Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH).

Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3' untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.

Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults.

Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.

Treatment of acute myeloid leukemia during the second and third trimesters of pregnancy.

Fortunately, the occurrence of acute myeloid leukemia (AML) during pregnancy is rare. We report a case of successful fetal outcome with standard induction and consolidation treatment in the second and third trimesters, respectively. A 37-year-old woman in her second trimester (21 wks) of pregnancy was found to have acute myeloid leukemia. She elected to maintain the pregnancy and underwent induction with cytarabine and idarubicin. Her hospital course was complicated by Pseudomonas vesicularis and gram-positive bacilli (not Bacillus anthracis) septicemia, but she obtained complete remission. After discharge, a fetal echocardiogram at 26 weeks revealed a mildly dilated right ventricle with mild systolic dysfunction, and the left ventricle appeared smaller than normal with mild systolic dysfunction. The patient then received consolidation therapy with high-dose cytarabine. On day 14 of consolidation, filgrastim 16 mug/kg was added to improve stem cell mobilization. A total of 19.8x10(6) CD34+ cells/kg were collected with a single apheresis session. At 37 weeks, she delivered a viable female infant weighing 3 lbs 12 oz. Fetal abnormalities included acrocyanosis, shallow sacral dimple, short digits and limbs, and prominent frontal skull with mild macrognathia. A postnatal echocardiogram revealed a moderate-sized membranous ventricular septal defect. The ventricular septal defect proved significant and required surgical repair at 5 months. Approximately 4 weeks after delivery, the mother underwent autologous peripheral stem cell transplantation. Unfortunately, 100 days after transplantation, she had a relapse of AML. After a brief remission from a second induction, the patient died.

Primary mediastinal large B-cell lymphoma.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct disease entity that has a relatively short history. The prognosis and therapy of patients with PMLBCL is still controversial. We summarize our experience with PMLBCL at the Medical University of South Carolina between 1997 and 2000.

The effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet recovery in breast cancer patients undergoing autologous bone marrow transplantation.

OBJECTIVE: To assess the safety and efficacy of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Two randomized, double-blind, placebo-controlled studies were done. In the phase 1/2 study, 75 breast cancer patients underwent a bone marrow harvest and myeloablative STAMP V chemotherapy and were randomized to receive placebo or one of three doses of PEG-rHuMGDF. In the phase 3 study, 64 patients were randomized to receive placebo or the minimally effective dose of PEG-rHuMGDF. The study drug was administered daily starting on the day of bone marrow infusion until the platelet count was greater than or equal to 50 x 10(9)/L (without transfusion) or for a maximum of 28 days. All patients received 10 microg/kg/day filgrastim starting on day 2 until neutrophil count recovery. RESULTS: PEG-rHuMGDF appeared to be safe and well tolerated. No significant differences were noted in mortality or disease progression rates. Antibodies to MGDF were not observed. In the phase 1/2 study, the time to platelet recovery to greater than or equal to 20 x 10(9)/L and platelet transfusion requirements were significantly reduced for patients treated with PEG-rHuMGDF compared with placebo (p < 0.05). In the phase 3 study, no significant differences in the kinetics of early thrombopoiesis or platelet transfusions after ABMT were observed. CONCLUSIONS: PEG-rHuMGDF was not consistently efficacious in reducing the duration of severe thrombocytopenia. The maximum platelet counts for PEG-rHuMGDF-treated patients occurred a median of 2 weeks after the last dose of drug, suggesting that the biologic effects of this hematopoietic cytokine are delayed compared with other hematopoietic cytokines.