Swerdlow SH, et al.：WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. IARC press. 2017: 39-53.
Tomonori Hidaka, Kotaro Shide, Haruko Shimoda, Takurou Kameda, Keiko Toyama, Keiko Katayose, Youko Kubuki, Kenji Nagata, Katsuto Takenaka, Koichi Akashi, Takashi Okamura, Yoshiyuki Niho, Hideaki Mizoguchi, Mitsuhiro Omine, Keiya Ozawa, Mine Harada, Kazuya Shimoda
The impact of cytogenetic abnormalities on the prognosis of primary myelofibrosis: a prospective survey of 202 cases in Japan.
Eur J Haematol. 2009 Oct;83(4):328-33. doi: 10.1111/j.1600-0609.2009.01298.x. Epub 2009 Jun 15.
Abstract/Text
Cytogenetic abnormalities were often observed in primary myelofibrosis patients. The presence of specific cytogenetic abnormalities, such as sole abnormalities of chromosome 13q-, 20q-, or -7/7q-, is reported to have the influence on the prognosis of primary myelofibrosis. We analyzed the data from the prospective survey of Japanese primary myelofibrosis patients which was conducted from 1999 to clarify the impact of cytogenetic abnormalities on the prognosis of primary myelofibrosis. A total of 202 primary myelofibrosis patients had the cytogenetic and the prognostic data. Eighty (40%) out of 202 cases had cytogenetic abnormalities, and an association was evident for platelet counts. Although the presence of an abnormal karyotype did not affect the prognosis, primary myelofibrosis patients with cytogenetic abnormalities other than 13q- and 20q- showed an inferior prognosis compared to patients with a normal karyotype or sole 13q- or 20q- abnormalities. Patients with an unfavorable cytogenetic profile (abnormal cytogenetics other than 13q- or 20q-) also had a greater tendency to transform to leukemia than patients with a favorable cytogenetic profile (normal cytogenetics, sole abnormalities of either chromosome 13q-, or 20q-). Abnormal cytogenetics other than 13q- or 20q- in primary myelofibrosis patients has the poor prognostic effect for both survival and the risk of leukemic transformation.
赤司浩一、下田和哉、桐戸敬太ほか：骨髄線維症診療の参照ガイド第6版 令和4年度改訂版：厚生労働科学研究補助金 難治性疾患政策研究事業 特発性造血障害に関する調査研究班（研究代表者 三谷絹子）、2023年.
Francisco Cervantes, Brigitte Dupriez, Arturo Pereira, Francesco Passamonti, John T Reilly, Enrica Morra, Alessandro M Vannucchi, Ruben A Mesa, Jean-Loup Demory, Giovanni Barosi, Elisa Rumi, Ayalew Tefferi
New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.
Blood. 2009 Mar 26;113(13):2895-901. doi: 10.1182/blood-2008-07-170449. Epub 2008 Nov 6.
Abstract/Text
Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 x 10(9)/L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P< .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival.
E Joanna Baxter, Linda M Scott, Peter J Campbell, Clare East, Nasios Fourouclas, Soheila Swanton, George S Vassiliou, Anthony J Bench, Elaine M Boyd, Natasha Curtin, Mike A Scott, Wendy N Erber, Anthony R Green, Cancer Genome Project
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
Lancet. 2005 Mar 19-25;365(9464):1054-61. doi: 10.1016/S0140-6736(05)71142-9.
Abstract/Text
BACKGROUND: Human myeloproliferative disorders form a range of clonal haematological malignant diseases, the main members of which are polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. The molecular pathogenesis of these disorders is unknown, but tyrosine kinases have been implicated in several related disorders. We investigated the role of the cytoplasmic tyrosine kinase JAK2 in patients with a myeloproliferative disorder.
