Comparative Analysis of Myelofibrosis Treatment Outcomes with the Use of Ruxolitinib Versus Ruxolitinib with Subsequent Allogeneic Hematopoietic Stem Cell Transplantation

AUTOIMMUNE THROMBOCYTOPENIA ,

MV Barabanshchikova, EV Morozova, YuYu Vlasova, TL Gindina, AV Evdokimov, IM Barkhatov, VV Baikov, IO Ivanova, TA Rudakova, EA Bakin, IS Moiseev, AD Kulagin

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Mariya Vladimirovna Barabanshchikova, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(911)164-01-57; e-mail: maria.barabanshikova.spb@gmail.com

For citation: Barabanshchikova MV, Morozova EV, Vlasova YuYu, et al. Comparative Analysis of Myelofibrosis Treatment Outcomes with the Use of Ruxolitinib Versus Ruxolitinib with Subsequent Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2021;14(1):22–30. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-22-30

ABSTRACT

Aim. To comparatively analyze myelofibrosis treatment outcomes with the use of ruxolitinib versus ruxolitinib with subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT) as well as to assess the efficacy of ruxolitinib in pre- and post-transplantation periods.

Materials & Methods. The study enrolled 78 myelofibrosis patients who were referred to the RM Gorbacheva Scientific Research Institute to determine the indications for allo-HSCT. Allo-HSCT was performed in 33 patients, among them 32 patients with ruxolitinib pre-conditioning (ruxolitinib + allo-HSCT group). They received reduced intensity conditioning (fludarabine 180 mg/m2 and busulfan 10 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclophosphamide 50 mg/kg on Day +3 and Day +4, ruxolitinib 10 mg per day from Day +5 to Day +100 (n = 31), rabbit antithymocyte globulin, tacrolimus, and mycophenolate mofetil (n = 2). Ruxolitinib without allo-HSCT was administered to 45 patients (ruxolitinib group). Between the groups there were no significant differences with respect to gender, age, diagnosis, and molecular genetic variant.

Results. Median therapy duration in ruxolitinib group was 16 months (range 2–78 months). In 2 (4 %) patients partial response was achieved, 8 (20 %) patients showed clinical improvement, in 16 (39 %) patients stable disease (SD) was reported, in 15 (37 %) patients disease progression (DP) was detected. The treatment succeeded in reducing the spleen size in 8 (20 %) patients and in relieving disease symptoms in 16 (39 %) patients. Cumulative incidence of progression within 3 years was 44 % (95% confidence interval [95% CI] 27–60 %). In ruxolitinib + allo-HSCT group median ruxolitinib therapy duration was 7 months (range 3–22 months.). As a result, clinical improvement in 9 (28 %) cases, SD in 17 cases (53 %), and DP in 6 (19 %) cases were observed. In 5 (20 %) patients acute GVHD of grade 2–4, in 3 (12 %) patients acute GVHD of grade 3–4, and in 6 (24 %) patients chronic medium severity GVHD were identified. Within 1 year non-relapse mortality was 28 % (95% CI 14–44 %). The 3-year cumulative incidence of relapse was 12 % (95% CI 3–28 %) in ruxolitinib + allo-HSCT group. According to the landmark analysis performed throughout 6 months from the first visit to the center, the 3-year overall survival in the group with allo-HSCT was 80 %, whereas in ruxolitinib group it was 41 % (p = 0.022), 12-month landmark analysis resulted in 77 % and 43 % (p = 0.028), and 18-month landmark analysis showed 86 % and 46 % (p = 0.015) in two groups, respectively.

Conclusion. Despite the efficacy of JAK1/2 inhibitor ruxolitinib, the risk of myelofibrosis progression is not to be underestimated. Therefore, in DIPSS intermediate-2 and high-risk patients the issue about performing allo-HSCT should be promptly clarified.

Keywords: myelofibrosis, ruxolitinib, allogeneic hematopoietic stem cell transplantation.

