Jasper H Smalberg, Lidia R Arends, Dominique C Valla, Jean-Jacques Kiladjian, Harry L A Janssen, Frank W G Leebeek
Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.
Blood. 2012 Dec 13;120(25):4921-8. doi: 10.1182/blood-2011-09-376517. Epub 2012 Oct 4.
Abstract/Text
Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients.
桐戸 敬太, 小池 道明, 野口 雅章, 木崎 昌弘, 杉本 由香, 片山 直之, 土橋 史明, 薄井 紀子小松 則夫. 骨髄増殖性腫瘍症例および健常者を対象にした新規JAK2V617F変異量測定キットの臨床性能試験. 臨床血液. 2018;59(6):669–674.
Pascal Mossuz, François Girodon, Magali Donnard, Véronique Latger-Cannard, Irène Dobo, Nathalie Boiret, Jean Claude Lecron, Christine Binquet, Claire Barro, Sylvie Hermouet, Vincent Praloran
Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis.
Haematologica. 2004 Oct;89(10):1194-8.
Abstract/Text
BACKGROUND AND OBJECTIVES: The diagnosis of polycythemia vera (PV) is based on clinical and biological criteria defined by either the Polycythemia Vera Study Group (PVSG) or the World Health Organization (WHO). Both the PVSG and WHO PV criteria have proved helpful and are extensively used, yet diagnostic strategies and scheduling of biological investigations vary. We assessed the value of measuring serum erythropoietin (Epo) as a first intention diagnostic test in patients with absolute erythrocytosis (AE).
DESIGN AND METHODS: Serum and bone marrow (BM) samples of 241 patients with a suspicion of erythrocytosis were collected in 8 hospital centers. One hundred and ninety had an absolute erythrocytosis (116 had PV, 66 had secondary erythrocytosis and 4 had idiopathic erythrocytosis). Serum Epo was assayed (ELISA) in 186. Statistical analysis (ROC curves) was used to define serum Epo thresholds that were specific for PV and secondary erythrocytosis and to analyze the diagnostic value of a low or high serum Epo level.
RESULTS: A large majority of PV patients (87% or 101/116) had a serum Epo level below the normal range in healthy patients (3.3 IU/L), giving this value a specificity of 97% with a 97.8% positive predictive value for the diagnosis of PV. Statistical analysis (ROC curves) defined two thresholds allowing a specific and direct diagnosis of 65.6% (65/99) of untreated PV (Epo < 1.4 IU/L) and 19.7% (13/66) of those with secondary erythrocytosis (Epo > 13.7 IU/L).
INTERPRETATION AND CONCLUSIONS: Based on these data, we propose that measurement of serum Epo level, a simple, reliable and inexpensive test, should be considered as a first intention diagnostic test for patients with absolute erythrocytosis.
Gilles Bonicelli, Khadija Abdulkarim, Morgane Mounier, Peter Johansson, Cédric Rossi, Valérie Jooste, Björn Andreasson, Marc Maynadié, François Girodon
Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients.
Br J Haematol. 2013 Jan;160(2):251-4. doi: 10.1111/bjh.12117. Epub 2012 Nov 15.
Abstract/Text
Three hundred and twenty-seven patients from two population-based cohorts with an established diagnosis of polycythaemia vera were studied for prognostic risk factors for survival and leukaemia in a long-term survey. The relative survival (RS) was 72% and 46% at 10 and 20 years respectively, from the time of diagnosis. Multivariate analysis identified age >70 years, white blood cell count >13 × 10(9) /l and thrombo-embolism at diagnosis as independent risk factors. Patients with two or three of these factors had a 10 year RS of 26%, compared with 59% and 84% in patients with one and no risk factors, respectively. Age and leucocyte count are the main predicting factors for survival in polycythaemia vera.
© 2012 Blackwell Publishing Ltd.
