Incidence, Risk Factors, Characteristics, and Outcome of Chronic Graft Versus Host Disease in Children Undergoing Haploidentical Peripheral Blood Stem Cell Transplant With Post-transplant Cyclophosphamide.

AIM: Chronic graft versus host disease (cGVHD) is a major cause of morbidity postallogeneic peripheral blood stem cell transplant (PBSCT). There is paucity of literature describing incidence, risk factors, characteristics, and outcome of cGVHD in children undergoing haploidentical PBSCT with post-transplant cyclophosphamide (PTCy). Here, we describe our experience from our center regarding the same. METHODS: All children who underwent haploidentical PBSCT with PTCy between January 2016 and December 2021 at our center and survived beyond day+100 post-transplant were included in this retrospective study. Conditioning regimens used were: Thiotepa-Fludarabine-Cyclophosphamide with 2 Gy single fraction total body irradiation, Thiotepa-Busulfan-Fludarabine, Fludarabine-total body irradiation and Fludarabine-Melphalan. Peripheral blood was used as stem cell source in all patients. GVHD prophylaxis was PTCy 50 mg/kg on day +3 and +4, Mycophenolate mofetil and Calcineurin inhibitors. Clinical and laboratory data was electronically retrieved and analyzed based on National Institute of Health Consensus Criteria-2014 at regular intervals. Impact of various patient, donor, and transplant-related factors on development of cGVHD were analyzed. Incidence of relapse, event free survival (EFS) and overall survival (OS) were calculated and compared between cGVHD and no cGVHD groups. Patients with rejection were excluded from risk factor analysis for cGVHD but were considered for survival analysis. RESULTS: Fifty-one children included in this study. Median age of transplant of our cohort was 7.5 years with male:female=1.6:1. Eight patients had rejection with autologous recovery. History of acute GVHD (aGVHD) was present in 15/51 (Grade III to IV in 7/51). cGVHD developed in 19/51 patients (mild-9/51, moderate-6/51, and severe-4/51). Skin was the most common organ involved (100%) followed by gastrointestinal tract (47.4%), liver (36.8%), eyes (21%), lungs (21%), mouth (15.7%), and joints (5.2%). Advanced donor age (>30 y) and previous aGVHD were found to be significantly associated with increased risk of developing cGVHD. At last follow-up, complete response and partial response of cGVHD was seen in 6/19 and 4/19 patients, respectively. Overall mortality was 15/51 (cause of mortality was relapse of cancer 8/15, cGVHD-3/15, other 4/15). EFS and OS of full cohort was 55% and 70.6%, respectively. Compared with patients without cGVHD, patients with cGVHD demonstrated a lower relapse (18.2% vs. 40%, P =0.2333), higher EFS (68.4% vs. 53.1%, P =0.283), and higher OS (73.7% vs. 68.8%, P =0.708). CONCLUSION: Incidence of cGVHD was high in children undergoing haploidentical PBSCT with PTCy. Other than PBSC graft source; donor age and previous aGVHD were the risks factors for development of cGVHD. Patients with cGVHD had lower incidence of relapse translating into better survival but this difference was not statistically significant.

Fatal Severe Cytokine Release Syndrome Post-haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide in an Infant With Severe Combined Immunodeficiency and Disseminated Bacille Calmette-Guérin Infection.

