Tsuneo Ninomiya

Effectiveness of high-dose MCNU therapy and hematopoietic stem cell autografts treatment of childhood acute leukemia/lymphoma with high-risk features.

Clinical and pharmacokinetic studies were performed regarding the toxicity of methyl 6‐[3‐(2‐chloroethyl)‐3‐nitrosoureido]‐6‐deoxy‐α‐D‐glucopyranoside (MCNU) with other drugs, in conjunction with a peripheral blood stem cell autograft (PBSCT), for treating 26 children with acute leukemia or lymphoma associated with high‐risk features. In the early phase of the study, MCNU (300 to 500 mg/m2) was administered with cytosine arabinoside (Ara‐C) (1.6 to 16 g/m2),etoposide (VP‐16) (0.8 to 1.6 g/m2), cyclophosphamide (CY) (100 to 200 mg/kg), or busulfan (16 mg/kg). No acute toxicity was noticed after this high‐dose therapy. The dose‐limiting factor of the regimens was significant but reversible interstitial pneumonitis (IP). In a subsequent trial with an MCNU/VP‐16/Ara‐C/CY (MCVAC) regimen in which the dose of MCNU was reduced, the risk of IP diminished. This study is still in progress, but the clinical response has so far been encouraging. Fifteen of 26 children are alive and well in unmaintained complete remission (CR) with a median follow‐up period of 11 months (range, 3 to 34 months) after transplantation.

Comparison of intermittent or continuous methotrexate plus 6-mercaptopurine in regimens for standard-risk acute lymphoblastic leukemia in childhood (JCCLSG-S811)

From 1981 to 1983, 131 previously untreated patients with acute lymphoblastic leukemia (ALL) standard‐risk group were entered to the protocol JCCLSG‐S811. Of 119 eligible patients, 115 (96.6%) attained complete remission by treatment with prednisone (PRD) plus vincristine (VCR) or vindesine (VDS). After preventive central nervous system (CNS) therapy including 18 Gy cranial irradiation and three doses of intrathecal methotrexate (MTX), the patients were assigned randomly to the two maintenance chemotherapies, Regimen A and Regimen B. Regimen A (intermittent regimen) consisted of PRD (120 mg/m2/day by mouth for 5 days) plus 6‐mercaptopurine (6MP) (175 mg/m2/day by mouth for 5 days) plus VCR (2.0 mg/m2 intravenously) alternating biweekly with MTX (225 mg/m2 intravenously). Regimen B (continuous regimen) consisted of 6MP (50 mg/m2/day by mouth) plus MTX (20 mg/m2/ week by mouth) combined with pulses of PRD and VCR (the same dosages as Regimen A) every 4 weeks. As the late intensification therapy (LIT), five courses of high‐dose MTX (2000 mg/m2 per dose per week intravenously for three doses every 12 weeks) with leucovorin rescue were administered to all patients who were in continuous complete remission (CCR) for more than 2 years. Sixty and 55 patients, respectively, were registered in Regimen A and B. The CCR rates in Regimen A and B were 75.1% ± 5.8% (mean ± 1 SE) and 49.7% ± 7.3% (P < 0.01) at 4 years, and 72.1% ± 6.3% and 49.7% ± 7.3% (P < 0.05) at 5 years, respectively. In Regimen B, CNS and testicular relapses increased after 3 years of CCR. In addition, the patients in Regimen B had a much higher incidence of infections than Regimen A. The LIT did not seem to have important effects on the duration of CCR. From these data we conclude that the intermittent cyclic regimen of 6MP and MTX may be more effective as compared to the continuous administration of these drugs in the maintenance chemotherapy.

Overview of Clinical Studies of Childhood Acute Lymphoblastic Leukemia for More Than Ten Years by the Japanese Children's Cancer and Leukemia Study Group

Since 1981, the Childrens Cancer and Leukemia Study Group (CCLSG) has developed a series of protocols for treatment of acute lymphoblastic leukemia (ALL) in childhood. In the first randomized controlled study of the 811 protocol (1981-1983) a comparison of conventional daily 6-mercaptopurine and methotrexate with a pulsed regimen of the two drugs was performed. The superiority of the pulsed regimen was shown. In the next 841 protocol (1984-1987) a comparison of two drugs and three drugs during induction therapy was conducted. The three-drug regimen resulted in a significantly higher event-free survival (EFS) rate. In the 874 protocol (1987-1990) two regimens with or without cranial irradiation were randomly compared, and there was no significant difference between the two regimens for the standard-risk group. To further improve the EFS rate a risk group-directed protocol 911 was conducted starting in January 1991. Life-table analysis of serial CCLSG protocols revealed that the outcome of overall ALL has gradually improved with an increase of the EFS rate; 41.4% +/- 3.6% at 14 years for the 811 protocol, 51.3% +/- 3.5% at 11 years for the 841 protocol, 56.7% +/- 3.1% at 8 years for the 874 protocol, and 78.2% +/- 3.1% at 4 years for the more recent 911 protocol.

