%) in the majority. Patients with a severe disease phenotype and Hb AS donor were significantly more likely to have recurrent vaso-occlusive pain crises as an indication for HCT (p=0.033), otherwise there were no differences in baseline patient or HCT characteristics between cohorts. With mean post-HCT follow up of 4.5 (3.9) and 5.1 (4.1) years in Hb AA and Hb AS donor cohorts (p=0.145), no significant differences were seen in recipient outcomes including time to neutrophil and platelet engraftment, number of or time to last platelet transfusion, myeloid or unsorted % donor chimerism, number with acute (day 100) or chronic GVHD (1 year), or time to discontinue immunosuppression (data not shown). Disease recurrence and need for 2 nd HCT were rare in both cohorts (AA: 2 [3%] and 2 [3%]; AS: 3 [3%] and 4 [3%]; p=0.665 and 1.0, respectively). Two (3%) and 5 (4%) patients died in the AA and AS cohorts, respectively (p=1.0). Aside from a statistically (but not clinically) significant difference in Hb at day 30 (p=0.044), no difference was seen in longitudinal Hb or markers of hemolysis (LDH and ARC; Figure). No significant difference was seen in median number of RBC units transfused (AA: 4.0 [2.0-6.0]; AS: 3.0 [2.0-6.0]; p=0.454) or days to last transfusion (AA: 23.0 [14.0-77.0]; AS: 22.0 [13.0-75.0]; p=0.86). SCD complications were rare post-HCT, with no difference seen between cohorts in number (%) with VOC (AA: 1 [2%; had 2 separate VOC events]; AS: 3 [3%]; p=1.0), ACS (none reported), chronic pain (AA: 0 [0%]; AS: 1 [&amp;lt;1%]; p=1.0), or other SCD-related complications (AA: 2 [3%]; AS: 9 [7%; had 11 separate other events]; p=0.456). Stroke occurred in a significantly higher proportion with an AA versus AS donor (5 [8%] and 2 [2%], respectively; p=0.04). No significant differences were seen in longitudinal (1 and 2 years and at last follow up) post-HCT cardiac (EF, SF, TRJ velocity), pulmonary (FEV1, FVC, DLCO), or renal (GFR) function between cohorts (data not shown). Our results indicate that in MRD HCT for SCD, AS and AA donors yield comparable long-term outcomes. In this retrospective and registry-based study design, detailed analyses did not show differences between the two cohorts at baseline or at any timepoint post-HCT. While there were some outcome differences between the cohorts, they were either not clinically significant or did not have a scientific rationale, and thus were likely due to chance alone (denoted by bolding in Table). Given the young age of our cohort at HCT and thus a smaller proportion with SCD-related organ dysfunction, our results may not be applicable to an older cohort with significant organ dysfunction which will require a separate analysis.

Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies

Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4–96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.

Hematopoietic cell transplantation for monogenic inflammatory bowel disease

The pathogenesis of inflammatory bowel disease (IBD) may include immune dysregulation. About 20% of inborn errors of immunity (IEIs) are related to IBD, and more than 60 IEIs are known to present IBD. Monogenic IBDs include those that are refractory to traditional treatment and can be cured by allogeneic hematopoietic cell transplantation (HCT), making early diagnosis and treatment essential. In this report, we present a series of monogenic IBDs that are relatively frequently found in Japan, such as interleukin (IL)-10/IL-10 receptor deficiency, chronic granulomatous disease, XIAP deficiency, immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, NEMO deficiency, and A20 haploinsufficiency and will describe the features of each IEI and the indications for HCT.

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., &amp;lt;7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (&amp;lt;6/8) HCT recipients (75% vs. 76%, respectively; P &amp;gt;0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = &amp;gt;0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

Improved GRFS after posttransplant cyclophosphamide-based vs ATG-based HLA-mismatched unrelated donor transplant