INTRODUCTION: Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency disorder characterized by absent or dysfunctional T lymphocytes, leading to defective cellular and humoral immunity requiring urgent hematopoietic stem cell transplantation (HSCT). We report a case of SCID with disseminated Bacille Calmette-Guérin (BCG) infection who developed cytokine release syndrome (CRS) and possible Immune reconstitution inflammatory syndrome (IRIS) after Haploidentical HSCT with post-transplant cyclophosphamide. METHODS: Data were retrospectively retrieved from electronic medical records. RESULT: A 5-month-old male infant was referred with fever, cough, and generalized maculopapular rash for 15 days, and had pallor without hepatosplenomegaly or lymphadenopathy. He had a history of previous male sibling death at 6 months of age due to pneumonia. Investigations: hemoglobin: 4.7 g/dL, TLC-6.37×103/uL, absolute lymphocytes: 0.98×103/uL, platelets: 319×103/uL, bilateral patchy opacities in both lung fields, and low immunoglobulin levels. Lymphocyte subset analysis revealed T-, B+, NK- SCID. Genetic analysis showed a hemizygous mutation in IL2RG (c.314A>G). The child received intravenous (IV) antibiotics, antifungal, antitubercular drugs, irradiated blood products, and IV immunoglobulins. Urgent haploidentical HSCT from the mother was planned. Conditioning was Fludarabine-40 mg/m2/d for 4 days, cyclophosphamide: 14.5 mg/kg/d for 2 days. He received peripheral blood hematopoietic stem cells with CD34- 15×106 cells/kg and CD3- 805×106 cells/kg. Within 2 hours of stem cell infusion, he developed respiratory distress, fever, shock, and flaring of rash. Methylprednisolone was started in view of CRS. On day+2, he had sudden desaturation and bradycardia needing mechanical ventilation and inotropes. His inflammatory markers were elevated (Ferritin: 3640 ng/mL, IL-6:5000 pg/mL, CRP:255 mg/L). In view of high-grade CRS, he received an injection of tocilizumab 8 mg/kg on day +2 and day +4. He received post-transplant cyclophosphamide 5 mg/kg on day +3. The endotracheal secretion GeneXpert was positive for Mycobacterium supporting the diagnosis of disseminated tuberculosis. Our patient had disseminated BCG infection which could also be contributory in the initiation of IRIS as the mother was immunized with the BCG vaccine in childhood so she must be having cytotoxic T cells specific for BCG, which were transferred to the infant with peripheral blood stem cell product. He succumbed to severe acute respiratory distress syndrome and multiorgan dysfunction on day +5 post-transplant. CONCLUSIONS: In haploidentical HSCT of SCID, post-transplant course can be complicated by CRS and IRIS as these patients are inefficient in mounting any response to infused donor lymphocytes resulting in their unregulated growth.

Wilms tumor with Mulibrey Nanism: A case report and review of literature.

BACKGROUND: Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. We report here a 2-year-old boy with WT and MUL and present a review of literature on WT in MUL. CASE: Our patient had associated cardiac problems of atrial septal defect, atrial flutter and an episode of sudden cardiac arrest. We managed him successfully with chemotherapy, surgery and multi-speciality care. He is alive and in remission at follow-up of 6 months. CONCLUSION: A total of 14 cases (including present case) of WT have been reported in MUL and treatment details were available for six cases. They were managed primarily with surgery, chemotherapy with/without radiotherapy, and all achieved remission. The outcome data is available only for two cases, one has been followed up till 15 years post treatment for WT and other is our patient.

Bacillus cereus infection in pediatric oncology patients: A case report and review of literature.

INTRODUCTION: Bacillus Cereus infection can be life-threatening in immunocompromised patients. We report here a case of Bacillus Cereus septicemia in a child with relapsed acute lymphoblastic leukemia (ALL) and present review of literature. METHODS: We collected clinical, laboratory and outcome data of our patient with relapsed ALL and Bacillus Cereus infection. We reviewed literature for Bacillus Cereus infection in pediatric oncology patients by searching MED-LINE/PubMed/Google/Google Scholar/Cochrane and summarized the data obtained. Various risk factors like presence of gastrointestinal or central nervous system (CNS) symptoms, neutropenia, central venous catheter in-situ, corticosteroids use, intrathecal chemotherapy and outcomes were analyzed using Fisher Exact Chi Square test. RESULTS: A 15-years-old boy with relapsed ALL on induction chemotherapy presented with giddiness and difficulty in breathing. He had an episode of hematemesis followed by fainting at home. He had refractory shock which did not respond to fluid boluses, inotropes and hydrocortisone. He had severe metabolic acidosis with high lactate and ammonia and died within 36-hours of onset of symptoms. His blood culture was positive for Bacillus Cereus. We came across 36 published cases of Bacillus Cereus in children with cancer including present case. Of these, 28 had acute leukemia and rest 8 had other cancers. CNS symptoms were present in 13 patients. Overall mortality was 25%. Patients with multisystem involvement had significantly higher mortality compared to those having localized disease (p-value 0.033). CONCLUSION: In pediatric oncology patients on chemotherapy, cultures positive for Bacillus Cereus should be considered significant. Mortality is higher in those with multisystem involvement.

