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 × 109/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.
Despite the lack of major improvements in the treatment of primary myelofibrosis (PMF), there are recent indications that the survival of patients might have increased over the years. This study was ...aimed at ascertaining whether survival prolongation has actually occurred in PMF.
A total of 802 patients diagnosed with PMF in four European countries were compared for the presentation of features and survival according to the diagnostic periods 1980 to 1995 (n = 434) and 1996 to 2007 (n = 368); relative survival was estimated for the two groups.
Patients diagnosed between 1996 and 2007 more often had constitutional symptoms (31% v 23%) but a lower incidence of marked anemia (31% v 39%), leukocytosis greater than 25 × 10(9)/L (9% v 13%), and blood blasts (27% v 33%); risk distribution was comparable between the two groups. Median survival was 4.6 years (95% CI, 4.0 to 5.1) for patients from 1980 to 1995 and 6.5 years (95% CI, 5.5 to 7.4) for patients from 1996 to 2007 (P < .001). The latter group of patients showed improved relative survival, especially for women, patients younger than age 65 years, and patients with low or intermediate-1-risk disease. Rates of PMF-attributable mortality at 5 and 10 years were significantly lower in the second period; this reduction in disease-specific mortality occurred across all patient subgroups, except in intermediate-2-risk or high-risk patients.
Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations.
We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers ...affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70
30 months after 2 years of treatment,
<10
).
allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the
allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.
Summary
Myeloproliferative neoplasm‐related myelofibrosis is associated with cytopenic or proliferative phases, splenomegaly and constitutional symptoms. Few effective treatments are available and ...small series suggested that interferon could be an option for myelofibrosis therapy. We performed a retrospective study of pegylated‐interferon α‐2a (Peg‐IFNα‐2a) therapy in myelofibrosis. Sixty‐two patients treated with Peg‐IFNα‐2a at 17 French and Belgian centres were included. Responses were determined based on the criteria established by the International Working Group for Myelofibrosis Research and Treatment. Mean follow‐up was 26 months. Sixteen of 25 anaemic patients (64%) (eight concomitantly receiving recombinant erythropoietin) achieved a complete response and transfusion‐independence was obtained in 5/13 patients (38·5%). Constitutional symptoms resolved in 82% of patients. All five leucopenic patients normalized their leucocyte counts, whereas a normal platelet count was obtained in 5/8 thrombocytopenic patients. Splenomegaly was reduced in 46·5% of patients, and complete resolution of thrombocytosis and leucocytosis were observed in 82·8% and 68·8% of patients, respectively. Side effects (mostly haematological) were mainly of grade 1–2. The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin. In conclusion, Peg‐IFNα‐2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.
The median survival of patients with primary myelofibrosis ranges from 3.5 to 5.5 years, and most patients die from cause related to the disease, including blast phase (BP, in 5%-30% of cases). ...Because identification of high-risk patients might use information collected during the clinical course, we assessed the prognostic value of time-dependent covariates for 2 competing risks (death and BP) in a series of 172 patients. Significant (P < .01) adverse time-dependent prognostic factors for the risk of death were the time to onset of anemia (hemoglobin < 100 g/L 10 g/dL), leukocytosis (leukocyte count > 30 × 109/L), thrombocytopenia (platelet count < 150 × 109/L), presence of circulating blasts, intermediate-high or high International Working Group for Myelofibrosis Research and Treatment score, and time to splenectomy. The first 3 dependent covariates and the time to chemotherapy initiation (P = .05) were prognostic factors for the risk of BP. The prognostic effect of onset of leukocytosis was significantly more pronounced for BP than for death. Thus, occurrence during the follow-up of characteristics associated with an adverse prognostic value at diagnosis also influenced the risks of death and BP. Patients with leukocytosis should be closely monitored. These data might efficiently help to evaluate the severity of the disease before treatment decision during the clinical course.
