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.

Handgrip strength: A simple and effective tool to predict mortality after liver transplantation.

INTRODUCTION: Malnutrition is a widely prevalent yet unrecognized problem of patients with end-stage liver disease (ESLD) awaiting liver transplant (LT). The aim of this study was to ascertain pre-LT nutritional status of adult Asian Indian patients with ESLD including functional deficit (frailty) and determine predictor/s of poor post-LT outcome (futility). METHODS: A prospective, longitudinal, single-center study which enrolled adults listed for LT between October 2014 and April 2018. Consecutive patients who consented, met the inclusion criteria, and underwent LT were included. The demographic data, nutritional, functional and dietary assessments from evaluation till 1-year-post-LT were documented. Data was analyzed using SPSS-25.0. RESULTS: One hundred and fifty two patients, aged 50.6 ± 8.3 years, predominantly men (82.9%), underwent LT (predominantly deceased donor LT (DDLT) 78.3%). One hundred and thirty five patients (88.8%) were discharged alive after LT. The presence of pre-LT hepatorenal syndrome (HRS), baseline handgrip strength (HGS) <20 kg and SGA rated malnutrition, 1st-pre-LT follow-up HGS (<20 kg), non-achievers of ≥80% targeted energy and protein intake were associated with increasing 1-year-post-LT mortality rate (p < 0.05). A cut-off of 18.15 kg HGS was found to predict 1-year-post-LT survival, with optimal sensitivity (77.4); specificity (43.5), and an area under a receiver operating curve (ROC) of 0.676 (p = 0.008), with a 95% CI [0.545-0.806]. Step-wise binary logistic regression indicated that non-achievers of ≥80% targeted protein at 1st-pre-LT follow-up and baseline HGS (<18.15 kg) are two independent factors that predict 1-year-post-LT survival with an odds ratio of 13.168 and 7.041, respectively. CONCLUSION: A cut-off of 18.15 kg baseline HGS before LT was found to be a significant predictor of poor survival in Asian Indian patients with ESLD. It was also instrumental in identifying patients at risk and helping to target intensive nutritional intervention therapy. Patients in whom ≥80% pre-LT nutritional goal was successfully achieved during the waiting period had an improved 1-year-post-LT survival.

Influence of tumor size in the progression of venous tumor thrombus in renal cell carcinoma: A 7-year single-center experience.

Objective: The objective of the study is to describe the perioperative outcomes, disease-specific, and overall survival status in patients diagnosed with renal cell carcinoma with inferior vena cava (IVC) tumor thrombus. Patients and Methods: We did a retrospective analysis of all patients who underwent radical nephrectomy along with IVC thrombectomy from the year 2013 to 2020. Mayo's classification was used to stratify the level of IVC thrombus. Demographic, perioperative, histopathology data, complications, and survival status were analyzed. Results: Total number of patients included in the study was 39, (Male: Female = 84.6%: 15.4%). Median age of patients was 58 (interquartile range [IQR] 50-63) years. Median size of renal tumor (in cms) was 9.5 (IQR 7.5-12), 8 (IQR 7-11.5), 8.5 (IQR 7-11.75), and 11 (IQR 9.5-11) (P = 0.998) in level 1,2,3, and 4 tumors, respectively. Clear cell variant was seen in 32 patients (82%) with R0 resection in 17 patients. Twelve patients (30.7%) had systemic metastasis on presentation. The overall mean survival time was 66.4 months with 95% confidence interval (CI) (52.4-80.5 months). Mean recurrence-free survival is 76 months with (63-90) CI of 95%. Mean survival in patients who presented with metastasis is 47 months with 95% CI (52.4-80.5). Perioperative mortality rate was 5.12% in this study. Conclusion: The tumor size does not have an influence on the progression of tumor thrombus into IVC. Significant difference in survival was observed between different levels of thrombus with high mortality in level four tumors.

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.

Treosulfan-Based Conditioning in Matched Family, Unrelated and Haploidentical Hematopoietic Stem Cell Transplantation for Genetic Hemophagocytic Lymphohistiocytosis: Experience and Outcomes over 10 Years from India.

