Page 85 - Haematologica3

Pegylated interferon-α in myelofibrosis
This is in contrast with the results obtained by Verger et al. in patients with essential thrombocythemia in whom a reduction of the median mutant CALR allele burden from 41 to 26% was observed in a cohort of 31 patients.32
Besides the classical driver mutations, we identified at least one additional mutation in 28/49 patients with a mean of 1.6 additional mutations per patient. The presence of at least one mutation significantly reduced leukemia- free survival and the presence of more than one mutation was associated with a decrease of both overall survival and leukemia-free survival. Such a negative impact of addition- al mutations on survival is in line with previous findings in myelofibrosis patients.7 Vannucchi et al. have reported that mutations in ASXL1, EZH2, SRSF2 or IDH1/2 carried a stronger adverse prognostic impact, defining a high molec- ular risk profile.6 In our study, the presence of these HMR mutations affected outcome, but not more than other non- HMR mutations did. ASXL1 mutations alone did not sig- nificantly affect survival, but this may be due to the limited number of patients carrying this mutation in our series. However, our data could indicate that the higher risk asso- ciated with mutations affecting ASXL1, EZH2, SRSF2 or IDH1/2 could be in part reduced by interferon therapy. Another possible explanation for the discrepancy between our results regarding HMR mutations and those published by Vannucchi and colleagues is that our cohort of patients included a higher proportion with secondary myelofibro- sis. Indeed, Rotunno et al. reported that only SRSF2 muta- tions affected survival in secondary myelofibrosis.33 Lastly, additional mutations were more frequently found in patients intolerant of or resistant to interferon, a finding in agreement with the results published by Silver et al. indi- cating that additional mutations are more frequent in patients who could not remain on pegylated interferon therapy.31 They also reported that a higher number of mutations, including HMR mutations, is associated with poorer response to interferon.
The limitations of our study include the absence of eval-
uation of symptoms and measurements of cytokine levels. Such studies were not possible due to the lack of a validat- ed specific tool in French for symptom assessment in myelofibrosis at the time the study was initiated, and to the absence of stored plasma or serum given the observa- tional nature of the study. Other important information would have been gained from sequential evaluation of bone marrow biopsies since it has been shown that inter- feron therapy may reduce fibrosis in selected cases.34 Although all patients had a biopsy for the diagnosis of their disease, investigators did not perform new biopsies after interferon therapy, so the impact of the treatment on this aspect of the disease could not be studied in this cohort of patients.
In conclusion, while we have previously reported the clinical and hematologic efficacy of pegylated interferon- α2a treatment in myelofibrosis patients, this long-term analysis suggests that interferon therapy may also improve overall survival and leukemia-free survival. In contrast, interferon therapy before ASCT could increase the risk of GvHD and should probably be avoided in this context. Intolerance of or resistance to interferon identifies a group of patients with a dismal outcome, as does the presence of additional mutations. These results indicate that even in the ruxolitinib era, the place of pegylated interferon-α2a should be discussed in patients with myelofibrosis, the optimal target population possibly being high-risk myelofibrosis patients without the prospect of ASCT and with proliferative disease.
Acknowledgments
The authors would like to thank all the clinical research team members who participated in data collection. We also thank the “Ligue contre le cancer” for their continuous support of research into myeloproliferative neoplasms at Brest Hospital. This study is part of the “CTIM3” project supported by a grant from the French Cancer Institute (INCa), TRANSLA13-140 and of the FIMBANK project (INCa BCB 2013).
References
1. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post poly- cythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofi- brosis (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.
2. Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(12): 1262-1271.
3. Cervantes F, Tassies D, Salgado C, Rovira M, Pereira A, Rozman C. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol. 1991;85(3):124-127.
4. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390.
5. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloprolifera- tive neoplasms with nonmutated JAK2. N
Engl J Med. 2013;369(25):2391-2405.
6. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-
1869.
7. Guglielmelli P, Lasho TL, Rotunno G, et al.
The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28(9):1804-1810.
8. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best avail- able therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.
9. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of rux- olitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
10. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9): 1139-1145.
11. Passamonti F, Vannucchi AM, Cervantes F, et al. Ruxolitinib and survival improvement in patients with myelofibrosis. Leukemia. 2015;29(3):739-740.
12. Cervantes F, Pereira A. Does ruxolitinib pro- long the survival of patients with myelofi- brosis? Blood. 2016;129(7):832-837.
13. Alchalby H, Kröger N. Allogeneic stem cell transplant vs. Janus kinase inhibition in the treatment of primary myelofibrosis or myelofibrosis after essential thrombo- cythemia or polycythemia vera. Clin Lymphoma Myeloma Leuk. 2014;14 (Suppl):S36-41.
14. Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN International Working Group. Leukemia. 2015;29(11):2126-2133.
15. Kröger N, Giorgino T, Scott BL, 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):3347-3350.
16. Robin M, Porcher R, Wolschke C, et al. Outcome after transplantation according to reduced-intensity conditioning regimen in patients undergoing transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2016;22(7):1206-1211.
17. Ianotto JC, Kiladjian JJ, Demory JL, et al. PEG-IFN-alpha-2a therapy in patients with
haematologica | 2018; 103(3)
445