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1
Tsutsui, Miyuki, Hajime Yasuda, Yasunori Ota, and Norio Komatsu. "Splenic Marginal Zone Lymphoma with Prominent Myelofibrosis Mimicking Triple-Negative Primary Myelofibrosis." Case Reports in Oncology 12, no. 3 (2019): 834–37. http://dx.doi.org/10.1159/000504129.
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Myelofibrosis (MF) can occur due to a wide variety of causes including malignant lymphoma. We report a case of splenic marginal zone lymphoma complicated by MF mimicking primary myelofibrosis (PMF). The JAK2, CALR and MPL mutations are detected in more than 90% of PMF cases, and when detected, the diagnosis of PMF is usually straight forward. Mutational analysis should be done in all cases of MF, and in triple-negative cases, an exhaustive investigation of other causes of MF should be carried out before a diagnosis of triple-negative PMF is rendered.
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Afroz, Sadia, AKM Nurul Kabir, Bishnu Pada Dey, et al. "Degree of fibrosis and its association with angiogenesis in the myelofibrotic bone marrow." Bangabandhu Sheikh Mujib Medical University Journal 16, no. 1 (2023): 26–34. http://dx.doi.org/10.3329/bsmmuj.v16i1.65664.
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Background: Primary and secondary myelofibrosis has become a global burden due to its increased mortality and morbidity. Angiogenesis is a significant driving force in the development of fibrogenesis in the bone marrow, which leads to myelofibrosis. The microvascular density (MVD) with immunomarker CD34 can be used to assess the degree of angiogenesis. The objective of this study was to examine the association between degree of myelofibrosis and angiogenesis in hematological malignancies. Methods: Forty-six trephine biopsy specimens of various hematological malignancies with myelofibrosis were studied at the Department of Pathology of Bangabandhu Sheikh Mujib Medical University. Extent of myelofibrosis in each case was assessed by examining the reticulin and Masson’s trichrome stained sections using a semiquantitative grading system of bone marrow fibrosis (MF) within a scale of MF-0 to MF-3. Angiogenesis was measured by counting MVD in the ‘hotspots’ after immunostaining with CD34 antibody. Results: The trephine biopsy cases were grouped into early fibrotic (MF-1) and advanced fibrotic (MF-2,3) consisting of 16 (34.8%) and 30 (65.2%) patients, respectively. Angiogenesis was estimated as mean MVD count which revealed 16.7 ± 5.4 and 32.0 ± 11.5 in these groups, respectively. Significant difference of mean MVD values (P<0.001) between the early and advanced fibrotic groups revealed the association of angiogenesis and degree of myelofibrosis. Conclusion: MVD may be used to measure angiogenesis in myelofibrotic marrow along with other clinical and laboratory indices as a marker of disease activity in hematological malignancies, thus aiding disease prognosis. Bangabandhu Sheikh Mujib Medical University Journal 2023;16(1): 26-34
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Feng, Qiutian, Shiwei Hu, Xinlu Zhang, and Jian Huang. "The Upregulation of the FBLN1 and HS3ST4 Genes May Represent a Potential Mechanism Driving the Fibrotic Progression in Primary Myelofibrosis and Leading to Adverse Prognosis." Blood 142, Supplement 1 (2023): 6348. http://dx.doi.org/10.1182/blood-2023-184842.
