[Show abstract][Hide abstract] ABSTRACT: Non-del(5q) transfusion-dependent low/int-1 MDS patients achieve an erythroid response with lenalidomide in 25-30% of cases. Addition of erythropoiesis-stimulating agent could improve the erythroid response rate. The impact of recurrent somatic mutations identified in the diseased clone on response to lenalidomide and the drug effects on clonal evolution remain unknown. We investigated recurrent mutations by next generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo2008 clinical trial to lenalidomide or lenalidomide + EPO. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases, and re-analyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Four genes had a mutation frequency over 10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%) and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15/20 responders compared to 10/22 non-responders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in non-responders (P<0.001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of the dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient and disease escape was associated with the re-emergence of the initially dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. The trial is registered to www.clinicaltrials.gov as NCT01718379.
[Show abstract][Hide abstract] ABSTRACT: After failure of erythropoiesis-stimulating agents (ESA), Lenalidomide (LEN) yields red blood cells (RBC) transfusion independence (TI) in 20-30% of lower risk non-del5q MDS. Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement 6 RBC units/8weeks) lower risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg/day, 21 days/4 weeks (L arm) or LEN (same schedule)+erythropoietin (EPO) beta, 60 000 U/week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles (primary endpoint) was 23.1% (95% CI: 13.5-35.2) in the L arm and 39.4% (95%CI: 27.6-52.2) in the LE arm (P=0.044), while RBC transfusion independence (TI) was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the 2 arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower risk non-del5q MDS patients with anemia resistant to ESA.Leukemia accepted article preview online, 26 October 2015. doi:10.1038/leu.2015.296.
Full-text · Article · Oct 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Background:
The clinical presentation of myelodysplastic syndromes is highly variable and so accurate prediction of outcomes in these patients is crucial. We aimed to assess whether self-reported fatigue severity predicts overall survival beyond gold-standard prognostic indices in patients with higher-risk myelodysplastic syndromes.
We did a multicentre, prospective, observational, cohort study of patients from 37 centres in Europe, USA, and east Asia. Adults (≥18 years) with myelodysplastic syndromes were consecutively enrolled within 6 months of diagnosis with an intermediate-2-risk or high-risk score according to the International Prognostic Scoring System (IPSS). Patients were enrolled irrespective of older age, comorbidities, performance status, and progression from a lower IPSS risk score category. All patients had to complete a quality of life assessment at baseline. With use of univariate and then multivariate Cox proportional hazards regression analysis, we constructed a multivariate model of how prognostic variables, including IPSS and fatigue score from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-core 30, predicted overall survival. The primary endpoint was overall survival by baseline self-reported fatigue scale ratings. This study was registered with ClinicalTrials.gov, number NCT00809575.
Between Nov 10, 2008, and Aug 13, 2012, we enrolled 280 patients with a median age of 71 years (IQR 64-77). The median follow-up was 15 months (IQR 8-27), and the last patient was assessed Feb 16, 2015. The median overall survival from diagnosis was 17 months (95% CI 15-19). In univariate analysis, the baseline factors that were significantly associated with reduced overall survival were increasing age, transfusion dependency (defined as having received at least one red blood cell transfusion every 8 weeks over a period of 4 months), Eastern Cooperative Oncology Group (ECOG) performance status of two or more, increased white blood cell count, high-risk IPSS score, and higher self-reported fatigue severity. In multivariate analysis, baseline factors independently associated with reduced overall survival were high-risk IPSS score (hazard ratio [HR] 2·525, 95% CI 1·357-4·697; p=0·0035) and a higher score for fatigue (1·110, 1·040-1·170, for every ten points of fatigue deterioration; p=0·0007). In further multivariate models for survival, including either the WHO-based prognostic scoring system or the revised version of the IPSS classification, fatigue remained a statistically significant independent prognostic factor with a HR of 1·120 (1·050-1·180, p=0.0003) and a HR of 1·130 (1·060-1·190, p=0·0002), respectively.
In patients with newly diagnosed higher-risk myelodysplastic syndromes, self-reported fatigue severity provides prognostic information for survival independent from gold-standard risk classifications. Our findings suggest that fatigue assessment should be included in routine diagnostic investigation for these patients and considered as a standard baseline stratification factor in future randomised controlled trials.
Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL).
Full-text · Article · Sep 2015 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: Findings among a cohort of 26 patients who had hematologic malignancies and hepatitis E virus (HEV) infection support that HEV can induce chronic hepatitis. However, a 3-month course of ribavirin can induce a rapid viral clearance, reducing the risk for chronic hepatitis and enabling continuation of cytotoxic treatments for underlying malignancies.
Preview · Article · Aug 2015 · Emerging Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Mastocytosis is a clonal haematological disease characterized by uncontrolled proliferation and the activation of mast cells. The value of FDG-PET/CT (FDG-PET) in mastocytosis has yet to be determined.
We retrospectively identified patients with an established diagnosis of systemic mastocytosis (SM), according to the WHO criteria, who underwent PET using the French Reference Centre for Mastocytosis database. Semi-quantitative and visual analysis of FDG-PET was performed and compared to the clinico-biological data.
Our cohort included 19 adult patients, median age 65 years [range 58-74], including three with smouldering SM (SSM), three with aggressive SM (ASM), 10 with an associated clonal haematological non-mast-cell lineage disease (SM-AHNMD), and three with mast cell sarcoma (MCS). FDG-PET was performed at the time of the SM diagnosis (15/19), to evaluate lymph node (LN) activity (3/19) or the efficacy of therapy (1/19). FDG uptake was observed in the bone marrow (BM) (9/19, 47 %), LN (6/19, 32 %), spleen (12/19, 63 %), or liver (1/19, 5 %). No significant FDG uptake was observed in the SSM and ASM patients. A pathological FDG uptake was observed in the BM of 6/10 patients with SM-AHNMD, appearing as diffuse and homogeneous, and in the LN of 5/10 patients. All 3 MCS patients showed intense and multifocal BM pathological uptake, mimicking metastasis. No correlation was found between the FDG-PET findings and serum tryptase levels, BM mast cell infiltration percentage, and CD30 and CD2 expression by mast cells.
FDG uptake does not appear to be a sensitive marker of mast cell activation or proliferation because no significant FDG uptake was observed in most common forms of mastocytosis (notably purely aggressive SM). However, pathological FDG uptake was observed in the SM-AHNMD and in MCS cases, suggesting a role of FDG-PET in their early identification and as a tool of therapeutic assessment in this subgroup of patients.
Full-text · Article · Jul 2015 · European Journal of Nuclear Medicine