A Tefferi, E Rumi, G Finazzi, H Gisslinger, A M Vannucchi, F Rodeghiero, M L Randi, R Vaidya, M Cazzola, A Rambaldi, B Gisslinger, L Pieri, M Ruggeri, I Bertozzi, N H Sulai, I Casetti, A Carobbio, G Jeryczynski, D R Larson, L Müllauer, A Pardanani, J Thiele, F Passamonti, T Barbui
Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.
Leukemia. 2013 Sep;27(9):1874-81. doi: 10.1038/leu.2013.163. Epub 2013 Jun 6.
Abstract/Text
Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.
Roberto Marchioli, Guido Finazzi, Raffaele Landolfi, Jack Kutti, Heinz Gisslinger, Carlo Patrono, Raphael Marilus, Ana Villegas, Gianni Tognoni, Tiziano Barbui
Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.
J Clin Oncol. 2005 Apr 1;23(10):2224-32. doi: 10.1200/JCO.2005.07.062. Epub 2005 Feb 14.
Abstract/Text
PURPOSE: The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments.
PATIENTS AND METHODS: Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively.
RESULTS: The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis.
CONCLUSION: The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.
Ayalew Tefferi, William Vainchenker
Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies.
J Clin Oncol. 2011 Feb 10;29(5):573-82. doi: 10.1200/JCO.2010.29.8711. Epub 2011 Jan 10.
Abstract/Text
To update oncologists on pathogenesis, contemporary diagnosis, risk stratification, and treatment strategies in BCR-ABL1-negative myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent literature was reviewed and interpreted in the context of the authors' own experience and expertise. Pathogenetic mechanisms in PV, ET, and PMF include stem cell-derived clonal myeloproliferation and secondary stromal changes in the bone marrow and spleen. Most patients carry an activating JAK2 or MPL mutation and a smaller subset also harbors LNK, CBL, TET2, ASXL1, IDH, IKZF1, or EZH2 mutations; the precise pathogenetic contribution of these mutations is under investigation. JAK2 mutation analysis is now a formal component of diagnostic criteria for PV, ET, and PMF, but its prognostic utility is limited. Life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively (and safely) managed by treatment with low-dose aspirin, phlebotomy, or hydroxyurea. In PMF, survival and quality of life are significantly worse and current therapy is inadequate. In ET and PV, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with nonconventional therapeutic approaches (eg, interferon-alfa). The unmet need for treatment in PMF dictates a different approach for assessing the therapeutic value of new drugs (eg, JAK inhibitors, pomalidomide) or allogeneic stem-cell transplantation.
Tiziano Barbui, Giovanni Barosi, Gunnar Birgegard, Francisco Cervantes, Guido Finazzi, Martin Griesshammer, Claire Harrison, Hans Carl Hasselbalch, Rudiger Hehlmann, Ronald Hoffman, Jean-Jacques Kiladjian, Nicolaus Kröger, Ruben Mesa, Mary F McMullin, Animesh Pardanani, Francesco Passamonti, Alessandro M Vannucchi, Andreas Reiter, Richard T Silver, Srdan Verstovsek, Ayalew Tefferi, European LeukemiaNet
Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.
J Clin Oncol. 2011 Feb 20;29(6):761-70. doi: 10.1200/JCO.2010.31.8436. Epub 2011 Jan 4.
Abstract/Text
We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.
Raffaele Landolfi, Leonardo Di Gennaro, Tiziano Barbui, Valerio De Stefano, Guido Finazzi, Rosamaria Marfisi, Gianni Tognoni, Roberto Marchioli, European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP)
Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera.
Blood. 2007 Mar 15;109(6):2446-52. doi: 10.1182/blood-2006-08-042515. Epub 2006 Nov 14.