We aimed to analyze data in children with primary hemophagocytic lymphohistiocytosis (HLH) who underwent hematopoietic stem cell transplantation (HSCT). We performed a retrospective study where children up to 18 years, with primary HLH and who underwent HSCT from January 2011 to December 2019, were included. Twenty-five children with genetic HLH underwent HSCT, including variants (Griscelli syndrome (GS2) 7, Chediak-Higashi syndrome (CHS) 2, XIAP mutation 2). Donors were matched family 8 (32%), umbilical cord blood unit 3 (12%), matched unrelated 2 (8%), haploidentical HSCT 12 (48%), (TCR alpha/beta depletion 2 and post-transplant cyclophosphamide 10). With treosulfan-based conditioning, engraftment was achieved in 23/25 (92%) transplants (100% in haplo-HSCT), with sustained complete chimerism in 87%. Disease-free survival was noted in 2/3 children with stable mixed chimerism. Graft-versus-host disease (GVHD) of grade I/II was noted in 6 (24%), grade III in 3 (13%); chronic limited skin GVHD in 2 (12%) children. Overall survival was 72% (87.5% in matched donor, 66.7% in the haplo-HSCT), 71% in GS2, 50% in CHS, 100% in XIAP. HSCT is curative in primary HLH with acceptable disease-free survival with mixed chimerism. Haplo-HSCT is a viable option for those without matched family or unrelated donors.

Independent diagnostic utility of CD20, CD200, CD43 and CD45 in chronic lymphocytic leukaemia.

Immunophenotyping plays a major role and is essential for establishing the diagnosis of chronic lymphocytic leukemia (CLL). Though CLL has a characteristic phenotype, diagnosis may be challenging due to immunophenotypic overlap with other B cell non-Hodgkin's lymphomas (B-NHL). Markers like CD200, CD43, CD20 and CD45 were found valuable in CLL and we investigated their diagnostic efficiency and accuracy in 174 patients with leukemic B-NHL. On the integration of four markers by a scoring system, 96% (49/51) of CLL cases showed a score of 3 or 4 and 90% (36/40) of non-CLL cases had a score of 0 or 1. This scoring system for CLL diagnosis showed a sensitivity of 98.2% and 96% in the analytical cohort and validation cohort respectively, which was significantly higher than the classical Matutes score. Hence we strongly suggest considering the expression of CD200, CD20, CD43 and CD45 in the diagnosis of B-NHL cases.

Thrombolysis in Acute Pulmonary Embolism: Are we overdoing it?

AIM AND METHODS: We aimed to study the clinical data and outcome of patients admitted in our center with acute pulmonary embolism (PE) over a 5-year period from May 2013 to April 2018. The main outcome data included were: in - hospital bleeding, in - hospital right ventricular (RV) function improvement, pulmonary arterial hypertension improvement, duration of hospital stay, and 30- and 90-day mortality. RESULTS: A total of 114 (69 m, 55 f) patients with the mean age of 55 ± 15 years were included. Patients who had involvement of central pulmonary trunk called as "Central PE" group (n = 82) and others as "Peripheral PE" group (n = 32). There were more women in the peripheral PE group (53.1% vs. 34.1%, P = 0.05), while RBBB (22% vs. 3.1%, P = 0.02) and RV dysfunction (59.8% vs. 25%, P = 0.002) were noted more in the central PE group. Systemic thrombolysis was done in 53 patients (49 central, 4 peripheral), of which only 3 had hypotension and 28 patients were in the Intermediate-high risk group. The overall inhospital, 30-day, and 90-day mortalities were 3.6, 13.2, and 22.8%, respectively. Bleeding was significantly higher in the thrombolysis group compared to the nonthrombolysis group (18.9% vs. 0, P = 0.0003). However, improvement in pulmonary hypertension was noted more in thrombolysis group compared to nonthrombolytic group (49% vs. 21.2%, P = 0.01). CONCLUSION: This retrospective data from a tertiary center in South India showed that short- and mid-term mortality of patients with PE still remains high. The high nonguideline use of thrombolysis has been reflected in the increased bleeding noted in our study.

Utility of various inflammatory markers in predicting outcomes of hospitalized patients with COVID-19 pneumonia: A single-center experience.

AIM: The aim of the study is to study the utility of various inflammatory markers in predicting outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia. PRIMARY OBJECTIVE: The primary objective of the study is to analyze the correlation between various inflammatory markers and in-hospital mortality. SECONDARY OBJECTIVES: The secondary objective of the study is to assess the correlation between the inflammatory markers and clinical category of patients, and other outcomes such as length of hospital stay and need for invasive ventilation. METHODS: A retrospective cross-sectional observational study was done in 221 hospitalized patients who were diagnosed with COVID-19 pneumonia in a tertiary care hospital in South India from May 2020 to July 2020. Clinical and laboratory data of patients diagnosed with COVID-19 pneumonia were collected. This included epidemiological data, clinical data, laboratory parameter (neutrophil: lymphocyte [N: L] ratio, C-reactive protein [CRP], ferritin, interleukin-6 [IL-6], lactate dehydrogenase, D-dimer, and procalcitonin), treatment details, and outcomes. RESULTS: IL-6 levels >60.5 pg/mL and D-dimer levels >0.5 mcg/mL predicted in-hospital mortality with sensitivities of 80% and 76.7%, respectively. N: L ratio and CRP levels had good correlation with the need for oxygen supplementation and/or invasive ventilation. CONCLUSIONS: Judicious use of COVID-19 biomarkers could help in disease prognostication and thereby provide guidance to devise appropriate management strategies.