AbstractA common method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT) from an HLA-mismatched unrelated donor (MMUD) is tacrolimus, methotrexate, and antithymocyte globulin (ATG). The use of posttransplant cyclophosphamide (PTCy) showed promise in a prospective trial for MMUD HCT. We compared 1-year graft-versus-host disease–free, relapse-free survival (GRFS) in 128 recipients of prophylaxis based on tacrolimus/methotrexate/ATG (ATG group, n = 46) vs PTCy, mycophenolate mofetil, and tacrolimus or sirolimus (PTCy group, n = 82) after MMUD HCT. Patients receiving HCT from a MMUD mismatched at ≥1 locus among HLA-A, HLA-B, HLA-C, and HLA-DRB1 were included. The 2 groups were well matched for HCT indication, high-risk disease, and HCT comorbidity index, whereas more patients on PTCy received bone marrow (50% vs 26%; P = .01) and >1 locus HLA-mismatched (30.5% vs 2.2%; P = .001) grafts. The 1-year GRFS was 16% (95% confidence interval (CI): 8%-31%) vs 54% (95% CI: 44%-66%; P < .001) in the ATG and PTCy groups, respectively. The multivariable adjusted hazard ratio for GRFS was 0.34 (95% CI: 0.21-0.55; P < .001) with the use of PTCy. The 1-year overall survival in the ATG group was 45% (95% CI: 32%-62%) vs 75% (95% CI: 66%-85%) in the PTCy group (P < .001). Relapse incidence was similar. One-year nonrelapse mortality was greater after ATG-based prophylaxis: 38% (95% CI: 23%-52%) vs 16% (95 CI: 9%-25%), P < .001. In summary, PTCy-based prophylaxis resulted in superior GRFS and overall survival in recipients of MMUD.

Conditioning regimens for inborn errors of immunity: current perspectives and future strategies.

Inborn errors of immunity (IEI) are caused by germline genetic mutations, resulting in defects of innate or acquired immunity. Hematopoietic cell transplantation (HCT) is indicated for curative therapy especially in patients with IEI who develop fatal opportunistic infections or severe manifestations of immune dysregulation. The first successful HCT for severe combined immunodeficiency (SCID) was reported in 1968. Since then, the indications for HCT have expanded from SCID to various non-SCID IEI. In general, HCT for IEI differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution. European Society for Blood and Marrow Transplantation/European Society for Immunodeficiencies guidelines recommend reduced-intensity conditioning to avoid treatment-related toxicity, and the optimal conditioning regimen should be considered for each IEI. We review conditioning regimens for some representative IEI disorders in Japanese and worldwide cohort studies, and future strategies for treating IEI.

The Clinical Significance of BCR-ABL1 Mutations in Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation

The global standard therapy for chronic myeloid leukemia (CML) is tyrosine kinase inhibitors (TKIs). One of the causes of therapeutic resistance to some TKIs corresponds to point mutations in the BCR-ABL1 fusion gene. Allogeneic hematopoietic cell transplantation (HCT) is a treatment option for high-risk CML, including TKI resistance. Although BCR-ABL1 point mutations comprise a major factor in the assessment of the indications for HCT, there is limited evidence for their significance in relation to transplant outcomes. This study aimed to evaluate the profiles and transplant outcomes of BCR-ABL1 mutations in allografted patients with CML. The retrospective study used a nationwide registry data including adult patients with CML who underwent their first HCT between 2006 and 2016. The inclusion criterion was the evaluation of the status of the BCR-ABL1 mutation before HCT. The cohort included 315 patients with a median age of 44 years (range 16-70 years). Point mutations were detected in 152 patients, of which 101 (66%) harbored T315I mutations and 51 harbored mutations other than T315I (non-T315I). With a median follow-up period of 38 months (range 2-114 months), overall survival (OS) at 3 years was worse in the mutation group than in the no-mutation group (53% versus 71%; P=.002), which was validated by multivariate analysis (hazard ratio [HR]=1.50; 95% confidence interval [CI], 1.0-2.2; P=.038); this difference was remarkable in the chronic phase of CML. OS in the non-T315I group was significantly worse than that in the no-mutation group (HR=1.69; 95% CI, 1.0-2.8; P=.035). The nationwide study has successfully evaluated the BCR-ABL1 mutational profile and its outcomes in patients with CML who received HCT. The mortality risk was significantly higher in patients with the BCR-ABL1 mutation than in patients without the mutation. These findings would be useful to understand the clinical significance of various BCR-ABL1 mutations in CML and provide insight into the on mid need for treatment strategies for cases of CML with BCR-ABL1 mutations.