Abstract/Text
In polycythemia vera, vascular risk assessment is based on age and thrombotic history, while the role of other potential predictors of this risk is still uncertain. Thus, we exploited the large database collected by the observational study of the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) to investigate the association of hematologic variables and cardiovascular risk factors with the thrombotic risk. Among 1638 polycythemic patients followed for 2.7 +/- 1.3 years, there were 205 thromboses. Subjects with hypertension had a mild nonsignificant increase in the risk of arterial thrombosis, while this risk was significantly increased by smoking (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.15-3.14; P = .012). The time-dependent analysis adjusted for potential confounders showed that patients with a white blood cell count above 15 x 10(9)/L, compared with those with a white blood cell count below 10 x 10(9)/L, had a significant increase in the risk of thrombosis (HR, 1.71; 95% CI, 1.10-2.65; P = .017), mainly deriving from an increased risk of myocardial infarction (HR, 2.84; 95% CI, 1.25-6.46; P = .013). Thus, leukocyte count may help in defining the vascular risk of polycythemic subjects.
Tiziano Barbui, Alessandra Carobbio, Alessandro Rambaldi, Guido Finazzi
Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor?
Blood. 2009 Jul 23;114(4):759-63. doi: 10.1182/blood-2009-02-206797. Epub 2009 Apr 16.
Abstract/Text
Leukocyte (WBC) count has been recently identified as an independent predictor of major thrombosis in both essential thrombocythemia (ET) and polycythemia vera (PV). However, whether leukocytosis should be simply considered a marker for vascular disease or whether elevated WBC levels actually contribute directly to causing such disorders is presently matter of many studies. By adopting epidemiologic criteria for causation, we have examined the characteristics to support this association such as (1) strength, (2) consistency, (3) specificity, (4) temporality, (5) biologic gradient, (6) plausibility, (7) experimental evidence, and (8) analogy. Our conclusion supports the notion that baseline leukocytosis in ET and PV patients adds prognostic significance to existing risk factors and that may be considered causative of vascular events. These developments could induce clinicians to incorporate WBC count into standard clinical practice. However, we need prospective clinical studies with stratification of patients according to their baseline leukocyte counts. Until such evidence is available, the decision on how to manage these patients should continue to follow conventional criteria.
F Passamonti, E Rumi, D Pietra, C Elena, E Boveri, L Arcaini, E Roncoroni, C Astori, M Merli, S Boggi, C Pascutto, M Lazzarino, M Cazzola
A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications.
Leukemia. 2010 Sep;24(9):1574-9. doi: 10.1038/leu.2010.148. Epub 2010 Jul 15.
Abstract/Text
We studied the relationship between JAK2 (V617F) mutant allele burden and clinical phenotype, disease progression and survival in patients with polycythemia vera (PV). The percentage of granulocyte mutant alleles was evaluated using a quantitative real-time polymerase chain reaction-based allelic discrimination assay. Of the 338 patients enrolled in this prospective study, 320 (94.7%) carried the JAK2 (V617F) mutation. Direct relationships were found between mutant allele burden and hemoglobin concentration (P=0.001), white blood cell count (P=0.001), spleen size (P=0.001) and age-adjusted bone marrow cellularity (P=0.002), while an inverse relationship was found with platelet count (P<0.001). During the study period, eight patients progressed to post-PV myelofibrosis (MF) (all carrying >50% mutant alleles), while 10 patients developed acute myeloid leukemia (AML). The mutant allele burden was significantly related to the risk of developing myelofibrosis (P=0.029) and retained its significant effect also in multivariable analysis (P=0.03). By contrast, the risk of developing AML as well as that of thrombosis was not significantly related to mutant allele burden. Leukocytosis did not affect thrombosis, MF, leukemia or survival. In conclusion, a JAK2 (V617F) allele burden >50% represents a risk factor for progression to MF in PV.
Magnus Björkholm, Asa R Derolf, Malin Hultcrantz, Sigurdur Y Kristinsson, Charlotta Ekstrand, Lynn R Goldin, Björn Andreasson, Gunnar Birgegård, Olle Linder, Claes Malm, Berit Markevärn, Lars Nilsson, Jan Samuelsson, Fredrik Granath, Ola Landgren
Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms.