After more than a century of research, the chronology of the deformation of the external part of the western Alpine belt (France) is still controversial for the Miocene epoch. In particular, the poor ...dating of the foreland basin sedimentary succession hampers a comprehensive understanding of the deformation kinematics. Here we focus on the Miocene molasse deposits of the northern subalpine massifs, southern Jura, Royans, Bas-Dauphiné, Crest, and La Bresse sedimentary basins through a multidisciplinary approach to build a basin-wide tectono-stratigraphic framework. Based on sequence stratigraphy constrained by biostratigraphical, chemostratigraphical (Sr isotopes), and magnetostratigraphical data between the late Aquitanian (∼ 21 Ma) and the Tortonian (∼ 8.2 Ma), the Miocene molasse chronostratigraphy is revised with a precision of ∼ 0.5 Ma. The Miocene molasse sediments encompass four different paleogeographical domains: (i) the oriental domain outlined by depositional sequences S1a to S3 (∼ 21 to ∼ 15 Ma), (ii) the median domain characterized by sequences S2 to S5 (∼ 17.8 to ∼ 12 Ma), (iii) the occidental domain in which sequences S2a to S8 (∼ 17.8 to ∼ 8.2 Ma) were deposited, and (iv) the Bressan domain where sedimentation is restricted to sequences S6 to S8 (∼ 12 to ∼ 8.2 Ma). A structural and tectono-sedimentary study is conducted based on new field observations and the reappraisal of regional seismic profiles, thereby allowing the identification of five major faults zones (FZs). The oriental, median, and occidental paleogeographical domains are clearly separated by FZ1, FZ2, and FZ3, suggesting strong interactions between tectonics and sedimentation during the Miocene. The evolution in time and space of the paleogeographical domains within a well-constrained structural framework reveals syntectonic deposits and a westward migration of the depocenters, allowing for proposing the succession of three deformation phases at the western Alpine front. (i) The first is a compressive phase (P1) corresponding to thrusting above the Chartreuse oriental thrust (FZ1), which was likely initiated during the Oligocene and rooted east of Belledonne. This tectonic phase generated reliefs that limited the Miocene transgression to the east. (ii) The second is a ∼ WNW–ESE-directed compressive phase (P2) lasting between 18.05 ± 0.25 Ma and ∼ 12 Ma, with thrusts rooted in the Belledonne basal thrust. Thrusts were activated from east to west: the Salève (SAL) and Gros Foug (GF) thrusts and then successively FZ2, FZ3, FZ4, and FZ5. Along two WNW–ESE balanced cross sections the amount of horizontal shortening is of ∼ 6.3 to 6.7 km, corresponding to average shortening rates of ∼ 1.2 km Myr−1 and migration of the deformation toward the west at a rate of ∼ 2.9 km Myr−1. During ∼ 6 Myr, the Miocene Sea was forced to regress rapidly westwards in response to westward migration of the active thrusts and exhumation of piggyback basins atop the fault zones. Phase P2 thus deeply shaped the Miocene paleogeographical evolution of the area and appears as a prominent compressive phase at the scale of the western Alps from the Swiss molasse basin to the Rhodano–Provencal one. (iii) The third is a ∼ 300 m phase of uplift in the Bas-Dauphiné (P3) of probable Tortonian age (∼ 10 Ma), which would have induced southward sea retreat and been coeval with the folding of the Jura in the north and possibly with back-thrusting east of the Chartreuse massif.
A phase II dose-escalation trial was conducted to ascertain low-dose thalidomide safety and response in patients with advanced myelofibrosis with myeloid metaplasia (MMM).
Thalidomide was ...administered together with current therapy to 63 patients, starting at 50 mg daily and increasing to 400 mg as tolerated.
Half of the patients sustained daily doses more than 100 mg and the drop-out rate was 51% at 6 months: the drop-out rate was lower in patients with high baseline fatigue score. At efficacy analysis, anemia was ameliorated in 22% of the patients and transfusions were eliminated in 39% of transfusion-dependent patients. Platelet count increased by 50 x 10(9)/L or more in 22% of patients with an initial count lower than 100 x 10(9)/L. Splenomegaly decreased by more than 50% of the initial size in 19% of patients. Reduction of an overall disease severity score occurred in 31% of patients and was associated with a significant reduction of fatigue. Disease severity amelioration was independently predicted by a high baseline myeloproliferative index (ie, large splenomegaly, thrombocytosis, or leukocytosis).
Low-dose thalidomide displays an acceptable toxicity profile and provides an objective and subjective advantage to a relevant portion of MMM patients.
Abstract
Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 ...countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year pt/y), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.
Treatment with alkylating agents or radiophosphorous (32P) has been shown to carry a certain leukemogenic risk in myeloproliferative disorders (MPDs), including essential thrombocytemia (ET). The ...leukemogenic risk associated to treatment with hydroxyurea in ET, on the other hand, is generally considered to be relatively low. Between 1970 and 1991, we diagnosed ET in 357 patients, who were monitored until 1996. One or several therapeutic agents had been admistered to 326 patients, including hydroxyurea (HU) in 251 (as only treatment in 201), pipobroman in 43, busulfan in 41, and32P in 40. With a median follow-up duration of 98 months, 17 patients (4.5%) had progressed to acute myeloid leukemia (AML; six cases) or myelodysplastic syndrome (MDS; 11 cases). Fourteen of these patients had received HU, as sole treatment in seven cases, and preceded or followed by other treatment in seven cases, mainly pipobroman (five cases). The remaining three leukemic progressions occurred in patients treated with 32P (two cases) and busulfan (one case). The incidence of AML and MDS after treatment, using 32P alone and 32P with other agents, busulfan alone and with other agents, HU alone and with others agents, and pipobroman alone and with other agents was 7% and 9%, 3% and 17%, 3.5% and 14%, and 0% and 16%, respectively. Thirteen of 17 patients who progressed to AML or MDS had successful cytogenetic analysis. Seven of them had rearrangements of chromosome 17 (unbalanced translocation, partial or complete deletion, isochromosome 17q) that resulted in 17p deletion. They also had a typical form of dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and vacuoles in neutrophils, and p53 mutation, as previously described in AML and MDS with 17p deletion. Those seven patients had all received HU, as the only therapeutic agent in three, and followed by pipobroman in three. The three patients who had received no HU and progressed to AML or MDS had no 17p deletion. A review of the literature found cytogenetic analysis in 35 cases of AML and MDS occurring after ET, 11 of whom had been treated with HU alone. Five of 35 patients had rearrangements that resulted in 17p deletion. Four of them had been treated with HU alone. These results show that treatment with HU alone is associated with a leukemic risk of approximately 3.5%. A high proportion of AML and MDS occurring in ET treated with HU (alone or possibly followed by pipobroman) have morphologic, cytogenetic, and molecular characteristics of the 17p− syndrome. These findings suggest that widespread and prolonged use of HU in ET may have to be reconsidered in some situations, such as asymptomatic ET.
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