A Randomized Open Label Pilot Study of Clostridium Butyricum Miyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation

A Randomized Open Label Pilot Study of Clostridium Butyricum Miyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation

Reduced Intensity Hematopoietic Cell Transplantation Improves Cerebral Hemodynamics in Children with Sickle Cell Disease

IntroductionAllogeneic hematopoietic cell transplantation (HCT) is increasingly being utilized in patients with sickle cell disease (SCD) to prevent progressive organ dysfunction, including for primary or secondary stroke prevention. However, outcomes after HCT have mostly been evaluated using broad measures such as overall survival and event free survival with limited direct physiologic evidence of improved cerebral hemodynamics. Cerebral blood flow (CBF; mL blood/100 g tissue/min) is increased in SCD to compensate for chronic anemia, reduced oxygen carrying capacity and to maintain adequate oxygen delivery to the brain tissue. In SCD patients, CBF is inversely associated with intelligence quotient (Strouse JJ, et al. Blood. 2006;108(1):379-381.) and working memory (Prussien KV, et al. Stroke. 2021;52(5):1830-1834.) and has been shown to improve with blood transfusions (Guilliams KP, et al. Blood. 2018;131(9):1012-1021.). Assessment of CBF may help predict long-term neurocognitive outcomes in patients with SCD and assess therapeutic responses to therapies. Additionally, the high metabolic demand of the brain potentially makes assessment of CBF a sensitive predictor of future multiorgan damage in patients with SCD and hence may be useful to help determine eligibility of patients for curative therapies.MethodsWe performed anatomical and hemodynamic magnetic resonance imaging (MRI) of the brain prior to, and at 6 months after HCT in children with SCD undergoing a reduced intensity conditioning based HCT on a clinical study (NCT04362293). All patients received pretransplant conditioning with hydroxyurea, azathioprine, alemtuzumab, thiotepa and low dose total body irradiation (200-400 cGy). All patients received an unmanipulated mobilized peripheral blood derived hematopoietic stem and progenitor cell graft. One patient who received the graft from a haploidentical (HAPLO) donor also received post-transplant cyclophosphamide. Graft versus host disease prophylaxis comprised of sirolimus. A 3-dimensional (3D) T1 sequence was used for gray/white matter segmentation. 3D-pulsed arterial spin labeling (ASL) perfusion imaging (3 mm isotropic) was acquired to measure resting CBF. Mean CBF values were calculated from gray matter. Mean ± standard deviation and median values for various variables are presented.ResultsFour consecutive patients had 2 serial MRIs performed (one before HCT and another 6 months after HCT). Median age at HCT was 14.5 years. Indications for HCT, donor type and whether patients were receiving chronic transfusion therapy (CTT) prior to HCT are indicated in the Table. No patient had prior evidence of overt stroke. All patients engrafted and had >99% donor myeloid chimerism at the time of the post-HCT imaging. Mean pre-HCT hemoglobin was 8.7 ± 0.8 g/dL (median 8.6 g/dL) and it increased to 12.5 ± 2.1 g/dL (median 12.4 g/dL) at 6 months after HCT. All patients exhibited elevated resting CBF values prior to HCT (123.8 ± 32.2 mL blood/100 g tissue/min, median 112.8 mL blood/100 g tissue/min), that decreased following HCT (71.1 ± 32.1 mL blood/100 g tissue/min, median 72.8 mL blood/100 g tissue/min) (Table and Figure). None of the patients had any clinical neurological complications or imaging evidence of new infarcts or anatomical abnormalities in the follow up period.ConclusionOur preliminary results indicate that it is feasible to quantify CBF in patients with SCD before and after HCT using MRI. We demonstrate that cerebral hemodynamics improve after HCT in children with SCD, indicated by a decrease in CBF to near normal values (normal CBF ~80 mL blood/100 g tissue/min). The more substantial changes (-50% and -78%) are seen in children who were not receiving CTT, suggesting that CTT might partially mitigate CBF elevation prior to HCT. Nevertheless, 2 patients receiving CTT prior to HCT also had a further modest decrease in CBF after HCT (-5% and -18%). We plan to follow these changes at serial time points annually after HCT and correlate them with changes in neurocognitive functioning and other functional MRI measures. Improved CBF is expected to reduce stroke risk and may also preserve or improve neurocognitive functioning, and prospective monitoring of these outcomes are underway.Data on all the study participants who have undergone an HCT and had 2 serial MRIs performed by the ASH annual meeting will be presented. [Display omitted] DisclosuresSharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Vindico Medical Education: Honoraria. Triplett: Miltenyi: Other: Travel, meeting registration. Hankins: Vindico Medical Education: Consultancy; UpToDate: Consultancy; Global Blood Therapeutics: Consultancy; Bluebird Bio: Consultancy.