J Clin Oncol. 2011 Jun 10;29(17):2410-5. doi: 10.1200/JCO.2011.34.7542. Epub 2011 May 2.
Abstract/Text
PURPOSE: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU).
METHODS: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk.
RESULTS: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation.
CONCLUSION: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.
A M Vannucchi, E Antonioli, P Guglielmelli, G Longo, A Pancrazzi, V Ponziani, C Bogani, P R Ferrini, A Rambaldi, V Guerini, A Bosi, T Barbui, MPD Research Consortium
Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden.
Leukemia. 2007 Sep;21(9):1952-9. doi: 10.1038/sj.leu.2404854. Epub 2007 Jul 12.
Abstract/Text
The aim of this study was to determine whether the burden of JAK2(V617F) allele correlated with major clinical outcomes in patients with polycythemia vera (PV). To this end, we determined JAK2 mutant allele levels in granulocytes of 173 PV patients at diagnosis. The mean (+/-s.d.) mutant allele burden was 52% (+/-29); 32 patients (18%) had greater than 75% mutant allele. The burden of JAK2(V617F) allele correlated with measurements of stimulated erythropoiesis (higher hematocrit, lower mean cell volume, serum ferritin and erythropoietin levels) and myelopoiesis (higher white cell count, neutrophil count and serum lactate dehydrogenase) and with markers of neutrophil activation (elevated leukocyte alkaline phosphatase and PRV-1 expression). As compared to those with less than 25% mutant allele, patients harboring greater than 75% JAK2(V617F) allele were at higher relative risk (RR) of presenting larger spleen (RR 4.7; P<0.001) or suffering from pruritus (RR 3.1; P<0.001). In these patients, the risk of requiring chemotherapy (RR 1.8; P=0.001) or developing major cardiovascular events (RR 7.1; P=0.003) during follow up were significantly increased. We conclude that a burden of JAK2(V617F) allele greater than 75% at diagnosis points to PV patients with high-risk disease.
Ayalew Tefferi, Terra L Lasho, Susan M Schwager, Jacob S Strand, Michelle Elliott, Ruben Mesa, Chin-Yang Li, Martha Wadleigh, Stephanie J Lee, D Gary Gilliland
The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera.
Cancer. 2006 Feb 1;106(3):631-5. doi: 10.1002/cncr.21645.
Abstract/Text
BACKGROUND: Several studies have recently reported on the occurrence of a JAK2(V617F) mutation in myeloid cells from the majority of patients with polycythemia vera (PV). The clinical relevance of this novel observation currently is under study.
METHODS: In a single institutional study, mutation screening for JAK2(V617F) was performed in DNA derived from archived blood granulocytes from 63 consecutive patients with PV in whom current diagnostic criteria were strictly applied and the diagnosis confirmed by bone marrow histology.
RESULTS: The JAK2(V617F) mutant allele was detected in 58 of the 63 patients (92%) with 21% homozygosity. The clinical phenotype of the five patients with the wild-type allele was otherwise typical for the disease. A statistical comparison between JAK2(V617F) heterozygotes (n=45 patients) and homozygotes (n=13 patients) did not reveal any significant associations with regard to age, gender, leukocyte or platelet count at the time of diagnosis, duration of disease, or the incidences of thrombosis or bleeding. However, compared with their heterozygote counterparts, JAK2(V617F) homozygote patients displayed a significantly higher hemoglobin level at the time of diagnosis (P=0.001), an increased incidence of pruritus (69% vs. 38%; P=0.04), a higher rate of fibrotic transformation (23% vs. 2%; P=0.009), and higher PRV-1 transcript levels in their blood granulocytes (P=0.07).
CONCLUSIONS: The results of the current clinical study support previous laboratory observations that link JAK2(V617F) with the PV phenotype by demonstrating a mutant allele dose effect on erythrocytosis and clinical and laboratory features characteristic of PV.
Copyright (c) 2005 American Cancer Society.
