Mauro Fiacchini

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.

Prospective, Randomized Study of Single Compared With Double Autologous Stem-Cell Transplantation for Multiple Myeloma: Bologna 96 Clinical Study

PURPOSE We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B). RESULTS As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70). CONCLUSION In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.

Splenectomy and the increasing risk of secondary acute leukemia in Hodgkin's disease.

PURPOSE Following irradiation alone, secondary acute nonlymphocytic leukemia (ANLL) is uncommon; following chemotherapy alone, the risk is increased, but not as much as when combined modality treatments are used. Because ANLL seems more likely to occur in splenectomized patients, attention is focused on an unexpected association between splenectomy and the risk of secondary leukemia. PATIENTS AND METHODS The risk of ANLL was assessed in 503 patients with Hodgkins disease (HD) homogeneously treated with combined modality therapy (mechlorethamine, vincristine, procarbazine, and prednisone [MOPP] plus radiotherapy). These patients were diagnosed from 1970 through 1984 and monitored until June 1991. RESULTS ANLL was observed in one of 145 (0.69%) patients not splenectomized and in 21 of 358 (5.86%) splenectomized patients, demonstrating a significantly higher frequency of ANLL in the group of patients who underwent splenectomy. The group of patients who developed ANLL received a statistically greater number of MOPP courses than did the group not developing ANLL. ANLL was statistically more frequent in those patients who received more than four cycles of MOPP. Sex, symptoms, extent of radiotherapy, splenectomy, age, and number of MOPP courses were assessed for their impact on ANLL incidence by multivariate analysis. CONCLUSION Coxs proportional hazards regression showed that splenectomy and, as previously described by others, the number of courses of MOPP are prognostic factors that increase the risk of secondary ANLL in HD patients treated with combined modality therapy. These data raise interesting questions regarding the possible role of the spleen in leukemia development.

Short-Term Thalidomide Incorporated Into Double Autologous Stem-Cell Transplantation Improves Outcomes in Comparison With Double Autotransplantation for Multiple Myeloma

PURPOSE To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide. RESULTS On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events. CONCLUSION In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.

Long-term follow-up of 386 consecutive patients with essential thrombocythemia: Safety of cytoreductive therapy†

Cytotoxic agents like Hydroxyurea, Busulfan and Interferon‐alpha are to date the most commonly used therapeutic approaches in Essential Thrombocythemia (ET). However, few data on the efficacy and safety of these agents in the long‐term are currently available. We report a retrospective analysis of the long‐term outcome of 386 consecutive ET patients, followed at single Institution for a median follow‐up of 9.5 years (range, 3–28.5). Cytoreductive therapy was administered to 338 patients (88%), obtaining a response in 86% of cases. Forty‐five patients (12%) experienced a thrombosis. Among baseline characteristics, only history of vascular events prior to ET diagnosis predicted a higher incidence of thrombosis. Evolution in acute leukemia/myelofibrosis occurred in 6 (1,5%) and 20 (5%) patients, and was significantly higher in patients receiving sequential cytotoxic agents. Overall survival was 38% at 19 years and was poorer for patients older than 60 years, with higher leukocytes count (>15 × 109/L), hypertension and mellitus diabetes at ET diagnosis and for patients experiencing a thrombotic event during follow‐up. Cytoreductive therapy was effective in decreasing platelet number with negligible toxicity; however, thrombocytosis control did not reduce the incidence of thrombosis and, for patients who received sequential therapies, the probability of disease evolution was higher and survival was poorer. Am. J. Hematol. 2009.

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients.

Fludarabine plus cytarabine (Ara‐C) and idarubicin (FLAI) is an effective and well‐tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara‐C and etoposide (ICE) in 112 newly diagnosed AML patients <60 years. Fifty‐seven patients received FLAI, as the first induction–remission course, and 55 patients received ICE. Post‐induction treatment consisted of high‐dose Ara‐C (HDAC). After HDAC, patients in complete remission (CR) received a second consolidation course (mitoxantrone, etoposide, Ara‐C) and autologous stem cell transplantation (auto‐SCT) or allogeneic (allo)‐SCT, according to the age, disease risk and donor availability. After a single induction course, CR rate was 74% in the FLAI arm and 51% in the ICE arm (P = 0·01), while death during induction was 2% and 9% respectively. Both haematological (P = 0·002) and non‐haematological (P = 0·0001) toxicities, especially gastrointestinal (i.e. nausea, vomiting, mucositis and diarrhoea), were significantly lower in FLAI arm. In both arms, relapses were more frequent in patients who were not submitted to allo‐SCT. After a median follow‐up of 17 months, 30% and 38% of the patients are in continuous CR in FLAI and ICE arm respectively. Our prospective randomised study confirmed the anti‐leukaemic effect and the low toxic profile of FLAI as induction treatment for newly diagnosed AML patients.

