Cytomegalovirus Reactivation as a Risk Factor for All-Cause Mortality in Children Undergoing Hematopoietic Stem Cell Transplantation: Experience Over Two Decades from a Tertiary Referral Center in India.

The aim of the study was to analyse the burden of cytomegalovirus (CMV) disease in children undergoing hematopoietic stem cell transplantation (HSCT) and its correlation with all-cause mortality. We performed a retrospective study in children up to 18 years of age who underwent allogeneic HSCT between February 2002 to December 2021 in the pediatric blood and marrow transplantation unit. A total of 1035 patients were included where five hundred forty-three (52.4%) patients underwent matched family donor (MFD) HSCT, 213 (20.5%) underwent matched unrelated donor (MUD) HSCT; 279 (26.9%) underwent haploidentical HSCT (T cell replete in 213 and T cell depleted in 66 patients). CMV reactivation was documented in 258 (24.9% patients). CMV was seen in 39 (7.2%) MFD, 77 (36.1%) MUD, 106 T cell replete (49.7%) and 36 T cell depleted (54.5%) transplants. CMV reactivation was predominantly documented in those where donor and recipient were positive (D + /R +) for CMV serostatus (77%)) prior to HSCT. Overall mortality rate was significantly higher in the CMV positive group (103/258, 39.9%), as compared to the CMV negative group (152/777, 19.6%) (p value = 0.0001). CMV was the direct cause of death in 13/1035 children (1.2%). GvHD as a cause of death was found to be significantly higher among those with CMV (n = 32) as compared to those without CMV (n = 14) (35.6 versus 9%, p value = 0.0001). The incidence of CMV reactivation was noted in 25% of HSCT recipients, and predominantly in haploidentical HSCTs. CMV reactivation was shown to significantly impact all-cause mortality and there was a significantly increased risk of mortality due to GvHD among those with CMV reactivation.

Hematopoietic stem cell Transplantation in Children with very Early Onset Inflammatory Bowel Disease Secondary to Monogenic Disorders of immune-dysregulation.

Background: Very early-onset inflammatory bowel disease (VEOIBD) is defined as IBD in children under six years of age. We present outcome data of hematopoietic stem cell transplantation (HSCT) in the above children. Patients and methods: We performed a retrospective study in children under six years of age who underwent HSCT for VEOIBD with an identified monogenic disorder from December 2012 to December 2020. Results: Of the 25 children included, the underlying diagnosis was IL10R deficiency (n = 4), Wiskott-Aldrich syndrome (n = 4), Leukocyte adhesion defect (n = 4), Hyper IgM syndrome (n = 3), Chronic granulomatous disease (n = 2), and one each with XIAP deficiency, severe congenital neutropenia, Omenn syndrome, Hyper IgE syndrome, Griscelli syndrome, MHC Class II deficiency, LRBA deficiency, and IPEX syndrome. Donors included a matched family donor in 10(40%); a matched unrelated donor in 8 (32%), haploidentical in 7 (28%) (T depleted 16%, T replete with post-transplant cyclophosphamide12%). Conditioning was myeloablative in 84% ofHSCTs. We documented engraftment in 22 (88%) children, primary graft failure in 2 children (8%), mixed chimerism in 6 (24%) children with mortality in 4/6 children. Children with a sustained chimerism of > 95% did not have recurrence of any features of IBD. Overall survival was 64%, with a median follow-up of 55 months. Mixed chimerism was associated with a significantly increased risk of mortality (p-value = 0.001). Conclusions: VEOIBD caused by monogenic disorders can be offered HSCT. Early recognition, optimal supportive care, and complete chimerism are essential components to achieving survival.

Risk Factors for Neutropenic Sepsis Related Mortality in Children Undergoing Allogenic Hematopoietic Stem Cell Transplantation.