T C Pearson, G Wetherley-Mein
Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia.
Lancet. 1978 Dec 9;2(8102):1219-22.
Abstract/Text
The relations between the incidence of vascular occlusive episodes and packed-cell volume (P.C.V) and platelet-count in patients with primary proliferative polycythaemia were determined retrospectively in patients treated by venesection with or without chemotherapy. The incidence of occlusive episodes correlated positively with P.C.V. level. The risk of vascular occlusive episodes was increased at moderately increased P.C.V. levels and the optimum P.C.V. level was rather lower than is often assumed. There was no statistically significant association between platelet-count, either alone or in combination with raised P.C.V., and incidence of vascular occlusion, though, episodes of occlusion were 1.5 times more common with platelet-counts above 400 x 10(9)/l. The results of this study indicate that P.C.V. should be maintained at less than 0.45 and the platelet-count at less than 400 x 10(9)/l in primary proliferative polycythaemia.
Marcello Di Nisio, Tiziano Barbui, Leonardo Di Gennaro, Giovanna Borrelli, Guido Finazzi, Raffaele Landolfi, Giuseppe Leone, Rosamaria Marfisi, Ettore Porreca, Marco Ruggeri, Anne W S Rutjes, Gianni Tognoni, Alessandro M Vannucchi, Roberto Marchioli, European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Investigators
The haematocrit and platelet target in polycythemia vera.
Br J Haematol. 2007 Jan;136(2):249-59. doi: 10.1111/j.1365-2141.2006.06430.x. Epub 2006 Dec 8.
Abstract/Text
Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low-dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8.85%) major thrombosis and 226 (13.8%) total thrombosis were encountered during 4393 person-years follow-up (median 2.8 years). In time-dependent multivariable analysis, a haematocrit in the evaluable range of 40-55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow-up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 x 10(9)/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.
Roberto Marchioli, Guido Finazzi, Giorgina Specchia, Rossella Cacciola, Riccardo Cavazzina, Daniela Cilloni, Valerio De Stefano, Elena Elli, Alessandra Iurlo, Roberto Latagliata, Francesca Lunghi, Monia Lunghi, Rosa Maria Marfisi, Pellegrino Musto, Arianna Masciulli, Caterina Musolino, Nicola Cascavilla, Giovanni Quarta, Maria Luigia Randi, Davide Rapezzi, Marco Ruggeri, Elisa Rumi, Anna Rita Scortechini, Simone Santini, Marco Scarano, Sergio Siragusa, Antonio Spadea, Alessia Tieghi, Emanuele Angelucci, Giuseppe Visani, Alessandro Maria Vannucchi, Tiziano Barbui, CYTO-PV Collaborative Group
Cardiovascular events and intensity of treatment in polycythemia vera.
N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8.
Abstract/Text
BACKGROUND: Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial.
METHODS: We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.
RESULTS: After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.
CONCLUSIONS: In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).
Raffaele Landolfi, Roberto Marchioli, Jack Kutti, Heinz Gisslinger, Gianni Tognoni, Carlo Patrono, Tiziano Barbui, European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators
Efficacy and safety of low-dose aspirin in polycythemia vera.
N Engl J Med. 2004 Jan 8;350(2):114-24. doi: 10.1056/NEJMoa035572.
Abstract/Text
BACKGROUND: The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial.
METHODS: We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years.
RESULTS: Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71).
CONCLUSIONS: Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.
Copyright 2004 Massachusetts Medical Society
Andreas Tiede, Jacob H Rand, Ulrich Budde, Arnold Ganser, Augusto B Federici
How I treat the acquired von Willebrand syndrome.
Blood. 2011 Jun 23;117(25):6777-85. doi: 10.1182/blood-2010-11-297580. Epub 2011 May 3.
Abstract/Text
The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations.
