Sibling Donor Bone Marrow Transplantation Research Articles

Isolated Optic Nerve Relapse in a Pediatric Patient With T-Cell Lymphoblastic Leukemia: A Brief Report.

Isolated optic nerve (ON) relapse is a rare occurrence in lymphoblastic leukemia (LBL). A 10-year-old boy with T-LBL presented 8 months after diagnosis with blurred vision and thickening of right ON on magnetic resonance imaging consistent with relapse. Cerebrospinal fluid and bone marrow were negative for leukemia. He received reinduction chemotherapy (including nelarabine and craniospinal radiation) followed by a myeloablative matched sibling donor bone marrow transplant. He remains in remission 2 years post-transplant with normal vision. We also review the literature for reports of isolated ON relapse in patients with LBL. Our patient's clinical course demonstrates that disease control can be achieved with early detection of ON relapse before disease progression.

Reduced toxicity matched sibling bone marrow transplant results in excellent outcomes for severe congenital neutropenia.

Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in ELANE, impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with ELANE-mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.

222 - Matched Sibling Donor Bone Marrow Transplant with Busulfan + Fludarabine Conditioning Results in Excellent Outcomes for Severe Congenital Neutropenia

222 - Matched Sibling Donor Bone Marrow Transplant with Busulfan + Fludarabine Conditioning Results in Excellent Outcomes for Severe Congenital Neutropenia

Patient and Caregiver Attitudes Towards Gene Therapy for Sickle Cell Disease: A Need for Partnership and Education

Background:Fewer than 20% of patients with sickle cell disease (SCD) have access to curative matched sibling donor bone marrow transplantation (MSD-BMT). Development of novel therapies to ameliorate the serious morbidity and early mortality caused by SCD is a National Institute of Health research priority. Gene therapy for SCD has emerged as a promising approach in early-stage clinical trials approach with the potential to reach greater numbers of patients than MSD-BMT. Knowledge and attitudes of individuals with SCD towards this investigational new therapy and their willingness to participate in early-stage clinical trials have not been systematically described.Methods:Patients with SCD at least 13 years of age (n=66) and caregivers of children with SCD (n=38) were surveyed about knowledge, attitudes, and beliefs regarding gene therapy for SCD. Most questions utilized a 5-item Likert response scale while The Newest Vital Sign was used to assess health literacy. To explore attitudes around gene therapy in further detail, we identified a regionally diverse focus group comprised of 12 patients/caregivers with SCD from across the United States. We audio-recorded, transcribed verbatim, and analyzed five focus group discussions using thematic content analysis to identify salient themes related to attitudes towards gene therapy for SCD. Our goal was to identify the educational needs and preferences of this patient / caregiver stakeholder group.Results:Survey: Of the 104 survey respondents 96% identified as Black and 4% as Hispanic. Respondents were between 13-64 years (mean 29.6, Std Dev 11.9 years). HbSS and HbSC were the most common genotypes (61.5% and 24%, respectively). Only 4.8% of participants (N=5) felt “extremely knowledgeable” about gene therapy for SCD while most (63.4%) reported no/slight knowledge. We found no association between health literacy levels and gene therapy knowledge (p=0.361). Nearly 30% of participants reported that the risk of cancer as a potential side effect would “probably not prevent their enrollment” on a gene therapy trial while 48% said it “definitely/probably would preclude their participation”. Most respondents had a neutral attitude regarding the safety of gene therapy for SCD and how good of a treatment it was (56.7% and 58.6%, respectively). Only a few respondents endorsed the idea that gene therapy was “unsafe” or “not a good treatment for SCD” (5.8% and 4.8% respectively). There was an association between increasing knowledge about gene therapy and agreement that it is safe (p=0.012) and a good treatment for SCD (p=0.031).Focus Groups: Among the focus group participants, there was consensus that communication about gene therapy is suboptimal. Participants noted that clinicians frequently use medical jargon, do not tailor their approach to the individual patient/caregiver, and fail to adequately disclose important details. Focus group members desired more information about side effects and risks associated with conditioning chemotherapy, immunosuppression, risk of infertility, and hair loss. Participants, particularly parents of children with SCD, were worried about future unknown risks and described the enormity of the decision to enroll in an early-phase trial. Focus group members verbalized the need for inclusion of patients with SCD as partners during the informed consent/assent process and ideally, at the outset of the clinical trial design.Conclusion:Very few patients with SCD described feeling knowledgeable about gene therapy for SCD; a majority have neutral feelings about the safety and utility (“good treatment for SCD”) of this new approach. Patient/caregiver-centered education about gene therapy in a manner that meets stakeholder informational needs is urgently needed. Given the temporary hold on lentiviral gene therapy trials for SCD (after some participants developed a myeloid neoplasm on an industry sponsored trial in February 2021) and the risk of cancer as a probable or definite barrier to enrollment in a gene therapy trial for many patients, transparency of information about these risks is essential. For the successful execution of novel trials in SCD, a community-based participatory research approach is vital. DisclosuresSharma: Medexus Inc: Consultancy; Spotlight Therapeutics: Consultancy; Novartis: Other: Salary support paid to institution; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Vindico Medical Education: Honoraria; CRISPR Therapeutics: Other, Research Funding. Johnson: CRISPR Therapeutics: Research Funding.

