D. Machover

Membranous Nephropathy in a Bone Marrow Transplant Recipient

A bone marrow transplant recipient is described who had development of nephrotic syndrome in association with chronic graft-versus-host disease (GVHD) and on cyclosporine (CsA) treatment withdrawal. Renal biopsy revealed a membranous glomerulonephritis (MG). The possible relationship between this autoimmune disorder, the immunological features of GVHD in experimental animals, and the influence of CsA is discussed.

Phase-II trial with vindesine for regression induction in patients with leukemias and hematosarcomas.

SummaryVindesine (VDS) has been submitted to a phase-II trial, the results of which were assessed in terms of regression induction. VDS was given weekly IV in doses of 2 mg/m2 on two consecutive days to 59 patients, 55 of whom were evaluable. A high proportion of complete (36%) and over 50% partial regressions were obtained in acute lymphoid leukemias (ALL) (overall response 63%) whatever the perceptible phase, in blastic crisis of chronic myeloid leukemia (55%), and some responses were recorded in lymphosarcoma (40%). No effect has so far been seen in acute myeloid leukemia or in Hodgkins disease. Malignant neoplasms of the immunoblastic type seem to be particularly sensitive to VDS. Continuous 48 h IV infusion can induce a remission where an IV push administration of the same dose has failed. One remarkable characteristic of VDS is the apparent absence of cross-resistance with VCR: in acute leukemic forms, 55% of patients who failed to obtain remission induction after three weekly injections of VCR (used in combination chemotherapy) achieved a complete or partial remission with VDS. The toxicity was mainly neurologic (paralytic ileus, constipation, paresthesias, loss of reflexes) and hematologic (leukopenia and thrombopenia), and was not more significant than with the other agents: four patients died of infection or hemorrhage.

Cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid.

Potentiation of the cytotoxic activity of 5-fluorouracil (FUra) by folinic acid (5-HCO-H4folate) is due to elevation of the methylene tetrahydrofolate (CH2-H4folate) level, which increases the stability of the ternary complex of thymidylate synthase (TS), fluorodeoxyuridine monophosphate, and CH2-H4folate that inactivates the TS. Methionine deprivation results in the production of tetrahydrofolate (H4folate) and, subsequently, CH2-H4folate from methyl tetrahydrofolate, as a consequence of the induction of methionine synthesis. We hypothesized that the efficacy of FUra could be augmented by the combination of high-concentration 5-HCO-H4folate and recombinant methioninase (rMETase), a methionine-cleaving enzyme. Studies in vitro were performed with the cell line CCRF-CEM. Cytotoxic synergism of FUra + rMETase and FUra + 5-HCO-H4folate + rMETase was demonstrated with the combination index throughout a broad concentration range of FUra and rMETase. A subcytotoxic concentration of rMETase reduced the IC50 of FUra by a factor of 3.6, and by a factor of 7.5, in the absence and in the presence of 5-HCO-H4folate, respectively. 5-HCO-H4folate increased the intracellular concentrations of CH2-H4folate and H4folate from their baseline levels. Concentrations of folates were not changed by exposure to rMETase. Levels of free TS in cells treated with FUra + 5-HCO-H4folate and with FUra + rMETase were lower than those in cells exposed to FUra alone. The decrease of TS was still more pronounced in cells treated with FUra + 5-HCO-H4folate + rMETase. The synergism described in this study will be a basis for further exploration of combinations of fluoropyrimidines, folates, and rMETase.

Preliminary results of a phase II trial of aclacinomycin in acute leukaemia and lymphosarcoma

SummaryA phase II trial of which preliminary results are available for 22 patients indicates that aclacinomycin applied in a continuous modality induced complete and partial remission in four of nine patients with acute lymphoid leukaemia that was resistant to all previously available drugs, and in four of eight patients with stage V lymphosarcoma (leukaemic).Bone-marrow toxicity was the major side-effect.Only one patient of 20 suffered from cardiac toxicity; no one had alopoecia. This very low incidence of myocardial lesions and the absence of hair loss had been predicted, respectively, by our electron microscope study of the myocardium and the light electron microscope study of the skin of golden hamsters [7], a test that detects frequent severe myocardium and skin toxicities for adriamycin and some anthracyclin analogues such as detorubicin, which was found to be toxic in a high percentage of patients in a clinical trial conducted by the E.O.R.T.C. Clinical Screening Group [8].

Some New Chemotherapeutic Agents and Combinations Possibly Available for New Adjuvant Therapies of Minimal Disease

There are several new chemotherapeutic agents that, as their combinations, are particularly active in advanced disease and should be considered in trials of adjuvant therapies of minimal residual disease (MRD).

Phase I-II study of aclarubicin for treatment of acute myeloid leukaemia

Aclarubicin (ACM) was administered as induction treatment to 38 evaluable patients with acute myeloid leukaemia (AML) who were either refractory to initial chemotherapy or in relapse. Thirteen patients received daily doses of ACM while the remaining 25 were given 10‐day courses with 10‐day intervals between courses. The overall CR rate was 34% and the incidence and severity of the toxic effects were related to the dose of ACM administered per course of therapy. Our results indicate that ACM is a major new drug for the treatment of AML.

Preliminary results of chemo-radiotherapy followed or not by active immunotherapy of stage III and IV lymphosarcoma and reticulosarcoma

SummaryWe treated 101 patients with advanced (stage III and IV) lymphosarcoma and reticulosarcoma at first presentation of the disease or in relapse according to a protocol combining initial chemotherapy, complementary radiotherapy on icebergs, supplementary chemotherapy, and, finally, active immunotherapy.The overall complete remission rate was about 79% for lymphosarcoma and 73% for reticulosarcoma. About 50% of the patients were still in remission in each of the two diseases at 2 years; 60% of lymphosarcoma and 44% of reticulosarcoma patients achieved 2-year survival.This study shows the prognostic value of the WHO classification for lymphosarcoma and reticulosarcoma: the prognosis of prolymphocytic (centrofollicular) lymphosarcoma is far better than that of the lymphoblastic type, which is in turn better than that of the very poor prognosis of the immunoblastic type. The prognosis of reticulosarcoma is intermediate between that of the best-prognosis and that of the poorest-prognosis type of lymphosarcoma.

An Intensive Chemo- or Chemoimmunotherapy Regimen for Patients with Intermediate and Poor-Prognosis Acute Lymphatic Leukemia and Leukemic Lymphoblastic Lymphosarcoma: Preliminary Results with 14-Month Median Follow-Up

We previously reported the prognostic factors that can be identified at the onset of acute lymphoid leukemia (ALL) [8]. The factors defining the prognosis are, according to our experience: the WHO Reference Center cytologic types (the “prolympho- blastic” type being always poor, the “microlymphoblastic” type good, and the “macrolymphoblastic” and the “prolymphocyte” intermediate [8]); the T-type is always poor, the null, as they were only characterized in our preceding protocols, intermediate [1]; and, in the cases of those above “intermediate” prognosis types, the volume (V) of the neoplasia plays a prognostic role, i.e., V+ (³ 104leukemic cells/mm3) and/or significant clinical masses suggest a poor prognosis [8].

Long-Term Administration of Vindesine in Maintenance Regimen for Acute Lymphoblastic Leukemia (ALL) with Poor Prognosis. Apparent Lack of Long-Term Cumulative Neurotoxicity

SummaryLong-term administration of vindesine, included in a maintenance regimen for acute lymphoblastic leukemia (ALL) with poor prognosis, proved to be effective. There was no apparent long-term cumulative neurotoxicity.