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Myelofibrosis is a group of diseases characterized by increased proliferation of bone marrow fibrous connective tissue and a decrease in hematopoietic cells, leading to impaired bone marrow hematopoietic function. Myelofibrosis includes primary myelofibrosis（PMF）, myelofibrosis secondary to polycythemia vera（post-PV MF）, and myelofibrosis secondary to essential thrombocythemia（post-ET MF）. Studies suggest that certain genes may be responsible for driving the development of myelofibrosis and causing adverse prognosis. By conducting RNA-Seq analysis, we investigated the differentially expressed genes and their impact on prognosis in primary myelofibrosis and secondary myelofibrosis. Furthermore, we analyzed the potential mechanisms driving the progression of fibrosis. Additionally, we performed a comparative analysis of the clinical features among various types of myelofibrosis. In this study, we performed transcriptome sequencing to analyze gene expression differences in 14 overt-PMF samples, 5 post-ET MF samples, and 3 post-PV MF samples.Functional and pathway analyses were conducted on these differentially expressed genes, and cluster heatmaps were used to visualize their expression patterns.Simultaneously, we performed a comparative analysis of clinical characteristics among 370 overt-PMF patients, 96 post-ET MF patients, and 52 post-PV MF patients.The study revealed that compared to post-PV MF, overt-PMF showed 81 upregulated and 2 downregulated differentially expressed genes, while compared to post-ET MF, overt-PMF displayed 19 upregulated and 3 downregulated differentially expressed genes (Figure a) (Figure b). Based on the similarity of gene expression profiles among the samples, a clustering analysis was performed (Figure c).The results demonstrated that in overt-PMF, the FBLN1 gene was significantly upregulated compared to post-PV MF and was enriched in pathways related to extracellular matrix formation and cell adhesion among the differentially expressed genes (Figure d). Additionally, the HS3ST4 gene was significantly upregulated in overt-PMF compared to post-ET MF and was enriched in pathways related to interleukin-8 generation and regulation of cytokine production involved in inflammatory responses.In the analysis of clinical characteristics among different types of myelofibrosis patients, it was observed that overt-PMF was more prone to transform into acute leukemia compared to post-PV MF, had a higher tendency to develop transfusion dependency (Figure e), and exhibited lower hemoglobin levels and hematocrit at the time of diagnosis (Figure f). Moreover, compared to post-ET MF, overt-PMF had a higher likelihood of transforming into acute leukemia and lower platelet counts at the time of diagnosis. The research findings indicate that the expressions of FBLN1 and HS3ST4 genes are significantly upregulated in overt-PMF, and patients with overt-PMF have a worse prognosis compared to those with post-PV MF and post-ET MF. Previous studies have shown that FBLN1 is involved in extracellular matrix assembly, promoting the formation and stabilization of collagen fibers. It can also interact with integrin receptors and other cell adhesion molecules, participating in cell-extracellular matrix signaling processes. On the other hand, HS3ST4 is involved in processes such as cell adhesion, cell migration, and cell signaling. Based on these findings, it is speculated that the upregulation of FBLN1 and HS3ST4 gene expressions may potentially drive the progression of fibrosis and lead to an adverse prognosis in patients with myelofibrosis. Acknowledgement: This research was funded by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; Zhejiang Medical Association Clinical Medical Research special fund project, No. 2022ZYC-D09. Correspondence to: Dr Jian Huang, Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine. No. 79 Qingchun Road. Hangzhou, Zhejiang, PR China. househuang@zju.edu.cn
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Shi, Guanfang, Sreenath Kodali, Ching Wong, Vladimir K. Gotlieb, and Jen-Chin Wang. "Defective Autophagy Process and Increased ROS Formation in Primary Myelofibrosis." Blood 132, Supplement 1 (2018): 3069. http://dx.doi.org/10.1182/blood-2018-99-112406.
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Abstract Introduction: We and others have reported markedly increased ROS formation in primary myelofibrosis (MF) including post-ET or PV-MF when compared with essential thrombocytosis (ET), polycythemia vera (PV) and normal controls. A growing body of evidence illustrates the interdependency between the Keap1-Nrf2 pathway and p62-mediated selective autophagy, are playing an important role in major cellular defense mechanisms against oxidative and electrophilic stress ; dysregulation of p62-Keap1-Nrf2 axis has been implicated in tumor development. Therefore, we studied p62 mediated autophagy and Nrf2 pathways in patients with MF ,ET and PV. M aterials and Methods :33 patients including 15 patients with MF, 7 patients with PV, 11 patients with ET and 10 normal controls were studied. Cellular ROS measurement: Cellular ROS was determined by a dichlorofluorescein (DCF) assay. The oxidation of H2DCFDA was measured by flow cytometry. Real-time PCR assay: Total RNA was extracted from normal control or patient mononuclear cells using RNeasy Kits from Qiagen (Germantown, MD). Real-time PCR was performed using SsoAdvanced™ Universal SYBR® Green Supermix (Bio-Rad, Hercules, CA) on Bio-Rad iQ5 Multicolor Real-Time PCR Detection System. Western blotting: Total cell lysates were obtained from normal control or patient mononuclear cells. Primary antibodies against Beclin-1, LC3 and p62 were purchased from Cell Signaling Technology (Danvers, MA). Results: Fig.1a shows significantly elevated ROS in MF (2127±261.6) when compared with PV (1090 ± 163.8) or ET (1031 ± 140.9) or controls (549.1 ± 52.50). Fig.1b. shows that Nrf2 protein levels (ratio to controls) was significantly reduced in MF (41.84 ± 29.33), PV (14.42 ± 2.96), ET (14.05 ± 3.02), than the controls ( 101.3 ± 7.64). Fig.1c shows that the RT-PCR values of p62 was significantly increased in MF (1.34 ± 0.06) and grouped PV (1.21 ± 0.07), ET (1.14 ± 0.08) and MF as MPN (1.27 ± 0.04) than controls (1.00 ± 0.05),( P<0.05); ET or PV were not significantly elevated than controls. Conclusions: Patients with MF had increased levels of ROS when compared with PV and ET while Nrf2 levels were significantly reduced in all three( ET,PV, MF) which implies defective detoxification process in MPNs. P62, a marker for defective autophagy was significantly increased in MF than controls . This implies that there is a defective autophagy process in MF, contributing further to the formation of P62 and ROS. There is also a defective detoxification mechanism which further leads to more ROS formation and further DNA damage. Further studies are in progress on other autophagy markers which will enlighten more about the pathophysiology of MF. Disclosures Wang: INCYTE: Other: clinical trial.