Disease Burden and Pre-Transplant Health-Related Quality of Life in Pediatric Sickle Cell Disease Patients Receiving Nonmyeloablative HLA-Identical Sibling Donor Transplantation

Title: Disease Burden and Pre-transplant Health-related Quality of Life in Pediatric Sickle Cell Disease Patients Receiving Nonmyeloablative HLA-identical Sibling Donor TransplantationBackground: Sickle cell disease (SCD) is a hemoglobinopathy characterized by recurrent pain crises, severe organ damage, and reduced health-related quality of life (HRQL). Bone marrow transplantation (BMT) is a proven curative treatment for SCD that can improve both disease burden and HRQL. Despite the benefits, relatively few patients pursue a cure through BMT. The decision to receive a BMT is nuanced and likely to be influenced by a number of factors. One study by Roth et al. showed SCD patients interested in BMT had a higher HRQL than those uninterested in BMT, suggesting some variability between SCD patients pursuing transplant and the general SCD patient population. To date the factors that may affect pre-transplant HRQL of pediatric SCD patients remain unclear, particularly in the nonmyeloablative setting.Objective: To evaluate the impact of disease-burden, patient demographics, and hydroxyurea treatment on pre-transplant HRQL.Methods: Children and young adults with SCD set to receive a nonmyeloablative HLA-identical sibling donor BMT were administered HRQL surveys (PedsQL) in the six months leading up to the start of the conditioning regimen. Patients' disease history and demographic information were captured and analyzed for their relationship to HRQL. PedsQL parent surveys were used when patient surveys were unavailable. The mean difference in HRQL between groups were compared using an unpaired t test or linear regression.Results: 32 patients were enrolled onto this study. Six of the 32 patients HRQL were not included due to withdrawal, delay of transplant, or completion of the survey outside of window. The median age at the time of survey administration was 13.5 years (range 2-21). 57.7% of patients were male and 88% of patients had genotypes hemoglobin SS or Sβ 0thalassemia. 12% of patients had a history of overt stroke. 52% of patients were hospitalized while receiving HU treatment. 32% of patients received chronic blood transfusions leading up to transplant. The median number of hospitalizations in the two years leading up to transplant was 2 (range 0-10). 16.7% of patients met the AAPT diagnostic criteria for chronic pain. 75% of patients received HU treatment leading up to transplant. The median hemoglobin F percentage was 10.4. The median HRQL for all patients was 77.17 (range 36.9-98.91, SD +/- 15.99).Sickle cell genotype (P=0.88), history of overt stroke (P=0.79), hospitalization while receiving HU treatment (P=0.78), and the number of hospitalizations in the two years before transplant (P=0.39) were not associated with lower HRQL. History of chronic transfusion leading up to transplant approached statistical significance for lower HRQL (P=0.06). Older age (P=0.17) and female gender (P=0.89) were not associated with worse HRQL. Patients receiving HU treatment had significantly higher HRQL than patients not receiving HU (P=0.0034), with median PedsQL scores of 80.06 and 58.64, respectively. The date of survey administration was not associated with HRQL (P=0.40). The number of eligibility criteria met (P=0.63), chronic pain (P=0.17), total number of RBC transfusions (P=0.45), and pre-transplant hemoglobin (P=0.25) were not associated with HRQL.Discussion: Patient demographics and several markers of disease burden appear to have minimal impact on HRQL. Interestingly, the use of HU therapy was associated with significantly higher pre-transplant HRQL. The etiology of this finding is unclear given that disease burden was not associated with HRQL and warrants further investigation. The absence of association between disease burden and HRQL through current disease severity eligibility paradigms suggests that other factors may impact HRQL in SCD patients choosing a low toxicity nonmyeloablative BMT. DisclosuresNo relevant conflicts of interest to declare.

Long Term Followup of Sickle Cell Disease Post Hematopoietic Stem Cell Transplant from Uganda

Introduction: Sickle cell disease (SCD) remains associated with high risk of morbidity and early death. Many patients in sub-Saharan Africa continue to experience severe complications despite best supportive care. Hematopoietic stem cell transplant (HSCT) can be considered for a select group of patients. When successful, HSCT is economical and improves quality of life. We report the experience from our south-south partnership whereby Ugandan patients with SCD have undergone HSCT at the Bone Marrow Transplant Center in Gurgaon, IndiaMaterial and methods: 23 consecutive patients suffering from SCD who underwent HSCT between June 2014 and July 2017 were included in the study. Eleven underwent matched sibling donor bone marrow transplant (BMT) using busulfan 3.2 mg/kg/day for 4 days, cyclophosphamid 50mg/kg/day for 4 days, and hATG (PfizerATGAM) 30mg/kg/day for 3 days. Two adult patients underwent matched sibling donor HSCT using reduced intensity conditioning with busulfan 3.2 mg/kg/day for 4 days, cyclophosphamid 60mg/kg/day for 2 days, and ATG (PfizerATGAM) 30mg/kg/day x 3 days. Immune suppression for for HSCT patients was cyclosporine 3mg/kg/day in 2 divided doses starting D-4 and methotrexate 10mg/m2 on D+1 followed by 7mg/m2 on day 3, 6 and 11 post HSCT. Ten patients underwent haploidentical HSCT using hypertransfusion (target Hb 11-13gm/dl), hydroxyurea (20mg/kg/day) and azathioprine (2mg/kg/day) from day -45, conditioned with Thiotepa 10mg/kg in two divided doses (D-7), fludarabine 30mg/m2 (D-6 to D-2), cyclophosphamide 14.5 mg/kg (D-5, D-4), TBI 2Gy with thymic shielding (D-1), rATG (Genzyme Thymoglobulin) 1.5 mg/kg (D-9 to D-7). GVHD prophylaxis included PTCy 50 mg/kg/day on D3 and 4, tacrolimus (target level 5-15 ng/ml) or sirolimus (target levels 10-15ng/ml) (till 6 months post HSCT) and MMF (till D35) starting from D5.Results: The median patient age was 8 years (range 10 months-31 years). Before transplantation all patients had repeated episodes of SCD complications warranting a transplant. All were non-responsive to hydroxyurea. Of the 23 patients, 18 survived without sickle cell disease with Lansky/Karnofsky scores of 100. One had a primary graft failure another secondary graft failure with recurrence of disease. At median follow up of 479 days (range 51-1204) the probabilities of survival, SCD-free survival, and transplant-related mortality after transplant were 87%, 78%, and 13%, respectively. Three children who underwent haploidentical HSCT died. One died due to PRES with intracranial hemorrhage at day 86 post BMT, another one due to primary graft failure with Klebsiella sepsis with shock. The third child died due to complicated falciparum malaria and possible invasive fungal infection at day 24 post HSCT. He had full donor chimerism.Conclusion: Outcomes of HSCT in SCD have improved significantly. With better conditioning regimens and improved supportive care, alternative donor transplant and adult HSCT have become viable therapeutic options. HSCT should be strongly considered as a curative modality for selected patients suffering from SCD. DisclosuresNo relevant conflicts of interest to declare.