Dengue virus transmission from donor to recipient during haploidentical stem cell transplantation.

Dengue fever is endemic in tropical and subtropical countries. Dengue virus transmission through hematopoietic stem cells is very rare and just two such cases have been reported previously. We report here only third case of dengue virus transmission in a 2-year-old child with thalassemia major who underwent hematopoietic stem cell transplant (HSCT) from a haploidentical related donor. One week after HSCT, the recipient developed fever, pancytopenia and signs of capillary leak. On day 10, his dengue NS1 antigen test was positive which confirmed diagnosis of dengue fever. Donor also had fever few days prior to stem cell donation which was later diagnosed to be due to dengue fever. Child had a severe clinical course of dengue leading to primary graft failure. However, he had autologous recovery of his own bone marrow and is alive and well on day+200 post HSCT. Our report highlights the transmission of dengue virus from donor to recipient through hematopoietic stem cell graft although rare but possible. We suggest that in tropical and subtropical countries where dengue is endemic, hematopoietic stem cell donors should be screened for it.

Peripheral blood stem cell mobilization with pegylated granulocyte colony stimulating factor in children.

BACKGROUND AND AIM: We report here our experience of using pegylated granulocyte colony stimulating factor (peg-GCSF) for peripheral blood stem cell (PBSC) mobilization in children. METHODS AND RESULTS: A total of nine children suffering from high-risk/relapsed solid tumors were mobilized with chemotherapy and peg-GCSF (100 microgram/kg single dose). Mean age was 7.7 years (range 2-15 years).The mean time from peg-GCSF administration to PBSC harvest was 9.7 days. Adequate stem cells (median dose 26.9 million/kg) could be harvested in all children by a single apheresis procedure. No major adverse events observed. CONCLUSION: It is feasible and safe to mobilize PBSC with peg-GCSF in children with cancer.

Successful Haploidentical Stem Cell Transplant With Posttransplant Cyclophosphamide for Isolated Central Nervous System Blast Crisis in a Child With Chronic Myeloid Leukemia.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder. The extramedullary blast crisis (BC) is a known complication of CML, but it usually accompanies a systemic disease. However, an isolated central nervous system (CNS) BC at relapse is very rare and has a very poor prognosis. Salvage is even more difficult for patients who relapse with a CNS BC after an allogeneic stem cell transplant (SCT). Here, we report successful treatment of an isolated CNS BC of CML in a 14-year-old boy who relapsed with isolated a CNS BC after matched sibling donor SCT by haploidentical SCT with posttransplant cyclophosphamide.

Successful Haploidentical Stem Cell Transplant With Posttransplant Cyclophosphamide for Hemophagocytic Lymphohistiocytosis.

Allogeneic hematopoietic stem cell transplant (HSCT) has been known to be a curative therapy for patients with hemophagocytic lymphohistiocytosis (HLH) but donor availability is an issue. Haploidentical HSCT with posttransplant cyclophosphamide (PTCy) has been investigated as a feasible option for various malignant and nonmalignant conditions with reduced incidence of acute graft versus host disease (GVHD) and graft rejection. However, its use has not been described in children with HLH and here we describe 2 boys who underwent successful haploidentical HSCT with PTCy. None had acute GVHD and 1 had limited chronic GVHD. Both are alive and disease-free at follow-up of 912 and 239 days, respectively. Haploidentical HSCT with PTCy is a feasible option for children with HLH lacking a matched sibling donor.

Skin involvement in Burkitt's lymphoma.

Skin involvement in Burkitt's lymphoma (BL) is rare, more so in the pediatric age group. There are very few cases of BL involving skin either at presentation or relapse reported in literature. We report a case of a 9-years old boy with stage 4 Burkitt's lymphoma with skin involvement who tested negative for human immune-deficiency virus.

Successful Nonmyeloablative Allogeneic Stem Cell Transplant in a Child With Emberger Syndrome and GATA2 Mutation.

