Indira Sahdev

Fatal cyclophosphamide-induced congestive heart failure in a 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation.

A 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure was treated with high-dose cyclophosphamide, busulfan, and antithymocyte globulin followed by an infusion of human leukocyte antigen-identical, mixed lymphocyte culture (MLC) non-reactive sibling bone marrow. He developed cardiac arrhythmias and intractable hypotension and died on day 23 posttransplant. Autopsy findings were consistent with cyclophosphamide-induced pancarditis. The bone marrow showed signs of early engraftment. Allogeneic bone marrow transplantation may be a treatment alternative for Shwachman-Diamond syndrome with severe bone marrow failure. However, fatal posttransplant pancarditis due to doses of cyclophosphamide not usually associated with cardiac death may be an unanticipated problem. Further trials of bone marrow transplantation as therapy for this syndrome may be warranted, perhaps using lower doses of cyclophosphamide or substituting for it other immunosuppressive and myelosuppressive agents.

Successful Matched Sibling Donor Marrow Transplantation Following Reduced Intensity Conditioning in Children with Hemoglobinopathies

Fifty‐two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion‐dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan–Meier probabilities of overall and event‐free survival at a median of 3.42 (range, 0.75–11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment‐related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17–18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901). Am. J. Hematol. 90:1093–1098, 2015.

Transformation of congenital neutropenia into monosomy 7 and acute nonlymphoblastic leukemia in a child treated with granulocyte colony-stimulating factor

A cytogenetically normal infant with Kostmann syndrome (severe congenital granulocytopenia) was treated with granulocyte colony-stimulating factor, which resulted in a rapid improvement in his neutrophil count and a resolution of recurrent infections. After 11 months of therapy, splenomegaly developed, with thrombocytopenia, anemia, circulating nucleated erythrocytes, and acquired monosomy 7, which evolved during a period of 7 months into acute nonlymphoblastic leukemia. The use of granulocyte colony-stimulating factor in patients with congenital marrow failure disorders may induce or hasten the onset of a malignant transformation.

Allogenic Bone Marrow Transplantation in Severe Gaucher Disease

ABSTRACT: Gaucher disease is the most prevalent lyso-somal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid β-glucosidase and the resultant accumulation of glucosylcer-amide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocvte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neu-ronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytoge-netic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete re-constitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8–12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12–24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and hugs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time coarse aid rationale for studies directed to gene therapy via BMT for this disease after introduction of acid β-glncosidase gene constructs into autologous plu-ripotent stem cells of selected Gaucher disease patients.

Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children's Oncology Group study.

The Childrens Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.

Clinical ResearchRandomized Trial of Hydroxychloroquine for Newly Diagnosed Chronic Graft-versus-Host Disease in Children: A Children’s Oncology Group Study

The Childrens Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.

Outcomes after Hematopoietic Stem Cell Transplantation for Children with I-Cell Disease

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.

Concordant rhabdoid tumor of the kidney in a set of identical twins with discordant outcomes.

We report identical twin boys who each had stage IV rhabdoid tumor of the left kidney at the age of 5 months and 2 years, respectively. The 5-month-old boy, despite receiving chemotherapy, died of progressive disease at the age of 12 months. Following resection of the tumor, his twin brother was treated with 6 cycles of combination chemotherapy consisting of cisplatinum, doxorubicin, vincristine, cyclophosphamide, and actinomycin-D alternating with ifosfamide and etoposide. After complete regression of lung and brain metastases, he received high-dose thiotepa, etoposide, and cyclophosphamide, followed by autologous peripheral stem cell rescue. The patient is presently alive and free of disease 6 years posttransplant. High-dose chemotherapy followed by autologous stem cell transplant may be an effective front-line therapeutic approach for patients with metastatic rhabdoid tumor of the kidney.

A Pilot Study of Addition of Amifostine to Melphalan, Carboplatin, Etoposide, and Cyclophosphamide With Autologous Hematopoietic Stem Cell Transplantation in Pediatric Solid Tumors–a Pediatric Blood and Marrow Transplant Consortium Study

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide ± cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m2 b.i.d. ×4 d) to melphalan (200 mg/m2), carboplatin (1200 mg/m2), and etoposide (800 mg/m2) (level 1) and escalating doses of cyclophosphamide (3000 mg/m2 and 3800 mg/m2, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m2 b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m2), cyclophosphamide (up to 3800 mg/m2), carboplatin (1200 mg/m2), and etoposide (800 mg/m2) with manageable toxicities.

A Multicenter Study of Bacterial Blood Stream Infections in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients: The Role of Acute Gastrointestinal Graft-versus-Host Disease

Blood stream infections (BSI) caused by enteric organisms are associated with a particularly high mortality rate in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We conducted a retrospective multicenter study aiming to analyze the risk factors associated with antibiotic resistance and impact of BSI on transplantation-related mortality (TRM) in children after alloHCT. During the study period from 2004 to 2014, 395 children (mean age, 9.4 years) with at least 1 BSI were included. The incidences of resistant gram-negative rods were 20.7% to piperacillin-tazobactam, 10.9% to cefepime, 21% to ceftazidime, 11.4% to levofloxacin, and 8.16% to meropenem. Thirty-eight percent of Enterococcus spp. isolates were resistant to vancomycin. More than 1 episode of BSI was associated with significant increase in the risk of resistance to piperacillin-tazobactam, cefepime, and vancomycin. On multivariate analysis of risk factors for TRM, achievement of neutrophil engraftment by day 30 was associated with lower TRM (P = .002). However, infection with an antibiotic-resistant organism was not associated with TRM. Development of enteric bacterial BSI after the onset of acute gastrointestinal graft-versus-host disease (GVHD) was the strongest predictor of TRM (hazard ratio, 4.786; 95% confidence interval, 2.833 to 8.087; P < .001). In patients with acute gastrointestinal GVHD who subsequently developed enteric bacterial BSI, the incidence of 1-year TRM was 33.4% (SE = 7%), compared with 15.3% (SE = 2%) for those without acute gastrointestinal GVHD (P = .004). Primary prevention of a first episode of BSI is arguably the most important intervention to decrease antibiotic resistance. It is also imperative that we develop strategies to maintain gastrointestinal health, especially in patients with gastrointestinal GVHD, in an effort to prevent subsequent enteric bacterial BSI and improve survival.