COVID-19 in Pediatric Hematopoietic Cell Transplant Recipients: A CIBMTR Study

Background: Adult recipients of hematopoietic cell transplantation (HCT) are at a very high risk of adverse outcomes after COVID-19 (Sharma A, Bhatt NS, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. The Lancet Haematology. 2021 Mar 1;8(3): e185-93). While children are known to have better outcomes after COVID-19 compared to adults in general, data on risk factors and outcomes of COVID-19 among pediatric recipients of HCT are lacking.Methods: Using the data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between March 2020 and May 2021, we describe characteristics, severity, treatment approaches, and outcomes of pediatric HCT recipients who were ≤21 years of age at COVID-19 diagnosis. All diagnoses, donor choice/graft sources, and conditioning regimens were included. Patient, disease, and HCT-related factors were described as frequency for categorical variables and median, range, and interquartile range (IQR) for continuous variables. The probability of overall survival after COVID-19 was calculated using the Kaplan Meier estimator. Additionally, an analysis was performed in the subset of allogeneic HCT COVID-19 cases from the United States (US) to identify risk factors for developing COVID-19. COVID-19 cases were compared with a cohort of all pediatric allogeneic HCT recipients without COVID-19 matched by the transplant center. Impact of hematopoietic cell transplant comorbidity index (HCT-CI), HCT indication, donor type, conditioning intensity, graft vs. host disease (GVHD) prophylaxis, and occurrence of acute and chronic GVHD on development of COVID-19 was examined using Cox proportional hazards model. Hazard ratio (HR) and 95% confidence intervals (CI) were provided. Cumulative incidence of COVID-19 among the US centers reporting at least 1 COVID-19 infection was also calculated, using death from any cause as a competing risk. P value <0.05 was considered statistically significant for the analyses.Results: A total of 167 pediatric HCT recipients (allogeneic, allo: 135 and autologous, auto: 32) met study inclusion criteria. Median age at COVID-19 diagnosis for allo and auto HCT recipients were 15 years (range <1-21y) and 7 years (range 1-21y), respectively. Median time from HCT to COVID-19 diagnosis was 15 months (IQR 7-45) for allo recipients and 16 months (IQR 6-59) for auto HCT recipients. Forty-two percent (42%) of the patients had at least one comorbidity prior to HCT. Thirteen percent (13%) were receiving immunosuppression within six months prior to COVID-19 diagnosis. COVID-19 disease severity was mild in 87% of patients, while 4% of patients had severe disease requiring mechanical ventilation or supplemental oxygen. Only 36 HCT recipients (22%) received any COVID-19 directed therapy. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (range 1-179) for allo and auto HCT recipients, respectively. The overall probability of survival at 45 days was 95% (95% CI 90-99%) and 90% (95% CI 74-99%) for allo and auto HCT recipients, respectively (Figure 1). Forty-five (45) day survival was lower among recipients transplanted at the transplant centers outside the US [non-US recipients 85% (95% CI 71-95%) versus US recipients 98% (95% CI 93-99%)]. No deaths occurred in patients who had received a transplant between 2000-2013. The primary cause of death was COVID-19 in 54% of patients and primary disease in 38% of patients. In the subset analysis restricted to pediatric allogeneic HCT recipients transplanted at the US centers (n=34), the cumulative incidence of COVID-19 infection was noted to be 1.9% (95% CI 1.2-2.9%) at 6 months post-HCT and increased to 4.7% (95% CI 3.4-6.3%) by 1-year post-HCT. Cox regression analysis showed that compared to HCT-CI score of 0, patients with HCT-CI score of 1-2 were more likely to develop COVID-19 (HR 1.95; 95% CI 1.03-3.69, p=0.042). Underlying diagnosis, donor type, treatment exposures, or GVHD did not predict COVID-19 incidence.Conclusions: This is the largest series to date summarizing the cumulative incidence, risk factors, and outcomes of pediatric HCT recipients with COVID-19. Patients with pre-HCT comorbidities were more likely to develop COVID-19. However, the overall disease severity and mortality after COVID-19 were low in this patient cohort. [Display omitted] DisclosuresBhatt: Rite Aid Corporation: Divested equity in a private or publicly-traded company in the past 24 months; Pfizer Inc.: Divested equity in a private or publicly-traded company in the past 24 months; Moderna, Inc.: Divested equity in a private or publicly-traded company in the past 24 months; Johnson & Johnson: Divested equity in a private or publicly-traded company in the past 24 months. Sharma: Medexus Inc: Consultancy; Spotlight Therapeutics: Consultancy; Vindico Medical Education: Honoraria; CRISPR Therapeutics: Other, Research Funding; Novartis: Other: Salary support paid to institution; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution. Riches: ATARA Biotherapeutics: Other: Payment; Jazz Pharmaceuticals: Other: Payment; BioIntelect: Membership on an entity's Board of Directors or advisory committees. Dandoy: Omeros: Other: Consulted and received Honorarium.

