Search

Hematopoietic cell transplantation (HCT) is an established cure for sickle cell disease (SCD) supported by long-term survival, but long-term organ function data are lacking. We sought to describe organ function and assess predictors for dysfunction in a retrospective cohort (n = 247) through the Sickle cell Transplant Advocacy and Research alliance. Patients with1-year follow-up or graft rejection/second HCT were excluded. Organ function data were collected from last follow-up. Primary measures were organ function, comparing pre- and post-HCT. Bivariable and multivariable analyses were performed for predictors of dysfunction. Median age at HCT was 9.4 years; the majority had HbSS (88.2%) and severe clinical phenotype (65.4%). Most received matched related (76.9%) bone marrow (83.3%) with myeloablative conditioning (MAC; 57.1%). Acute and chronic graft-versus-host disease (GVHD) developed in 24.0% and 24.8%. Thirteen patients (5.3%) died ≥1 year after HCT, primarily from GVHD or infection. More post-HCT patients had low ejection or shortening fractions than pre-HCT (0.6% → 6.0%, P = .007 and 0% → 4.6%, P = .003). The proportion with lung disease remained stable. Eight patients (3.2%) had overt stroke; most had normal (28.3%) or stable (50.3%) brain magnetic resonance imaging. On multivariable analysis, cardiac dysfunction was associated with MAC (odds ratio [OR] = 2.71; 95% confidence interval [CI], 1.09-6.77; P = .033) and severe acute GVHD (OR = 2.41; 95% CI, 1.04-5.62; P = .041). Neurologic events were associated with central nervous system indication (OR = 2.88; 95% CI, 2.00-4.12; P.001). Overall organ dysfunction was associated with age ≥16 years (OR = 2.26; 95% CI, 1.35-3.78; P = .002) and clinically severe disease (OR = 1.64; 95% CI, 1.02-2.63; P = .043). In conclusion, our results support consideration of HCT at younger age and use of less intense conditioning.

Background Parvovirus B19 (PVB19) infection has been implicated in allograft failure or dysfunction in solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo‐HSCT), but the literature is limited. Case Two pediatric patients were diagnosed with PVB19 infection around the time of allo‐HSCT graft failure. Both cases were secondary graft failure and required second allo‐HSCT. Conclusion There are many risk factors and potential confounders in determining the exact etiology of graft failure after allo‐HSCT. These two cases highlight the importance of including PVB19 in the diagnostic evaluation for graft failure. PVB19 infection may be an important risk factor for allo‐HSCT graft failure.

Background The Covid-19 pandemic has profoundly disrupted healthcare operations for vulnerable transplant and cell therapy patients. The Sarah Cannon Blood Cancer Network (SCBCN) comprises six Healthcare Corporation of America hospitals that have been certified based upon defined metrics of infrastructure, staffing, processes and volume. The SCBCN actively coordinated a response by integrating information from the framework of federal, state, network, hospital and individual transplant programs. Dynamic standards were developed taking into account operational aspects (such as PPE conservation, staffing, isolation policy, etc.), external regulations, and input from professional societies in order to balance the needs for life-saving therapy while reducing the likelihood of adverse consequences. In this study, we describe the impact of the Covid-19 across our network on transplant and cell therapy activity as well as the outcomes of the patients who were treated. Methods Data was integrated from electronic health records and a center survey questionnaire. The period of observation (defined as Covid era) was from March 15, 2020 to June 15th, 2020 to allow sufficient time for analysis of early outcomes. Transplant and cell therapy data from the prior 12 months was used as a comparator. Results: Within the SCBCN there was a decrease in overall transplant and cell therapy activity in the Covid era. Autologous transplantation was mainly diminished, particularly in the first 2 months. There was no significant impact on allogeneic or CAR-T therapy volumes. For allogeneic transplantation, there was a modest reduction in marrow grafts (11% to 8%) and a significant increase in cryopreservation (16% to 79%, P Conclusions: We describe a deliberate and coordinated reduction in transplant and cell therapy activity across our network compared to the prior year. For those patients who were selectively transplanted during the Covid19 pandemic, outcomes were not impaired. Our analysis will be updated at the time of presentation with data covering the Covid era from July-Oct '20. Figure Disclosures Bachier: Sanofi: Speakers Bureau; AlloVir: Honoraria; CRISPR: Honoraria; Juno Therapeutics, a Bristol-Myers Squibb Company: Honoraria. Kambhampati:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fred Hutchinson: Patents & Royalties; Colorado Blood Cancer Institute: Current Employment. Ramakrishnan:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Safah:Verastem: Honoraria; Astellas: Speakers Bureau; Amgen: Honoraria; Janssen: Speakers Bureau.

BackgroundAllogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.ObjectiveThe effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.MethodsWe studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.ResultsFour regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P< .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P< .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P= .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P= .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P< .001).ConclusionsGiven the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

Introduction: HLA-Haploidentical bone marrow transplant (haplo-BMT) is a curative approach for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor. Haplo-BMT expands the donor pool among adults and children with SCD to > 90% and is a less toxic treatment option than myeloablative matched related donor transplant, gene therapy or gene editing. In 2013, our research team developed a multi-institution learning collaborative with the main objective of optimizing haplo-BMT. In a Phase II clinical trial, to improve engraftment rates, we augmented the original Hopkins haplo-BMT protocol (Bolaños-Meade et al. Blood 2012) with thiotepa (10 mg/kg). The trial was conducted at 3 sites and showed durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection), and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present results of extension of this ongoing trial comprising additional sites and participants. Material and methods: The trial was approved by the Institutional Review Board (IRB) at each participating site and opened in October 2013 (ClinicalTrials.gov identifier NCT01850108). The global learning collaborative includes 22 sites, in 10 countries, meets weekly via conference calls for sharing of SCD Haplo-BMT knowledge and patient related questions. Each site has a standalone institutionally IRB protocol, with similar eligibility criteria, and data sharing agreement with Vanderbilt University Medical Center. The agreements for aggregate REDCap data sharing and DSMB assessment of the outcomes with stopping rules. Common conditioning regimen included: rabbit ATG 4.5 mg/kg, thiotepa (10 mg/kg), fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included posttransplant cyclophosphamide (PTCy) 100 mg/kg, mycophenolate mofetil and sirolimus. Bone marrow mobilized with filgrastim (5-10 μg/kg/d x5 days) was initially used, 27% (11/41), but later stopped at several sites. Primary graft failure was defined as 5% donor (myeloid) cells by day +42. The primary endpoint was 1-year EFS. Primary or secondary graft rejection, stroke, and death were considered events. Safety stopping rules were implemented, independent of age, using graft failure, death, grade III or IV acute GVHD or moderate or severe chronic GVHD. Results: We enrolled 41 consecutive participants from 8/14/2014 - 6/30/2020. Participant genotype included 39 patients with HbSS, 1 patient each with HbSC and Sβ0 thalassemia. Median age was 16.9 years (range 1.3 to 43), and 51% (21/41) of participants were 500/mcL) and platelet (>50 x 109/L) counts were 20 days (17.0, 24.2) and 32 days (27.0, 36.8) respectively. Incidence of grades III-IV acute and moderate chronic GVHD were 9.7% (4/41) and 12.1% (5/41), respectively. No participant had severe GVHD. Among durably engrafted participants, 81.8% (27/33) were off immunosuppression at 1-year posttransplant. Kaplan-Meier probabilities of EFS and OS were 75.5% (95% CI 61.3%, 92.9%) and 87.9% (95% CI 75.5%, 100.0%) at one year, respectively (Figure). Mortality was 7.3% (3/41). Graft failure was 12% (5/41; 3-primary and 2-secondary). All graft failures were in participants Conclusion: Our novel global learning collaborative effort for haplo-BMT for SCD is a scalable and efficient approach to sharing knowledge and implementing curative therapy for SCD. Importantly all haplo-BMT candidate had donors. An unexpected outcome in this trial, not likely to occur by chance, is that all graft rejections occurred in young participants (< 18 years), and all older participants (> 18 years) engrafted. The trial will add new stopping rules by age strata ( or = to 18 years) and will modify the conditioning regimen in pediatric stratum. Disclosures Black: HRSA: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Micelle BioPharma: Research Funding; NHLBI: Research Funding. DeBaun:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees.