We aimed to analyze infections in children undergoing hematopoietic stem cell transplantation (HSCT) until engraftment. The spectrum and risk factors associated will help plan interventions to reduce mortality. We performed a retrospective analysis on the infections, associated risk factors, and mortality until engraftment in children up to 18 years of age undergoing HSCT from January 2017 to August 2020. A total of 399 children were included, with a male: female ratio of 1.9:1, with matched related donor HSCT in 36.6%, a matched unrelated donor in 18.3%, and haploidentical HSCT in 38.1% of children. Culture positive bacteremia was documented in 22.1% transplants with gram-negative bacteria (GNB) isolated in 71/88 (80%). Among the GNB, the predominant organism was Klebsiella pneumonia in 38 (53%), E.coli in 16 (22%), Pseudomonas in 9 (12%). Carbapenem resistance was documented in 24/71 (33%). The incidence of possible, probable, and proven fungal infections in the cohort was 63 (15%), 28 (7%), and 6 (1.5%), respectively. Mortality up to engraftment due to sepsis in our cohort is 3.3% (n = 13). There was a significant association between mortality and a perianal focus (30.8%, p value 0.029) and the presence of carbapenem resistance (38%, p value 0.002). Mortality among those who developed proven fungal infections was significantly higher than those with bacteremia (p value 0.004). Our study has identified fungal sepsis and carbapenem-resistant GNB sepsis as high-risk groups for mortality. Risk directed interventions in these groups would help ensure survival and optimal outcomes.

Hematopoietic Stem Cell Transplantation for Children With Inborn Errors of Metabolism: Single Center Experience Over Two Decades.

OBJECTIVE: We present outcome data on hematopoietic stem cell transplantation (HSCT) in children with inborn errors of metabolism (IEM). METHODS: We retrospectively analyzed data on children up to 18 years of age, diagnosed with IEM, who underwent HSCT between January, 2002 and December, 2020. RESULTS: 24 children, (mucopolysaccharidosis - 13, Gaucher disease - 4, X-linked adrenoleukodystrophy - 4, metachromatic leukodystrophy - 2, Krabbe disease - 1) were included. Donors were matched family donors in 24%, matched unrelated donors in 34%, and haploidentical fathers in 42% of the transplants, with engraftment in 91% of children. Overall survival was 72% (55-100%) with a median follow-up of 76.5 (10-120 ) months, and progression-free survival of 68% (MPS-76%, X-ALD -60%, Gaucher disease - 50%, and 100% in MLD and Krabbe disease). CONCLUSION: HSCT is an available curative option, and early age at HSCT prevents end-organ damage.

Donor Characteristics Predict the Success of Allogeneic Hematopoietic Stem Cell Transplantation in Thalassemia Major: A Single-Center Analysis of 250 Patients.

Introduction We present data on the impact of donor characteristics in a uniform cohort of children who underwent hematopoietic stem cell transplantation (HSCT) for thalassemia major. Patients and methods We performed a retrospective study in children undergoing matched related (MRD) or unrelated (MUD) HSCT from January 2009 to December 2019. Results We analyzed data on 250 patients (age seven months-19 years), MRD n = 187, MUD n = 63. We documented sex mismatch in 44% of HSCTs. The graft rejection rate was 3.7%; all had a sex mismatched HSCT (P value = 0.001). Graft versus host disease (GVHD) was higher when donors were above two years as compared to less than two years (23%vs.6.5%, P value = 0.006), with higher rates of mixed chimerism when donors were < two years at 33.3%vs.8.3% in > two years (P value = 0.0001). Mortality and GVHD were higher in the MUD group as compared to the MRD group (15%vs.5%, P value = 0.009; 42.9%vs. 23.4%, P value = 0.0001 respectively). Overall survival was 92.8% with a median follow up of 5.4 years, and was superior in MRD versus MUD group (9.4 years versus 4.8 years P = 0.008). Conclusion The risk of graft rejection was higher with donor-recipient sex mismatch; while initial mortality and chronic GVHD was higher with MUD HSCT.

Post-transplant strategies to improve relapse-free survival in childhood leukemia: Whole blood donor lymphocyte infusions and lenalidomide for inducing graft-versus-leukemia effect.

INTRODUCTION: Post-transplant graft-versus-leukemia (GVL) effect has been shown to be an important determinant of a successful outcome following hematopoietic stem cell transplantation (HSCT) in children with acute leukemia. PATIENTS AND METHODS: We performed a retrospective analysis of the children up to 18 years of age with acute leukemia who underwent HSCT between November 2002 and November 2018. GVL induction strategies included whole blood donor lymphocyte infusions (DLI) and/or lenalidomide. RESULTS: A total of 134 children were included with engraftment in 125 children (93%). Acute graft-versus-host disease (GVHD) was documented in 85 (63%) children without any induction strategies. GVL induction strategies were employed in 19 children (14%); DLI (n = 12), Lenalidomide (n = 2), DLI + lenalidomide (n = 5). Among the 19, 12 children (63%) are alive without relapse; 6 children died of relapse (31%). Among the 6 who died of relapse despite induction strategies, 5/6 had ALL and one child had AML. GVL induction was effective in preventing relapse in 7/12 (58%) children with ALL and 5/6 (83%) children with AML. Relapse-free survival in the cohort is 73/134 (55%) with a median follow-up of 32 months. GVHD of any grade was significantly associated with a lower risk of relapse (p = .008). Median survival time was 160.3 days (range 132-187) in those with chronic GVHD versus 88.3 days (range 68-107) in those without (p value = .004). CONCLUSION: Pre-emptive whole blood DLIs in graded aliquots, and lenalidomide are important tools for post HSCT GVL induction, which significantly impacts relapse-free survival in childhood leukemia.