METHODS: We obtained DNA samples from patients with polycythaemia vera, essential thrombocythaemia, or idiopathic myelofibrosis. The coding exons of JAK2 were bidirectionally sequenced from peripheral-blood granulocytes, T cells, or both. Allele-specific PCR, molecular cytogenetic studies, microsatellite PCR, Affymetrix single nucleotide polymorphism array analyses, and colony assays were undertaken on subgroups of patients.
FINDINGS: A single point mutation (Val617Phe) was identified in JAK2 in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis. The mutation is acquired, is present in a variable proportion of granulocytes, alters a highly conserved valine present in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as a result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. The mutation was present in all erythropoietin-independent erythroid colonies.
INTERPRETATION: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder. Its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.
RELEVANCE TO PRACTICE: Identification of the Val617Phe JAK2 mutation lays the foundation for new approaches to the diagnosis, classification, and treatment of myeloproliferative disorders.
Chloé James, Valérie Ugo, Jean-Pierre Le Couédic, Judith Staerk, François Delhommeau, Catherine Lacout, Loïc Garçon, Hana Raslova, Roland Berger, Annelise Bennaceur-Griscelli, Jean Luc Villeval, Stefan N Constantinescu, Nicole Casadevall, William Vainchenker
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.
Nature. 2005 Apr 28;434(7037):1144-8. doi: 10.1038/nature03546.
Abstract/Text
Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.
Robert Kralovics, Francesco Passamonti, Andreas S Buser, Soon-Siong Teo, Ralph Tiedt, Jakob R Passweg, Andre Tichelli, Mario Cazzola, Radek C Skoda
A gain-of-function mutation of JAK2 in myeloproliferative disorders.
N Engl J Med. 2005 Apr 28;352(17):1779-90. doi: 10.1056/NEJMoa051113.
Abstract/Text
BACKGROUND: Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases.
METHODS: We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis).
RESULTS: Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 (JAK2) gene. In patients with 9pLOH, JAK2 had a homozygous G-->T transversion, causing phenylalanine to be substituted for valine at position 617 of JAK2 (V617F). All 51 patients with 9pLOH had the V617F mutation. Of 193 patients without 9pLOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65 percent among patients with polycythemia vera (83 of 128), 57 percent among patients with idiopathic myelofibrosis (13 of 23), and 23 percent among patients with essential thrombocythemia (21 of 93). V617F is a somatic mutation present in hematopoietic cells. Mitotic recombination probably causes both 9pLOH and the transition from heterozygosity to homozygosity for V617F. Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages. Patients with the V617F mutation had a significantly longer duration of disease and a higher rate of complications (fibrosis, hemorrhage, and thrombosis) and treatment with cytoreductive therapy than patients with wild-type JAK2.
CONCLUSIONS: A high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
Copyright 2005 Massachusetts Medical Society.
Ross L Levine, Martha Wadleigh, Jan Cools, Benjamin L Ebert, Gerlinde Wernig, Brian J P Huntly, Titus J Boggon, Iwona Wlodarska, Jennifer J Clark, Sandra Moore, Jennifer Adelsperger, Sumin Koo, Jeffrey C Lee, Stacey Gabriel, Thomas Mercher, Alan D'Andrea, Stefan Fröhling, Konstanze Döhner, Peter Marynen, Peter Vandenberghe, Ruben A Mesa, Ayalew Tefferi, James D Griffin, Michael J Eck, William R Sellers, Matthew Meyerson, Todd R Golub, Stephanie J Lee, D Gary Gilliland
Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.
Cancer Cell. 2005 Apr;7(4):387-97. doi: 10.1016/j.ccr.2005.03.023.
Abstract/Text
Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.
Animesh D Pardanani, Ross L Levine, Terra Lasho, Yana Pikman, Ruben A Mesa, Martha Wadleigh, David P Steensma, Michelle A Elliott, Alexandra P Wolanskyj, William J Hogan, Rebecca F McClure, Mark R Litzow, D Gary Gilliland, Ayalew Tefferi
MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.
Blood. 2006 Nov 15;108(10):3472-6. doi: 10.1182/blood-2006-04-018879. Epub 2006 Jul 25.
