Latest Research on Myelofibrosis : Nov 2020


New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment

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 × 109/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. [1]

Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis

BACKGROUND

Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor.

METHODS

We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis.

RESULTS

A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.

CONCLUSIONS

INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. [2]

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)

The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic myeloid metaplasia (AMM), myelofibrosis with myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) “leukemic” transformation will be recognized as blast phase disease. [3]

The Prevalence of JAK2-V617F Mutation in Sudanese Patients with Chronic Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are clonal malignant diseases that represent a group of conditions including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The JAK2-V617F mutation has been described as a frequent genetic event in majority of patients with MPNs. The aim of this study was to determine the frequency of JAK2-V617Fmutation in Sudanese patients with myeloproliferative disorders referred to Isotope Center, and to investigate the differences of laboratory parameters between patients with JAK2-V617F positive myeloproliferative neoplasms (MPNs) and JAK2 wild type MPNs. A total of 259 patients with MPNs; 159 with polycythemia vera (PV), 55 with essential thrombocytosis (ET) and 45 with primary myelofibrosis (PMF), and11 healthy adult individuals were enrolled in this study from March 2013 to November 2015. DNA was isolated from peripheral blood leukocytes by innuPREP kit, and JAK2-V617F mutation gene detected by allele specific PCR. The JAK2-V617F mutation was detected in 71% (184/259) patients with MPNs. The prevalence of the mutation was 81.7% in PV, 56.4% inET, and 51.1% in PMF. Mutation was not detected in 11 healthy adult people. The presence of JAK2-V617F was not associated with Hb level, Hct, or the platelet count for PV and ET, whoever the mutation positively correlated with high Hb (P=.039), Hct (P=.04) in PMF patients, and with high erythrocytes count in PV. The JAK2-V617F mutation can be frequently detected in the Sudanese patients with MPNs. [4]

Palliative Radiotherapy for Spinal Extramedullary Hematopoiesis in Thalassemia Major

Introduction: Non-hepatosplenic Extramedullary Hematopoiesis (NHEMH) is seen as a compensation mechanism in the patients with hematologic dysfunction. Thalassemia is an autosomal recessive hematologic disorder. The tissue involvement is seen very rarely in thalasemia major.

Case: A 45-years old patient diagnosed with thalassemia major was presented in this case report. The patient had splenectomy after 12 years from diagnosis and he was followed with continuous blood transfusions. Due to the newly emerged chest pain and dyspnea, he was evaluated with computed tomography. The operation was done for paraspinal masses caused by NHEMH. But same complaints were seen after 5 years from the operation. Paraspinal and sacral recurrences were detected in screening examinations. External palliative radiotherapy (ERT) was given to the patient with 3000 cGy total doses. Both clinical and radiological response was obtained with ERT.

Conclusion: Radiotherapy might be considered as an efficient palliative treatment option for the thalassemia major patients with NHEMH masses recurring after operation. [5]

Reference

[1] Cervantes, F., Dupriez, B., Pereira, A., Passamonti, F., Reilly, J.T., Morra, E., Vannucchi, A.M., Mesa, R.A., Demory, J.L., Barosi, G. and Rumi, E., 2009. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood, 113(13), pp.2895-2901.

[2] Verstovsek, S., Kantarjian, H., Mesa, R.A., Pardanani, A.D., Cortes-Franco, J., Thomas, D.A., Estrov, Z., Fridman, J.S., Bradley, E.C., Erickson-Viitanen, S. and Vaddi, K., 2010. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. New England Journal of Medicine, 363(12), pp.1117-1127.

[3] Mesa, R.A., Verstovsek, S., Cervantes, F., Barosi, G., Reilly, J.T., Dupriez, B., Levine, R., Le Bousse-Kerdiles, M.C., Wadleigh, M., Campbell, P.J. and Silver, R.T., 2007. 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). Leukemia research, 31(6), pp.737-740.

[4] Abkar, H. M., Mohamed, B. A. and Hassan, F. M. (2016) “The Prevalence of JAK2-V617F Mutation in Sudanese Patients with Chronic Myeloproliferative Neoplasms”, Journal of Advances in Medicine and Medical Research, 14(5), pp. 1-7. doi: 10.9734/BJMMR/2016/24741.

[5] Karaca, F., Usul Afsar, C., Sert, F., Guner, S., Ercolak, V., Erkurt, E. and Tunali, C. (2015) “Palliative Radiotherapy for Spinal Extramedullary Hematopoiesis in Thalassemia Major”, International Blood Research & Reviews, 3(3), pp. 124-129. doi: 10.9734/IBRR/2015/17235.

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