In vivo Dose-Response Effect of Recombinant Human Granulocyte Colony-Stimulating Factor on Increase in Granulocytes after Peripheral Blood Stem Cell Autotransplantation

The in vivo dose-response potential of recombinant human granulocyte colony-stimulating factor (rG-CSF) in facilitating reconstitution of granulopoiesis was evaluated in an 11-year-old girl who received autotransplantation of peripheral blood stem cells (PBSC) after marrow-ablative therapy for relapsing acute lymphoblastic leukemia. The recovery of hematopoiesis was slow when a small number of progenitors were collected and reinfused into the patient, but administration of rG-CSF led to significant dose-dependent increase in peripheral blood granulocytes.

Successful autograft with peripheral blood stem cells in a child with T-lymphoblastic leukemia

Peripheral blood stem cells (PBSC) were collected by two leukaphereses and cryopreserved in a 3-year-old girl with T-lymphoblastic leukemia; this was after remission was induced by an investigative regimen when she failed to respond to a first-line induction therapy. The patient received marrow-ablative chemotherapy 4.5 months after the diagnosis; this was followed by the infusion of thawed PBSC (203 x 10(4) CFU-GM/kg). The peripheral granulocyte count reached 0.5 x 10(9)/L by day +7 and the platelet count reached 20 x 10(9)/L by day + 9. Thereafter, the leukocyte count increased to 38 x 10(9)/L by day +14, with a gradual decline to normal levels. She has remained in unmaintained, complete remission 47 months after the autograft, with full school activity. This case illustrates the PBSC autograft is useful as an alternative to bone-marrow transplantation in a selected patient population, and extends the application of cure-oriented therapy to refractory childhood leukemia.

A simplified and rapid limiting dilution assay of T lymphocytes

We report here the development of an alternative limiting dilution assay (LDA) of T lymphocytes (T cells). Blood mononuclear cells were first stimulated for 60 hr with PHA and then cultured in microwells in the presence of recombinant interleukin-2 without feeder cells. After 4 days of culture, wells were scored for proliferation. Clonal expansion of T cells followed the single-hit model of the Poisson distribution. The progenitor frequency (f) in the mononuclear cells and E-rosette-positive cells from normal donors were 0.082 +/- 0.025 (n = 12) and 0.236 +/- 0.029 (n = 5), respectively, but this was markedly decreased in patients who underwent marrow-ablative chemotherapy and autografts with blood hematopoietic stem cells. This LDA system should be of value in routine use for the evaluation of T cell proliferative activities.

Peripheral Blood Stem Cell Autografts in Children with Acute Leukemia and Lymphoma

There is considerable interest in the use of peripheral blood hematopoietic stem cells (PBSC) in autograft settings (PBSCT), and in this paper, a clinical and laboratory experience of PBSCT at a single institute is presented. Twenty-eight children with various types of cancer underwent a total of 90 leukaphereses to collect PBSC and 17 of them subsequently received marrow-ablative therapy and autografts with such collected and stored PBSC. We found that frozen-thawed progenitor dose is important in determining the rate of hematopoietic recovery and that cytoreductive regimens without TBI used in the study are effective against leukemia in the current standards. Although it is not known yet whether PBSCT is better than autologous bone marrow transplantation to prolong the remission interval, and ultimately the cure, the preliminary clinical data justify the incorporation of PBSCT in the design of a pilot therapeutic protocol for the salvage treatment of refractory acute leukemias/lymphoma. Not all collections from patients yield a sufficient number of progenitors for a safe autograft, but the value of preleukapheresis administration of G-CSF to such patients to expand the stem cell pool awaits proof.

“Pulse” Methylprednisolone Therapy in the Treatment of Idiopathic Thrombocytopenic Purpura: A preliminary Report

Pulse‐mode methylprednisolone therapy was instituted in the treatment of idiopathic thrombocytopenic purpura (ITP), both acute and chronic forms. This regimen induced a rapid increase in the platelet count in a short time and was less toxic than the conventional mode of therapy, i.e. oral steroid hormone administration. This regimen is of value in the management of patients with ITP who are at the substantial risk of fatal hemorrhage. And this is also useful as a short‐term presplenectomy preparation or as a “medical splenectomy” program. Impressive responses in our experience encouraged us to evaluate this mode of therapy.