Abstract/Text
Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.
Yana Pikman, Benjamin H Lee, Thomas Mercher, Elizabeth McDowell, Benjamin L Ebert, Maricel Gozo, Adam Cuker, Gerlinde Wernig, Sandra Moore, Ilene Galinsky, Daniel J DeAngelo, Jennifer J Clark, Stephanie J Lee, Todd R Golub, Martha Wadleigh, D Gary Gilliland, Ross L Levine
MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
PLoS Med. 2006 Jul;3(7):e270. doi: 10.1371/journal.pmed.0030270.
Abstract/Text
BACKGROUND: The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR).
METHODS AND FINDINGS: DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis.
CONCLUSIONS: Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD.
J Nangalia, C E Massie, E J Baxter, F L Nice, G Gundem, D C Wedge, E Avezov, J Li, K Kollmann, D G Kent, A Aziz, A L Godfrey, J Hinton, I Martincorena, P Van Loo, A V Jones, P Guglielmelli, P Tarpey, H P Harding, J D Fitzpatrick, C T Goudie, C A Ortmann, S J Loughran, K Raine, D R Jones, A P Butler, J W Teague, S O'Meara, S McLaren, M Bianchi, Y Silber, D Dimitropoulou, D Bloxham, L Mudie, M Maddison, B Robinson, C Keohane, C Maclean, K Hill, K Orchard, S Tauro, M-Q Du, M Greaves, D Bowen, B J P Huntly, C N Harrison, N C P Cross, D Ron, A M Vannucchi, E Papaemmanuil, P J Campbell, A R Green
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.
N Engl J Med. 2013 Dec 19;369(25):2391-405. doi: 10.1056/NEJMoa1312542. Epub 2013 Dec 10.
Abstract/Text
BACKGROUND: Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge.
METHODS: We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry.
RESULTS: Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients.
CONCLUSIONS: Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).
Thorsten Klampfl, Heinz Gisslinger, Ashot S Harutyunyan, Harini Nivarthi, Elisa Rumi, Jelena D Milosevic, Nicole C C Them, Tiina Berg, Bettina Gisslinger, Daniela Pietra, Doris Chen, Gregory I Vladimer, Klaudia Bagienski, Chiara Milanesi, Ilaria Carola Casetti, Emanuela Sant'Antonio, Virginia Ferretti, Chiara Elena, Fiorella Schischlik, Ciara Cleary, Melanie Six, Martin Schalling, Andreas Schönegger, Christoph Bock, Luca Malcovati, Cristiana Pascutto, Giulio Superti-Furga, Mario Cazzola, Robert Kralovics
Somatic mutations of calreticulin in myeloproliferative neoplasms.
N Engl J Med. 2013 Dec 19;369(25):2379-90. doi: 10.1056/NEJMoa1311347. Epub 2013 Dec 10.
Abstract/Text
BACKGROUND: Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients.
METHODS: We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms.
RESULTS: Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2.
CONCLUSIONS: Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).
T Okamura, N Kinukawa, Y Niho, H Mizoguchi
Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients.
Int J Hematol. 2001 Feb;73(2):194-8.
Abstract/Text
We retrospectively analyzed 336 patients with primary chronic myelofibrosis from 203 medical institutes in Japan. Notwithstanding their heterogeneous treatments, the median survival in 298 patients that could be evaluated was 10.0 years. Average age at onset was 60.7 years. Men were affected 1.4 times more frequently than women. The factors associated with shorter survival included anemia, leukocytosis/leukocytopenia, thrombocytopenia, and increased blasts in the peripheral blood, and sex (male), age (>60), and the presence of symptoms. A new scoring system based on the peripheral blood findings (hemoglobin [Hb] level, platelet count, and rate of blast formation) at initial diagnosis clearly correlated with survival rate. Accordingly, patients could be categorized into 3 groups by severity grading. Through stepwise multivariate survival analysis, the significant prognostic factors were identified as the severity grading based on the new scoring system (P = .0002), age (P = .0024), sex (P = .0153), and Hb (P = .0198). Chromosomal abnormalities were found in 58 of 154 patients (38%), although these did not influence survival.