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

Background Parvovirus B19 (PVB19) is a single-stranded DNA virus that infects erythroid progenitor cells, classically causing a pure red cell aplasia, but sometimes causing fulminant pancytopenia. PVB19 has been implicated in solid organ allograft failure, but no such literature exists for allogeneic hematopoietic stem cell transplantation (allo-HSCT). PVB19 may be an underappreciated complication in allo-HSCT. Methods Retrospective report of two pediatric patients diagnosed with PVB19 infection and allo-HSCT graft failure. Results Case #1: 1 year-old male with leukocyte adhesion deficiency (LAD) received reduced intensity conditioning with alemtuzumab, fludarabine, thiotepa, and melphalan, followed by a 10/10 HLA- matched, ABO-compatible, sibling donor bone marrow graft (4.85 × 108 TNC/kg and 9.74 × 106 CD34+ cells/kg). He achieved neutrophil and platelet engraftment by days +23 and +25, respectively. Day +29 chimerism was 100% donor unseparated. Patient had biopsy-proven acute GI GVHD at day +77, responsive to systemic steroids. Evaluation for unexplained transfusion-dependent normocytic normochromic anemia at day +88 revealed PVB19 by PCR (3900 copies/mL). Patient had history of intermittent, non-palpable, and non-specific blanching erythematous rash. At day +105, donor chimerism decreased to 9% unseparated and 5% myeloid engraftment. Flow cytometry revealed repopulation of original LAD phenotype, confirming secondary graft failure. The patient received a second allo-HSCT using the same donor at day +225. Case #2: 13 year-old male with acute myeloid leukemia received myeloablative conditioning with fludarabine and busulfan followed by a T cell-replete, 5/10 HLA-mismatched, ABO-compatible, sibling bone marrow graft (3.60 × 108 TNC/kg and 4.51 × 106 CD34+ cells/kg). GVHD prophylaxis included post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. He achieved neutrophil engraftment by day +16. Patient had non-specific blanching rash with bone pain during the post-HSCT recovery period. Patient had low level CMV viremia treated with ganciclovir and valganciclovir early post-HSCT. Day +26 donor chimerism showed 89% unseparated and 100% myeloid engraftment. Patient developed pancytopenia unresponsive to G-CSF. Bone marrow exam on day +40 showed mixed chimerism, no recurrent AML, but detectable PVB19 by PCR. Blood PVB19 PCR was positive (312 copies/mL). The patient was diagnosed with secondary graft failure with persistent severe pancytopenia. He received a rescue allo-HSCT from the same donor at day + 69. Conclusions There are many risk factors and potential confounders in determining the exact etiology of graft failure after allo-HSCT. These two cases highlight the importance of including PVB19 PCR in the diagnostic evaluation for graft failure. PVB19 infection may be an important risk factor for allo-HSCT graft failure.

Background Clostridium difficile infection (CDI) is a major source of morbidity for patients undergoing autologous and allogeneic hematopoietic stem cell transplantation (HSCT). CDI can complicate gastrointestinal mucositis, lead to mucosal barrier infections or sepsis, and compromise nutrition after HSCT. CDI may contribute to acute gastrointestinal graft-versus-host disease (GI aGVHD) and reduce overall survival in allogeneic HSCT patients. Use of enteral vancomycin as CDI prophylaxis may reduce morbidity and improve outcomes in HSCT recipients. Methods As a quality improvement initiative, enteral vancomycin was instituted as CDI prophylaxis in all autologous and allogeneic HSCT recipients at Methodist Children's Hospital beginning 02/13/19. Patients were prescribed vancomycin 125 mg oral/enteral twice daily (Ganetsky et al. Clin Infect Disease 2019; 68 (12):2003-2009) from HSCT admission to discharge home. Patients readmitted during the first 100 days after HSCT resumed enteral vancomycin while hospitalized. Physicians, advanced practice providers, and pharmacists monitored enteral vancomycin administration. The infectious disease and prevention team monitored CDI and weekly vancomycin resistant enterococcus (VRE) stool testing per institutional policy. Pre- and post-implementation data was retrospectively reviewed (number of HSCT patients, CDI, VRE, adverse events of enteral vancomycin, and GI aGVHD). Two-sided Fisher's exact test was used to compare CDI before and after institution of enteral vancomycin prophylaxis. Results Between 01/05/2018 and 02/12/2019, the rate of CDI was 29% (n=9/31). After implementation of CDI prophylaxis (02/13/19 to 09/16/19), the rate of CDI was 0% (n=0/23). Enteral vancomycin resulted in a significant reduction in the number of CDI cases (p=0.0068). Prior to implementation of CDI prophylaxis, 26% (n=7/27) of allogeneic HSCT recipients developed GI aGVHD. Of the 7 patients that developed GI aGVHD, 6 had a history of CDI. After implementation of CDI prophylaxis, 7% (n=1/14) of allogeneic HSCT recipients developed GI aGVHD. There were no VRE positive screens or infections. There were no adverse events related to enteral vancomycin. Conclusions Enteral vancomycin appears to be safe and effective CDI prophylaxis in pediatric, adolescent, and young adult HSCT recipients. Since institution of enteral vancomycin prophylaxis, there has been a significant reduction of CDI in our HSCT patients. This quality improvement project is ongoing and future analyses will compare GI aGVHD and overall survival with CDI pre- and post-implementation of enteral vancomycin prophylaxis.

