Incidence of blast phase in myelofibrosis patients according to anemia severity at ruxolitinib start and during therapy.
anemia
blast phase
myelofibrosis
ruxolitinib
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
15 Apr 2024
15 Apr 2024
Historique:
revised:
19
10
2023
received:
07
09
2023
accepted:
14
11
2023
pubmed:
28
12
2023
medline:
28
12
2023
entrez:
28
12
2023
Statut:
ppublish
Résumé
Anemia is frequently present in patients with myelofibrosis (MF), and it may be exacerbated by treatment with the JAK2-inhibitor ruxolitinib (RUX). Recently, a relevant blast phase (BP) incidence has been reported in anemic MF patients unexposed to RUX. The authors investigated the incidence of BP in 886 RUX-treated MF patients, included in the "RUX-MF" retrospective study. The BP incidence rate ratio (IRR) was 3.74 per 100 patient-years (3.74 %p-y). At therapy start, Common Terminology Criteria for Adverse Events grade 3-4 anemia (hemoglobin [Hb] <8 g/dL) and severe sex/severity-adjusted anemia (Hb <8/<9 g/dL in women/men) were present in 22.5% and 25% patients, respectively. IRR of BP was 2.34 in patients with no baseline anemia and reached respectively 4.22, 4.89, and 4.93 %p-y in patients with grade 1, 2, and 3-4 anemia. Considering the sex/severity-adjusted Hb thresholds, IRR of BP was 2.85, 4.97, and 4.89 %p-y in patients with mild/no anemia, moderate, and severe anemia. Transfusion-dependent patients had the highest IRR (5.03 %p-y). Progression-free survival at 5 years was 70%, 52%, 43%, and 27% in patients with no, grade 1, 2, and 3-4 anemia, respectively (p < .001). At 6 months, 260 of 289 patients with no baseline anemia were receiving ruxolitinib, and 9.2% had developed a grade 3-4 anemia. By 6-month landmark analysis, BP-free survival was significantly worse in patients acquiring grade 3-4 anemia (69.3% vs. 88.1% at 5 years, p < .001). This study highlights that anemia correlates with an increased risk of evolution into BP, both when present at baseline and when acquired during RUX monotherapy. Innovative anemia therapies and disease-modifying agents are warranted in these patients.
Sections du résumé
BACKGROUND
BACKGROUND
Anemia is frequently present in patients with myelofibrosis (MF), and it may be exacerbated by treatment with the JAK2-inhibitor ruxolitinib (RUX). Recently, a relevant blast phase (BP) incidence has been reported in anemic MF patients unexposed to RUX.
METHODS
METHODS
The authors investigated the incidence of BP in 886 RUX-treated MF patients, included in the "RUX-MF" retrospective study.
RESULTS
RESULTS
The BP incidence rate ratio (IRR) was 3.74 per 100 patient-years (3.74 %p-y). At therapy start, Common Terminology Criteria for Adverse Events grade 3-4 anemia (hemoglobin [Hb] <8 g/dL) and severe sex/severity-adjusted anemia (Hb <8/<9 g/dL in women/men) were present in 22.5% and 25% patients, respectively. IRR of BP was 2.34 in patients with no baseline anemia and reached respectively 4.22, 4.89, and 4.93 %p-y in patients with grade 1, 2, and 3-4 anemia. Considering the sex/severity-adjusted Hb thresholds, IRR of BP was 2.85, 4.97, and 4.89 %p-y in patients with mild/no anemia, moderate, and severe anemia. Transfusion-dependent patients had the highest IRR (5.03 %p-y). Progression-free survival at 5 years was 70%, 52%, 43%, and 27% in patients with no, grade 1, 2, and 3-4 anemia, respectively (p < .001). At 6 months, 260 of 289 patients with no baseline anemia were receiving ruxolitinib, and 9.2% had developed a grade 3-4 anemia. By 6-month landmark analysis, BP-free survival was significantly worse in patients acquiring grade 3-4 anemia (69.3% vs. 88.1% at 5 years, p < .001).
