Intensified and high-dose chemotherapy with granulocyte colony-stimulating factor and autologous stem-cell transplantation support as first-line therapy in high-risk diffuse large-cell lymphoma.

PURPOSE: In our previous study with MACOPB, we identified a high-risk group of patients with a poor 3-year survival rate of 29%. These patients were defined as having at diagnosis advanced-stage disease with high tumor burden (TB) and elevated lactate dehydrogenase (LDH) level or bone marrow (BM) involvement. A novel therapeutic scheme was investigated to improve the outcome of these patients. PATIENTS AND METHODS: Fifty patients with high-risk diffuse large-cell lymphoma (DLCL) were enrolled. The therapeutic scheme includes three phases: induction with 8 weeks of MACOPB; intensification with a 3-day course of mitoxantrone 8 mg/m2 plus high-dose cytarabine (HDARA-C) 2 g/m2 every 12 hours plus dexamethasone 4 mg/m2 every 12 hours (MAD protocol) and granulocyte colony-stimulating factor (G-CSF) 5 microg/kg on days 4 to 17 to harvest peripheral-blood progenitor cells (PBPC); consolidation with carmustine (BCNU), etoposide, ARA-C, and melphalan (BEAM) regimen; plus autologous stem-cell transplantation (ASCT) with PBPC, marrow, or both. RESULTS: Thirty-six patients (72%) achieved a complete response (CR), 11 (22%) showed no response (NR), and three (6%) died of toxicity. Among the 22 PRs or NRs after the induction phase, 56% of patients achieved a CR with subsequent intensified therapy. With a median follow-up duration of 32 months, the overall survival and failure-free survival rates were 56% and 50%, respectively. The disease-free survival rate is 69% at 32 months. Leukapheresis after MAD and G-CSF yielded a median of 32 x 10(6)/kg CD34+ cells and 80 x 10(4)/kg granulocyte-macrophage colony-forming units (CFU-GM). Thirty-nine patients were autografted and 11 did not undergo ASCT: six because of disease progression, four due to toxicity, and one because of patient refusal. The median times to achieve engrafment were 11 days (range, 7 to 19) to a neutrophil count greater than 0.5 x 10(9)/L and 12 days (range, 8 to 60) to a platelet count greater than 50 x 10(9)/L. CONCLUSION: This sequential scheme with intensified and high-dose chemotherapy with ASCT is feasible with moderate toxicity and may improve the outcome in high-risk DLCL.

Gamma-IFN induces a differential expression of HLA-DR, DQ and DP antigens on peripheral blood myeloid leukemic blasts at various stages of differentiation.

Using specific monoclonal antibodies and the indirect immunofluorescence technique, peripheral blood myeloid leukemic blasts from 49 patients were studied for DR expression, 42 for DQ and nine for DP after four days of culture without and with gamma-IFN. The expression of class II molecules on untreated cells depended upon the stage of differentiation and was maximal for DR antigens and lower for DP, while DQ was present only in a small percentage of M2, M4 or M5 blasts. M3 blasts lacked both DR and DQ. Maximal increase of surface expression induced by gamma-IFN was observed for DR molecules independently from the differentiation stage. No significant modification was seen for DQ. Preliminary data concerning DP indicate an increased expression in some of the tested samples. Thus the results obtained on peripheral blood blasts parallel previous observations on leukemic cell lines.

A short-term chemosensitivity test with different labeled precursors of DNA or protein synthesis: correlation with clinical response.

Blood or bone marrow samples from 15 patients with newly diagnosed acute myeloblastic leukemia undergoing remission induction treatment with daunorubicin, cytosine-arabinoside and 6-thioguanine were tested in vitro. Leukemic cells were incubated for 24 h at 37 degrees C with or without the drugs alone or in combination. A 3-h pulse with labelled precursors of DNA synthesis (3H-thymidine) or protein synthesis (3H-leucine) was then given separately. In vitro growth, expressed as the percentage ratio between labeled precursor uptake in treated cells and in control cells, was compared with the clinical results obtained. Three patients were not considered evaluable (death occurred too early), 8 had a complete response (CR), and 4 were disease resistant to chemotherapy. Leukemic cells of resistant-disease patients showed a significantly lower growth inhibition than cells taken from CR patients, with each drug alone or in combination, when measured with thymidine. Inhibition of leucine uptake was not related to the clinical outcome.

HLA class I- like antigen expression on human leukemic cells.

The expression of HLA class I- like molecules was analyzed on human acute and chronic leukemic cells. The presence on leukemic cells of class I- like molecules, absent on the patient's normal lymphocytes, was examined by complement- dependent lymphocytotoxicity using platelet absorbed alloantisera that recognize HLA-linked, 45-12 kd, beta-2-microglobulin associated molecules, selectively expressed on PHA-activated cells. A positive reactivity of the anti- class I- like alloantisera was found in 50% of the acute leukemias (cALL, T-ALL and AML), independently of the lineage of differentiation, while chronic lymphocytic leukemias (B-CLL) were constantly negative. It is suggested that beta-2-microglobulin associated HLA molecules may represent markers of leukemic blast activation and/or maturation state.

Use of peripheral blood stem cells to accelerate hemopoietic recovery following autologous bone marrow transplantation.

Twenty-one patients with high risk non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) underwent autologous bone marrow transplantation (ABMT). Nine out of 21 patients received in addition to bone marrow (BM) cells also peripheral blood (PB) cells collected by leucapheresis performed in the recovery phase after high-doses of either cyclophosphamide or etoposide (7 patients), or after ara-C (2 patient). All patients receiving BM + PB cells had ABMT as salvage therapy following extensive relapse or progression of their disease. The addition of PB cells to BM cells allowed a significantly faster recovery after ABMT. Median time to reach WBC greater than 1,000/microL was 14 days versus 20.5 days for patients receiving BM only. Furthermore, a reduced requirement of supportive care and a shorter period of isolation was observed. These results confirm that PB cells combined with BM cells allow a prompt hematopoietic reconstitution after myeloablation. In addition, the data demonstrate the efficacy of PB cells collected after various cytotoxic drugs, even in patients previously exposed to cytoreductive regimens.