Allogeneic HCT practice patterns for PID changed between 1974–2016. Three-year survival improved to >70% for SCID and non-SCID patients after 1999, and further increased to 94% for SCID patients transplanted 2010–2016 following newborn screening diagnosis.

Hematopoietic cell transplantation (HCT) is a complex procedure that requires availability of adequate infrastructure, personnel, and resources at transplantation centers. We conducted a national survey of transplantation centers in the United States to obtain data on their personnel, infrastructure, and care delivery models. A 42-item web-based survey was administered to medical directors of transplantation centers in the United States that reported any allogeneic HCT to the Center for International Blood and Marrow Transplant Research in 2011. The response rate for the survey was 79% for adult programs (85 of 108 centers) and 82% for pediatric programs (54 of 66 centers). For describing results, we categorized centers into groups with similar volumes based on 2010 total HCT activity (adult centers, 9 categories; pediatric centers, 6 categories). We observed considerable variation in available resources, infrastructure, personnel, and care delivery models among adult and pediatric transplantation centers. Characteristics varied substantially among centers with comparable transplantation volumes. Transplantation centers may find these data helpful in assessing their present capacity and use them to evaluate potential resource needs for personnel, infrastructure, and care delivery and in planning for growth.

We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD.

Background Little is known about adherence to guidelines recommending yearly screening with transcranial Doppler (TCD) ultrasonography to detect stroke risk for children with severe sickle cell disease. The objective was to determine the proportion of children with hemoglobin SS (HbSS) or sickle-β0-thalassemia (HbSβ0) aged 2–16 years who received recommended TCD screening from 1997 to 2008, and to identify factors associated with adherence. Procedure A retrospective cohort study included patients enrolled in Tennessee Medicaid with HbSS or HbSβ0 who received care at the two largest sickle cell centers in Tennessee. The outcome of interest was adherence with guidelines for annual screening TCD's, identified from computer claims and validated through medical record review. The cumulative rate of children who received a TCD per year was calculated using the Kaplan–Meier method. Cox proportional hazards regression was used to examine the association of child, family, and health care use characteristics with receiving a TCD. Results Among 338 TCD eligible at-risk children, 232 (68.6%) had at least one TCD during the study period. The yearly cumulative incidence of annual TCD's increased from 2.5% in 1997 to 68.3% in 2008. In multivariate models, calendar year, maternal education, and increased number of sickle cell related outpatient visits were associated with an increased rate of receiving a TCD. Conclusions Publicly insured children with HbSS or HbSβ0 had increasing adherence with TCD screening guidelines between 1997 and 2008, though 31% had no TCD at all during follow-up. Increasing number of sickle cell related outpatient visits was associated with increasing adherence to screening guidelines. Pediatr Blood Cancer 2013;60:270–274. © 2012 Wiley Periodicals, Inc.

Iron overload is a major toxicity of chronic transfusions. Myocardial iron overload is associated with cardiac dysfunction. Cardiac and liver magnetic resonance imaging (MRI) was performed on 14 chronically transfused sickle cell disease (SCD) and non-sickle cell disease (non-SCD) patients seen at Vanderbilt Children's Hospital from 1 January 2000 to 10 March 2010. Retrospective review was conducted to assess cardiac T2*, liver T2*, ventricular dimensions and function, echocardiogram, length of transfusion, hemoglobin, and ferritin measurements. Ten patients had SCD and 4 had non-SCD, including α-thalassemia, β-thalassemia, and Diamond-Blackfan anemia. Cardiac T2* was normal in all SCD patients (mean 39 ± 12 ms), but abnormal in 3 of 4 non-SCD patients (mean 11.8 ± 2.4 ms). Liver T2* was similar between SCD (mean 6.2 ± 1.6 ms) and non-SCD patients (mean 5.9 ± 1.9 ms), and did not correlate with serum ferritin. Comparing SCD and non-SCD patients with similar transfusion duration, SCD patients had normal cardiac T2* and non-SCD patients had abnormal cardiac T2*. No patients had cardiomyopathy, but ventricular dilatation was common among SCD patients. Chronically transfused pediatric SCD patients are relatively spared of myocardial iron overload, which is unlikely to be due to lower total body iron burden in SCD patients than non-SCD patients.