日本血液学会. 造血器腫瘍ガイドライン2013年版 追記; 2013.
Francisco Cervantes, Alberto Alvarez-Larrán, Abel Domingo, Eduardo Arellano-Rodrigo, Emili Montserrat
Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients.
Br J Haematol. 2005 Jun;129(6):771-5. doi: 10.1111/j.1365-2141.2005.05524.x.
Abstract/Text
Androgens are considered the treatment of choice for the anaemia of myelofibrosis with myeloid metaplasia (MMM). Good results have been reported in a few patients treated with danazol, a synthetic attenuated androgen. The long-term efficacy and tolerability of danazol as treatment for the anaemia of MMM was evaluated in 30 patients, who received 600 mg/d, with progressive tapering to the minimum effective dose in the responders after 6 months. Complete response (CR) was defined as transfusion cessation with normal Hb and partial response (PR) as an Hb increase >/=1.5 g/dl with transfusion-independent Hb values >10 g/dl maintained for at least 8 weeks. Median follow-up was 20.5 months (range: 3.5-58 months). Response was achieved in 11 patients (37%), including eight CRs and three PRs. Median time to response was 5 months (range: 1-9 months). Four patients stopped responding at 6-24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3.5-42 months. Pretreatment variables associated with response were lack of transfusion requirement (P= 0.001) and higher Hb at treatment start (P= 0.02). Toxicity was usually moderate, leading to treatment withdrawal in only two cases. Danazol is effective and well tolerated in a substantial proportion of MMM patients with anaemia.
Kazuya Shimoda, Kotaro Shide, Kenjirou Kamezaki, Takashi Okamura, Naoki Harada, Naoko Kinukawa, Kazuma Ohyashiki, Yoshiyuki Niho, Hideaki Mizoguchi, Mitsuhiro Omine, Keiya Ozawa, Mine Haradaa
The effect of anabolic steroids on anemia in myelofibrosis with myeloid metaplasia: retrospective analysis of 39 patients in Japan.
Int J Hematol. 2007 May;85(4):338-43. doi: 10.1532/IJH97.06135.
Abstract/Text
Between 1999 and 2005, 285 patients received new diagnoses of myelofibrosis with myeloid metaplasia (MMM) in Japan. Anemic symptoms were present in 162 patients, and hemoglobin (Hb) concentrations were <10 g/dL in 197 patients. Fifty-five MMM patients were treated with anabolic steroids, and their effect on anemia during MMM was evaluated in 39 patients. A "good" response was defined as an Hb increase of >or=1.5 g/dL, cessation of transfusion dependence, and an Hb concentration of >10 g/dL maintained for at least 8 weeks. A "minimum" response was defined as an Hb increase of >or=1.5 g/dL and transfusion independence for at least 8 weeks. Both good and minimum responses were considered "favorable." Favorable responses were achieved in 17 patients (44%, 8 good and 9 minimum responses). None of the pretreatment variables, such as the lack of transfusion dependence, a higher Hb concentration at the start of treatment, or the absence of cytogenetic abnormalities, were associated with a response to anabolic steroid therapy. Adverse events associated with anabolic steroid therapy were moderate and transient. Two patients required definitive withdrawal of treatment. Thus, anabolic steroids are well tolerated and effective for the treatment of anemia in a subset of MMM patients.
Nicolaus Kröger, Toni Giorgino, Bart L Scott, Markus Ditschkowski, Haefaa Alchalby, Francisco Cervantes, Alessandro Vannucchi, Mario Cazzola, Enrica Morra, Tatjana Zabelina, Margherita Maffioli, Arturo Pereira, Dietrich Beelen, H Joachim Deeg, Francesco Passamonti
Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.
Blood. 2015 May 21;125(21):3347-50; quiz 3364. doi: 10.1182/blood-2014-10-608315. Epub 2015 Mar 17.