Post-Transplant Cyclophosphamide Is Associated with Improved Clinical Outcomes in HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Post-Transplant Cyclophosphamide Is Associated with Improved Clinical Outcomes in HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients

PurposeDeficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2.MethodsWe conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS).ResultsThirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT.ConclusionHCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency.Clinical ImplicationsHCT is a definitive cure for DADA2 with > 95% survival.

Characterizing Ionizing Radiation Exposure after T-Cell Depleted Allogeneic Hematopoietic Cell Transplantation

INTRODUCTION: Recipients of allogeneic hematopoietic cell transplantation (HCT) routinely undergo diagnostic radiographic tests in the course of their transplant care. While concerns have been raised over the risk of mutagenic events resulting from such exposure to low-dose ionizing radiation, effects in immunocompromised post-HCT hosts are unknown. We thus sought to quantify radiation exposure from medical imaging in a large cohort of allogeneic HCT patients and to evaluate its impact on transplant outcomes.METHODS: This single-center retrospective study included recipients of first allogeneic HCT with T-cell depleted grafts for AML, ALL, or MDS from 2000 to 2013 who were alive at 1 year post-transplant. The analysis excluded patients who received a second allogeneic HCT before the 1-year landmark. All radiology exams performed in the first year post-HCT were tabulated. We then calculated total cumulative 1-year baseline radiation dosing for each patient using published estimates of doses corresponding to the individual imaging exams (National Council on Radiation Protection [NCRP] and Measurements, Publication No. 160, 2009; Kanal et al., Radiology 2017; Quinn et al., BMC Med Imaging 2016; Gao et al., BMC Med Imaging 2017). Overall survival (OS) and relapse-free survival (RFS) after the landmark were estimated by Kaplan-Meier methods. Relapse, non-relapse mortality (NRM), and development of late malignancies were estimated with the cumulative incidence method for competing risks. Association of categories of baseline radiation exposure with OS and RFS were evaluated using the logrank test, and associations with NRM, relapse, and late malignancy were evaluated using Gray's test.RESULTS: A total of 476 patients underwent TCD HCT from 2000 to 2013, of whom 337 met eligibility criteria for the landmark analysis. Patient characteristics are shown in Table 1. The median number of radiographic tests in the first year was 9 (range 1-127), and median radiation exposure was 21.2 mSv (range 0.0-388.6; 1 mSv = 1 mGy). Given the wide range of radiation exposures, patients were divided into the following groups: 0-10 mSv of cumulative annual ionizing radiation (n = 107, 32%), 10-20 (n = 51, 15%), 20-40 (n = 77, 23%), 40-60 (n = 40, 12%), 60-80 (n = 29, 9%), and > 80 (n = 33, 10%). Across the entire cohort, OS was 78% (95% CI 73-82) at 2 years and 71% at 5 years (95% CI 66-76) after the 1-year landmark; RFS was 81% (95% CI 76-85) at 2 years and 74% (95% CI 69-79) at 5 years. Greater degrees of radiation exposure were associated with significantly poorer OS and RFS (Fig. 1). OS 2 years after the landmark, for instance, ranged from 45% (95% CI 31-66) in patients with > 80 mSv of radiation exposure to 90% (95% CI 84-96) in patients exposed to ≤ 10 mSv. Radiation exposure was also associated with significantly increased cumulative incidence of NRM (Fig. 2), which was, e.g., 40% (95% CI 22.4-57.0) at 2 years in patients exposed to > 80 mSv compared with 2% (95% CI 0.4-6.4) with ≤ 10 mSv. Cumulative incidence of relapse was 6.8% (95% CI 4.4-10.0) at 2 years and 10.4% (95% CI 7.2-14.3) at 5 years after the landmark. There was no significant association between radiation exposure and relapse (Fig. 2). As for late malignancies, cumulative incidence of secondary cancers or recurrence of prior cancers other than the indication for HCT was 2.4% (95% CI 1.1-4.5) at 2 years and 5.1% (95% CI 3.0-8.1) at 5 years after the landmark. Differences in radiation exposure were not significantly associated with development of such malignancies.CONCLUSION: This is, to our knowledge, the first large-scale systematic quantification of ionizing radiation exposure after allogeneic HCT. Median radiation exposure from radiology exams alone in the first year post-transplant was more than 3 times the annual US average of 6.2 mSv from all causes as estimated by the NCRP, with a substantial number of patients exposed to upwards of 10 times this amount. Greater degrees of radiation exposure were associated with poorer survival and increased NRM, reflecting the more frequent use of diagnostic imaging among patients with post-transplant complications. However, radiation exposure did not correspond to significantly increased risk of relapse or late malignancy in this analysis. [Display omitted] DisclosuresO'Reilly:Atara: Patents & Royalties, Research Funding. van den Brink:PureTech Health: Consultancy; Jazz Pharmaceuticals: Consultancy; Seres: Research Funding; Therakos Institute: Other: Speaking engagement.