Paediatric severe aplastic anaemia treatment: where to start?

Paediatric severe aplastic anaemia treatment: where to start?

HLA Matched Sibling Donor (MSD) Bone Marrow Transplantation (BMT) for Children with Limited Financial Resources in a Government Hospital (Maharaja Yashwantrao Holker Hospital [MYH]) in Indore, India: A Collaborative Project between East and West.

<h3>Introduction</h3> In India, most MSD-BMTs are conducted in private hospitals and are associated with a cost of $20-30,000, which most poor families cannot afford. To serve children with limited financial resources (below the poverty line or with a yearly family income of <$7,000), we have developed a BMT unit at MYH in Indore, India. <h3>Methods</h3> Collaboration Model- Figure <h3>Team</h3> Two general pediatricians were trained for 6 months at Columbia University, NY, where they developed SOP and protocols. <h3>Blood Bank</h3> Able to provide PRBC and platelets, could perform plasma but no RBC depletion. <h3>Patient Recruitment</h3> HLA typing camps were conducted in 5 cities, 253 families were typed, 72 pts had 10/10 HLA MSD. DKMS Germany performed HLA typing free of cost. <h3>Financial Support</h3> To provide free BMT, Airport Authority of India and Bina Refinery provided financial support through corporate social responsibility. <h3>Conditioning Regimen</h3> Majority of patients (pts) received r-ATG-6mg/kg, FLU-150mg/m², BU-12.8-16mg/kg (without PK studies) and cytoxan-200mg/kg. Prophylaxis; aGVHD: CSA/MTX. Acyclovir until day 100. Fluconazole until ANC >1000/mm³. Bactrim for PCP. G-CSF was not routinely administered. <h3>Follow-Up</h3> Pts stayed in the hospital vicinity for up to 6 months post-BMT. The majority of outpatient medications were also provided free of charge. <h3>Results</h3> Donors: 13F and 7M, median age 8 yrs (2-18). The median number of CD34+ cells harvested from bone marrow was 5.5 × 10⁶/kg (1.5-21.6); only 2 donors were G-CSF mobilized. <h3>Patients</h3> First BMT was conducted in April 2018. Median FU 9 months (3-17). Of the first 20 pts, 12 were males. Pts were ages 2-5Y (n=9), 5-10Y (n=8) and >10Y (n=3). 19/20 pts were heavily transfused. Thalassemia spectrum (16/20), SCD (n=1), MDS (n=1), SAA (n=1), and CML (n=1). 4 pts with major ABO incompatibility underwent RBC desensitization. Median time for ALC >500/mm³, neutrophil and platelet engraftment was 19d (12 -30), 27d (14-33) and 25d (15-50), respectively. Two pts had graft failure (one died). At last follow up, two pts have stable mixed chimerism and 16 (80%) have donor chimerism >90%, all 18 engrafted pts are transfusion independent. Overall survival is 95%. The median cost of BMT was $11,000 ($6,000-22,000). <h3>Conclusion</h3> Early results demonstrate the feasibility of our model. With appropriate remote supervision and dedicated general pediatricians and nurses with limited BMT training, we can successfully conduct MSD BMT in a resource-constrained set up. Despite living in remote villages, poverty, facing socio-cultural challenges, families can be trained to provide appropriate care at home. Multi-drug resistant bacteraemia and GI infections remain a major concern.

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia

AbstractAllogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Eculizumab to Treat Posterior Reversible Encephalopathy Syndrome Due to Underlying Transplant-Associated Thrombotic Microangiopathy in Patients Receiving Allogeneic Hematopoietic Cell Transplant for Sickle Cell Disease

Pre-existing endothelial dysfunction and vascular injury sustained during allogeneic hematopoietic stem cell transplantation (HCT) increases risk for endothelial injury-related complications like posterior reversible encephalopathy (PRES) and transplant-associated thrombotic microangiopathy (TA-TMA) in patients with sickle cell disease (SCD). Herein, we report two SCD HCT recipients in whom PRES-related symptoms resolved only after eculizumab therapy was initiated for underlying TA-TMA. Case 1 25-year-old male with SCD developed PRES-related seizures and headaches on Day+30 following matched sibling donor bone marrow transplant (BMT) and reduced-intensity conditioning (RIC) with fludarabine/melphalan/alemtuzumab and graft-versus-host disease (GvHD) prophylaxis with tacrolimus and methotrexate (MTX). Symptoms initially resolved after discontinuing tacrolimus. However, on Day+60, he presented with hypertension (HTN), status epilepticus, and right intracranial hemorrhage. Despite adequate HTN control and maximal anti-epileptic therapy, his symptoms persisted. Two weeks later, laboratory testing confirmed TA-TMA. Both PRES and TA-TMA symptoms and signs resolved after five weeks of eculizumab therapy (Figure 1). Case 2 Eight-year-old female with SCD underwent 10/10 matched unrelated BMT following RIC with fludarabine/melphalan/thiotepa/alemtuzumab and MTX/tacrolimus/abatacept for GvHD prophylaxis. She developed altered mental status, seizures, and HTN and Day+74 MRI brain confirmed PRES. Her symptoms also persisted despite tacrolimus cessation and effective HTN control. One week later, laboratory testing confirmed TA-TMA. Complete resolution of neurological symptoms occurred after three weeks of eculizumab therapy. (Figure 2). Conclusion Our cases highlight maintaining a high level of clinical suspicion for TA-TMA in SCD patients presenting with PRES post-HCT and consideration for eculizumab therapy in such patients.