Abstract/Text
Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21-0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate-1 risk.
© 2015 by The American Society of Hematology.
Nico Gagelmann, Markus Ditschkowski, Rashit Bogdanov, Swann Bredin, Marie Robin, Bruno Cassinat, Rabia Shahswar, Felicitas Thol, Michael Heuser, Gerard Socié, Dietrich Beelen, Ioanna Triviai, Anita Badbaran, Nicolaus Kröger
Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation.
Blood. 2019 May 16;133(20):2233-2242. doi: 10.1182/blood-2018-12-890889. Epub 2019 Feb 13.
Abstract/Text
Allogeneic hematopoietic stem cell transplantation is curative in myelofibrosis, and current prognostic scoring systems aim to select patients for transplantation. Here, we aimed to develop a prognostic score to determine prognosis after transplantation itself, using clinical, molecular, and transplant-specific information from a total of 361 patients with myelofibrosis. Of these, 205 patients were used as a training cohort to create a clinical-molecular myelofibrosis transplant scoring system (MTSS), which was then externally validated in a cohort of 156 patients. Multivariable analysis on survival identified age at least 57 years, Karnofsky performance status lower than 90%, platelet count lower than 150 × 109/L, leukocyte count higher than 25 × 109/L before transplantation, HLA-mismatched unrelated donor, ASXL1 mutation, and non-CALR/MPL driver mutation genotype being independent predictors of outcome. The uncorrected concordance index for the final survival model was 0.723, and bias-corrected indices were similar. Risk factors were incorporated into a 4-level MTSS: low (score, 0-2), intermediate (score, 3-4), high (score, 5), and very high (score, >5). The 5-year survival according to risk groups in the validation cohort was 83% (95% confidence interval [CI], 71%-95%), 64% (95% CI, 53%-75%), 37% (95% CI, 17%-57%), and 22% (95% CI, 4%-39%), respectively (P < .001). Increasing score was predictive of nonrelapse mortality (P < .001) and remained applicable to primary (0.718) and post-essential thrombocythemia (ET)/polycythemia vera (PV) myelofibrosis (0.701) improving prognostic ability in comparison with all currently available disease-specific systems. In conclusion, this MTSS predicts outcome of patients with primary and post-ET/PV myelofibrosis undergoing allogeneic stem cell transplantation.
© 2019 by The American Society of Hematology.
Constantine S Tam, Hagop Kantarjian, Jorge Cortes, Alice Lynn, Sherry Pierce, Lingsha Zhou, Michael J Keating, Deborah A Thomas, Srdan Verstovsek
Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
J Clin Oncol. 2009 Nov 20;27(33):5587-93. doi: 10.1200/JCO.2009.22.8833. Epub 2009 Sep 28.
Abstract/Text
PURPOSE: Current prognostic tools in myelofibrosis (MF) fail to identify patients at the highest risk of death and are limited by their applicability only to the time of diagnosis. We aimed to define an accelerated phase (AP) in MF by characterizing disease features that can identify patients with median overall survival of PATIENTS AND METHODS: Baseline characteristics of 370 consecutive patients with MF from a single center were analyzed to identify features associated with a median overall survival of RESULTS: The following three characteristics were associated with poor survival at baseline and were selected as putative AP features: blasts in blood or bone marrow >or= 10%, platelets less than 50 x 10(9)/L, and chromosome 17 aberrations (median overall survival, 10, 12, and 5 months, respectively). In the validation phase, chronic-phase patients who developed AP features during follow-up were found to have short subsequent survival times (median overall survival, 12, 15, and 6 months, respectively). AP was a necessary step in the progression to blast phase, with leukemic transformation being exceedingly rare (3% risk at 10 years) in patients who remained persistently in chronic phase.
CONCLUSION: Blood or bone marrow blasts >or= 10%, platelets less than 50 x 10(9)/L, and chromosome 17 aberrations defined AP in patients with MF. Patients in AP should be candidates for intensive therapeutic interventions.