Management of Peripheral T-Cell Lymphoma in Children and Adolescents Including STAT 3 Mutation Hyper-IgE Syndrome: One Size Does Not Fit All.

Peripheral T-cell lymphoma (PTCL) is a rare form of lymphoma in children with limited published data on treatment and lack of a uniformly accepted treatment algorithm. We retrospectively analyzed the data in children up to 18 years of age diagnosed to have PTCL from January 2016 to June 2020. The study included six children with a median age of 10 years, the youngest being a 7-month-old girl. According to the WHO-PTCL classification, three had PTCL-not otherwise specified (NOS), 2 had hepatosplenic TCL, and 1 had subcutaneous panniculitis-like TCL. All children had presented with advanced disease, 4 in St. Jude stage IV, 2 in St. Jude stage III. Three children received CHOEP chemotherapy including cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, while 1 child received CHOP. Two children received induction as per acute lymphoblastic leukemia followed by Bendamustine. Two patients succumbed to progressive disease, the infant with PTCL-NOS and 1 child with hepatosplenic TCL. Three children were in remission (median follow up of 44 mo). One child with PTCL-NOS Stage IV had an underlying STAT3 mutated hyperimmunoglobulin E syndrome and was in remission 12 months post a matched unrelated donor hematopoietic stem cell transplantation. He had grade 4 skin graft versus host disease and required extracorporeal photopheresis and ibrutinib, to which he had responded. CHOEP chemotherapy is well-tolerated and subcutaneous panniculitis-like TCL has the best prognosis thus far.

Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Fanconi Anemia: Improving Outcomes with Improved Supportive Care in India.

Fanconi anemia is the most common inherited bone marrow failure syndrome, and hematopoietic stem cell transplantation (HSCT) is the only curative option. Post-transplant cyclophosphamide (PTCy) is challenging in this group of children, given their increased sensitivity to chemotherapy. We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019. Nineteen children (male/female, 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low-dose cyclophosphamide, and 200 centi-gray total body irradiation were included in the conditioning regimen with 25 mg/kg PTCy on days +3 and +4. Haplo-graft was from a sibling in 38% and father in 57% of transplants. The source of stem cells was peripheral blood stem cells in 81% and bone marrow in 19% of transplants, with a median CD34 dose of 5.0 × 106/kg. We documented engraftment in 84% and primary graft failure in 10% of transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Grade 2 and 3 mucositis was lower among those who received NAC as compared to those who did not (30% and 15% versus 33% and 50%), while transaminitis was higher among those who did not receive the infusion. The incidence of acute graft-versus-host disease (GVHD) was 68%, and 81% of these were steroid responsive (grade I/II). We documented chronic GVHD in 25% children, predominantly involving the skin and mouth, which responded to low-dose steroids and ruxolitinib. Serum ferritin was monitored twice weekly as a surrogate marker for cytokine release syndrome due to nonavailability of IL-6 levels. A 1- or 2-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the periengraftment period. The mean survival was found to be less among those with high serum ferritin (>10,000 ng/dL) in the periengraftment period as compared to those with ferritin <10,000 ng/dL (mean survival of 25 ± 10 months versus 50 ± 6 months, respectively). The overall survival in our cohort was 68.4%, with a mean survival time of 41.5 months (95% confidence interval, 29.3 to 53.8 months), with a statistically significant correlation between inferior outcome and having received over 15 transfusions before HSCT (P = .01). PTCy can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of HSCTs. Focused interventions in this subset of children help improve survival outcomes. Early identification of cytokine release syndrome and risk-adapted steroid therapy during engraftment helps prevent mortality. The concomitant use of NAC during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and regimen-related toxicity.