Claire N Harrison, Jyoti Nangalia, Rebecca Boucher, Aimee Jackson, Christina Yap, Jennifer O'Sullivan, Sonia Fox, Isaak Ailts, Amylou C Dueck, Holly L Geyer, Ruben A Mesa, William G Dunn, Eugene Nadezhdin, Natalia Curto-Garcia, Anna Green, Bridget Wilkins, Jason Coppell, John Laurie, Mamta Garg, Joanne Ewing, Steven Knapper, Josephine Crowe, Frederick Chen, Ioannis Koutsavlis, Anna Godfrey, Siamak Arami, Mark Drummond, Jennifer Byrne, Fiona Clark, Carolyn Mead-Harvey, Elizabeth Joanna Baxter, Mary Frances McMullin, Adam J Mead
Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial.
J Clin Oncol. 2023 Jul 1;41(19):3534-3544. doi: 10.1200/JCO.22.01935. Epub 2023 May 1.
Abstract/Text
PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms.
PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response.
RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported.
CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
Jean-Jacques Kiladjian, Christoph Klade, Pencho Georgiev, Dorota Krochmalczyk, Liana Gercheva-Kyuchukova, Miklos Egyed, Petr Dulicek, Arpad Illes, Halyna Pylypenko, Lylia Sivcheva, Jiří Mayer, Vera Yablokova, Kurt Krejcy, Victoria Empson, Hans C Hasselbalch, Robert Kralovics, Heinz Gisslinger, PROUD-PV Study Group
Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b.
Leukemia. 2022 Feb 24;. doi: 10.1038/s41375-022-01528-x. Epub 2022 Feb 24.
Abstract/Text
Susan Robinson, Susan Bewley, Beverley J Hunt, Deepti H Radia, Claire N Harrison
The management and outcome of 18 pregnancies in women with polycythemia vera.
Haematologica. 2005 Nov;90(11):1477-83.
Abstract/Text
BACKGROUND AND OBJECTIVES: Polycythemia vera (PV) is rare in women of childbearing age with only 20 previous pregnancies reported.
DESIGN AND METHODS: We report a series of 18 pregnancies (19 fetuses) in eight women with PV managed prior to or following implementation of management guidelines tailored to PV in pregnancy, and review the literature.
RESULTS: Seven of these pregnancies were managed by standard antenatal care (group A) without specific attention to the women's PV. All remaining 11 pregnancies (group B) were managed following a formal protocol and received tailored management principally comprising tight control of the hematocrit by venesection, and the use of interferon ? in three patients, in addition to aspirin 75 mg, and prophylactic low molecular weight heparin (LMWH). Each pregnancy was monitored with uterine artery Doppler examinations and regular fetal scanning. In group A (n=7) there was one live birth, which required delivery at 34 weeks due to placental insufficiency, three first trimester miscarriages, two stillbirths and one combined stillbirth and neonatal death (twins) associated with placental dysfunction. All 11 patients in group B received aspirin and post-partum LMWH; four also received venesection (during pregnancy), three interferon-a and three antenatal LMWH. There were ten live births, nine at term, one first trimester miscarriage and no intrauterine growth retardation.
INTERPRETATION AND CONCLUSIONS: Pregnancy in PV without meticulous attention to hematocrit is associated with poor fetal outcome. Aggressive intervention with control of hematocrit, aspirin and some LMWH appears to be associated with significantly better outcome (p=0.0017).
正岡徹、木村禧代二ほか編： Methyl-6-〔〔〔(2-chloroethyl)nitrosoamino〕carbonyl〕amino〕-6-deoxy-α-D-glucopyranoside(MCNU)の造血器疾患に対するPhase II study,癌と化学療法, 1983,10(6)；1518-1523.
Alessandro M Vannucchi, Jean Jacques Kiladjian, Martin Griesshammer, Tamas Masszi, Simon Durrant, Francesco Passamonti, Claire N Harrison, Fabrizio Pane, Pierre Zachee, Ruben Mesa, Shui He, Mark M Jones, William Garrett, Jingjin Li, Ulrich Pirron, Dany Habr, Srdan Verstovsek
Ruxolitinib versus standard therapy for the treatment of polycythemia vera.