Francesco Passamonti, Francisco Cervantes, Alessandro Maria Vannucchi, Enrica Morra, Elisa Rumi, Arturo Pereira, Paola Guglielmelli, Ester Pungolino, Marianna Caramella, Margherita Maffioli, Cristiana Pascutto, Mario Lazzarino, Mario Cazzola, Ayalew Tefferi
A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).
Blood. 2010 Mar 4;115(9):1703-8. doi: 10.1182/blood-2009-09-245837. Epub 2009 Dec 14.
Abstract/Text
Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 x 10(9)/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.
Naseema Gangat, Domenica Caramazza, Rakhee Vaidya, Geeta George, Kebede Begna, Susan Schwager, Daniel Van Dyke, Curtis Hanson, Wenting Wu, Animesh Pardanani, Francisco Cervantes, Francesco Passamonti, Ayalew Tefferi
DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.
J Clin Oncol. 2011 Feb 1;29(4):392-7. doi: 10.1200/JCO.2010.32.2446. Epub 2010 Dec 13.
Abstract/Text
PURPOSE: The Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis (PMF) uses five risk factors to predict survival: age older than 65 years, hemoglobin lower than 10 g/dL, leukocytes higher than 25 × 10(9)/L, circulating blasts ≥ 1%, and constitutional symptoms. The main objective of this study was to refine DIPSS by incorporating prognostic information from karyotype, platelet count, and transfusion status.
PATIENTS AND METHODS: Mayo Clinic databases for PMF were used to identify patients with available bone marrow histologic and cytogenetic information.
RESULTS: Seven hundred ninety-three consecutive patients were selected and divided into two groups based on whether or not their referral occurred within (n = 428; training set) or after (n = 365; test set) 1 year of diagnosis. Multivariable analysis identified DIPSS, unfavorable karyotype, platelets lower than 100 × 10(9)/L, and transfusion need as independent predictors of inferior survival. Hazard ratio (HR)-weighted adverse points were assigned to these variables to develop a composite prognostic model using the training set. The model was subsequently validated in the test set, and its application to all 793 patients resulted in median survivals of 185, 78, 35, and 16 months for low, intermediate-1 (HR, 2.2; 95% CI, 1.4 to 3.6), intermediate-2 (HR, 4.9; 95% CI, 3.2 to 7.7), and high-risk groups (HR, 10.7; 95% CI, 6.8 to 16.9), respectively (P < .001). Leukemia-free survival was predicted by the presence of thrombocytopenia or unfavorable karyotype (10-year risk of 31% v 12%; HR, 3.3; 95% CI, 1.9 to 5.6).
CONCLUSION: DIPSS plus effectively combines prognostic information from DIPSS, karyotype, platelet count, and transfusion status to predict overall survival in PMF. In addition, unfavorable karyotype or thrombocytopenia predicts inferior leukemia-free survival.
Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Richard S Levy, Vikas Gupta, John F DiPersio, John V Catalano, Michael Deininger, Carole Miller, Richard T Silver, Moshe Talpaz, Elliott F Winton, Jimmie H Harvey, Murat O Arcasoy, Elizabeth Hexner, Roger M Lyons, Ronald Paquette, Azra Raza, Kris Vaddi, Susan Erickson-Viitanen, Iphigenia L Koumenis, William Sun, Victor Sandor, Hagop M Kantarjian
A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.
N Engl J Med. 2012 Mar 1;366(9):799-807. doi: 10.1056/NEJMoa1110557.
Abstract/Text
BACKGROUND: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.
METHODS: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.
RESULTS: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.
CONCLUSIONS: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).
Claire Harrison, Jean-Jacques Kiladjian, Haifa Kathrin Al-Ali, Heinz Gisslinger, Roger Waltzman, Viktoriya Stalbovskaya, Mari McQuitty, Deborah S Hunter, Richard Levy, Laurent Knoops, Francisco Cervantes, Alessandro M Vannucchi, Tiziano Barbui, Giovanni Barosi
JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.
