Sante Tura

Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia

BACKGROUND In view of studies showing that interferon alfa was effective treatment for chronic myeloid leukemia and that it prolonged survival, we organized a prospective, controlled comparative study of this treatment. METHODS We compared recombinant interferon alfa-2a with conventional chemotherapy (hydroxyurea or busulfan) in a trial designed to have a power of 80 percent to detect a difference of 20 percent in median survival between the group given interferon and the group given conventional chemotherapy. Between 1986 and 1988, 322 patients with previously untreated or minimally treated Philadelphia chromosome-positive chronic myeloid leukemia were randomly assigned to treatment with either interferon alfa-2a (218 patients) or conventional chemotherapy (104 patients). RESULTS The rate of karyotypic response (defined as > 33 percent of metaphases negative for the Philadelphia chromosome) was 30 percent in the interferon group and 5 percent in the conventional-chemotherapy group (P < 0.001). The time to progression from the chronic phase of leukemia to an accelerated or a blastic phase was longer in the interferon group than in the conventional-chemotherapy group (median, > 72 vs. 45 months; P < 0.001), as was survival (median, 72 vs. 52 months; 6-year survival, 50 percent vs. 29 percent; P = 0.002 for both comparisons). There was one treatment-related death in each group. Treatment was discontinued because of side effects (mainly influenza-like, gastrointestinal, or neurologic symptoms) in 35 patients given interferon alfa-2a (16 percent). The cost of interferon treatment was 200 times that of the conventional treatment. CONCLUSIONS During long-term treatment of Philadelphia chromosome-positive chronic myeloid leukemia, interferon alfa-2a induced more karyotypic responses than conventional chemotherapy, delayed disease progression longer, and prolonged overall survival more.

THROMBOPOIETIN AND INTERLEUKIN 11 HAVE DIFFERENT MODULATORY EFFECTS ON CELL CYCLE AND PROGRAMMED CELL DEATH IN PRIMARY ACUTE MYELOID LEUKEMIA CELLS

The c-mpl ligand, thrombopoietin (TPO), is a physiologic regulator of platelet and megakaryocytic production, acting synergistically on thrombopoiesis with the growth factors interleukin 11 (IL-11), stem cell factor, interleukin 3 (IL-3), interleukin 6 (IL-6), and granulocyte-macrophage colony-stimulating factor. Because some of these growth factors, especially TPO and IL-11, are now being evaluated clinically to reduce chemotherapy-associated thrombocytopenia in cancer patients, we evaluated 25 acute myeloid leukemia (AML) samples to test whether TPO, IL-11, and other early-acting megakaryocyte growth factors can affect leukemic cell proliferation, cell cycle activation, and programmed cell death (PCD) protection. TPO induced proliferation in the majority of AML samples from an overall mean proportion of S-phase cells of 7.8% +/-1.5% to 14.5% +/- 2.1% (p = 0.0006). Concurrent G0 cell depletion was found in 47.3% of AML samples. TPO-supported leukemic cell precursor (CFU-L) proliferation was reported in 5 of 17 (29.4%) of the samples with a mean colony number of 21.4 +/- 9.6 x 10(5) cells plated. In 13 of 19 samples, a significant protection from PCD (from an overall mean value of 13% +/-0.7% to 8.8% +/- 1.8%;p = 0.05) was detected after TPO exposure. Conversely, IL-11-induced cell cycle changes (recruitment from G0 to S phase) were detected in only 2 of 14 samples (14.2%). In addition, IL-11 showed little, if any, effect on CFU-L growth (mean colony number = 17.5 9.5) or apoptosis. Combination of TPO with IL-11 resulted in only a slight increase in the number of CFU-L, whereas IL-3 and stem cell factor significantly raised the mean colony numbers up to 119.2 +/- 68.3 and 52.9 +/- 22.1 x 10(5) cells plated, respectively. We conclude that TPO induces cell cycle activation in a significant proportion of cases and generally protects the majority of AML blast cells from PCD. On the other hand, IL-11 has little effect on the cell cycle or PCD. Combination of both TPO and IL-11 is rarely synergistic in stimulating AML clonogenic growth. These findings may be useful for designing clinical studies aimed at reducing chemotherapy-associated thrombocytopenia in AML patients.