The development of PTLD is a rare severe adverse event following ASCT. We report on a child with DS who developed PTLD following autologous transplant for relapsed Hodgkins disease. He was successfully treated with cyclophosphamide, prednisone and rituximab. We also present a comprehensive review of the literature of PTLD in pediatric patients following ASCT.

The first bone marrow transplantation in Latin America was performed more than 30 years ago and since then several countries have started transplant programs. The Center for International Blood and Marrow Transplant Research captured information on 13,473 transplants performed in Latin America from 1981 to 2009. The current report summarizes this activity. Argentina, Mexico, and Brazil have the largest activity in the region. Despite increase in the annual number of transplants, the activity is limited to sibling donor and autologous transplants. Indications are similar to other regions with a proportionally higher number of pediatric transplants for treatment of non-malignant diseases. Unrelated donor transplant activity is also increasing through collaborations with international donor registries and the development of the first national donor registry in Brazil. Umbilical cord transplants were also reported in Latin American centers, mainly in Brazil and most commonly used for treatment of children with malignant diseases. In conclusion, hematopoietic cell transplantation is routinely performed in several centers in Latin America. However, the activity is low compared to the population in need. Challenges with costs of transplantation, donor availability, number of centers of excellence, and trained personnel need to be addressed for further development of this field in the region. Additionally, more integration between countries and transplant centers is an important next step and can assist in improving awareness for the field and maximizing the transplant activity in Latin America.

We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD.

Event-free survival for recurrent alveolar rhabdomyosarcoma (ARMS) is poor, and a consensus approach to treatment in the relapse setting has not been established. Recent studies suggest that a combination regimen of vincristine, irinotecan, and temozolomide (VITA) is active against recurrent sarcomas. We present our single-institution experience with this regimen for relapsed ARMS in heavily pretreated patients, including those with prior exposure to a combination regimen of vincristine and irinotecan. We observed a complete radiographic response in 1 of 4 patients who received VITA as a fifth attempted salvage regimen. Radiographic remission for the responsive patient was sustained for 27 weeks before disease recurrence. All therapies were administered in the outpatient setting and no grade III or grade IV toxicities were observed. These findings suggest that for patients with refractory ARMS, VITA in combination should be among the treatment options considered. They also reinforce the need for biological correlates to prospectively identify patients who may benefit from this treatment.

Little is known about adherence to guidelines recommending yearly screening with transcranial Doppler (TCD) ultrasonography to detect stroke risk for children with severe sickle cell disease. The objective was to determine the proportion of children with hemoglobin SS (HbSS) or sickle-β(0) -thalassemia (HbSβ(0) ) aged 2-16 years who received recommended TCD screening from 1997 to 2008, and to identify factors associated with adherence.A retrospective cohort study included patients enrolled in Tennessee Medicaid with HbSS or HbSβ(0) who received care at the two largest sickle cell centers in Tennessee. The outcome of interest was adherence with guidelines for annual screening TCD's, identified from computer claims and validated through medical record review. The cumulative rate of children who received a TCD per year was calculated using the Kaplan-Meier method. Cox proportional hazards regression was used to examine the association of child, family, and health care use characteristics with receiving a TCD.Among 338 TCD eligible at-risk children, 232 (68.6%) had at least one TCD during the study period. The yearly cumulative incidence of annual TCD's increased from 2.5% in 1997 to 68.3% in 2008. In multivariate models, calendar year, maternal education, and increased number of sickle cell related outpatient visits were associated with an increased rate of receiving a TCD.Publicly insured children with HbSS or HbSβ(0) had increasing adherence with TCD screening guidelines between 1997 and 2008, though 31% had no TCD at all during follow-up. Increasing number of sickle cell related outpatient visits was associated with increasing adherence to screening guidelines.

X-linked lymphoproliferative syndrome is a well-described syndrome often characterized by progression to fatal infectious mononucleosis. Many mutations of the SH2D1A gene have been identified in patients with X-linked lymphoproliferative syndrome. These mutations are often associated with either decreased or impaired function of the protein product, signaling lymphocytic activation molecule-associated protein. We describe a patient with a novel missense mutation in SH2D1A. We report on his unique presentation, clinical course and subsequent successful treatment with a matched unrelated donor bone marrow transplant.