Successful Allogeneic HCT for W.H.I.M. Unexpectedly Complicated By Hypersensitivity Pneumonitis

Intro/Objectives Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency defined by its symptoms and CXC chemokine receptor 4 (CXCR4) gene mutation. This leads to myelokathexis in which mature neutrophils cannot exit the bone marrow, causing severe neutropenia. Use of hematopoietic cell transplant (HCT) to correct a primary immunodeficiency is well accepted; yet, due to the rarity of WHIM, data on HCT in this setting are limited. We present a successful matched sibling donor (MSD) bone marrow (BM) transplant in a 6 year old male with WHIM who developed unexpected respiratory complications post HCT. Methods/Results The patient was initially followed for congenital neutropenia and therapy consisted of weekly filgrastim. At age 5 years, he was diagnosed with WHIM by CXCR4 sequencing. Treatment was changed to plerixafor, but he required frequent dose escalation. HLA typing revealed his brother was an 8/8 allele match. Patient's history was significant for asthma, but no recent flares. He was unable to perform pulmonary function tests due to age. At 6 years old he received an MSD BM graft after myeloablative conditioning with busulfan, cyclophosphamide, and ATG. GVHD prophylaxis consisted of cyclosporine and short course methotrexate. Myeloid engraftment ocurred on day +20 with >95% donor chimerism after day +55. On days +76, +87, and +104, he was admitted for respiratory distress. Infectious evaluations only revealed EBV PCR in a BAL specimen obtained during the second admission. For this he received four weeks of rituximab. On each admission, he improved quickly with albuterol and systemic steroids, but symptoms recurred soon after returning home. During his third admission it was found that he was exposed to an African Grey Parrot in his home. Due to the close association of his symptoms with returning home, and his exquisite response to steroids, Pulmonology consultation lead to a diagnosis of hypersensitivity pneumonitis. The bird was relocated, the home extensively cleaned, and while staying in temporary housing from day +110 to +275 the patient did not relapse. After returning home the patient had no further respiratory events. The bird was allowed to return on day +367. Patient has remained well on inhaled corticosteroids as of day +473. Conclusion Hypersensitivity pneumonitis is a type IV hypersensitivity reaction that can be linked to bird exposure. It is T cell mediated and IgE independent. Acquisition of IgE mediated allergies has been reported after HCT, but there are no reports of new type IV hypersensitivity development. Neither patient nor donor had previous hypersensitivity to the bird. Due to the transient nature of the pneumonitis in our patient, this likely represents an unusual case of abnormal T cell maturation post HCT. This case also emphasizes the importance of environmental exposures in post HCT respiratory symptoms.

The Fountain of Youth: Outcomes of Nonmyeloablative (NMA), HLA-Haploidentical Related (Haplo) Bone Marrow Transplantation (BMT) with Post-Transplantation Cyclophosphamide (PTCy) Best with Younger Donors Regardless of Relationship to Patient

▪NMA haplo BMT with PTCy is an increasingly used therapeutic strategy in patients with hematological malignancies (HM). Data demonstrating the safety of this NMA approach in older patients has led to an increased percentage of BMT performed in patients aged > 60 years. Consequently, the average age of potential related donors to be evaluated is also increasing. We sought to determine if donor age and donor relationship to the patient affected outcomes in patients undergoing NMA haplo BMT with PTCy.We retrospectively evaluated 586 adult and pediatric patients with HM who underwent NMA haplo BMT with PTCy from October 2002 through 2015. All patients received NMA conditioning with fludarabine, Cy, and total body irradiation, followed by allografting bone marrow stem cells from a first-degree relative. Graft-versus-host disease (GVHD) prophylaxis consisted of two doses of high-dose PTCy, mycophenolate mofetil and either sirolimus or tacrolimus. Donor age range was categorized into <30 years, 30-45 years and >45 years. Patients not receiving their first allogenic BMT were excluded.The median patient age was 57 years (range 1-76) and 63% were male. The indication for BMT was AML in 163 patients (27.8%), MDS in 34 (5.8%), MPN in 7 (1.2%), ALL in 52 (8.9%), CML in 15 (2.6%),CMML in 6 (1.0%), biphenotypic leukemia in 6 (1.0%), aggressive B cell lymphoma (BCL) in 94 (16.0%), T cell lymphoma in 36 (6.1%), mantle cell lymphoma in 31 (5.3%), Hodgkin's lymphoma in 54 (9.2%), indolent BCL in 34 (5.8%), CLL in 33 (5.6%), multiple myeloma in 13 (2.2%) and other HM in 8 (1.4%). Donor age ranged from 13-79 years. Donors were divided into three age categories: 146 of donors were <30 years (24.9%), 231 were 30-45 years (39.4%) and 209 were >45 years (35.7%). The most common donor relationship to the patient was children (83.6%) from donors <30 years, children (69.7%) from donors 30-45 years and siblings (56.9%) from donors >45 years. There was no correlation between donor and recipient age, with the older patients having the youngest donors and vice versa (Figure 1). Disease Risk Index score (DRI) was low in 90 patients (15.4%), intermediate in 368 (62.8%), high/very high in 94 (16.0%) and not determined in 34 (5.8%). Median follow-up was 2.9 years (range 9 days-11.4 years). Median CD34 infused was 4.61x106/kg from donors <30 years, 4.11x106/kg from donors 30-45 years and 3.62x106/kg from donors >45 years (p=0.0001). Younger donors were associated with lower non-relapse mortality (NRM); on competing-risk analysis, the cumulative incidence of NRM was 6% (95% CI 2−10%) at 3 years in patients with donors <30 years, 16% (95% CI 11−22%) in patients with donors 30−45 years and 15% (95% CI 10−20%) in patients with donors >45 years (p=0.02, Figure 2A).The probability of progression free survival (PFS) at 3 years was 45% (95% CI 37−55%) in patients with donors <30 years, 37% (95% CI 30-44%) 30-45 years and 37% (95% CI 31−45%) >45 years (p=0.23). The probability of overall survival (OS) at 3 years was 61% (95% CI 52−71%) in donors <30 years, 49% (95% CI 42−57%) 30-45 years, and 49% (95% CI 43−57%) >45 years (p=0.08, Figure 2B). The donor relationship did not influence outcomes with the probability of PFS at 3 years 40% (95% CI 30−54%) with parental donors, 39% (95% CI 32−47%) with sibling donors, and 39% (95% CI 33−45%) in child donors (p= 0.99). The probability of OS at 3 years was 53% (95% CI 42−67%) with parental donors, 51% (95% CI 44−59%) with sibling donors and 52% (95% CI 46−59%) in child donors (p= 0.97).These results confirm the benefit of using donors <30 years of age for NMA haplo BMT with PTCy. This adds to the increasing evidence that donor age is a universal risk factor in BMT. Although reasons for this association have been suggested (i.e. a higher proportion of memory T cells in older donors), this requires further analysis. The data also illustrate that the donor's relationship to the patient (i.e. sibling, child or parent) had no significant impact on NRM, OS, or PFS. With this transplantation platform, the youngest haplo relative, regardless of their relationship to the patient, should be considered the preferred donor source for patients in need of BMT. Since previous analyses have shown no difference between haplo with PTCy and matched sibling donor (MSD) BMT, consideration should be given to selecting a younger haplo donor over an older MSD; however, further work in this area is needed before adopting such a strategy widely. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease.

Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort. We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014. Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5-8.3) and donor age of 6 years (IQR 3-10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2-4 acute GVHD was 25.5%, grades 3-4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194-318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4-90.6%) and event-free survival was 78.9% (95% CI: 65.1-87.7%). No patient experienced graft failure. Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population.

Hematopoietic stem cell transplantation for acquired aplastic anemia.

There has been a steady improvement in outcomes with allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA), because of progress in optimization of the conditioning regimens, donor hematopoietic cell source, and supportive care. Here, we review recently published data that highlight the improvements and current issues in the treatment of SAA. Approximately one-third of aplastic anemia patients treated with immune suppressive therapy (IST) have acquired mutations in myeloid cancer candidate genes. Because of the greater probability for eventual failure of IST, human leukocyte antigen (HLA)-matched sibling donor BMT is the first-line of treatment for SAA. HLA-matched unrelated donor (URD) BMT is generally recommended for patients who have failed IST. However, in younger patients for whom a 10/10-HLA-allele matched URD can be rapidly identified, there is a strong rationale to proceed with URD BMT as first-line therapy. HLA-haploidentical BMT using posttransplant cyclophosphamide conditioning regimens is now a reasonable second-line treatment for patients who failed IST. Improved outcomes have led to an increased first-line role of BMT for treatment of SAA. The optimal cell source from an HLA-matched donor is bone marrow. Additional studies are needed to determine the optimal conditioning regimen for HLA-haploidentical donors.

Allogeneic Hematopoietic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia- a Report from the Acute Leukemia Working Party of the EBMT

Secondary acute myeloid leukemia (sAML) is a very heterogeneous group of disease derived from myelodysplasia, chronic myeloproliferative disorders or after exposure to chemotherapy and or radiation therapy (therapy related AML) or due to exposure to environmental carcinogens. sAML has traditionally been considered a devastating disease with inferior outcomes compared to de novo AML, affecting a vulnerable population of heavily pretreated, especially older patients. Allogeneic hematopoietic stem cell transplantation (HCT) is the only potential curative therapy and usually considered in patients with low comorbidities and transplant related risk score. However, relapse is the most frequent cause of failure after HCT, occurring in more than 50% of the patients. No systematic large analysis of HCT for sAML is available to study the risk factors and outcome. Therefore, the EBMT Acute Leukemia Working Party has performed a retrospective registry study on patients with sAML (n=4256) undergoing HCT. Patients who underwent HLA-identical sibling (n=2290) or unrelated donor (n=1966) peripheral blood (n=3781) or bone marrow transplantation (n=475) from 2000 to 2013 are included in the study. All unrelated donors were Human Leucocyte Antigens (HLA)-matched (10/10) (n=1532) or one locus mismatched (9/10) (n=434). 1901 (45%) patients received ablative (MAC) and 2355 (55%) reduced-intensity conditioning (RIC) regimen. Median age at transplant was 56 years, IQR 48-63 (MAC 51, IQR 42-58; RIC 60, IQR 54-64). Median time from diagnosis of sAML to HCT was 6.2 months, IQR 4.1-12.0 (MAC 5.6, IQR 3.8-9.7; RIC 7.0, IQR 4.4-14.12; p Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 33% (95% CI, 32-35%) and 25% (95% CI, 24-27%), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 46% (95% CI, 44-48%) and 41% (95% CI, 39-43%), respectively. Acute GVHD (grade II-IV) occurred in 1043 (26%) patients. The 2-year cumulative incidence of chronic GVHD was 54% (95% CI, 51-56). Two year OS, LFS, RI and NRM of MAC and RIC groups were 48% (95% CI, 46-50) vs. 44% (95% CI, 42-47), p=0.06, 44% (95% CI, 41-46) vs. 39% (95% CI, 37-41), p=0.003, 30% (95% CI, 28-32) vs. 36% (95% CI, 34-38), p In multivariate analysis adjusted for variable with different distribution between groups, the type of conditioning (RIC vs. MAC) had no impact on OS and LFS, however RIC group had higher RI (HR, 1.3, 95% CI 1.12-1.44, p=0.0001) and lower NRM (HR 0.8, 95% CI 0.72-0.96, p=0.01). Older age at HCT was an independent adverse prognostic factor for OS, LFS and NRM. Time from diagnosis to HCT had no impact on transplant outcome. Patients receiving PB grafts had superior OS (HR 0.84, 95% CI 0.73-0.97, p=0.01), LFS (HR 0.85, 95% CI 0.74-0.97, p=0.02) and lower RI (HR 0.83, 95% CI 0.70-0.99, p=0.049) compared with BM. Patients in remission and receiving HCT from HLA-identical siblings were independently associated better outcome. In summary, our registry study in the largest cohort of patients studied so far receiving HCT for secondary AML, demonstrated that about 45% of patients with secondary AML can attain long term survival after HCT. Patients receiving ablative regimens were associated with lower relapse risk and patients in remission had superior survival. Patients receiving PB grafts were associated potent graft-versus leukemia effects with decreased relapse risk and improved survival. Post- transplant pre-emptive therapy to decrease relapse risk might improve outcome further in these high risk populations. Disclosures Niederwieser: Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Glass: Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Esteve: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Schmid: Janssen Cilag: Other: Travel grand; Neovii: Consultancy.