Testing Sokal's and the new prognostic score for chronic myeloid leukaemia treated with α‐interferon

As it has been shown that α‐interferon (αIFN) treatment modifies the survival of chronic myeloid leukaemia (CML) patients in comparison with conventional chemotherapy, a new prognostic score was devised with the aim of providing a treatment‐adapted risk evaluation. We have tested the new prognostic score (the Euro score) in an independent series of 272 patients less than 56 years old with previously untreated, chronic phase, Philadelphia (Ph)‐positive CML who had been assigned prospectively to αIFN treatment between 1989 and 1991. The Sokal score system was used as a reference. The new Euro score predicted the response to αIFN as the Sokal score. The median survival of low‐risk, intermediate‐risk and high‐risk patients was similar using the Euro score (105, 65 and 45 months) and Sokal score (105, 76 and 45 months) but, by multivariate analysis, the Euro was more potent than Sokal for predicting survival time. The new Euro score identified more low‐risk cases (59% vs. 48%) and fewer high‐risk cases (9% vs. 23%) than the Sokal score. The main differences between the Euro and Sokal scores concerned age (it is more important in the Euro than in Sokal), spleen size and the percentage of myeloblasts in peripheral blood (more important in Sokal than in Euro). We conclude that the new Euro score marks an improvement in the prognostic evaluation of CML treated with αIFN. By comparison with the Sokal score, the Euro was more potent and identified more low‐risk patients but left only a small number of cases in the high‐risk group.

Fludarabine in patients with advanced and/or resistant B-chronic lymphocytic leukemia

Abstract:  In this study, we evaluated the efficacy of fludarabine (FLU), an adenine nucleoside analogue, in 35 previously treated patients with advanced and progressed B‐cell chronic lymphocytic leukemia (B‐CLL) and in 6 at diagnosis. All patients were treated at a dose of 25 mg/m2 per day for 5 consecutive days (mean number of courses was 5, with a range from 4 to 6). The majority of patients experienced a beneficial effect on hematological parameters. In particular, a remarkable reduction of lymphocyte count together with an increase of neutrophils and platelets was observed. The overall response rate was 42% with 1 complete response and 16 partial responses. Ten patients achieved minor responses and the remaining 14 showed no benefit from treatment. An increased response rate was achieved in 6 untreated patients who showed an overall response rate of 67% (4/6). The major complications observed were neutropenia (66%) and febrile episodes (44%) that were generally infection‐related and were fatal in 3 cases. Because we were dealing with patients whose disease was advanced and/or resistant to treatment, the overall results may be considered encouraging with acceptable toxic reactions not superior to those frequently observed with polychemotherapy.

JAK2V617F mutation in essential thrombocythemia: correlation with clinical characteristics, response to therapy and long-term outcome in a cohort of 275 patients

The JAK2V617F mutation occurs in 50% of patients with essential thrombocythemia (ET). We investigated the correlation between the JAK2V617F mutation and clinical and laboratory characteristics, thrombohemorrhagic risk and incidence of disease evolution in 275 patients with ET followed for a median follow-up of 7 years. JAK2V617F mutation was detected in 175 patients (64%), of whom 173 were heterozygous. Patients with the mutation were older and displayed higher hemoglobin and hematocrit levels, but lower platelet count. Cytotoxic treatment requirement was similar in the two groups, but patients with the mutation showed better responses. Incidence of thrombosis and disease evolution was comparable. JAK2 mutational status assessment was valuable to distinguish two populations of patients with ET, showing distinctive hematologic and clinical features.

Acute Promyelocytic Leukemia: Results of Therapy and Analysis of 13 Cases

Acute promyelocytic leukemia (APL) was diagnosed in 13 of 84 adult patients (15.4%) with acute myeloid leukemia (AML) first admitted between 1972 and 1976. All patients had clinical and/or laboratory evidence of defibrination syndrome. Four patients died of cerebral hemorrhage within 2 days of admission. Two patients died of generalized infection on days 7, and 16, respectively, after admission. The remaining 7 patients (54%) underwent complete remission (CR) with daunomycin, arabinosyl cytosine, and adriamycin. All patients received massive platelet transfusion, no heparin, and no granulocyte transfusion. CR was more frequent in patients with a very low blast cell count and a fibrinogen level higher than 100 mg/100 ml. Median survival of these seven CR patients with APL is similar (15 months) to that of CR patients with other types of AML treated at the same institution during the same period.