Received: September 28, 2020

Accepted: December 15, 2020

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REFERENCES

  1. Arber D, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.
  2. Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635–42. doi: 10.1182/blood-2014-07-575373.
  3. Меликян А.Л., Ковригина А.М., Суборцева И.Н. и др. Национальные клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз) (редакция 2018 г.). Гематология и трансфузиология. 2018;63(3):275–315.
    [Melikyan AL, Kovrigina AM, Subortseva IN, et al. National clinical recommendations for diagnosis and therapy of Ph-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis) (edition of 2018). Gematologiya i transfuziologiya. 2018;63(3):275–315. (In Russ)]
  4. Verstovsek S, Mesa R, 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.
  5. 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.
  6. Morozova E, Barabanshikova M, Gindina T, et al. Hematopoietic stem cell transplantation and other therapeutic options in primary myelofibrosis: a review and two case reports. Cell Ther Transplant. 2016;5(2):21–32. doi: 10.18620/1866-8836-2016-5-2-21-32.
  7. Kroger N, Giorgino T, Scott B, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347–50. doi: 10.1182/blood-2014-10-608315.
  8. Passamonti F, Cervantes F, Vannucchi A, 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):1703–8. doi: 10.1182/blood-2009-09-245837.
  9. Kroger N, Holler E, Kobbe G, et al. 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;114(26):5264–70. doi: 10.1182/blood-2009-07-234880.
  10. Morozova E, Barabanshikova M, Moiseev I, et al. A Prospective Pilot Study of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis. Acta Haematologica. 2020:1–8. doi: 10.1159/000506758.
  11. Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128–32.
  12. 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):1395–8. doi: 10.1182/blood-2013-03-488098.
  13. Singer M, Deutschman C, Seymour C, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801. doi: 10.1001/jama.2016.0287.
  14. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21. doi: 10.1086/588660.
  15. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118(4):255–67. doi: 10.7326/0003-4819-118-4-199302150-00003.
  16. Gowin K, Ballen K, Ahn K, et al. Survival following allogeneic transplant in patients with myelofibrosis. Blood Adv. 2020;4(9):1965–73. doi: 10.1182/bloodadvances.2019001084.
  17. Dafni U. Landmark Analysis at the 25-Year Landmark Point. Circ Cardiovasc Qual Outcomes. 2011;4(3):363–71. doi: 10.1161/circoutcomes.110.957951.
  18. Барабанщикова М.В. Клинико-морфологические особенности и факторы прогноза при Ph-негативных хронических миелопролиферативных заболеваниях: Автореф. дис. … мед. наук. СПб., 2016.
    [Barabanshchikova MV. Kliniko-morfologicheskie osobennosti i faktory prognoza pri Ph-negativnykh khronicheskikh mieloproliferativnykh zabolevaniyakh. (Clinical morphological characteristics and prognostic factors in Ph-negative chronic myeloproliferative diseases.) [dissertation] Saint Petersburg; (In Russ)]
  19. Gowin K, Ballen K, Ahn K, et al. Survival following allogeneic transplant in patients with myelofibrosis. Blood Adv. 2020;4(9):1965–73. doi: 10.1182/bloodadvances.2019001084.
  20. Ruggiu M, Cassinat B, Kiladjian J, et al. Should Transplantation Still Be Considered for Ph1-Negative Myeloproliferative Neoplasms in Transformation? Biol Blood Marrow Transplant. 2020;26(6):1160–70. doi: 10.1016/j.bbmt.2020.02.019.
  21. Shanavas M, Popat U, Michaelis L, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. Biol Blood Marrow Transplant. 2016;22(3):432–40. doi: 10.1016/j.bbmt.2015.10.005.
  22. Alchalby H, Yunus D, Zabelina T, et al. Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2016;51(9):1223–7. doi: 10.1038/bmt.2016.98.
  23. Рудакова Т.А., Кулагин А.Д., Климова О.У. и др. Тяжелая гипофункция трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток у взрослых пациентов: частота, факторы риска, исходы. Клиническая онкогематология. 2019;12(3):309–18. doi: 10.21320/2500-2139-2019-12-3-309-318.
    [Rudakova TA, Kulagin AD, Klimova OU, et al. Severe “Poor Graft Function” after Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients: Incidence, Risk Factors, and Outcomes. Clinical oncohematology. 2019;12(3):309–18. doi: 10.21320/2500-2139-2019-12-3-309-318. (In Russ)]
  24. Rashidi A, Hamadani M, Zhang M, et al. Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission. Blood Adv. 2019;3(12):1826–36. doi: 10.1182/bloodadvances.2019000050.
  25. Gupta V, Kosiorek HE, Mead A, et al. Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study. Biol Blood Marrow Transplant. 2019;25(2):256–64. doi: 10.1016/j.bbmt.2018.09.001.
  26. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020;382(19):1800–10. doi: 10.1056/nejmoa1917635.
  27. Pu JJ, Poulose J, Malysz J, et al. Impact of ruxolitinib on myelofibrosis patients post allogeneic stem cell transplant—a pilot study. Br J Haematol. 2019;186(5):е130–е133. doi: 10.1111/bjh.15967.
  28. Kroger N, Shahnaz Syed Abd Kadir S, Zabelina T, et al. Peritransplantation Ruxolitinib Prevents Acute Graft-versus-Host Disease in Patients with Myelofibrosis Undergoing Allogenic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018;24(10):2152–6. doi: 10.1016/j.bbmt.2018.05.023.
  29. Choi J, Cooper ML, Alahmari B, et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PLoS ONE. 2014;9(10):e109799. doi: 10.1371/journal.pone.0109799.