A Multicenter Phase II Trial of Unrelated Donor Reduced Intensity Bone Marrow Transplantation for Children with Severe Sickle Cell Disease (SCURT): Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0601) Study

▪Background:Children with severe sickle cell disease (SCD) experience organ damage, poor quality of life, and a risk of premature mortality. Allogeneic bone marrow transplantation (BMT) halts disease progression when stable donor erythropoiesis is established. Myeloablative conditioning (MAC) followed by HLA matched sibling donor BMT is effective, but most patients with SCD lack a matched sibling donor and long term side effects from MAC (e.g., infertility) can be barriers to patient acceptance of BMT. The SCURT trial was designed as a prospective, multicenter phase II trial to evaluate outcomes after HLA matched unrelated donor (MUD) BMT with reduced intensity conditioning (RIC). We hypothesized that an intensely immunosuppressive RIC regimen would be sufficient for donor engraftment and could limit toxicity. The primary endpoint was one year event free survival (EFS) (alive and disease free) ≥75%. All patients were evaluable for the primary endpoint for the purpose of this report.Methods:Children between 3 and 19.75 years of age who had ≥1of the following complications - stroke, high transcranial doppler velocity, recurrent acute chest syndrome, or significant vaso-occlusive pain crises were eligible. An independent review committee confirmed eligibility. The preparative regimen consisted of alemtuzumab (48 mg) (day-22 to -19), fludarabine (150 mg/m2) (day-8 to -4), and melphalan (140mg/m2) (day-3). Donors and recipients were matched at the HLA allele-level at HLA-A, -B, -C and -DRB1 loci. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus or cyclosporine, methotrexate (7.5 mg/m2)on days +1, +3 and +6, and methylprednisolone (1 mg/kg/day) from day +7, tapered after day +28.Results:Thirty patients were enrolled between 2008 and 2014. One patient was excluded from analysis for a major eligibility violation at the DSMB's recommendation. Twenty-nine patients (16 M, 13F), 5.9-19.3 years old (median 14.0 years) from 19 centers were evaluable with median follow up of 25.2 months (range, 12-61.5 months). All patients recovered neutrophils (median 12 days) and platelets >50x109/L (median 24 days). Graft rejection (GR) in 3 patients (10%) occurred before day +100, and was followed by autologous hematopoietic recovery. No late GR has been observed. The primary endpoint was met with1-year EFS of 76% (Figure 1A). The 1-year probability of overall survival (OS) was 86% (Figure 1B). The cumulative incidence (CINC) of grade II-IV and III-IV acute GVHD at day 180 were 31% and 17% respectively (Figure 2A). The CINC of chronic GVHD at 1-year was 62%. Chronic GVHD was extensive in 38% (Figure 2B). GVHD when present was noted by 12 months post-BMT. There were 7 deaths, all in patients >14 years at time of BMT. One death occurred after a second transplant for graft rejection. The other 6 deaths occurred between 143 and 960 days post BMT, from GVHD. Non-fatal toxicities included posterior reversible encephalopathy syndrome (PRES) associated with hypertension and seizures in 35%. All cases were observed in the first 6 months post-BMT; all patients recovered with no obvious sequelae. No patient developed veno-occlusive disease, idiopathic pneumonia syndrome or cerebral hemorrhage. Infections were common, and occurred in 76% of patients. CMV and EBV reactivation each occurred in 23% of recipients. Surviving patients report performance scores of 100% (n=14), 90% (n=5), and 80% (n=3) at 2 years or at the time of last assessment. At last follow up, 13 patients had successfully discontinued immunosuppressive therapy.Conclusion:In summary, the RIC regimen employed in this trial of MUD BMT in children with severe SCD resulted in low rates of regimen-related organ toxicity (other than a high rate of PRES) and 1-year EFS of 76%, associated with regression of SCD manifestations. . The risk of graft rejection/disease recurrence was similar to that observed after conventional HLA-identical sibling donor BMT. Chronic GVHD occurred in 62% of patients and was the leading cause of toxicity and mortality. Future trials should focus on effective GVHD prophylaxis after URD BMT. Secondary outcome analyses including health-related quality of life and neurocognitive performance are ongoing. [Display omitted] [Display omitted] DisclosuresWalters:ViaCord and AllCells, Inc: Other: Medical director. Levine:Novartis: Consultancy.

Allogeneic Hematopoietic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia- a Report from the Acute Leukemia Working Party of the EBMT

