Sara Chaffee

High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors.

PURPOSE We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens. PATIENTS AND METHODS Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care. RESULTS Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation. CONCLUSION The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.

Enzyme Replacement Therapy with Polyethylene Glycol-Adenosine Deaminase in Adenosine Deaminase Deficiency: Overview and Case Reports of Three Patients, Including Two Now Receiving Gene Therapy

ABSTRACT: During the past 6 y, 29 adenosine deaminase (ADA)-deficient patients with combined immunodeficiency have been treated with polyethylene glycol (PEG)-modified bovine ADA (PEG-ADA). We have monitored plasma ADA activity, metabolic effects of treatment, and the evolution of antibody to PEG-ADA in these patients, in collaboration with immunologists and clinicians in North America, Europe, and Australia, who have monitored immune function and clinical response to treatment. This article summarizes the current status of PEG-ADA therapy and provides recommendations for its use. Recovery of specific immune function during treatment with PEG-ADA is illustrated for three patients, who represent early, delayed, and late onset of immunodeficiency disease. Two of these patients have entered a trial of gene therapy, but continue to receive enzyme replacement.

Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency.

T lymphocytes cultured from a patient (T.D.) with adenosine deaminase (ADA) deficiency expressed ADA activity in the normal range, inconsistent with her severe immunodeficiency, metabolic abnormalities, and with the absence of ADA activity in her B lymphocytes and other nucleated hematopoietic cells. ADA from T.D. T cells had normal Km, heat stability, and sensitivity to ADA inhibitors. Examination of HLA phenotype and polymorphic DNA loci indicated that T.D. was neither chimeric nor a genetic mosaic. Amplified and subcloned ADA cDNA from ADA+ T.D. T cells was shown by allele-specific oligonucleotide hybridization to possess the same mutations (Arg101----Trp, Arg211----His) previously found in the ADA-T.D. B cell line GM 2606 (Akeson, A. L., D. A. Wiginton, M. R. Dusing, J. C. States, and J. J. Hutton. 1988. J. Biol. Chem. 263:16291-16296). Our findings suggest that one of these mutant alleles can be expressed selectively in IL-2-dependent T cells as stable, active enzyme. Cultured T cells from other patients with the Arg211----His mutation did not express significant ADA activity, while some B cell lines from a patient with an Arg101----Gln mutation have been found to express normal ADA activity. We speculate that Arg101 may be at a site that determines degradation of ADA by a protease that is under negative control by IL-2 in T cells, and is variably expressed in B cells. Il-2 might increase ADA expression in T cells of patients who possess mutations of Arg101.

Treatment of trilateral retinoblastoma with vincristine and cyclophosphamide

Current therapy for patients with trilateral retinoblastoma, consisting primarily of surgical intervention and radiotherapy, has resulted in no long-term survivors. The use of adjuvant chemotherapy has not improved this outcome. After observing a tumor response to cyclophosphamide in a patient with suprasellar retinoblastoma, we treated a subsequent patient with trilateral retinoblastoma with both vincristine and cyclophosphamide. Objective tumor regression resulted. Although the tumor ultimately progressed in both patients, these findings suggest that vincristine and cyclophosphamide are active in patients with intracranial (trilateral) retinoblastoma.

Efficacy of intravenous gamma globulin in autoimmune-mediated pediatric blood dyscrasias.

Sixteen pediatric patients diagnosed with a variety of autoimmune-mediated hematocytopenias were treated with one to 50 courses of intravenous gamma globulin (IVIG), pH 4.25, over the course of one to 30 months. Thirteen patients had immune thrombocytopenic purpura (ITP), two had autoimmune neutropenia, and one had autoimmune hemolytic anemia. In one patient, chronic ITP was associated with systemic lupus erythematosis, and in a second patient, acute ITP was the presenting manifestation of infection with human immunodeficiency virus. Initial therapy consisted of 400 mg/kg/dose daily for five days for the first seven patients treated, and 1,000 mg/kg/dose daily for two days for the remaining nine patients. In 15 of 16 patients, there was a response to IVIG therapy. In nine of 16 patients, maintenance IVIG therapy for two to more than 30 months was required. Minimal toxicity was experienced in four of 210 separate infusions. Data are presented to support the use of IVIG in the management of childhood autoimmune disorders.

Pharmacologic purging of malignant T cells from human bone marrow using 9-β-D- arabinofuranosylguanine

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide tri-phosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 μM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.

Treatment of platelet alloimmunization with intravenous immunoglobulin: Two case reports and review of the literature

Two pediatric patients with severe aplastic anemia, elevated antiplatelet antibody levels, refractoriness to human lymphocyte antigen-matched platelet transfusions, and sustained bleeding problems were treated with intravenous immunoglobulin (IVIG), pH 4.25, for three to over nine months. Improved responses to platelet infusions and improved hemostasis were demonstrated in both patients. A review of the published literature analyzing the role of IVIG in the treatment of platelet alloimmunization is presented.

Management of human immunodeficiency virus-associated thrombocytopenia with intravenous gamma globulin.

A 17-month-old boy in whom immune-mediated throm-bocytopenia (ITP) was the presenting manifestation of infection with human immunodeficiency virus (HIV) is being successfully managed with intermittent high-dose intravenous gamma globulin (IVIG) allowing maintenance of hemostatic platelet counts while avoiding the immunosuppression associated with other therapeutic modalities used to treat ITP. He continues to demonstrate marked responsiveness to IVIG, and has been maintained on weekly or bimonthly infusions for 12 months. The serendipitous documentation of HIV infection prior to IVIG therapy for immune-mediated thrombocytopenia in this child documents the importance of HIV testing prior to IVIG therapy to prevent erroneous assignment of IVIG as the vehicle responsible for transmission of HIV infection. This case history also documents the importance of HIV testing in the diagnostic evaluation of immune-mediated thrombocytopenias.

Toxicity, pharmacology and feasibility of administration of PEG-L-asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic leukemia

We attempted to administer PEG-L-asparaginase (PEG-L-A) following hematologic recovery to 38 patients undergoing autologous or allogeneic marrow transplantation for acute lymphoblastic leukemia (ALL). Twenty-four patients (12 of 22 receiving allogeneic and 12 of 16 receiving autologous transplants) received between one and 12 doses of PEG-L-A, including nine who completed the planned 12 doses of therapy. The toxicities encountered were similar to those observed in non-transplanted patients undergoing therapy with PEG-L-A and included allergic reactions, pancreatitis, weight loss, hypoalbuminemia, and low levels of anti-thrombin III. Of the 24 who received the drug, eight remain in remission. Of 12 patients in second remission at the time of transplantation who received PEG-L-A, five of seven who received allogeneic and two of five who received autologous transplants remain in remission, 16+ to 46+ months from transplant. While PEG-L-A could be administered to most of the patients undergoing marrow transplantation for ALL, most patients either relapsed while receiving the drug or developed toxicities which resulted in abbreviated courses. At this time, we cannot recommend PEG-L-A as single agent, post-BMT chemotherapy.

ε-Aminocaproic acid-associated myopathy in a child

Purpose A 12-year-old girl developed severe autoimmune thrombocytopenia after a bone marrow transplant for acute lymphoblastic leukemia. Results Although epsilon-aminocaproic acid helped to control her bleeding, it eventually caused a rare myopathy previously undescribed in a pediatric patient. Conclusions The myopathy resolved when the drug was discontinued and a different antifibrinolytic agent was used.