N Engl J Med. 2015 Jan 29;372(5):426-35. doi: 10.1056/NEJMoa1409002.
Abstract/Text
BACKGROUND: Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.
METHODS: We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.
RESULTS: The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.
CONCLUSIONS: In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).
Jean-Jacques Kiladjian, Pierre Zachee, Masayuki Hino, Fabrizio Pane, Tamas Masszi, Claire N Harrison, Ruben Mesa, Carole B Miller, Francesco Passamonti, Simon Durrant, Martin Griesshammer, Keita Kirito, Carlos Besses, Beatriz Moiraghi, Elisa Rumi, Vittorio Rosti, Igor Wolfgang Blau, Nathalie Francillard, Tuochuan Dong, Monika Wroclawska, Alessandro M Vannucchi, Srdan Verstovsek
Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study.
Lancet Haematol. 2020 Jan 23;. doi: 10.1016/S2352-3026(19)30207-8. Epub 2020 Jan 23.
Abstract/Text
BACKGROUND: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea.
METHODS: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944.
FINDINGS: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment.
INTERPRETATION: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population.
FUNDING: Novartis Pharmaceuticals Corporation.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Annkristin Heine, Peter Brossart, Dominik Wolf
Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis?
Blood. 2013 Nov 28;122(23):3843-4. doi: 10.1182/blood-2013-10-531103.
Abstract/Text
G Caocci, F Murgia, L Podda, A Solinas, S Atzeni, G La Nasa
Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis.
Leukemia. 2014 Jan;28(1):225-7. doi: 10.1038/leu.2013.235. Epub 2013 Aug 9.
Abstract/Text
Nicholas G Wysham, Donald R Sullivan, Gopal Allada
An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor.
Chest. 2013 May;143(5):1478-9. doi: 10.1378/chest.12-1604.
Abstract/Text
We report a case of Cryptococcus neoformans pneumonia in a patient taking ruxolitinib, a janus kinase 1,2 inhibitor approved for the treatment of myelofibrosis. We hypothesize that ruxolitinib contributed to this infection through its effects on cell-mediated immunity. Clinicians should be aware of the potential for intracellular or opportunistic infections associated with this novel drug class.
Heinz Gisslinger, Christoph Klade, Pencho Georgiev, Dorota Krochmalczyk, Liana Gercheva-Kyuchukova, Miklos Egyed, Viktor Rossiev, Petr Dulicek, Arpad Illes, Halyna Pylypenko, Lylia Sivcheva, Jiri Mayer, Vera Yablokova, Kurt Krejcy, Barbara Grohmann-Izay, Hans C Hasselbalch, Robert Kralovics, Jean-Jacques Kiladjian, PROUD-PV Study Group
Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study.
Lancet Haematol. 2020 Mar;7(3):e196-e208. doi: 10.1016/S2352-3026(19)30236-4. Epub 2020 Jan 31.
Abstract/Text
BACKGROUND: The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.
METHODS: PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
FINDINGS: Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).
INTERPRETATION: In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.
FUNDING: AOP Orphan Pharmaceuticals AG.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Yoko Edahiro, Kohshi Ohishi, Akihiko Gotoh, Katsuto Takenaka, Hirohiko Shibayama, Takayuki Shimizu, Kensuke Usuki, Kazuya Shimoda, Masafumi Ito, Scott A VanWart, Oleh Zagrijtschuk, Albert Qin, Hiroaki Kawase, Narihisa Miyachi, Toshiaki Sato, Norio Komatsu, Keita Kirito
Efficacy and safety of ropeginterferon alfa-2b in Japanese patients with polycythemia vera: an open-label, single-arm, phase 2 study.
Int J Hematol. 2022 Aug;116(2):215-227. doi: 10.1007/s12185-022-03341-9. Epub 2022 Apr 16.