Variability in the Hemodynamic Response to Fluid Bolus in Pediatric Septic Shock.

OBJECTIVES: Fluid boluses are commonly administered to improve the cardiac output and tissue oxygen delivery in pediatric septic shock. The objective of this study is to evaluate the effect of an early fluid bolus administered to children with septic shock on the cardiac index and mean arterial pressure, as well as on the hemodynamic response and its relationship with outcome. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: We prospectively collected hemodynamic data from children with septic shock presenting to the emergency department or the PICU who received a fluid bolus (10 mL/kg of Ringers Lactate over 30 min). A clinically significant response in cardiac index-responder and mean arterial pressure-responder was both defined as an increase of greater than or equal to 10% 10 minutes after fluid bolus. MEASUREMENTS AND MAIN RESULTS: Forty-two children with septic shock, 1 month to 16 years old, median Pediatric Risk of Mortality-III of 13 (interquartile range, 9-19), of whom 66% were hypotensive and received fluid bolus within the first hour of shock recognition. Cardiac index- and mean arterial pressure-responsiveness rates were 31% and 38%, respectively. We failed to identify any association between cardiac index and mean arterial pressure changes (r = 0.203; p = 0.196). Cardiac function was similar in mean arterial pressure- and cardiac index-responders and nonresponders. Mean arterial pressure-responders increased systolic, diastolic, and perfusion pressures (mean arterial pressure - central venous pressure) after fluid bolus due to higher indexed systemic vascular resistance and arterial elastance index. Mean arterial pressure-nonresponders required greater vasoactive-inotrope support and had higher mortality. CONCLUSIONS: The hemodynamic response to fluid bolus in pediatric septic shock was variable and unpredictable. We failed to find a relationship between mean arterial pressure and cardiac index changes. The adverse effects of fluid bolus extended beyond fluid overload and, in some cases, was associated with reduced mean arterial pressure, perfusion pressures and higher vasoactive support. Mean arterial pressure-nonresponders had increased mortality. The response to the initial fluid bolus may be helpful to understand each patient's individualized physiologic response and guide continued hemodynamic management.

Lower pretreatment hemoglobin status and treatment breaks in locally advanced head and neck squamous cell carcinoma during concurrent chemoradiation.

BACKGROUND: Treatment breaks during radiation for locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the important factors affecting the loco-regional control rate. We prospectively analysed the role lower pre-treatment hemoglobin (pre-T Hb) status and its influence on treatment breaks amongst patients undergoing concurrent chemoradiation (CRT). METHODS: One hundred and twenty HNSCC (T3-T4a, N1-N2c) patients treated by CRT were prospectively analysed for influence of pre-T Hb on treatment breaks. Sub-sites included oral cavity, oropharynx, hypopharynx & larynx. All patients received radiation to a total dose of 66Gy to PTV along with weekly Inj. Cisplatin 40 mg/m2. All patients were evaluated weekly and at the end of 6 weeks by hemogram, physician and radiological examination. RESULTS: Our study population had a mean age (±standard deviation) of 55 (± 10.7) years (range: 27 - 69 years), 85 men and 35 women with a performance status of the Eastern Cooperative Oncology Group (ECOG) 1-2. The mean pre-T Hb calculated (using receiver operating characteristic curve [ROC]) was 10.3 g/dL. Among 120 patients, in the pre-T Hb of ≤10.3 g/dL group, 44 (75.9%) patients had treatment breaks of ≥5 days and 11 (17.7%) patients had treatment breaks < 5 days; in the pre-T Hb of >10.3 g/dL group, 14 (24.1%) patients had treatment breaks of ≥5 days and 51 (82.3%) patients had treatment breaks < 5 days (P = 0.001). CONCLUSION: Lower pre-T Hb level of ≤ 10.3 g/dL is statistically significantly associated with higher treatment breaks of ≥ 5 days.

FLAG With Bortezomib in Childhood Relapsed/Refractory Leukemia: Remission Induction With Limited Toxicity in the Era of Multidrug-resistant Bacteria.

