Richard McMasters

Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults

Low‐dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1–4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long‐term CR.

The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations

Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group. Pediatr Blood Cancer 2012; 58: 462–465.

Lineage Switch in MLL-Rearranged Infant Leukemia Following CD19-Directed Therapy

Rearrangements of the mixed lineage leukemia (MLL) gene occur frequently in infants with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Conversions of leukemia cell lineage are rare, but occur most commonly in the setting of MLL‐rearrangement. Blinatumomab is a bidirectional antibody targeting CD19 with significant activity in relapsed B‐precursor ALL. We report an infant with ALL with t(4;11)(q21;q23) refractory to cytotoxic chemotherapy who was treated with blinatumomab. Following rapid initial clearance of peripheral lymphoblasts, bone marrow evaluation demonstrated a leukemic lineage switch to CD19‐negative monoblastic AML. Complete remission was achieved with myeloid‐directed chemotherapy.

11-Month-Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism

History of the present illness This patient was a former 32-week premature female infant, born by elective cesarean section due to concern for hydrops. After delivery she was found to have ascites and ultimately conjugated hyperbilirubinemia, but was without other congenital abnormalities. She had a normal newborn screening and no family history of congenital or metabolic disorders. An extensive evaluation for biliary atresia, perinatal iron storage disorders, Wilson’s disease, a1-antitrypsin, and metabolic diseases was unrevealing. Liver biopsy findings on day of life 25 showed mild chronic hepatitis with portal and periportal fibrosis and mild persistence of extramedullary hematopoiesis. She had a prolonged neonatal intensive care unit stay secondary to respiratory insufficiency, and remained on supplemental oxygen at the time of discharge. Throughout her hospitalization she had a persistently elevated C-reactive protein (CRP) level, as well as aminotransferases and direct bilirubin, although these had stabilized prior to discharge. Starting at 2 months of age, she developed recurrent episodes of fever, respiratory distress, abdominal distension, and feeding intolerance, lasting 5–7 days and occurring every 3–5 weeks, and beginning shortly after her first round of immunizations. During episodes she developed transient hepatosplenomegaly and ascites, elevated aminotransferases and CRP level, anemia, and thrombocytopenia. Empiric antibiotics were typically started, but all cultures were negative. With her third episode she required mechanical ventilation for 5 weeks. During this prolonged hospitalization an extensive diagnostic evaluation was pursued, summarized in Table 1. Repeat liver biopsy was performed showing chronic hepatitis with moderate periportal and pericellular fibrosis. Bone marrow biopsy findings showed mild granulocytic hyperplasia, mild dyserythropoiesis, and increased interstitial histiocytes without hemophagocytic activity. Ultimately, due to suspected autoimmune process, methylprednisolone 2 mg/kg/day was administered, after which she was weaned off all respiratory support. However, as steroids were weaned she continued to have febrile episodes lasting several days, which were managed with increasing steroids and empiric antibiotics. Due to a finding of reduced transitional B cells and concern for B cell immunodeficiency, at age 9 months she was started on monthly intravenous immunoglobulin (IVIG) therapy; however, this did not alter the frequency of her febrile episodes.

MEVALONATE KINASE DEFICIENCY ASSOCIATED WITH RECURRENT LIVER DYSFUNCTION, MACROPHAGE ACTIVATION SYNDROME AND PERFORIN GENE POLYMORPHISM

History of the present illness This patient was a former 32-week premature female infant, born by elective cesarean section due to concern for hydrops. After delivery she was found to have ascites and ultimately conjugated hyperbilirubinemia, but was without other congenital abnormalities. She had a normal newborn screening and no family history of congenital or metabolic disorders. An extensive evaluation for biliary atresia, perinatal iron storage disorders, Wilson’s disease, a1-antitrypsin, and metabolic diseases was unrevealing. Liver biopsy findings on day of life 25 showed mild chronic hepatitis with portal and periportal fibrosis and mild persistence of extramedullary hematopoiesis. She had a prolonged neonatal intensive care unit stay secondary to respiratory insufficiency, and remained on supplemental oxygen at the time of discharge. Throughout her hospitalization she had a persistently elevated C-reactive protein (CRP) level, as well as aminotransferases and direct bilirubin, although these had stabilized prior to discharge. Starting at 2 months of age, she developed recurrent episodes of fever, respiratory distress, abdominal distension, and feeding intolerance, lasting 5–7 days and occurring every 3–5 weeks, and beginning shortly after her first round of immunizations. During episodes she developed transient hepatosplenomegaly and ascites, elevated aminotransferases and CRP level, anemia, and thrombocytopenia. Empiric antibiotics were typically started, but all cultures were negative. With her third episode she required mechanical ventilation for 5 weeks. During this prolonged hospitalization an extensive diagnostic evaluation was pursued, summarized in Table 1. Repeat liver biopsy was performed showing chronic hepatitis with moderate periportal and pericellular fibrosis. Bone marrow biopsy findings showed mild granulocytic hyperplasia, mild dyserythropoiesis, and increased interstitial histiocytes without hemophagocytic activity. Ultimately, due to suspected autoimmune process, methylprednisolone 2 mg/kg/day was administered, after which she was weaned off all respiratory support. However, as steroids were weaned she continued to have febrile episodes lasting several days, which were managed with increasing steroids and empiric antibiotics. Due to a finding of reduced transitional B cells and concern for B cell immunodeficiency, at age 9 months she was started on monthly intravenous immunoglobulin (IVIG) therapy; however, this did not alter the frequency of her febrile episodes.

Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation

Monosomy 7 is a well‐documented cytogenetic aberration in pediatric acute myeloid leukemia (AML) and may occur in combinations with molecular abnormalities including PTPN11 mutation. PTPN11 mutations contribute to leukemogenesis through upregulation of Ras pathway signaling. We present the case of a 3‐year‐old female with AML with monosomy 7 and somatic PTPN11 mutation who was refractory to conventional AML chemotherapy but responded to a novel regimen of azacitidine and sorafenib followed by stem cell transplantation. Combination therapy with azacitidine and sorafenib may be an effective therapeutic strategy for patients with AML with Ras pathway abnormalities.

Polyarticular Arthritis and Skin Nodulosis in a 14-Year-Old Female

History of the present illness. A 14-year-old female patient presented to our pediatric rheumatology clinic for a second opinion regarding joint pain and skin nodules. Five years prior to this initial visit, she began to experience arthralgias followed by joint swelling, which gradually worsened and involved bilateral elbows, knees, and fingers. Three years after the onset of symptoms, the patient was diagnosed with antinuclear antibody (ANA)–positive, rheumatoid factor (RF)–negative, polyarticular juvenile idiopathic arthritis (JIA). For her JIA, she was treated with nonsteroidal antiinflammatory medications (NSAIDs), followed by methotrexate (MTX) and etanercept. Prior to the initiation of treatment with MTX, the patient experienced an acute onset of nodulosis, involving the dorsal and volar aspects of both her hands and fingers. These nodules appeared without known triggers and were moderately and constantly painful. Nodulosis failed to respond to naproxen, MTX, etanercept, and hydroxychloroquine. Therefore, select especially tender nodules were removed surgically from 1 finger for histologic study. Concomitantly, the patient developed mild to moderate Raynaud’s phenomenon; she lacked digital ulcers and pulp tissue loss. There was also mild facial acne that started around the time of the appearance of the nodulosis. The patient denied oral ulcers, photosensitivity, alopecia, easy bruising, cough, chest pain, dyspnea, headaches or neurologic symptoms, dry eyes or mouth, and eye pain or redness. There were no fevers, weight loss, or known renal, gastrointestinal, or pulmonary disease. Past medical, social, and family history. The patient was adopted by her current caregiver, but has one biological brother. There is no known pertinent family medical history of autoimmune or rheumatologic disease. The patient was diagnosed with bipolar disorder at age 14 years, and had peptic ulcer disease at age 12 years that limited the ability to use NSAIDs at that time. Her medications at the time of her initial clinic visit included acetaminophen, tramadol, and gabapentin for pain management. She was treated with MTX, etanercept, glucosamine sulfate, and hydroxychloroquine for her chronic arthritis, as well as aripiprazole for her bipolar disorder. She also received vitamin D, folic acid, and vitamin B12 supplements.

11-Month-Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism: Clinicopathologic Conference

History of the present illness This patient was a former 32-week premature female infant, born by elective cesarean section due to concern for hydrops. After delivery she was found to have ascites and ultimately conjugated hyperbilirubinemia, but was without other congenital abnormalities. She had a normal newborn screening and no family history of congenital or metabolic disorders. An extensive evaluation for biliary atresia, perinatal iron storage disorders, Wilson’s disease, a1-antitrypsin, and metabolic diseases was unrevealing. Liver biopsy findings on day of life 25 showed mild chronic hepatitis with portal and periportal fibrosis and mild persistence of extramedullary hematopoiesis. She had a prolonged neonatal intensive care unit stay secondary to respiratory insufficiency, and remained on supplemental oxygen at the time of discharge. Throughout her hospitalization she had a persistently elevated C-reactive protein (CRP) level, as well as aminotransferases and direct bilirubin, although these had stabilized prior to discharge. Starting at 2 months of age, she developed recurrent episodes of fever, respiratory distress, abdominal distension, and feeding intolerance, lasting 5–7 days and occurring every 3–5 weeks, and beginning shortly after her first round of immunizations. During episodes she developed transient hepatosplenomegaly and ascites, elevated aminotransferases and CRP level, anemia, and thrombocytopenia. Empiric antibiotics were typically started, but all cultures were negative. With her third episode she required mechanical ventilation for 5 weeks. During this prolonged hospitalization an extensive diagnostic evaluation was pursued, summarized in Table 1. Repeat liver biopsy was performed showing chronic hepatitis with moderate periportal and pericellular fibrosis. Bone marrow biopsy findings showed mild granulocytic hyperplasia, mild dyserythropoiesis, and increased interstitial histiocytes without hemophagocytic activity. Ultimately, due to suspected autoimmune process, methylprednisolone 2 mg/kg/day was administered, after which she was weaned off all respiratory support. However, as steroids were weaned she continued to have febrile episodes lasting several days, which were managed with increasing steroids and empiric antibiotics. Due to a finding of reduced transitional B cells and concern for B cell immunodeficiency, at age 9 months she was started on monthly intravenous immunoglobulin (IVIG) therapy; however, this did not alter the frequency of her febrile episodes.