Background: NK alloreactivity based on KIR (Killer Immunoglobulin-like Receptor) expression by natural killer cells has been reported to decrease the risk of leukemia relapse after HLA-haploidentical stem cell transplantation (SCT). The use of donors with high KIR B-content score has been correlated with a decreased risk of relapse. Objective: We examined the outcome of leukemia relapse following CD34-positive selected T-cell depleted haploidentical donor peripheral blood SCT followed by donor lymphocyte infusion with methotrexate prophylaxis. Methods: Between 2009-2015, twenty patients underwent haploidentical donor CD34-selected, T cell-depleted peripheral blood SCT on an IRB-approved protocol. Nine patients had acute lymphoblastic leukemia (ALL), and eleven had myeloid leukemia (10 AML, 1 JMML). Among ALL patients, remission status was CR1 in 5, with either induction failure or MRD+ after consolidation, 3 were in CR2 and 1 was CR3. Four patients had T-cell disease. Among AML patients, 5 were in CR1, one had refractory disease and 5 were CR2 or beyond. Ligand-ligand NK alloreactivity based on HLA typing was available for all patients. Receptor-ligand NK alloreactivity based on immunophenotyping of KIR was available in 16 patients and KIR B-content score was available in twelve patients. Patients were considered to have receptor-ligand NK alloreactivity if immunophenotyping of the donor had >5 (cells/uL) expressing KIR2DL1 (recognizes C2 group) or KIR2DL1/2DL13 (recognizes C1 group). Patients with alloreactive KIR only recognizing BW4 were not considered alloreactive due to predicted weak alloreactivity. All patients received a uniform conditioning regimen including TBI 1200cGy, thiotepa 10mg/kg, fludarabine 200mg/m2, and rabbit-anti-thymocyte globulin (rATG) 6mg/kg, with no post-transplant immunosuppression. All patients received a planned donor lymphocyte infusion (DLI) 3-5 x 104 CD3+ cells/kg between days 30- 42 after transplant and received weekly IV methotrexate prophylaxis following DLI. The incidence of relapse and GVHD was evaluated. Results: Based on a ligand-ligand model of NK alloreactivity, only 4/20 patients had NK alloreactivity predicted. Seven patients expressed all 3 ligands and blocked all possible NK alloreactivity. Median follow-up was 306 days (range 45 days-5 years). Four of 20 patients relapsed (1/4 with predicted NK alloreactivity and 3/16 without). Median time to relapse was 110 days (range 124-455 days). NK alloreactivity based on receptor-ligand as defined above was present in 5/16 patients and relapse occurred in 2/5 with and 1/11 without. Donor KIR B-content was >=2 in 4 patients and 0-1 in 8 patients. Relapse occurred in 1/4 with 2 and 2/8 with 0-1. No donors had KIR B-content score of 3-4. The incidence of grade II-IV acute graft-versus-host disease after prophylactic DLI was 25%, with 2 grade II, 3 grade III and no grade IV GVHD. Three patients developed cGVHD, two mild and one severe by NIH consensus criteria. Conclusion: An approach using a DLI followed by methotrexate prophylaxis after a CD34-selected, T-cell depleted SCT for pediatric leukemia diminishes the effect of NK alloreactivity and KIR B-content. Disclosures No relevant conflicts of interest to declare.