We present our experience on the use of fludarabine, cytarabine, granulocyte colony-stimulating factor in combination with Bortezomib. In total, 13 children with relapsed/refractory leukemia (acute lymphoblastic leukemia=9 and acute myeloid leukemia=4) were included from January 2018 to May 2019. Culture-positive sepsis and intensive care unit admission rates were 38% and 30%, respectively, with no postchemotherapy mortality in this cohort. Morphologic remission was documented in 92% and negative minimal residual disease was achieved in 61%, with 100% remission in those with acute myeloid leukemia. These results bear significant relevance in developing countries where multidrug-resistant sepsis is on the rise.

Augmented immunosuppression and PTCY-based haploidentical hematopoietic stem cell transplantation for thalassemia major.

Alternate donor HSCT for thalassemia major from a matched unrelated donor or haploidentical family donor is a feasible therapeutic option in children with no matched family donor. Aggressive pretransplant immunosuppression, reduced toxicity conditioning, and PTCY result in excellent thalassemia-free survival. We describe here our experience in this cohort. We performed a retrospective analysis of the data on children who underwent a haploidentical HSCT for thalassemia major with PTCY at our center from August 2017 to August 2019. All children received pretransplant immune suppression for 6 weeks with fludarabine and dexamethasone, hypertransfusion and chelation with intravenous desferrioxamine. Conditioning included thiotepa, fludarabine, rabbit ATG, and cyclophosphamide, and GvHD prophylaxis included PTCY with tacrolimus. Twenty children were included and nineteen children engrafted. Acute hypertension occurred in five children, bacterial infection in eight children and viral respiratory infection in three children. Three children suffered from graft rejection. Reactivation of viruses namely CMV, adenovirus, and BK virus was seen in 60% of children. Grades 1-2 acute GvHD of the skin in four children (20%) and limited chronic GvHD of the skin in four children (20%). Immune cytopenia was documented in three children (15%). Haploidentical HSCT offers a therapeutic option for children with thalassemia major with no suitably matched family or unrelated donors. Our reduced toxicity regimen with PTCY offers a DFS of 75% and OS of 95% with low transplant-related mortality of 5%.

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.

Matched Family versus Alternative Donor Hematopoietic Stem Cell Transplantation for Patients with Thalassemia Major: Experience from a Tertiary Referral Center in South India.

Hematopoietic stem cell transplantation (HSCT) is the only curative option available for patients with thalassemia major in India with increasing access to alternate donor transplantation for patients with no matched family donor. We aimed to analyze the impact of family and alternate donor HSCT on morbidity and mortality post-HSCT. We conducted a retrospective study in the department between July 2007 and December 2018 where all children who underwent HSCT for thalassemia major were included. A total of 264 children were included with a median age of 6 years (male/female, 1.4:1). The graft source was matched related donor (MRD) (76%; parent 15%, sibling 85%) and matched unrelated donor (MUD) (22%). All children received a myeloablative conditioning regimen with treosulfan/thiotepa/fludarabine in 93% and busulfan/cyclophosphamide in 7%. The source of stem cells was peripheral blood in 61%, bone marrow in 38%, and umbilical cord blood in 3%. The incidence of bacteremia was 14% versus 25% in MRD versus MUD groups. There was a higher incidence of posterior reversible encephalopathy syndrome (PRES) in the MUD group (10% versus 3%). Engraftment occurred in 97% with a higher trend toward mixed chimerism in the MRD group (12% versus 2%). When indicated, whole-blood donor lymphocyte infusion was used to ensure complete chimerism in children in the MRD group. A statistically significant difference was found in the incidence of graft versus host disease (GVHD), both acute and chronic between the MUD versus MRD groups, 60% versus 20% and 41% versus 17%, respectively (P = .001). Similarly, immune cytopenia and cytomegalovirus reactivation were also significantly higher in the MUD group, 27% versus 1.4% and 25% versus 2%, respectively (P = .001). Thalassemia-free survival in our cohort was 96%, 94%, and 84% with a median follow-up of 65 months in the matched sibling donor, matched family donor, and MUD groups, respectively. Overall survival of 95% and 90% with a median follow-up of 65 months was noted in those who underwent transplantation less than and greater than 7 years of age, respectively. MUD transplantation for patients with thalassemia major involves specific challenges such as PRES and unusual manifestations of GVHD such as immune cytopenia. Early interventions to optimize supportive care and measures to reduce GVHD are required to ensure survival rates of over 90%.

