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 x 10(9)/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.

Resolution of a Pseudomonas aeruginosa outbreak in a hematology unit with the use of disposable sterile water filters.

We observed a significant increase of Pseudomonas aeruginosa bacteremias during 2002. Eighty-five microbiological samples were taken from different potential sources of infection. Twenty-nine out of 46 specimens obtained from water taps, shower heads and siphons tested positive for Pseudomonas aeruginosa. Weekly pharyngeal and rectal swabs in high risk patients, use of tap water after running the tap for at least 5 minutes and use of weekly disposable sterile filters in all taps and showers resulted in a significant decrease in Pseudomonas aeruginosa bacteremias. Moreover, we observed a significant reduction in Pseudomonas aeruginosa-positive surveillance cultures after implementation of these measures.

A risk prediction score for invasive mold disease in patients with hematological malignancies.

BACKGROUND: A risk score for invasive mold disease (IMD) in patients with hematological malignancies could facilitate patient screening and improve the targeted use of antifungal prophylaxis. METHODS: We retrospectively analyzed 1,709 hospital admissions of 840 patients with hematological malignancies (2005-2008) to collect data on 17 epidemiological and treatment-related risk factors for IMD. Multivariate regression was used to develop a weighted risk score based on independent risk factors associated with proven or probable IMD, which was prospectively validated during 1,746 hospital admissions of 855 patients from 2009-2012. RESULTS: Of the 17 candidate variables analyzed, 11 correlated with IMD by univariate analysis, but only 4 risk factors (neutropenia, lymphocytopenia or lymphocyte dysfunction in allogeneic hematopoietic stem cell transplant recipients, malignancy status, and prior IMD) were retained in the final multivariate model, resulting in a weighted risk score 0-13. A risk score of < 6 discriminated patients with low (< 1%) versus higher incidence rates (> 5%) of IMD, with a negative predictive value (NPV) of 0.99, (95% CI 0.98-0.99). During 2009-2012, patients with a calculated risk score at admission of < 6 had significantly lower 90-day incidence rates of IMD compared to patients with scores > 6 (0.9% vs. 10.6%, P <0.001). CONCLUSION: An objective, weighted risk score for IMD can accurately discriminate patients with hematological malignancies at low risk for developing mold disease, and could possibly facilitate "screening-out" of low risk patients less likely to benefit from intensive diagnostic monitoring or mold-directed antifungal prophylaxis.

JAK2 V617F mutation in essential thrombocythemia: correlation with clinical characteristics, response to therapy and long-term outcome in a cohort of 275 patients.

The JAK2(V617F) mutation occurs in 50% of patients with essential thrombocythemia (ET). We investigated the correlation between the JAK2(V617F) 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. JAK2(V617F) 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.

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.

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.

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.

Interferon alfa-2a as compared with conventional chemotherapy for the treatment of 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.

A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia.

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: final analysis of a randomized clinical study.

BACKGROUND AND OBJECTIVES: In the absence of a cure for multiple myeloma (MM) with standard-dose therapy, any strategy that can be expected to increase tumor reduction and to extend survival duration is likely to be of clinical relevance. The primary end-point of the present study was to investigate whether the alternating combination of vincristine-doxorubicin-dexamethasone (VAD) and melphalan-prednisone (MP) or vincristine-mitoxantrone-dexamethasone (VND) and MP could improve the clinical outcome of MM patients thus treated in comparison with those receiving MP alone. DESIGN AND METHODS: Between November 1990 and April 1994, 527 previously untreated, stage I-III, MM patients from 29 Italian institutions were randomized to receive one of three remission induction chemotherapy regimens consisting of 8-monthly courses of either MP alone or alternating VAD/MP or VND/MP. RESULTS: On an intent-to-treat basis, the objective response rates were 53% with MP (objective + minor: 67%), 47% with VAD/MP (objective + minor: 61%) and 49% with VND/MP (objective + minor: 61%). Median survival duration was 36.5 months with MP, 29 months with VAD/MP and 32.5 months with VND/MP. The difference among these groups was not statistically significant, even after stratifying patients into high-risk and low-risk subgroups, as assessed by a multifactor proportional hazard analysis. In both younger and elderly patients, severe granulocytopenia and related infections were significantly more frequent with VND/MP compared to the remaining arms of treatment (p < 0.001 and p = 0.009, respectively). Similarly, the frequency of WHO grade III-IV cardiovascular events was significantly higher for patients receiving anthracycline-containing regimens (VND/MP and VAD/MP) than for those treated with MP alone (p = 0.04). INTERPRETATION AND CONCLUSIONS: Alternating VAD/MP and VND/MP failed to improve the clinical outcome for MM patients, at the cost of increased toxicity and morbidity. Resistance to standard-dose chemotherapy remains a significant obstacle to the treatment of MM.