Many children who need a hematopoietic stem cell transplant do not have a matched related or unrelated donor. The use of alternative donors including mismatched family members can provide a donor for almost all patients. The use of such donors is associated with a high risk of graft-versus-host disease (GVHD). We present the results of a prospective study using the CliniMACS® device for CD34-selection of peripheral blood stem cell (PBSC) grafts to prevent GVHD under BB-IND 14045. Patients did not receive immunosuppression after transplant. The approach was also used as a platform for a companion post-transplant immunotherapy study. The study included patients with malignant (MD) and non-malignant (NMD) disorders receiving unrelated donor (UD) and mismatched related donors (MMRD) to evaluate the broad applicability of this approach for GVHD prevention. The primary endpoint was acute GVHD incidence and there was a stopping rule for primary graft failure. Overall survival was a secondary endpoint. Between 2009-2013, 30 children underwent CD34-selected PBSC transplantation from an alternative donor. Fifteen patients had MD (ALL 4, AML 8, JMML 1, acute mast cell leukemia 1, Ewing’s sarcoma 1) and 15 had NMD (sickle cell 6, immunodeficiency 5, bone marrow failure 4). Twenty-three patients had MMRD and 7 had UD (all 7 had NMD). The conditioning regimen consisted of TBI 1200 cGy (MD) or melphalan 140mg/m2 (NMD), thiotepa 5mg/kg x2, fludarabine 40 mg/m2x5, and rabbit-ATG 1.5 (MD) or 2.5 (NMD) mg/kg x4. Seven patients with NMD received rituximab x1 during conditioning. Twenty-two patients received a planned (P) donor lymphocyte infusion (DLI) between days 30 and 42 with methotrexate GVHD prophylaxis on a companion study. Eight patients received a therapeutic (T) DLI for decreasing donor chimerism or viral infection. The median age at transplantation was 10 years (range 0.3-17). Median CD34+ dose was 21 x 10^6/kg (range 10-25) and all patients received < 1 x 10^4 CD3/kg. The ANC was > 500 at median 14 days (range 9-16). Acute GVHD prior to DLI occurred in 1 patient (3%; stage I skin which resolved with a brief course of prednisone). Primary graft failure occurred in 1 patient (3%). The patient subsequently engrafted after a CD34-selected transplant from the other parent. Two patients who had active disease at transplant (mast cell leukemia, Ewing’s) and early relapse are excluded from the following analyses. Twenty-one of 28 patients are alive with median follow-up of 2 years (range 1 mo-4 yrs). The Kaplan-Meier estimated 100 day and 1 year survival is 96% and 74%, respectively. Relapse occurred in 1/10 MD patients with at least 100 days follow-up. Grade II-IV acute GVHD and chronic GVHD occurred only after DLI. Acute GVHD grade II-IV occurred in 21% (3 P, 3 T) and chronic GVHD (3 P) in 11%. Viral reactivation was common, but viral disease was less common - CMV 12% and EBV-related PTLD 11% [at risk patients only] and adenovirus 11%. Invasive fungal infections occurred in 7%. All deaths were due to infection, with thrombotic microangiopathy present in 6/7. All outcomes were similar for MD and NMD and for MMRD and UD except for acute GVHD which occurred in 26% MMRD and 0% UD transplants and for EBV-PTLD which only occurred in NMD patients. EBV-PTLD has been reduced in NMD patients by using rituximab in the conditioning. The use of a CD34-selected, T cell-depleted alternative donor PBSC transplant successfully prevented acute GVHD without the need for post-transplant immunosuppression. The use of this approach and the conditioning regimens employed provided reliable engraftment and a very low incidence of Day 100 transplant-related mortality and relapse (for patients without active disease). Future efforts will focus on approaches for post-transplant immunotherapy to decrease morbidity and mortality due to viral infections. Disclosures: No relevant conflicts of interest to declare.

Abstract 762 Background: To date, neither the effect of transplant center volume nor other transplant center-specific characteristics have been described for pediatric hematopoietic cell transplantations (HCT) in the U.S. Therefore, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), we explored the effect of transplant center characteristics on day-100 and 1-year survival for pediatric HCT in the U.S. for the years 2008 and 2009. Methods: Center Directors of all pediatric and combined adult and pediatric transplant centers that performed HCT in patients younger than 18 years were surveyed. Eighty-four transplant centers were queried and 68 centers responded (response rate 80%) representing patients from 42 pediatric and 26 combined adult and pediatric centers in the U.S. The survey instrument collected relevant transplant center characteristics, including transplant unit activities and resources, medical care team structure, and physician and healthcare provider characteristics. Patient, disease and HCT characteristics on 2228 consecutive pediatric allogeneic transplants performed at these centers between 2008–2009 were obtained from the CIBMTR. All centers performed transplantations during both study years. Prior to analysis of potential center effects, stepwise multivariate logistic regression was built to determine patient-related (age, performance score, sex, race), disease-related (disease and disease status) and HCT-related (donor [matched related, mismatched related, matched unrelated, mismatched unrelated], HCT-conditioning regimen [myeloablative vs. reduced intensity conditioning regimens], and graft-versus-host disease prophylaxis) factors associated with mortality. Thereafter, marginal logistic regression models were built using the generalized estimating equation approach to determine the effect of individual center characteristics on mortality, adjusting for significant patient, disease and HCT characteristics. Results: The median pediatric and pediatric and adult combined transplant center volume during the study period were 55 and 144, respectively. The results of multivariate analysis are shown in Table 1. After adjusting for performance score, donor type, and disease/disease status at transplant, day-100 mortality risks were higher at transplant centers that performed 16 or fewer allogeneic transplants over the two-year study period and at transplant centers where the number of inpatients per on-service transplant physician was five or fewer (median number of transplants was 24 per year). After adjusting for age, donor type, disease and disease status at transplant and CMV serostatus, 1-year mortality risks were also higher at transplant centers where the number of inpatients per on-service transplant physician was five or fewer, and in the absence of a dedicated transplant outpatient clinic during the weekend. Conclusions: These data suggest that center volume is important to maximize survival for pediatric transplantation. Centers where there were fewer than five inpatients per on-service transplant physician were associated with higher mortality risks at both early and later post-transplant periods. Furthermore, a potentially modifiable center characteristic that may improve survival for pediatric HCT patients is access to specialized care (outpatient transplant clinic) on the weekend. Disclosures: No relevant conflicts of interest to declare.