N Engl J Med. 2012 Mar 1;366(9):787-98. doi: 10.1056/NEJMoa1110556.
Abstract/Text
BACKGROUND: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis.
METHODS: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography.
RESULTS: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy.
CONCLUSIONS: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).
Srdan Verstovsek, Jason Gotlib, Ruben A Mesa, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Francisco Cervantes, Claire N Harrison, Ronald Paquette, William Sun, Ahmad Naim, Peter Langmuir, Tuochuan Dong, Prashanth Gopalakrishna, Vikas Gupta
Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses.
J Hematol Oncol. 2017 Sep 29;10(1):156. doi: 10.1186/s13045-017-0527-7. Epub 2017 Sep 29.
Abstract/Text
BACKGROUND: Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.
METHODS: This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.
RESULTS: A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.
CONCLUSIONS: These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.
TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .
Francesco Passamonti, Margherita Maffioli, Francisco Cervantes, Alessandro Maria Vannucchi, Enrica Morra, Tiziano Barbui, Domenica Caramazza, Lisa Pieri, Elisa Rumi, Heinz Gisslinger, Laurent Knoops, Jean Jaques Kiladjian, Barbara Mora, Norbert Hollaender, Cristiana Pascutto, Claire Harrison, Mario Cazzola
Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts.
Blood. 2014 Mar 20;123(12):1833-5. doi: 10.1182/blood-2013-12-544411. Epub 2014 Jan 17.
Abstract/Text
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.
Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Richard S Levy, Vikas Gupta, John F DiPersio, John V Catalano, Michael W N Deininger, Carole B Miller, Richard T Silver, Moshe Talpaz, Elliott F Winton, Jimmie H Harvey, Murat O Arcasoy, Elizabeth O Hexner, Roger M Lyons, Ronald Paquette, Azra Raza, Kris Vaddi, Susan Erickson-Viitanen, William Sun, Victor Sandor, Hagop M Kantarjian
Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I.
Haematologica. 2013 Dec;98(12):1865-71. doi: 10.3324/haematol.2013.092155. Epub 2013 Sep 13.
Abstract/Text
COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.
Francesca Patriarca, Andrea Bacigalupo, Alessandra Sperotto, Miriam Isola, Franca Soldano, Barbara Bruno, Maria Teresa van Lint, Anna Paola Iori, Stella Santarone, Ferdinando Porretto, Pietro Pioltelli, Giuseppe Visani, Pasquale Iacopino, Renato Fanin, Alberto Bosi, GITMO
Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
Haematologica. 2008 Oct;93(10):1514-22. doi: 10.3324/haematol.12828. Epub 2008 Aug 25.
Abstract/Text
BACKGROUND: Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors.
DESIGN AND METHODS: One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients' characteristics and the clinical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses.
RESULTS: The median age of the patients at the time of stem cell transplantation was 49 years (range, 21-68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87-0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome.
CONCLUSIONS: We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.
Nicolaus Kröger, Ernst Holler, Guido Kobbe, Martin Bornhäuser, Rainer Schwerdtfeger, Herrad Baurmann, Arnon Nagler, Wolfgang Bethge, Matthias Stelljes, Lutz Uharek, Hannes Wandt, Andreas Burchert, Paolo Corradini, Jörg Schubert, Martin Kaufmann, Peter Dreger, Gerald G Wulf, Hermann Einsele, Tatjana Zabelina, Hans Michael Kvasnicka, Jürgen Thiele, Ronald Brand, Axel R Zander, Dietger Niederwieser, Theo M de Witte
Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
Blood. 2009 Dec 17;114(26):5264-70. doi: 10.1182/blood-2009-07-234880. Epub 2009 Oct 7.
Abstract/Text
From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m(2))-based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P = .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P = .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio = 2.70; P = .02) and human leukocyte antigen-mismatched donor (hazard ratio = 3.04; P = .006) remained significant factors for survival. The study was registered at www.clinicaltrials.gov as #NCT 00599547.