Development of a Multi-Center Cohort to Evaluate Long-Term Outcomes and Late Effects Following Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Initiative

Background: Hematopoietic cell transplantation (HCT) is currently the only cure for sickle cell disease (SCD), with excellent survival using a matched related donor (MRD). Disease specific HCT registries have significantly advanced understanding of outcomes, via more comprehensive data collection in a larger number of patients. Such data may provide long-term outcomes after HCT, resulting in identification of advantages and disadvantages over conservative therapy, helping to focus future efforts on avoiding or improving the latter.Objective: To investigate the long-term outcomes of HCT in pediatric SCD, related to transplant, disease complications, and organ function.Methods: A multicenter retrospective registry of transplanted SCD patients was created through the Sickle Transplant Alliance for Research (STAR). Baseline, transplant, and long-term (most recent if >2 yrs from HCT, otherwise 1 yr) outcome data was collected from 10 centers. Disease recurrence was defined as acute SCD symptoms with hemoglobin S >50%. Graft rejection was defined as whole blood or myeloid donor chimerism <5%. Pulmonary function testing values were converted to functional categories per previous reports. Pre- and post-HCT values were compared using McNemar's test and extensions. P-values <0.05 were considered statistically significant.Results: Overall, 174 of 196 patients survived ≥1-yr post-HCT, with last assessment at 1186 d (Interquartile range, IQR: 760, 2351). Of these, 70.4% underwent HCT for clinically severe SCD from 1993-2016 (median, 2011), at 9.8±5.2 yrs (range, 1.6-25.6). Seventy-five percent (n=131) of patients received stem cells (87.0% marrow) from a MRD, and 58.1% received myeloablative conditioning, 93.7% with in vivo T cell depletion. Fourteen patients (8.1%) had rejection/disease recurrence 0.8-3.4 mo post-HCT; of these, 7 underwent a 2nd HCT. Overall, 45 patients (25.9%) developed chronic GVHD, at a median of 226 d (IQR: 140, 336), which was severe in 11 (24.4%) and extensive in 5 (11.1%). Ten patients required systemic immunosuppression 15-39 mo post-HCT, while 157 patients discontinued such at a median of 237 d (IQR: 173, 408). Donor chimerism was maintained long-term at a median of 100% in unsorted (n=101) and sorted (T: n=85, myeloid: n=69) samples, as reflected in median post-HCT hemoglobin levels of 13.0 g/dL (n=169; IQR: 11.8, 13.9). Posterior reversible encephalopathy syndrome (PRES) was reported in 18 patients (10.3%); 12 developed seizures with PRES and 9 without (12.1% with seizures). Of the 105 patients with available pre- and post-HCT brain MRIs, 2 developed new infarcts, 6 had new vasculopathy, and 10 had progression of previous infarct or vasculopathy; all but 2 of these patients had CNS disease pre-HCT (Table 1). While there was no difference between pre- and post-HCT pulmonary functions (P=0.79; n=91), 10 patients normalized and 11 had deterioration (Table 2). In the 13 patients with either a restrictive or obstructive pattern post-HCT, 47% had acute chest syndrome as an indication for HCT. One patient with poor cardiac function transitioned to normal function post-HCT, while 5 had a lower EF (p=0.103) and 4 a lower SF (p=0.05) post-HCT (Table 3). All patients who developed an abnormal EF or SF received myeloablative conditioning (88.9%) or underwent HCT for clinically severe SCD (66.7%). Mean TR jet velocity was normal in the 64 patients that underwent this evaluation post-HCT. Immune reconstitution was robust, with median ALC 2587 (n=151; IQR: 2000, 3357) and present/normal splenic uptake on nuclear medicine scan in 90.9% (n=44). Bone age was delayed in 44.9% (n=69). Bone mineral density showed a mean spine and body Z score of -0.56 and -0.50, respectively (n=92). In post-pubertal females, 22 had normal menstruation (48.9%) and 23 menstrual irregularity (51.1%), with 13 on hormone replacement therapy; data was not obtained in 15.Discussion: In this comprehensive retrospective registry with detailed long-term data, we were able to identify transplant-related sequelae, albeit in a minority of patients. Progression of SCD and HCT-related complications, though rare, merit careful follow up for potential intervention. Our data supports the establishment of prospective long-term registries post-HCT to ensure adequate healthcare, more accurate identification of the risks and benefits of transplant for SCD, and opportunity to improve outcomes. [Display omitted] DisclosuresKanter:Apopharma: Research Funding; Sancillo: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; American Society of Hematology (Sickle Cell Disease Guideline Panel): Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; MUSC: Other: The site PI for sponsored research conducted at MUSC who receives funds from: Novartis, bluebird bio, GBT, Sancillo, Apopharma, Pfizer; GBT: Research Funding; NHLBI (sickle cell disease research advisory committee): Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Guilcher:Jazz pharmaceuticals: Consultancy; Canada Market Research: Consultancy; Patient Access Solutions: Consultancy.