Abstract 1020 Severe aplastic anemia (SAA) is the most common non-malignant indication for hematopoietic cell transplantation (HCT). Although survival after HCT for SAA has improved in recent years, it is not known whether the observed higher survival rates are uniform across racial groups or whether there are differences similar to those seen with HCT for hematologic malignancies. Our primary objective was to compare overall survival after HCT for SAA in patients of African American and Caucasian races. The study population included patients who received HCT in the U.S. between 1990 and 2008. Eighty-four African Americans (cases) and 215 Caucasians (controls) were matched on factors known to be associated with survival after HCT for SAA, including age at HCT (±3 years), donor type (HLA-matched sibling, matched unrelated donor, mismatched unrelated donor), graft type (bone marrow or peripheral blood progenitor cells) and transplant year (±1 year). For 39 cases the match ratio for controls was 1:4, for 14 cases, 1:3, for 22 cases, 1:2 and the remaining 9 cases, 1:1. The median age of cases and controls was 17 years and the median interval from diagnosis to HCT was 3.4 months. Forty-five percent of transplants were from unrelated and 55% from HLA-matched sibling donors. A third of unrelated donor-recipient pairs were HLA-mismatched. Bone marrow was the predominant source of stem cells. The median follow-up of cases and controls was 5 years. In multivariate analysis, risk of overall mortality was higher for African Americans compared to Caucasians, relative risk [RR] 1.75, 95% CI 1.14–2.69, p=0.01. Risks of overall mortality were also higher during the early post-transplant period; odds ratio (OR) 2.42, 95% CI 1.09–5.37, p=0.03) and OR 2.61, 95% CI 1.33–5.47, p=0.005) at 3-months and 1-year post-transplantation, respectively. The 5-year probability of overall survival adjusted for interval from diagnosis to HCT, performance score and conditioning regimen, the other significant variables associated with higher mortality was 58% for African Americans and 73% for Caucasians. The likelihood of neutrophil recovery was similar in both groups (OR 1.03, 95% CI 0.46–2.33, p=0.94). Acute grades II–IV graft-versus-host disease (GVHD) risks did not differ between African Americans and Caucasians (RR 0.81, 95% CI 0.56–1.17, p=0.26). However, chronic GVHD risk was higher for African Americans, although the difference did not reach statistical significance (RR 1.55, 95% CI 0.98–2.44, p=0.06). Thirty-seven (45%) of 82 African Americans died compared to 56 (27%) of 207 Caucasians. The proportion of patients dying with GVHD was higher in African Americans (12 of 37; 32%) than among Caucasians (9 of 56; 16%). Death secondary to organ failure was higher in Caucasians (12 of 56; 26%) compared to African Americans (4 of 37; 11%). There were no differences between African Americans and Caucasian in regards to deaths from graft failure, infection or hemorrhage. These data suggest recent improvements in overall survival rates after HCT for SAA are largely limited to Caucasians. Higher mortality in African Americans may be explained by greater genetic diversity, which renders the identification of donors by high-resolution HLA-typing more challenging, genetic polymorphisms impacting drug metabolism and unmeasured co-morbidities. Novel strategies aimed at lowering acute and chronic GVHD rates are needed to lower GVHD-related deaths. Disclosures: No relevant conflicts of interest to declare.

Abstract 3506 Recurrent disease is the most important cause of treatment failure after HCT. Total body irradiation (TBI)-containing conditioning regimens are associated with fewer relapses and longer leukemia-free survival (LFS) in children and adolescents with ALL. While TBI TRM Relapse LFS 1) TBI dose Disclosures: No relevant conflicts of interest to declare.