Ghada Abusin

The genomic landscape of juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

X‐linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B‐cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patients leukemia. Pediatr Blood Cancer 2015;62:1674–1676.

Recombinant human keratinocyte growth factor: Successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation

Recombinant human keratinocyte growth factor: successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation

Severe transplant-associated thrombotic microangiopathy in patients with hemoglobinopathies

Incidence and severity of transplant‐associated thrombotic microangiopathy (TA‐TMA) in patients with hemoglobinopathies receiving hematopoietic cell transplant is unknown. We report the outcomes for two patients with TA‐TMA who received eculizumab. A 2.5‐year‐old male with sickle cell disease developed TA‐TMA‐associated pericardial tamponade, severe hypertension, and acute kidney injury 2 months after transplant. A 7‐year‐old female with β‐thalassemia major developed TA‐TMA‐related acute kidney injury, severe hypertension, and seizures at 6 months after transplant. Both patients progressed to chronic kidney disease (CKD). In patients with hemoglobinopathies, preexisting endothelial dysfunction may place them at a greater risk for TA‐TMA and subsequent CKD.

Corrigendum: The genomic landscape of juvenile myelomonocytic leukemia.

Nat. Genet. 47, 1326–1333 (2015); published online 12 October 2015; corrected after print 7 December 2015 In the version of this article initially published, two patients were stated on page 5 to have been excluded owing to insufficient follow-up data. These patients were included in the final analysis, but two additional patients were excluded owing to the presence of Noonan syndrome.

The role of continuous renal replacement therapy in the management of acute kidney injury associated with sinusoidal obstruction syndrome following hematopoietic cell transplantation

Maintaining fluid balance, pre‐ and post‐MA‐HCT is essential and usually requires frequent administration of diuretics. Hepatic sinusoidal obstructive syndrome is potentially life‐threatening, especially when associated with AKI and MOF. This study describes six patients who developed AKI‐associated SOS and diuretic‐resistant FO who subsequently underwent CRRT using standardized management guidelines for fluid balance post‐HCT. Retrospective chart review was done for HCT patients between September 2011 and October 2013 at a tertiary care childrens hospital. Thirty‐four patients underwent MA‐HCT in the study period. Six patients had SOS complicated by diuretic‐resistant FO and underwent CRRT. Defibrotide was used in three patients. Median time on CRRT was 10.5 days. Sixty‐six percent (N = 4 of 6) of patients had full resolution of SOS symptoms with a mortality rate of 34% (N = 2 of 6). Among patients who had full recovery of SOS symptoms, one patient developed AKI, end‐stage renal diseases and underwent kidney transplantation 34‐months post‐HCT. Thus, of six included patients, two died and one developed ESRD with only 50% (N = 3 of 6) good outcome. Use of a standardized, evidence‐based fluid balance protocol and early initiation of CRRT for HCT‐related AKI/SOS was associated with good outcomes.

Successful Management of Blue Rubber Bleb Nevus Syndrome (BRBNS) with Sirolimus

Blue rubber bleb nevus syndrome (BRBNS) is a rare disease with vascular malformations in several systems of the body, most commonly the skin and gastrointestinal tract. Bleeding from the gastrointestinal (GI) tract is a major complication, which may lead to chronic iron deficiency anemia and the need for frequent blood transfusions due to ongoing gastrointestinal blood loss. In this case report, we describe a now 19-year-old female with BRBNS who required six blood transfusions per year and after starting sirolimus is symptom- and transfusion-free.

Successful treatment of tacrolimus-related pure red cell aplasia and autoimmune hemolytic anemia with rituximab in a pediatric cardiac transplant patient

Acquired pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) are rare complications of immunosuppression in pediatric solid organ transplant patients. We report a 14‐month‐old female child who developed Coombs positive hemolytic anemia and reticulocytopenia while on tacrolimus after cardiac transplantation. She was successfully treated with rituximab after failing treatment with corticosteroids and intravenous immunoglobulins. Clinicians should consider PRCA differential diagnosis in a patient presenting with reticulocytopenia and hemolysis. In addition, the coexistence of PRCA with AIHA, and the response to therapy with rituximab, supports a common immune‐mediated pathogenesis for both disorders.

Favorable outcome to glucocorticoid therapy for engraftment syndrome in pediatric autologous hematopoietic cell transplant.

ES remains an important cause of morbidity and mortality in children undergoing auto‐HCT. Glucocorticoid use in ES is an area of debate. We retrospectively analyzed single‐institution experience from September 2000 through December 2012 to evaluate the use of glucocorticoids in auto‐HCT patients. ES was defined by the occurrence of new onset of non‐infectious fever plus diarrhea, rash, or pulmonary infiltrates 24‐h before or within five days after neutrophil engraftment. Sixty‐five pediatric patients (<21 yr) with different solid tumors underwent auto‐HCTs in the study period. Fifteen patients (23%) fulfilled criteria for ES, of which 13 received methylprednisolone (2 mg/kg IV for 3–5 days). Clinical improvement occurred in all patients within 48 h without significant complications. In the non‐ES group, 11 patients received glucocorticoid without significant complications as well. MEL‐based regimens were found to be significant factor for ES (p < 0.05). Fever, edema, non‐infectious diarrhea, and serum albumin concentration were statistically different between the two groups. Median hospital length of stay was higher in the ES group. Conclusion: ES is a common complication in children after auto‐HCT and short‐course glucocorticoid therapy is an effective and well‐tolerated treatment, even in those who did not completely fulfill diagnostic criteria.

Erratum: Corrigendum: The genomic landscape of juvenile myelomonocytic leukemia

Nat. Genet. 47, 1326–1333 (2015); published online 12 October 2015; corrected after print 7 December 2015 In the version of this article initially published, two patients were stated on page 5 to have been excluded owing to insufficient follow-up data. These patients were included in the final analysis, but two additional patients were excluded owing to the presence of Noonan syndrome.