Transfusion- Related Iron Overload (TRIO) Is Associated with Delayed Engraftment and Increased Non Relapse Mortality (NRM) in Patients Undergoing Umbilical Cord Blood (UCB) Hematopoietic Cell Transplantation (HCT)

▪TRIO has been shown to be associate with higher risk of morbidity (infections, venocclusive disease and hepatic dysfunction) and mortality after allogeneic HCT. A high transplant iron score (>25 red cell unit transfused prior to HCT, serum ferritin > 1000 ng/ml and a bone marrow (BM) iron stain of +6) was associated with 50% decrease in survival at one year (Storey J. Hem & Oncol 2009). TRIO in BM macrophages can generate free radicals resulting in oxidant stress thereby altering the hematopoietic microenvironment. This could have adverse effects on hematopoiesis and affect engraftment after HCT. To date, limited data are available on the effect of TRIO on outcomes of UCB HCT. We examined whether TRIO quantified based on serum ferritin (sF) and BM iron score (MIS) impact outcomes of UCB HCT, particularly with regards to engraftment.We reviewed 150 consecutive patients (pts) who underwent UCB HCT between March 2006 and September 2015 at City of Hope. Median age at time of HCT was 33.5 years (yrs) (range: 0-70 years) with 55% male and 23% < 18 yrs of age. sF was available within 30 days before HCT for 65%, and MIS was assessed on the pre-HCT BM biopsy for 40% of pts. HCT indications included bone marrow failure (n=13), hemoglobinopathies (n=2), lymphoma (n=23), acute leukemia (n=104), and chronic leukemia (n=8). Disease risk index (DRI) was high/very-high in 38% and 20% of pts had HCT comorbidity index of more than 2. One cord graft was received for 20% of pts. Median TNC of 4.9X10^7/kg (range: 1.8-26.6) and median CD34 count of 1.8X10^5/kg (range: 0.2-122.4). HLA match status was 4/6, 5/6, 6/6 in 93, 48, and 9 pts. Almost 60% of pts received myeloablative conditioning regimen (MAC) and 80% had calcineurin inhibitor/mycophenolate mofetil for graft versus host disease (GVHD) prophylaxis.With a median follow-up of 48.1 months (range: 5.8- 119.6), 2- and 5-yrs progression free survival (PFS) were 41% and 35.5% while 2- and 5-yrs OS were 47% and 36%, respectively. Cumulative incidence (CI) of NRM at 2 and 5 yrs were 35.7 and 40.6% and CI of relapse at 2- and 5-yrs were 23 and 24%, respectively. Day 100 grade II-IV and grade III/IV aGvHD were 56.7% and 28.7%. 2 yrs CI of cGvHD was 51.7% with 38.8% extensive cGvHD. DRI was found to be significant factor for relapse (HR 1.74 95%CI 0.88-3.45 p<0.001) and conditioning regimen significantly affect OS (HR= 1.92 95%CI 1.24-2.96; p=0.003), PFS (HR= 2.12 CI 1.39-3.24; p<0.001) and relapse rate (HR= 4.07 CI 1.95-8.49; p<0.001) when non-myeloablative/reduced intensity conditioning was compared with MAC. However, day 100 grade II-IV and III/IV aGVHD was increased in pts with MAC (65.1% vs 45.3%; p=0.006 and 37.2% vs 17.2%; p=0.005; respectively) with no significant effect seen on the NRM (p=0.9).In multivariable analysis, sF <1000 ng/ml independently predicted for shorter OS (HR=0.49; CI 0.27-0.88 p=0.015). When the impact of sF was examined by quartiles, pts in the highest sF quartile (>1948 ng/ml) had shorter OS (HR=3.05, 95%CI: 1.40-6.66; p=0.03) and higher NRM (HR=2.79, 95%CI: 1.16-6.72; p=0.03) compared to those in the lowest quartile (<530 ng/ml) (Fig 1a and b). There was no statistically