pentostatin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Forty-nine children with recurrent acute lymphoblastic leukemia (ALL) were entered into a randomized Phase II trial evaluating 2'-deoxycoformycin (dCF) alone or in combination with adenine arabinoside (ara-A). 2'-Deoxycoformycin is an inhibitor of adenosine deaminase (ADA), an enzyme found in relatively high amounts in malignant lymphoid cells. Ara-A inhibits DNA polymerase and DNA synthesis. Because its efficacy in vivo as an anticancer agent is limited by its rapid inactivation by ADA, ara-A was combined with dCF to produce cytoreductive levels of ara-A. Twenty-four patients were assigned to receive dCF alone and 25 to receive the combination. No patient responded to dCF alone, and one patient developed a complete remission after treatment with the combination. The toxicity of dCF alone was minimal, except for one patient who became obtunded on day 5 following the first cycle of therapy. In contrast, five patients developed severe toxicity with the combination, including renal failure (three patients), hepatic failure (three patients), and neurologic toxicity (two patients). These results indicate that, at the doses and schedule used in this study, the combination of dCF and ara-A has significant toxicity and minimal activity against recurrent ALL in children.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Drug Synergism; Humans; Immunophenotyping; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Vidarabine

Chronic graft-versus-host disease (cGVHD) is a major barrier to successful allogeneic stem cell transplantation. Pentostatin has been used to treat cGVHD in a small series of pediatric patients. The authors report the results of the first five pediatric patients receiving pentostatin for refractory cGVHD at Johns Hopkins Hospital. In this early experience, the authors saw considerable symptom response in their patients. Every patient in this series demonstrated a significant improvement in skin and oral symptoms. An increased incidence of infection secondary to pentostatin was not observed. No patient was permanently discontinued from pentostatin subsequent to side effects. If these promising results continue, a trial of pentostatin as a first-line therapy for cGVHD should be considered to potentially reduce our dependence on high-dose steroids for its treatment.

Topics: beta-Thalassemia; Bone Marrow Transplantation; Child; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Male; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Stem Cell Transplantation

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, 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 microM 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.

Topics: Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Bone Marrow Purging; Cell Death; Cell Division; Cell Separation; Clone Cells; Erythroid Precursor Cells; Guanosine Triphosphate; Humans; Leukemia-Lymphoma, Adult T-Cell; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tumor Cells, Cultured

2-Deoxycoformycin (DCF) was added to an intensive Pediatric Oncology Group protocol (#8303) for children with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma in first relapse. Twenty-seven patients received one or more courses of DCF at 15 mg/m2/day as a 3-day continuous infusion immediately after achieving a second remission with a four-drug reinduction regimen. Renal and neuromuscular toxicities were frequent and occasionally severe despite the provision of a source of adenosine deaminase by means of a packed red cell transfusion 1 day following the infusion of DCF. Hepatic toxicity, manifested by transaminase elevations, accompanied 62% of the courses. The median duration of the second complete remission was 4 months (range 2-16+ months), with only two of the 27 patients still in remission at 13+ and 16+ months. Plasma concentrations of deoxyadenosine (dAdo) and the ratio of red cell deoxyadenosine triphosphate to adenosine triphosphate (dATP:ATP) were measured prior to the DCF infusion and on day 4. A dATP:ATP ratio of 1.0 or greater was seen in two patients with acute renal failure. There was no apparent correlation between toxicity or response and the plasma dAdo concentrations. DCF administered according to this dose and schedule was excessively toxic and did not appreciably prolong the duration of the second complete remission in children with T-cell lymphoblastic malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Coformycin; Cytarabine; Daunorubicin; Humans; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Ribonucleosides; T-Lymphocytes; Teniposide; Vincristine