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PubMed | Hematology and Bone Marrow Transplant Unit, University of Leipzig, University of Barcelona, Fred Hutchinson Cancer Research Center and 15 more.
Type: Journal Article | Journal: Leukemia | Year: 2015

The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.


Verstovsek S.,University of Houston | Kantarjian H.M.,University of Houston | Estrov Z.,University of Houston | Cortes J.E.,University of Houston | And 11 more authors.
Blood | Year: 2012

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit. © 2012 by The American Society of Hematology.


Passamonti F.,University Hospital Ospedale Of Circolo ndazione Macchi | Maffioli M.,University Hospital Ospedale Of Circolo ndazione Macchi | Cervantes F.,University of Barcelona | Vannucchi A.M.,University of Florence | And 13 more authors.
Blood | Year: 2014

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF. © 2014 by The American Society of Hematology.


Passamonti F.,University Hospital Ospedale Of Circolo ndazione Macchi
Leukemia | Year: 2012

My diagnostic approach in case of isolated erythrocytosis is based on the visit and the interview of patients, and on checking the causes of secondary erythrocytosis. If causes of secondary erythrocytosis are not evident and serum erythropoietin level is low-normal, I study JAK2 mutations. In the case of a patient with erythrocytosis and other signs of myeloproliferation, such as leukocytosis, thrombocytosis or splenomegaly, the diagnosis of polycythemia vera (PV) is likely, and I test serum erythropoietin and JAK2 mutations first. I stratify patients at diagnosis of PV according to age and history of thrombosis. I start hydroxyurea for patients who are at a high risk of thrombosis (that is, with one or two risk factors), while I continue only phlebotomy in other cases. All PV patients, if not contraindicated, receive aspirin. I follow up patients monthly until normalization of their blood cell counts or splenomegaly, and afterwards every 2 months with visit, cell blood count and blood smear evaluation. After diagnosis, I perform bone marrow biopsy only in the case of clinical signs of disease evolution. © 2012 Macmillan Publishers Limited All rights reserved.


Barbui T.,Ospedali Riuniti di Bergamo | Finazzi G.,Ospedali Riuniti di Bergamo | Carobbio A.,Ospedali Riuniti di Bergamo | Thiele J.,University of Cologne | And 13 more authors.
Blood | Year: 2012

Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO) - defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2 V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2 V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events. © 2012 by The American Society of Hematology.


Passamonti F.,University Hospital Ospedale Of Circolo ndazione Macchi | Thiele J.,University of Cologne | Girodon F.,Center Hospitalier University | Rumi E.,University of Pavia | And 25 more authors.
Blood | Year: 2012

Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 109/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group-defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 109/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET. © 2012 by The American Society of Hematology.


Passamonti F.,University Hospital Ospedale Of Circolo ndazione Macchi
Blood | Year: 2012

Polycythemia vera (PV) is a clonal disorder characterized by unwarranted production of red blood cells. In the majority of cases, PV is driven by oncogenic mutations that constitutively activate the JAK-STAT signal transduction pathway, such as JAK2 V617F, or exon 12 mutations or LNK mutations. Diagnosis of PV is based on the WHO criteria. Diagnosis of post-PV myelofibrosis is established according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Different clinical presentations of PV are discussed. Prognostication of PV is tailored to the most frequent complication during follow-up, namely, thrombosis. Age older than 60 years and prior history of thrombosis are the 2 main risk factors for disease stratification. Correlations are emerging between leukocytosis, JAK2(V617F) mutation, BM fibrosis, and different outcomes of PV, which need to be confirmed in prospective studies. In my practice, hydroxyurea is still the "gold standard" when cytoreduction is needed, even though pegylated IFN-alfa-2a and ruxolitinib might be useful in particular settings. Results of phase 1 or 2 studies concerning these latter agents should however be confirmed by the ongoing randomized phase 3 clinical trials. In this paper, I discuss the main problems encountered in daily clinical practice with PV patients regarding diagnosis, prognostication, and therapy. © 2012 by The American Society of Hematology.


Tefferi A.,Mayo Medical School | Wassie E.A.,Mayo Medical School | Guglielmelli P.,University of Florence | Gangat N.,Mayo Medical School | And 12 more authors.
American Journal of Hematology | Year: 2014

CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n=402) and validation (n=625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P=0.005) and younger age with type-2 (P=0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P=0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P=0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121-E124, 2014. © 2014 Wiley Periodicals, Inc.


Passamonti F.,University Hospital Ospedale Of Circolo ndazione Macchi
Blood | Year: 2014

In this issue of Blood, Cheah et al provide long-term data on the use of imatinib to treat patients with eosinophilia and myeloid neoplasms carrying the PDGFRB fusion gene, which is a very rare condition in medicine. © 2014 by The American Society of Hematology.


Passamonti F.,University Hospital Ospedale Of Circolo ndazione Macchi | Caramazza D.,University Hospital Ospedale Of Circolo ndazione Macchi | Mora B.,University Hospital Ospedale Of Circolo ndazione Macchi | Casalone R.,University Hospital Ospedale Of Circolo ndazione Macchi | Maffioli M.,University Hospital Ospedale Of Circolo ndazione Macchi
Best Practice and Research: Clinical Haematology | Year: 2014

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms to be diagnosed according to the WHO classification. Molecular profiling must include the analysis of JAK2 (looking for the V617F point-mutation in PV and ET, screening exon 12 for mutations only in V617F-negative PV), CALR and MPL mutations (both in V617F-negative ET). The current risk stratification to predict thrombosis requires two parameters: age over 60 years and prior history of thrombosis. On the basis of these two risk factors patients can be stratified in low-risk and high-risk and receive a proper treatment. However, a modern stratification of thrombotic risk might consider "new" low-risk patients: conventional low-risk plus absence of leukocytosis from diagnosis onwards and a hematocrit level below 45% during the course of disease for PV; conventional low-risk plus absence of leukocytosis from diagnosis onwards, JAK2 negativity, CALR positivity, and absence of cardiovascular risk factors for ET. © 2014 Published by Elsevier Ltd.

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