CONCLUSIONS
CONCLUSIONS
This study highlights that anemia correlates with an increased risk of evolution into BP, both when present at baseline and when acquired during RUX monotherapy. Innovative anemia therapies and disease-modifying agents are warranted in these patients.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1270-1280Subventions
Organisme : Ministero della Salute
ID : RC-2023-2778976
Informations de copyright
© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
Références
Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/BLOOD.2022015850
Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res. 2007;31(6):737-740. doi:10.1016/J.LEUKRES.2006.12.002
Passamonti F, Mora B. Myelofibrosis. Blood. 2023;141(16):1954-1970. doi:10.1182/BLOOD.2022017423
Naymagon L, Mascarenhas J. Myelofibrosis-related anemia: current and emerging therapeutic strategies. Hemasphere. 2017;1(1):e1. doi:10.1097/HS9.0000000000000001
Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo Clinic experience. Mayo Clin Proc. 2012;87(1):25-33. doi:10.1016/J.MAYOCP.2011.11.001
Tefferi A, Hudgens S, Mesa R, et al. Use of the functional assessment of cancer therapy--anemia in persons with myeloproliferative neoplasm-associated myelofibrosis and anemia. Clin Therapeut. 2014;36(4):560-566. doi:10.1016/J.CLINTHERA.2014.02.016
Passamonti F, Cervantes F, Vannucchi AM, et al. 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;115(9):1703-1708. doi:10.1182/BLOOD-2009-09-245837
Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31(12):2726-2731. doi:10.1038/LEU.2017.169
Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901. doi:10.1182/BLOOD-2008-07-170449
Passamonti F, Cervantes F, Vannucchi AM, et al. Dynamic International Prognostic Scoring System (DIPSS) predicts progression to acute myeloid leukemia in primary myelofibrosis. Blood. 2010;116(15):2857-2858. doi:10.1182/BLOOD-2010-06-293415
Vallapureddy RR, Mudireddy M, Penna D, et al. Leukemic transformation among 1306 patients with primary myelofibrosis: risk factors and development of a predictive model. Blood Cancer J. 2019;9(2):12. doi:10.1038/S41408-019-0175-Y
Mora B, Maffioli M, Rumi E, et al. Incidence of blast phase in myelofibrosis according to anemia severity. EJHaem. 2023;4(3):679-689. doi:10.1002/jha2.745
Harrison CN, Schaap N, Vannucchi AM, et al. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: an updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure. Am J Hematol. 2020;95(6):594-603. doi:10.1002/AJH.25777
Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073-79086. doi:10.18632/ONCOTARGET.18674
Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMOA1110556
Gupta V, Harrison C, Hexner EO, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica. 2016;101(12):e482-e484. doi:10.3324/HAEMATOL.2016.151449
Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/S41408-018-0054-Y
Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108(5):1497-1503. doi:10.1182/BLOOD-2006-03-009746
Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128-1132. doi:10.1159/000101708
Gangat N, Caramazza D, Vaidya R, et al. 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;29(4):392-397. doi:10.1200/JCO.2010.32.2446
Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30(33):4098-4103. doi:10.1200/JCO.2012.42.3863
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122(8):1395-1398. doi:10.1182/BLOOD-2013-03-488098
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 2017. Accessed July 20, 2023. https://www.meddra.org/
Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol. 2018;36(17):1769-1770. doi:10.1200/JCO.2018.78.9867
Iurlo A, Cattaneo D, Gianelli U. Blast transformation in myeloproliferative neoplasms: risk factors, biological findings, and targeted therapeutic options. Int J Mol Sci 2019;20(8):1839. doi:10.3390/IJMS20081839
Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. 2020;126(6):1243-1252. doi:10.1002/CNCR.32664
Tallarico M, Odenike O. Secondary acute myeloid leukemias arising from Philadelphia chromosome negative myeloproliferative neoplasms: pathogenesis, risk factors, and therapeutic strategies. Curr Hematol Malig Rep. 2015;10(2):112-117. doi:10.1007/S11899-015-0259-0/METRICS
Tashi T, Yu J, Pandya S, Dieyi C, Scherber R, Parasuraman S. Trends in overall mortality among US veterans with primary myelofibrosis. BMC Cancer. 2023;23(1):1-8. doi:10.1186/S12885-022-10495-6/FIGURES/2
Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate-to high-risk myelofibrosis: impact of ruxolitinib approval. Ann Hematol. 2022;101(1):131-137. doi:10.1007/S00277-021-04682-X
Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/S13045-017-0527-7
Palandri F, Breccia M, Tiribelli M, et al. Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: real-world data. Hematol Oncol. 2020;38(3):372-380. doi:10.1002/HON.2737
Passamonti F, Rumi E, Elena C, et al. Incidence of leukaemia in patients with primary myelofibrosis and RBC-transfusion-dependence. Br J Haematol. 2010;150(6):719-721. doi:10.1111/J.1365-2141.2010.08275.X
Huang J, Li CY, Mesa RA, et al. Risk factors for leukemic transformation in patients with primary myelofibrosis. Cancer. 2008;112(12):2726-2732. doi:10.1002/CNCR.23505
Palandri F, Breccia M, Mazzoni C, et al. Ruxolitinib in cytopenic myelofibrosis: response, toxicity, drug discontinuation, and outcome. Cancer. 2023;129(11):1704-1713. doi:10.1002/CNCR.34722
Dupriez B, Morel P, Demory J, et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996;88(3):1013-1018. doi:10.1182/BLOOD.V88.3.1013.1013
Vaidya R, Caramazza D, Begna KH, et al. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood. 2011;117(21):5612-5615. doi:10.1182/BLOOD-2010-11-320002
Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-1869. doi:10.1038/LEU.2013.119
Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494-1500. doi:10.1038/LEU.2014.57
Verstovsek S. How I manage anemia related to myelofibrosis and its treatment regimens. Ann Hematol. 2023;102(4):689-698. doi:10.1007/S00277-023-05126-4
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMOA1110557/SUPPL_FILE/NEJMOA1110557_DISCLOSURES.PDF
Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864. doi:10.1182/BLOODADVANCES.2021006889
Scalzulli E, Ielo C, Luise C, et al. RR6 prognostic model provides information about survival for myelofibrosis treated with ruxolitinib: validation in a real-life cohort. Blood Adv. 2022;6(15):4424-4426. doi:10.1182/BLOODADVANCES.2022008158
Duminuco A, Nardo A, Garibaldi B, et al. Prediction of survival and prognosis migration from gold-standard scores in myelofibrosis patients treated with ruxolitinib applying the RR6 prognostic model in a monocentric real-life setting. J Clin Med. 2022;11(24):7418. doi:10.3390/JCM11247418
Palumbo GA, Galimberti S, Barcellini W, et al. From biology to clinical practice: iron chelation therapy with deferasirox. Front Oncol. 2021;11. doi:10.3389/FONC.2021.752192
Isidori A, Borin L, Elli E, et al. Iron toxicity-its effect on the bone marrow. Blood Rev. 2018;32(6):473-479. doi:10.1016/J.BLRE.2018.04.004
Elli EM, Di Veroli A, Bartoletti D, et al. Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: the multicentre retrospective RUX-IOL study. Br J Haematol. 2022;197(2):190-200. doi:10.1111/BJH.18057
Passamonti F, Harrison CN, Mesa RA, Kiladjian JJ, Vannucchi AM, Verstovsek S. Anemia in myelofibrosis: current and emerging treatment options. Crit Rev Oncol Hematol. 2022;180:103862. doi:10.1016/J.CRITREVONC.2022.103862