Alfredo Molteni

Deferasirox for transfusion-dependent patients with myelodysplastic syndromes: safety, efficacy, and beyond (GIMEMA MDS0306 Trial)

In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion‐dependent patients with myelodysplastic syndromes (MDS), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted.

Prognostic value of circulating CD34+ cells in myelodysplastic syndromes.

We studied circulating (C)CD34(+) cells by flow cytometry in 96 patients with myelodysplastic syndromes (MDS) at diagnosis, and in a subset of 35 cases during follow-up. CCD34(+) counts were stratified within both International Prognostic Scoring System (IPSS) and World Health Organization (WHO) categories. Counts >10/microl were associated with poorer leukemia-free survival, a prognostic value for evolution independent from that of WHO, and a higher progression probability within intermediate-risk IPSS and WHO classes. When serial measurements were performed, counts >10/microl more frequently correlated to evolution. Separating newly diagnosed patients on the basis of 10/microl cut-off of circulating CD34(+) cells retains prognostic utility, especially in intermediate-risk MDS.

Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial

BACKGROUND In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia. METHODS EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 109 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33. FINDINGS Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4-24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5-211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3-4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ2=7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ2=0·06, p=0·81). INTERPRETATION Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. FUNDING Associazione QOL-ONE.

Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

Health-related quality of life in transfusion-dependent patients with myelodysplastic syndromes: a prospective study to assess the impact of iron chelation therapy

Objective The primary objective of this study was to evaluate the health-related quality of life (HRQOL) in lower-risk, transfusion-dependent patients with myelodysplastic syndromes (MDS) treated with deferasirox. A secondary objective was to investigate the relationship between HRQOL, serum ferritin levels and transfusion dependency. Patients and methods This was a prospective multicentre study enrolling 159 patients, of whom 152 received at least one dose of deferasirox. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline and then at 3, 6, 9 and 12 months. Primary analysis was performed estimating mean HRQOL scores over time by a linear mixed model on selected scales. Results The median age of treated patients was 72 years (range 24–87 years). No statistically significant changes over time were found in mean scores for global health status/quality of life (p=0.564), physical functioning (p=0.409) and fatigue (p=0.471) scales. Also, no significant changes were found for constipation (p=0.292), diarrhoea (p=0.815) and nausea and vomiting (p=0.643). Serum ferritin levels were not associated with HRQOL outcomes. A higher patient-reported baseline pain severity was an independent predictive factor of an earlier achievement of transfusion independence with a HR of 1.032 (99% CI 1.004 to 1.060; p=0.003). Conclusions HRQOL of transfusion-dependent patients with MDS receiving deferasirox therapy remains stable over time. HRQOL assessment might also provide important predictive information on treatment outcomes. Trial registration number NCT00469560.

Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience

Abstract Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.

Cerebral hemorrhage treated with NovoSeven in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by a life-threatening coagulopathy which in the past resulted in hemorrhagic mortality in 20 – 30% of patients. Th e introduction of all- trans -retinoic acid (ATRA) completely revolutionized the management and the outcome of the disease, and in clinical trials hemorrhagic deaths were reported as reduced to 5 – 10% of patients [1]. However, because not all patients enter in clinical trials, early mortality might be underestimated [2]. In a recent [3] report regarding US population-based datasets of all newly diagnosed patients with APL, the rate of early death changed only modestly over the years (22.7% in 1992 – 1996, 18.1% in 2002 – 2007), and it appears signifi cantly higher than reported in clinical trials. Th erefore, despite the optimal results of ATRA and anthracycline-based therapy, mortality due to severe intracranial bleeding still occurs and

Prognostic relevance of the flow cytometric count of medullar blasts in myelodysplastic syndromes

The medullar blast count is a milestone in the prognostic assessment in myelodysplastic syndromes (MDS). The optical microscopy (OM) may sometimes be inaccurate in this disease. The aim of this work is to test the flow immunocytometric (FCM) determinations of medullar immature cells (CD45±) and the expression, among them, of CD33, CD34, and CD117 markers, for their prognostic relevance.

Three copies of isochromosome 8q in Ph+ B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (ALL) is characterized by bnormal proliferation of immature lymphoid cells [1]. The most requently observed chromosomal aberration is the Philadelphia Ph) chromosome predicting poor outcome, with little chance of ure other than allogeneic stem cell transplantation [2]. Additional hromosomal abnormalities are associated with even worse progosis [3]. Although very rare in man as constitutional abnormalities, sochromosomes are frequently found as acquired aberrations in eoplastic cells [4]. Isochromosome for the long arm of chroosome 8 [i(8)(q10)] has been reported in ALL, never more han one copy [5–7]. We report a B-cell ALL case with doule Ph chromosome and three i(8)(q10) copies, as detected by onventional cytogenetics and fluorescent in situ hybridization FISH).

Bone Marrow Fibrosis and Early Hematological Response as Predictors of Poor Outcome in Azacitidine Treated High Risk-Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

Azacitidine (AZA) treatment is effective treatment for patients with myeloid disorders, and factors predictive of treatment outcome are under investigation. Little is known about the effect of bone marrow fibrosis on response to AZA therapy. We, retrospectively, evaluated clinical predictors of overall survival (OS) and overall response rate (ORR) for patients treated with AZA in a real-life cohort. We evaluated 94 consecutive patients treated with AZA outside of clinical trials (75mg/m2/day for 7 days every 28 days; 5 + 2 + 2 schedule), from June 2009 to February 2016. Ninety-three patients were evaluated for response. After a median of 6 cycles, ORR-complete response (CR; including marrow CR) + partial response (PR) + hematological improvement (HI)-was 41.9% (CR = 18.3%; PR = 11.8%; HI = 11.8%). Stable disease was observed in 21.5%, and failure in 36.5%. Pre-AZA bone marrow blast percentage, International Prognostic Scoring System (IPSS) or IPSS-R category, and time from diagnosis to AZA had no effect on response. Median OS from start of therapy was 18.5 months, and was significantly related to higher IPSS category (P = .01), poor cytogenetics according to the IPSS (P = .01), poor and very poor cytogenetics according to the IPSS-R (P = .02), and lower ORR (P = .006). Patients with MF-0 pre-AZA demonstrated significantly higher ORR, (CR + PR + HI) and stable disease, and lower failure rates than those with any grade of fibrosis. Indeed, cases with pre-AZA fibrosis > MF-1 had shorter OS (P = .005). Achievement of HI before 4 cycles of treatment negatively impacted OS (P = .009).