Multicenter Outcome of Hematopoietic Stem Cell Transplantation for Primary Immune Deficiency Disorders in India.

Background: Hematopoietic stem cell transplantation (HSCT) is the curative option for many primary immune deficiency disorders (PID). In the last 5 years, increased awareness, availability of diagnostics based on flow cytometry, genetic testing, improved supportive care, use of reduced toxicity conditioning, and success of haploidentical donor HSCT have improved access to HSCT for children with PID in India. We present results on children with PID who underwent HSCT across India and the factors that influenced outcome. Patients and Methods: We collected retrospective data on the outcome of HSCT for PID from seven centers. We analyzed the impact of the type of PID, conditioning regimen, time period of HSCT- before or after January 2016, graft versus host disease prophylaxis, cause of mortality and overall survival. Results: A total of 228 children underwent HSCT for PID at a median age of 12 months (range, 1 to 220 months) with a median follow up of 14.4 months. Infants accounted for 51.3% of the cohort and the male female ratio was 3:1. SCID (25%) and HLH (25%) were the more frequent diagnoses. Matched family donor was available in 36.4% and 44.3% children had a haploidentical HSCT. Reduced and myeloablative conditioning regimens were used with 64% children receiving a treosulfan based conditioning regimen. Peripheral blood stem cells were the predominant graft source at 69.3%. The survival in infants (60.2%) was inferior to children aged over 1 year (75.7% p value = 0.01). Children with Wiskott Aldrich syndrome (74.3%) and chronic granulomatous disease (82.6%) had the best outcomes. The survival was superior in children receiving HSCT from a matched sibling (78%) versus an alternate donor HSCT (61% p value = 0.04). In the cohort transplanted after January 2016 survival improved from 26.8% to 77.5% (p value = 0.00). Infection remains the main cause of mortality at in over 50% children. The 5-year overall survival rate was 68%. Conclusion: Survival of children with PID undergoing HSCT in India has improved dramatically in last 5 years. Alternate donor HSCT is now feasible and has made a therapeutic option accessible to all children with PID.

Haploidentical Stem Cell Transplantation in Children with Benign Disorders: Improved Survival and Cost-Effective Care Over 15 Years from a Single Center in India.

We present our experience in haploidentical stem cell transplantation (haplo SCT) in children with benign disorders. We performed a retrospective study where children aged up to 18 years diagnosed to have benign disorders and underwent haplo SCT from 2002 to September 2017 were included. Of the 54 children, the most common indications were Fanconi anaemia 12 (22%), severe aplastic anaemia 8 (14%) and primary immune deficiency disorders (PID) 25 (46%). Post-transplant cyclophosphamide (PTCy) was used in 41 (75.9%) and ex vivo T depletion in 13 (24.1%). Engraftment rates were 70% with acute graft versus host disease in 36% and cytomegalovirus reactivation in 55% children. There was a statistically significant difference found between survival with siblings as donors as compared to parents (p value 0.018). Overall survival was 60% which is the 1-year survival, with 68% survival among those with PIDs. Cytokine release syndrome was noted in 12/41 (29%) of children who received T replete graft and PTCy. In children over 6 months of age, PTCy at a cost of INR 1200 provides cost effective T cell depletion comparable with TCR α/ß depletion priced at INR 1200,000. Haplo SCT is feasible option for cure in children with benign disorder.

Safety and efficacy of fresh whole blood donor lymphocyte infusion in children.

Donor lymphocyte infusion (DLI) is a form of cellular immunotherapy which is known to be effective in preventing relapse in leukemia by inducing graft versus leukemia (GVL) effect. In hematopoietic stem cell transplantation (HSCT) for benign hematological conditions including primary immune deficiency, mixed chimerism is seen with the use of reduced intensity conditioning. DLI can help prevent graft rejection by boosting the existing graft in these situations. There is scant data on the use of DLI in children who have undergone HSCT for benign hematological disorders. We present our case series with early withdrawal of immunosuppression and DLI as a means to mitigate relapse of leukemia and prevent graft rejection in mixed chimerism in children transplanted for benign hematological disorders. Donor lymphocyte infusion was given in a graded regimen with the cell dose of 1 × 105 CD3 cells/kg (1 × 104/kg in haploidentical transplant), 5 × 105 CD3 cells/kg, 1 × 106 CD3 cells/kg depending on the graft kinetics and the clinical status of the children. A total of fifty eight children including those with haploidentical donors underwent DLI with an overall survival of 81.1%. The use of fresh whole blood in very small aliquots from the donor has made this technique cost effective and an attractive form of immunotherapy.