Robert A. Krance

Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia: potential selective effect in T-cell leukemia

One hundred seventy‐seven children with acute lymphoblastic leukemia (ALL) were admitted to a study designed to determine whether pulses of cytosine arabinoside (ara‐C) and cyclophosphamide (cyclo) would improve disease‐free survival (DFS). All patients received vincristine, prednisone, and asparaginase for remission induction, CNS prophylaxis with cranial irradiation and intrathecal methotrexate, and continuation therapy with 6‐mercaptopurine plus methotrexate. Forty‐seven of 101 patients with non‐T ALL and 18 of 26 patients with T‐cell ALL received ara‐C/cyclo pulses every eight weeks during continuation therapy. The age, sex, and initial white cell count distributions were similar in both treatment groups. Patients with non‐T‐cell ALL had similar DFS with or without ara‐C/cyclo pulses (36% versus 48%; P = 0.32). Ara‐C/cyclo pulses significantly improved DFS in children with T‐cell ALL (36% versus 0%; P = 0.015). Toxicities of the ara‐C/cyclo pulses included reversible pancytopenia, drug induced fever, fever associated with neutropenia, and death in one patient from systemic candidiasis while neutropenic. This is the first clinical evidence to indicate that the combination of ara‐C/cyclo used during continuation therapy is selectively beneficial in T‐cell ALL.

Peripheral T-cell lymphoma. A case report demonstrating morphologic heterogeneity and progression, and atypical immune reactions

Peripheral T‐cell lymphomas (PTCL) comprise a morphologically heterogeneous group of non‐Hodgkins lymphomas. The authors report on PTCL occurring in a 13‐year‐old girl, in whom they were able to evaluate histologic material from 11 biopsy specimens obtained during her 8‐month clinical course. These biopsy specimens demonstrated morphologic progression from atypical immune reactions and diffuse mixed cell lymphoma observed at different anatomic sites during early stages of the disease to pleomorphic large cell lymphoma with erythrophagocytic tumor cells at the time of her death. Morphologic variability of PTCL that may occur during the course of a patients illness was demonstrated, and discordant histologic findings in biopsy specimens obtained simultaneously from different anatomic sites was noted. The morphologic evolution of PTCL was expressed, in sequential biopsy specimens, by a progressive cellular pleomorphism with the appearance of large, often bizarre lymphoid cells. This was associated with the gradual diminution and disappearance of the B‐cell areas and epithelioid histiocytic reactions which were present initially in the biopsy specimens. The findings suggest that some of the various morphologic descriptions of PTCL given in the literature may represent transient histologic expressions of the lymphoma at various stages in its natural history. Cancer 57:2329–2342, 1986.

Biochemical interactions between methotrexate and 1-β-d-arabinofuranosylcytosine in hematopoietic cells of children: a Pediatric Oncology Group study

SummaryChildren with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1-β-d-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.

Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission

SummaryWe treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute nonlymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1 320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (± SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74±9%; acute nonlymphoblastic leukemia = 50±11%; and chronic myelogenous leukemia = 55±11%. Actuarial relapse rates for these three diagnoses were 19±9%, 17±11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59±7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.

Successful second bone marrow transplantation in a patient with myositis ossificans progressiva and aplastic anemia.

Bone marrow transplantation has become the treatment of choice for patients with severe aplastic anemia who are fortunate enough to have allogeneic sibling donors. As patients have been transplanted earlier in the course of their disease, significant improvements have been obtained in long-term survival. However, in patients who have been sensitized by previous blood product transfusions, graft rejection continues to be a significant problem and second transplants when performed are frequently unsuccessful. This case report deals with a patient with myositis ossificans progressiva (MOP) who developed severe idiopathic aplastic anemia. He rejected his first graft after 160 days. However, he was successfully reingrafted with marrow from the same donor using a different conditioning regimen.

Outcome of bone marrow transplantation in patients with extramedullary involvement of acute leukemia

SummaryInfiltration of extrahemopoietic tissue with leukemic cells was evaluated as a prognostic indicator in 18 patients with acute leukemia undergoing bone marrow transplantation. When compared to 107 patients who did not have extramedullary leukemia at any time prior to marrow grafting, the patients with leukemic invasion into organs outside the hemopoietic system had a significant increase of leukemic recurrence and a significant decrease in survival after marrow transplantation. Extramedullary leukemia may be a negative prognostic indicator for bone marrow transplantation candidates.