Emberger syndrome with underlying guanine-adenine-thymine-adenine 2 (GATA2) mutation is a rare disorder and very few successful nonmyeloablative allogeneic hematopoietic stem cell transplants (HSCTs) have been reported. We report a case of Emberger syndrome with GATA2 mutation in a 9-year-old girl who presented with congenital sensorineural deafness, warts, lymphedema, and Myelodysplastic syndrome. Her sister had died of a similar illness. She underwent a nonmyeloablative matched related donor peripheral blood HSCT with rabbit antithymoglobulin (5 mg/kg), fludarabine (160 mg/m), cyclophophamide (29 mg/kg), and total body irradiation (2 Gray). Graft versus host disease prophylaxis consisted of tacrolimus and mycophenolate moefetil. She had neutrophil engraftment on day+15 and fully donor chimerism by day+30. She developed limited chronic skin graft versus host disease on tapering off immunosuppression. She is disease free on day+475. The review of literature showed a total of 28 patients with GATA2 mutation have undergone HSCT mostly nonmyeloablative and overall survival is 75%. Nonmyeloablatove HSCT is feasible and safe for the patients with GATA2 mutation.

Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders.

We describe here the outcomes of reduced-toxicity alternate-donor stem cell transplant (SCT) with posttransplant cyclophosphamide (PTCy) for primary immunodeficiency disorders (PIDs) in eight children (haploidentical-seven and matched unrelated donor-one). The conditioning was with serotherapy (alemtuzumab-3/rabbit-anti-thymoglobulin-5); fludarabine, cyclophosphamide, and total body irradiation-5 (additional thiotepa-3); fludarabine and treosulfan-2; and fludarabine and busulfan-1. All received PTCy 50 mg/kg on days 3 and 4 as graft versus host disease prophylaxis along with tacrolimus and mycophenolate. Mean CD34 dose was 13.8 × 106 /kg. Two children died because of PIDs. Acute graft versus host disease up to grades I and II was seen in three children. All six survivors are fully donor and disease free at median follow-up of 753 days. Alternate donor SCT with PTCy is feasible in PID and has good outcomes.

Successful Reduced Intensity Conditioning Alternate Donor Stem Cell Transplant for Wiskott-Aldrich Syndrome.

There are very few reports of reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) with alternate donor for Wiskott-Aldrich syndrome (WAS) and there is no report of RIC with posttransplant cyclophosphamide (PTCy) in WAS. There is only 1 report of T cell receptor αß and CD19-depleted haploidentical HSCT for WAS. Here we report successful outcome in 3 children with WAS who underwent successful RIC alternate donor HSCT of whom 2 (matched unrelated donor and T-cell replete haploidentical) received PTCy and 1 underwent T cell receptor αß and CD19-depleted haploidentical HSCT. We modified conditioning used by Luznik for haploidentical HSCT by adding thiotepa 8 mg/kg and Campath or rabbit antithymoglobulin for 2 cases who received PTCy. In third case we gave fludarabine, thiotepa, and treosulfan-based conditioning. The mean duration of follow-up for these patients was 23.6 months posttransplant (range, 21 to 26 mo). All 3 patients are transfusion independent. Acute graft versus host disease (GVHD) grade I occurred in 1 and none had chronic GVHD. Chimerism of all 3 was fully donor (>95% donor) at D+30 and D+100 posttransplant. All are alive, healthy, and doing well. Our 3 cases highlight that with newer conditioning and GVHD prophylaxis approach alternate donor HSCT in WAS can become a safe and effective treatment option.

Meningitis and intracranial bleed in a child with steroid-resistant nephrotic syndrome.

Meningitis and associated intracranial bleeding have been rarely reported in patients with steroid-resistant nephrotic syndrome. We present such a case with raised intracranial tension in a 13-year-old child and discuss the management issues. Prompt recognition and appropriate treatment of these complications can be life saving in a child with nephrotic syndrome.

Kawasaki disease with autoimmune hemolytic anemia.

BACKGROUND: Association of autoimmune haemolytic anaemia has been seldom reported with Kawasaki disease. CASE CHARACTERISTICS: A 7-month-old boy, presented with prolonged fever, erythematous rash, severe pallor and hepatosplenomegaly. OBSERVATIONS: Positive Direct Coombs test and coronary artery aneurysm on echocardiography. He was managed with steroids along with intravenous immunoglobulins and aspirin. OUTCOME: Early identification of the condition helped in the management. MESSAGE: Patients of autoimmune hemolytic anemia with unusual features such as prolonged fever, skin rash, and mixed antibody response in Coombs test should be evaluated for underlying Kawasaki disease as a possible etiology.