Secondary acute myeloid leukemia (sAML) is a very heterogeneous group of disease derived from myelodysplasia, chronic myeloproliferative disorders or after exposure to chemotherapy and or radiation therapy (therapy related AML) or due to exposure to environmental carcinogens. sAML has traditionally been considered a devastating disease with inferior outcomes compared to de novo AML, affecting a vulnerable population of heavily pretreated, especially older patients. Allogeneic hematopoietic stem cell transplantation (HCT) is the only potential curative therapy and usually considered in patients with low comorbidities and transplant related risk score. However, relapse is the most frequent cause of failure after HCT, occurring in more than 50% of the patients. No systematic large analysis of HCT for sAML is available to study the risk factors and outcome. Therefore, the EBMT Acute Leukemia Working Party has performed a retrospective registry study on patients with sAML (n=4256) undergoing HCT.Patients who underwent HLA-identical sibling (n=2290) or unrelated donor (n=1966) peripheral blood (n=3781) or bone marrow transplantation (n=475) from 2000 to 2013 are included in the study. All unrelated donors were Human Leucocyte Antigens (HLA)-matched (10/10) (n=1532) or one locus mismatched (9/10) (n=434). 1901 (45%) patients received ablative (MAC) and 2355 (55%) reduced-intensity conditioning (RIC) regimen. Median age at transplant was 56 years, IQR 48-63 (MAC 51, IQR 42-58; RIC 60, IQR 54-64). Median time from diagnosis of sAML to HCT was 6.2 months, IQR 4.1-12.0 (MAC 5.6, IQR 3.8-9.7; RIC 7.0, IQR 4.4-14.12; p<0.0001). At time of transplant, 2313 (54%) patients were in CR1, 278 (7%) in ≥CR2 and active diseases in 1665 (39%) patients. 158 (4%) patients had prior autologous HCT (MAC 58 [3%], RIC 100 [4%], p=0.049). Median follow-up of surviving patients was 26 months (IQR 7 -56).Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 33% (95% CI, 32-35%) and 25% (95% CI, 24-27%), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 46% (95% CI, 44-48%) and 41% (95% CI, 39-43%), respectively. Acute GVHD (grade II-IV) occurred in 1043 (26%) patients. The 2-year cumulative incidence of chronic GVHD was 54% (95% CI, 51-56). Two year OS, LFS, RI and NRM of MAC and RIC groups were 48% (95% CI, 46-50) vs. 44% (95% CI, 42-47), p=0.06, 44% (95% CI, 41-46) vs. 39% (95% CI, 37-41), p=0.003, 30% (95% CI, 28-32) vs. 36% (95% CI, 34-38), p<0.0001, 26% (95% CI, 24-28) vs. 25% (95% CI, 24-27), p=0.273, respectively. Two year OS of patients in CR1, ≥CR2 and active disease before HCT was 54% (95% CI, 52-56), 45% (95% CI, 39-52) and 35% (95% CI, 33-38), respectively (p<0.0001).In multivariate analysis adjusted for variable with different distribution between groups, the type of conditioning (RIC vs. MAC) had no impact on OS and LFS, however RIC group had higher RI (HR, 1.3, 95% CI 1.12-1.44, p=0.0001) and lower NRM (HR 0.8, 95% CI 0.72-0.96, p=0.01). Older age at HCT was an independent adverse prognostic factor for OS, LFS and NRM. Time from diagnosis to HCT had no impact on transplant outcome. Patients receiving PB grafts had superior OS (HR 0.84, 95% CI 0.73-0.97, p=0.01), LFS (HR 0.85, 95% CI 0.74-0.97, p=0.02) and lower RI (HR 0.83, 95% CI 0.70-0.99, p=0.049) compared with BM. Patients in remission and receiving HCT from HLA-identical siblings were independently associated better outcome.In summary, our registry study in the largest cohort of patients studied so far receiving HCT for secondary AML, demonstrated that about 45% of patients with secondary AML can attain long term survival after HCT. Patients receiving ablative regimens were associated with lower relapse risk and patients in remission had superior survival. Patients receiving PB grafts were associated potent graft-versus leukemia effects with decreased relapse risk and improved survival. Post- transplant pre-emptive therapy to decrease relapse risk might improve outcome further in these high risk populations. DisclosuresNiederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Schmid:Janssen Cilag: Other: Travel grand; Neovii: Consultancy.

DOCK8 primary immunodeficiency syndrome

A 3-year-old boy presented to our dermatology department in July, 2013, with a history of moderate atopic dermatitis, food allergy to cow’s milk protein and hen’s egg, and a 4 week history of very extensive molluscum contagiosum. Initial treatment with topical cantharidin and imiquimod had been unsuccessful. The family had no history of immunodefi ciency. Investigations showed lymphopenia with abnormal T-cell subsets (CD4 lymphocyte count of 0·384 × 109 cells per L [normal range 0·5–2·4 × 109 cells per L], CD3 lymphocyte count of 0·462 × 109 cells per L [0·9–4·5 × 109 cells per L], and CD8 lymphocyte count of 0·074 × 109 cells per L [0·3–1·6 × 109 cells per L]), increased IgE (2567 kIU/L [ 3%). Pneumococcal antibody serotypes, except 23F, were detected at negligible concentrations, despite previous vaccination. Clinical examination showed extensive sheets of molluscum on the trunk, genital region, ears, and eyelids with occipital and submandibular lymphadenopathy (fi gure). Naso pharyn geal swabs detected adenovirus DNA. The molluscum did not improve with two intravenous infusions of cidofovir in July, 2013. Because the clinical manifestations and the initial immunology screen suggested DOCK8 immuno defi ciency syndrome we ordered Sanger sequencing that subsequently identifi ed two compound heterozygous mutations in the DOCK8 gene on chromosome 9q24. Mutations in DOCK8 underlie most cases of autosomal recessive hyper-IgE syndrome and are associated with reduced numbers of T cells, B cells, and natural killer cells, with impaired CD8 T-cell proliferation and activation. Aff ected individuals have increased susceptibility to viral, bacterial, and fungal infections and have atopic manifestations including atopic dermatitis and food allergies. In our patient, the unusual severity of the molluscum infection along with the mild atopic dermatitis and food allergy suggested the diagnosis of DOCK8 primary immunodefi ciency syndrome, prompting further work-up. Presentation is characterised by recurrent infections with staphylococcus, cutaneous herpes, or human papillomavirus, respiratory and gastrointestinal infections, and an increased risk of squamous-cell carcinomas. Development of substantial numbers of molluscum contagiosum should raise suspicions about this condition. Management of DOCK8 immunodefi ciency includes prophylactic antibiotic, antifungal, and antiviral therapy. In view of the high risk of early death from opportunistic infection or malignancy, we have transplanted fi ve patients with DOCK8 defi ciency, all of whom are alive and well and free of all symptoms. In January, 2014, our patient received an HLA-identical sibling donor bone marrow transplant. He developed grade 2 skin graft versus host disease which resolved by 1 year after the transplantation, with complete clearance of the molluscum lesions and good immune reconstitution with 100% donor chimerism.