significant difference in regards to disease relapse, or incidence of acute or chronic GVHD across sF groups.Patients in the highest sF quartile had delayed platelet engraftment compared to those in the lowest quartile (HR=0.46, 95%CI: 0.24-0.89, p=0.03). A trend towards delayed neutrophil engraftment was also observed between these 2 groups (HR=0.57, 95%CI: 0.33-0.99; p=0.055) (Fig 1c and d). No significant difference was seen in neutrophil (p=0.67) or platelet engraftment (p=0.92) based on MIS. But there was a statistically significant increase of grade II-IV aGVHD in pts with MIS of 3-4 (63.8% vs 30.8% at day 100; p=0.04). This however did not translate into worse OS, NRM or relapse.In conclusion, TRIO measured by sF has an adverse impact on OS and NRM in recipients of UCB HCT. Elevated sF is also associated with delay in platelet and neutrophil engraftment after UCB HCT. MIS was not associated with time to engraftment, however, this value was available in only 40% of pts. Therefore, TRIO should be considered as a risk factor for adverse outcome and poor graft function after UCB HCT. [Display omitted] DisclosuresNademanee:seattle Genetics: Speakers Bureau.

Association of Factors Influencing Selection of Upfront Hematopoietic Cell Transplantation versus Nontransplantation Therapies in Myelofibrosis

Despite the curative potential of allogeneic hematopoietic cell transplantation (HCT) for myelofibrosis (MF), a significant number of patients with MF do not undergo HCT. Factors influencing treatment preferences in these patients have not been well studied. This study was conducted to identify patient-, disease-, and donor-related factors influencing the decision regarding HCT in patients with MF. A secondary objective was to compare survival between patients who elected upfront HCT and those who opted for nontransplantation therapy. We conducted a retrospective chart review amongst patients meeting criteria for transplant indication, evaluating clinical characteristics, treatment preferences, and outcomes. Of the 183 study eligible patients age <70 years, 129 (70%) developed an HCT indication. Age >60 years was significantly associated with higher rates of HLA-typing refusal (13 of 72 versus 1 of 44; P=.02). Caucasian ethnicity was significantly associated with an increased rate of identifying well-matched donors compared with non-Caucasian ethnicity (75% versus 48%; P=.02). Of the 69 patients with well-matched donors, 34 (49%) preferred to not pursue upfront HCT despite an indication for transplantation. Patient preference for nontransplantation therapies was the most common reason for declining HCT. We did not find any difference in survival between patients pursuing upfront HCT and those opting for nontransplantation therapies, although more patients in the HCT arm were in remission at the last follow-up. Patients of Caucasian ethnicity were significantly more likely than non-Caucasian patients to identify a well-matched donor. Despite availability of a well-matched donor, a significant proportion of MF patients with an indication for transplantation do not pursue HCT. Patient age, donor type, and patient preference play major roles in the selection of upfront HCT. Although a survival difference was not observed between upfront HCT versus non-transplant therapy, more patients in the HCT arm were in remission at the last follow-up.