Marie Robin, Reza Tabrizi, Mohamad Mohty, Sabine Furst, Mauricette Michallet, Jacques-Olivier Bay, Jean-Yves Cahn, Eric De Coninck, Nathalie Dhedin, Marc Bernard, Bernard Rio, Agnès Buzyn, Anne Huynh, Karin Bilger, Pierre Bordigoni, Nathalie Contentin, Raphaël Porcher, Gérard Socié, Noel Milpied
Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).
Br J Haematol. 2011 Feb;152(3):331-9. doi: 10.1111/j.1365-2141.2010.08417.x. Epub 2010 Dec 7.
Abstract/Text
Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non-relapse mortality (NRM), overall survival (OS) and progression-free survival (PFS) were analysed. One hundred and forty-seven patients, aged 20-68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre-transplant thrombocytopenia. Four-year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31-50), 32% (95%CI: 24-43) and 39% (95%CI 30-48), respectively. Multivariate analysis indicated that HLA-identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.
© 2010 Blackwell Publishing Ltd.
Karen K Ballen, Smriti Shrestha, Kathleen A Sobocinski, Mei-Jie Zhang, Asad Bashey, Brian J Bolwell, Francisco Cervantes, Steven M Devine, Robert Peter Gale, Vikas Gupta, Theresa E Hahn, William J Hogan, Nicolaus Kröger, Mark R Litzow, David I Marks, Richard T Maziarz, Philip L McCarthy, Gary Schiller, Harry C Schouten, Vivek Roy, Peter H Wiernik, Mary M Horowitz, Sergio A Giralt, Mukta Arora
Outcome of transplantation for myelofibrosis.
Biol Blood Marrow Transplant. 2010 Mar;16(3):358-67. doi: 10.1016/j.bbmt.2009.10.025. Epub 2009 Oct 30.
Abstract/Text
Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients.
Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Daniella M B Kerbauy, Theodore A Gooley, George E Sale, Mary E D Flowers, Kristine C Doney, George E Georges, Joanne E Greene, Michael Linenberger, Effie Petersdorf, Brenda M Sandmaier, Bart L Scott, Mohamed Sorror, Derek L Stirewalt, F Marc Stewart, Robert P Witherspoon, Rainer Storb, Frederick R Appelbaum, H Joachim Deeg
Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia.
Biol Blood Marrow Transplant. 2007 Mar;13(3):355-65. doi: 10.1016/j.bbmt.2006.11.004.
Abstract/Text
A total of 104 patients, aged 18 to 70 years, with a diagnosis of chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), or essential thrombocythemia (ET) with marrow fibrosis were transplanted from allogeneic (56 related and 45 unrelated) or syngeneic (n = 3) donors. Busulfan (BU) or total body irradiation (TBI)-based myeloablative conditioning regimens were used in 95 patients, and a nonmyeloablative regimen of fludarabine plus TBI was used in 9 patients. The source of stem cells was bone marrow in 43 patients and peripheral blood in 61 patients. A total of 63 patients were alive at a follow-up of 1.3-15.2 years (median, 5.3 years), for an estimated 7-year actuarial survival rate of 61%. Eleven patients had recurrent/persistent disease, of whom 8 died. Nonrelapse mortality was 34% at 5 years. Patients conditioned with targeted BU (plasma levels 800-900 ng/mL) plus cyclophosphamide (tBUCY) had a higher probability of survival (68%) than other patients. Dupriez score, platelet count, patient age, and comorbidity score were statistically significantly associated with mortality in univariate models. In a multivariable regression model, use of tBUCY (P = .03), high platelet count at transplantation (P = .01 for PV/ET; P = .39 for other diagnoses), younger patient age (P = .04), and decreased comorbidity score (P = .03) remained statistically significant for improved survival. Our findings show that hematopoietic cell transplantation offers potentially curative treatment for patients with ICMF, PV, or ET.