No Effect of Birth Order on Relapse, Graft-Versus-Host Disease or Transplant Related Mortality in Matched Sibling Donor Bone Marrow Transplant in Pediatric Patients with Leukemia

Introduction: The impact of birth order of patient and donor in matched sibling hematopoietic stem cell transplantation (HSCT) has not been fully defined. It has been postulated that as a result of fetomaternal trafficking donors who are younger than the transplant patient may develop in utero tolerance to patient cells. A large registry study of adult and pediatric patients found that using a donor younger than the recipient (R>D) was associated with decreased acute GVHD; single center studies found this to be correlated with decreased relapse and improved overall survival as well. We hypothesized that in pediatric patients with hematologic malignancies and a presumed low incidence of acute GVHD that birth order would not have an impact on relapse incidence.Methods: We performed an IRB -approved retrospective chart review of consecutive patients with acute leukemia undergoing matched sibling transplant bone marrow transplantation at Dana Farber/ Boston Children’s Hospital between 1/1/2001 and 10/31/ 2013. All patients were conditioned ablatively with a Busulfan or TBI based regimen. No product underwent T cell depletion. Patients with twin donors or with secondary leukemia were excluded. Basic patient demographics were collected including development of Grade II-IV acute GVHD, relapse and transplant-related mortality (TRM). Patients were assigned a Low Risk (HSCT in 1st remission) or High Risk (all others) disease status. Patients were then divided into 2 groups: those with donor older than recipient (D>R) and those with donor younger (R>D). Chi-Square test was used to assess for significant differences in relapse between patients.Results:We reviewed 91 patients with AML or ALL. Age range was 7 months to 24 years (median 11 years). 43 patients were D>R and 48 were R>D. The overall incidence of acute GVHD (Grade II-IV) was 16 % and TRM 4%; neither was significantly different between the two cohorts. Only 1 patient experienced graft rejection (R>D/ALL). For the population as a whole the relapse incidence was not statistically different - 35% in the R>D cohort vs 25% in the D>R cohort (p=0.46). There was also no difference detected in relapse rate when AML and ALL were evaluated separately (p=0.45 and p=0.57 respectively). We also compared the relapse rate by disease risk status. While previous data (Dobbelstein, ASH abstract 2008) suggested fewer relapses in R>D patients, our data revealed a similar trend but only in high risk patients (24% vs 41%), and statistical significance was not achieved (p=0.25). For low risk patients birth order had no effect on relapse incidence (p=0.88).Conclusion:Previous studies, primarily involving adult patients, have demonstrated an effect of birth order in matched sibling transplants for hematologic malignancies. A decrease in acute GVHD when the donor in younger than recipient (R>D) has been the most consistent finding although single center studies have shown an effect on relapse rate and overall survival as well. In our single institution retrospective study of a similarly treated cohort of pediatric patients we saw no effect of birth order on GVHD, TRM or relapse. Perhaps in the pediatric setting when the incidence of significant GVHD and TRM is low, maternally induced donor tolerance or sensitization to patient cells has less impact and other factors including disease status or patient age predominate. Thus our results suggest that birth order need not be considered as an important factor in matched sibling donor selection for pediatric patients with acute leukemias. DisclosuresNo relevant conflicts of interest to declare.

Steroid Responsive T-Cell Mediated Pure Red Cell Aplasia Following Allogeneic Hematopoietic Stem Cell Transplantation

Pure red cell aplasia (PRCA) is an unusual complication following allogeneic hematopoietic stem cell transplantation (HSCT), the true incidence of which is not known. Almost all cases reported in the literature describe major ABO-incompatibility between the recipient and the donor as the major risk factor for this complication. Delayed recovery of reticulocyte counts and hypoplasia of erythroblasts in the marrow is attributed to incompatible hemagglutinins in recipients. There are reports of successful treatment of PRCA using different strategies include rapid tapering of calcineurin inhibitors, corticosteroids, donor lymphocyte infusion, rituximab, and/or plasma exchange. Additional causes of PRCA following allogeneic HSCT include parvovirus B19 infection and graft-versus-host disease (GVHD). The pathogenesis of PRCA in parvovirus infection is thought to be viral-mediated suppression of erythroid precursors in the bone marrow and this is due to the tropism of this virus for erythroid progenitor cells. Nonmyeloablative and reduced intensity conditioning regimens have been reported to have an increased risk of PRCA due to persistence of recipient lymphocytes. Here we report two cases of PRCA following allogeneic HSCT from major ABO mismatched donors. Both cases were correlated with the presence of a T-cell clone in the peripheral blood and bone marrow, and there was complete resolution of anemia with a short course of steroid treatment, as well as disappearance of the T-cell clone. Patient # 1 – A 24 year old female of Mediterranean descent underwent an HLA- 8/10 matched and major ABO-mismatched sibling donor bone marrow transplant for Sickle-Beta Thalassemia. She received a myeloablative but reduced toxicity conditioning regimen consisting of busulfan 16mg/kg, fludarabine 140mg/m2, cyclophosphamide 105mg/kg, and alemtuzumab 52mg/m2. Her immediate post-transplant course was relatively benign and significant for a mild CMV colitis which responded with resolution after treatment with anti-viral therapy. Her red cell transfusion needs had significantly decreased to every four weeks by day 130. However, at day 146 from HSCT, she started requiring red cell transfusions every two weeks, with a drop in the reticulocyte count to 0.6%. No antibodies were detected, and the patient was negative for parvovirus B19 and did not have any evidence of GVHD. However, her bone marrow showed an marked erythroid hypoplasia, and was positive for a T-cell clone with gamma chain gene rearrangement in the T-cell receptor. Due to a new onset of transfusion need, she was treated with a short course of steroids with an excellent response and disappearance of the T-cell clone from peripheral blood. She remained on immunosuppression during this entire period with a calcineurin inhibitor. Patient# 2 – A 10 year old Hispanic girl underwent a 10/10 HLA-matched and major ABO-mismatced sibling donor bone marrow transplant for idiopathic acquired severe aplastic anemia. Her preparative regimen consisted of 200 mg/kg of cyclophosphamide and 16mg/kg of rabbit-anti-thymocyte globulin. Her immediate post-transplant course was complicated by E.coli bacteremia. She had prompt engraftment and became transfusion independent on day 86. A cyclosporine taper was initiated at day 100 but held at day 119 when anemia was first noted. Peripheral blood showed a T-cell clone with gamma and beta chain gene rearrangement. She was started on a moderate dose of steroids with a good response, and has been tapered down to physiologic replacement dose of steroids with normal Hb and transfusion independence. With the resolution of anemia, the gamma chain gene rearrangement is not seen in the T-cell clonality assay, however, the beta chain gene rearrangement persists. To our knowledge, this is the first report of a T-cell mediated PRCA following allogeneic HSCT. Moreover, the PRCA was steroid responsive and not associated with GVHD in both the patients. Disclosures:No relevant conflicts of interest to declare.