Arturo Pereira

New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.

Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 x 10(9)/L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P< .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival.

A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment)

Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 x 10(9)/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.

Mutations and prognosis in primary myelofibrosis

Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

Myelofibrosis with myeloid metaplasia in young indidviduals: disease characteristics, prognostic factors and identification of risk groups

Myelofibrosis with myeloid metaplasia (MMM) is an uncommon disorder in young individuals, for whom haemopoietic stem cell transplantation offers the only possibility of cure. However, although the latter procedure is associated with significant morbidity and mortality, the clinical course of MMM is variable, with some patients surviving for less than a year and others showing an indolent course. Selection of young MMM patients for transplantation or other newer therapies is currently difficult since no prognostic data exists for this subgroup. In the present collaborative study a number of initial clinical and laboratory parameters have been evaluated for prognosis in 121 MMM patients aged 55 years or less. Median survival of the series was 128 months (95% CI 90–172). In the Cox proportional hazard regression model three initial variables were independently associated with shorter survival: Hb <10 g/dl (P < 0.0001), the presence of constitutional symptoms (fever, sweats, weight loss) (P = 0.001), and circulating blasts ≥ 1% (P = 0.003). Based on the above three criteria, of the 116 patients with complete data, two groups were identified: a ‘low‐risk’ group, characterized by 88 patients with up to one adverse prognostic factor, in whom MMM had an indolent course (median survival 176 months, 95% CI 130–188), and a ‘high‐risk’ group, including 28 patients with two or three factors, who had a more aggressive disease (median survival 33 months, 95% CI 20–42). The above prognostic scoring system showed a high positive predictive value, sensitivity and specificity to predict survival in the series, and could be of help in making treatment decisions in young patients with MMM.

Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients.

To determine the clinicohematological factors predictive for the appearance of major vascular complications (MVC) in patients with essential thrombocythemia (ET), 148 consecutive such patients were retrospectively assessed for the development of MVC during a median follow-up of 58.5 months. Seventy-seven patients had vascular risk factors, and 37 a history of MVC at ET diagnosis. Forty-nine MVC were registered in 33 patients during the follow-up period. The actuarial probability of MVC was 27% at 6 years in the whole series, 35.6% for patients above 60 years, and 21.4% for patients younger than 60 years, whereas only one of the 36 patients younger than 45 years had MVC. At multivariate analysis, age >60 years, history of major ischemia and hypercholesterolemia were the variables associated with an increased MVC risk. These results suggest that all ET patients above 60 years should be treated, whereas in younger patients treatment decisions should be primarily based on the existence of risk factors for MVC.

Identification of ‘short-lived’ and ‘long-lived’ patients at presentation of idiopathic myelofibrosis

To contribute to a better knowledge of the prognosis of idiopathic myelofibrosis (IM), the prognostic value of the presenting features in 106 patients diagnosed with IM at a single institution during a 21‐year period was retrospectively analysed. Median survival was 59.4 months (95% CI 40.7–75.4). Using univariate analysis, age < 64 years, constitutional symptoms (fever, night sweats, weight loss), Hb < 10 g/dl, circulating blasts (≫1%), and serum LDH > 3 times upper normal level were associated with a significantly shorter survival; male sex, platelet count <100×109/l, blood percentage of immature granulocytes (excluding blasts), low cholesterol levels and advanced marrow histological stage had borderline significance. Using multivariate study, only age > 64 years, constitutional symptoms, Hb < 10 g/dl, and circulating blasts retained their prognostic relevance. The latter three variables confirmed their predictive value in patients above and below the series median age, and were able to identify two groups of patients: a low‐risk group of 67 patients with none or one bad prognostic factor, in whom IM had an indolent course (median survival 98.8 months, 95% CI 68.7–127.6), and a high‐risk group, including 39 patients with two or three factors, with a more aggressive disease (median survival 20.6 months, 95% CI 10–28.2). Finally, the application of two recently proposed scoring systems (in which three prognostic groups are considered) was unable to separate intermediate‐ from high‐risk patients.

Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia

The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 low-risk patients with ET treated with antiplatelet drugs as monotherapy (n = 198) or followed with careful observation (n = 102). Follow-up was 802 and 848 person-years for antiplatelet therapy and observation, respectively. Rates of thrombotic events were 21.2 and 17.7 per 1000 person-years for antiplatelet therapy and observation, respectively (P = .6). JAK2 V617F-positive patients not receiving antiplatelet medication showed an increased risk of venous thrombosis (incidence rate ratio [IRR]: 4.0; 95% CI: 1.2-12.9; P = .02). Patients with cardiovascular risk factors had increased rates of arterial thrombosis while on observation (IRR: 2.5; 95% CI: 1.02-6.1; P = .047). An increased risk of major bleeding was observed in patients with platelet count greater than 1000 x 10(9)/L under antiplatelet therapy (IRR: 5.4; 95% CI: 1.7-17.2; P = .004). In conclusion, antiplatelet therapy reduces the incidence of venous thrombosis in patients with JAK2-positive ET and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In the remaining low-risk patients, this therapy is not effective as primary prophylaxis of thrombosis, and observation may be an adequate option.

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five ‘prognostically detrimental’ mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the ‘number’ of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6–5.7) vs 7.0 years (HR 1.9, 95% CI 1.4–2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6–3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2–3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5–10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the ‘number’ of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.

NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome

NOTCH1 has been found recurrently mutated in a subset of patients with chronic lymphocytic leukemia (CLL). To analyze biological features and clinical impact of NOTCH1 mutations in CLL, we sequenced this gene in 565 patients. NOTCH1 mutations, found in 63 patients (11%), were associated with unmutated IGHV, high expression of CD38 and ZAP-70, trisomy 12, advanced stage and elevated lactate dehydrogenase. Sequential analysis in 200 patients demonstrated acquisition of mutation in one case (0.5%) and disappearance after treatment in two. Binet A and B patients with NOTCH1-mutated had a shorter time to treatment. NOTCH1-mutated patients were more frequently refractory to therapy and showed shorter progression-free and overall survival after complete remission. Overall survival was shorter in NOTCH1-mutated patients, although not independently from IGHV. NOTCH1 mutation increased the risk of transformation to diffuse large B-cell lymphoma independently from IGHV, with this being validated in resampling tests of replicability. In summary, NOTCH1 mutational status, that was rarely acquired during the course of the disease, identify a genetic subgroup with high risk of transformation and poor outcome. This recently identified genetic subgroup of CLL patients deserves prospective studies to define their best management.

Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clinic of Barcelona experience.

Whether advances in treatment are prolonging survival of patients with chronic lymphocytic leukemia (CLL) is unclear. We analyzed presentation patterns and survival over time in 929 patients followed from 1980 to 2008 at the Hospital Clinic of Barcelona. The 5- and 10-year relative survival (adjusted for the expected survival in the general population) was estimated in patients seen in 2 periods of time: 1980-1994 (n = 451) and 1995-2004 (n = 365). We found that CLL shortens life expectancy in all age groups independently of clinical features at diagnosis. Nevertheless, survival is improving, particularly in some groups of patients. Thus, relative survival was significantly higher in the 1995-2004 cohort than in the 1980-1994 group both at 5 years (incidence rate ratio [IRR] = 0.46; P = .004) and 10 years (IRR = 0.65; P = .007) from diagnosis. The improved survival was largely due to a decrease in CLL-attributable mortality in patients younger than 70 years in Binet stage B or C at diagnosis (IRR = 0.40; P = .001 at 5 years; IRR = 0.33; P < .001 at 10 years). These results suggest that newer treatments are changing the prognosis of CLL, particularly in younger patients with advanced disease, whereas no improvement is yet observed in older subjects or those with lower-risk disease.