Abstract/Text
Ropeginterferon alfa-2b is a novel, site-selective, monopegylated recombinant human interferon alfa-2b. Safety and efficacy of ropeginterferon alfa-2b for the treatment of polycythemia vera were demonstrated in clinical studies conducted in European countries, but clinical studies in Japanese patients are lacking. This phase 2, open-label, multicenter, single-arm study investigated the safety and efficacy of ropeginterferon alfa-2b in 29 Japanese patients with polycythemia vera including young patients and patients with low thrombosis risk who are difficult to receive guideline-based standard treatments. The primary outcome of durable complete hematologic response without phlebotomy at months 9 and 12 was achieved by 8/29 (27.6%) patients. The fastest complete hematologic response was observed at week 12. A corresponding reduction in the JAK2 V617F allele burden from baseline to 52 weeks was also observed (mean ± standard deviation = - 19.2% ± 22.6%). No new safety concerns were identified in Japanese patients when compared with previous studies of ropeginterferon alfa-2b in European populations; the most common treatment-related adverse events were alopecia (55.2%), fatigue (27.6%) and influenza-like illness (27.6%). Most treatment-related adverse events were mild or moderate, with none of grade ≥ 3. Ropeginterferon alfa-2b is a safe and efficacious treatment option in Japanese patients with polycythemia vera.
© 2022. Japanese Society of Hematology.
Tiziano Barbui, Alessandro Maria Vannucchi, Valerio De Stefano, Arianna Masciulli, Alessandra Carobbio, Alberto Ferrari, Arianna Ghirardi, Elena Rossi, Fabio Ciceri, Massimiliano Bonifacio, Alessandra Iurlo, Francesca Palandri, Giulia Benevolo, Fabrizio Pane, Alessandra Ricco, Giuseppe Carli, Marianna Caramella, Davide Rapezzi, Caterina Musolino, Sergio Siragusa, Elisa Rumi, Andrea Patriarca, Nicola Cascavilla, Barbara Mora, Emma Cacciola, Carmela Mannarelli, Giuseppe Gaetano Loscocco, Paola Guglielmelli, Silvia Betti, Francesca Lunghi, Luigi Scaffidi, Cristina Bucelli, Nicola Vianelli, Marta Bellini, Maria Chiara Finazzi, Gianni Tognoni, Alessandro Rambaldi
Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial.
Lancet Haematol. 2021 Mar;8(3):e175-e184. doi: 10.1016/S2352-3026(20)30373-2. Epub 2021 Jan 18.
Abstract/Text
BACKGROUND: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone.
METHODS: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325.
FINDINGS: Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred.
INTERPRETATION: Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera.
FUNDING: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Keita Kirito
Silent Thyroiditis Associated with Ropeginterferon Alfa-2b in a Patient with Polycythemia Vera.
Intern Med. 2023 Aug 2;. doi: 10.2169/internalmedicine.2171-23. Epub 2023 Aug 2.
Abstract/Text
Interferon is an emerging treatment option for myeloproliferative neoplasms (MPNs), especially for polycythemia vera (PV). Previous studies of interferon used therapeutically for hepatitis C have demonstrated that one of the most important adverse events associated with interferon treatment is thyroid dysfunction, and a management strategy for thyroid dysfunction has been established. However, whether or not the recommendation is also suitable for MPN settings is unclear. In this study, one PV patient developed silent thyroiditis during a phase 2 study of ropeginterferon alpha 2b. This case suggests that thyroid dysfunction is an important clinical issue to consider in interferon treatment for PV.
Naseema Gangat, Natasha Szuber, Hassan Alkhateeb, Aref Al-Kali, Animesh Pardanani, Ayalew Tefferi
JAK2 wild-type erythrocytosis associated with sodium-glucose cotransporter 2 inhibitor therapy.
Blood. 2021 Dec 30;138(26):2886-2889. doi: 10.1182/blood.2021013996.
Abstract/Text