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Resti, Nimas, Mohammad Rizki, and Dita Kholida Nurlalwani. "PRIMARY MYELOPHYBROSIS: RECOGNIZING ONCET TO COMPLICATIONS." Jurnal Ilmu Kesehatan 10, no. 2 (2022): 134–44. http://dx.doi.org/10.30650/jik.v10i2.3568.
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Myelofibrosis is the accumulation of scar tissue in the bone marrow so that blood cells cannot develop properly. Myeloproliferative disorders, myelofibrosis is classified into two, namely primary myelofibrosis and secondary myelofibrosis. In contrast to secondary myelofibrosis, primary myelofibrosis can occur without being preceded by myeloproliferative disorders or other diseases. In a 2013 meta-analysis study in Europe, the incidence of primary myelofibrosis (PMF) was around 0.3 per 100,000 per year. PMF may result from increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling. The most common clinical features found in patients with PMF are splenomegaly, hepatomegaly, fatigue, anemia, leukocytosis, and thrombocytosis. Currently the only treatment modality capable of prolonging survival or healing potential in MF is allogeneic hematopoietic stem cell transplantation (AHSCT) especially for high or very high risk patients.
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Gill, Harinder, Lester Au, Rita Yim, et al. "Ropeginterferon alfa-2b for pre-fibrotic primary myelofibrosis and DIPSS low/intermediate-risk myelofibrosis." Journal of Clinical Oncology 43, no. 16_suppl (2025): 6573. https://doi.org/10.1200/jco.2025.43.16_suppl.6573.
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6573 Background: There is currently no consensus on the optimal treatment for primary myelofibrosis (PMF) in pre-/early fibrotic stage (pre-PMF) and DIPPS low/intermediate-1 risk MF. Ropeginterferon alfa 2b (Ropeg-IFN-α2b) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). Methods: Key eligibility included morphologically confirmed pre-PMF, and DIPSS low/intermediate-1 risk overt PMF, post-polycythemia vera MF (PPV-MF), and post-essential thrombocythemia MF (PET-MF) in patients requiring cytoreduction. The primary end-points were responses in hemoglobin (from 10 g/dL to upper reference range), white blood cell (to < 10 x 10 9 /L) and platelet (to ≤ 400 x 10 9 /L) at 24 and 52 weeks. Secondary endpoints included safety (adverse events, AEs), reductions in variant allele frequencies (VAF) of driver and non-driver genes, spleen length by palpation, Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPNSAF-TSS), and bone marrow fibrosis. Patients received Ropeg-IFN-α2b at a dose of 250 mcg at Week 0, followed by 350 mcg at Week 2 and 500 mcg every 2 weeks from Week 4 onwards. Results: At the data cut-off of 30 June 2024, 71 patients (40 men and 31 women) with a median age of 60 (range: 31-86) years were enrolled. At a median follow up of 119 (10-131) weeks, responses in hemoglobin, white blood cell and platelet counts were 73.9%, 82.6% and 100% at Week 24; and 76.2%, 79.4% and 100% at Week 52, respectively. Reduction in JAK2 V617F VAF was found in 16 of 47 evaluable patients (34%) at Week 24, and 20 of 41 evaluable patients (44%) at Week 52. Reduction in CALR VAF was found in 10 of 19 evaluable patients (53%) at Week 24, and 6 of 14 evaluable patients (43%) at Week 52. Reduction of spleen size was found in 9 of 19 patients (47%) at Week 24, and 9 of 17 patients (53%) at Week 52. Reduction in MPNSAF-TSS of ≥50% was found in 27 of 63 evaluable patients (42.9%) at Week 24, and 23 of 57 patients (42.1%) at Week 52. The most common non-hematologic AEs included transaminitis (grade 1-2, N=35, 49.2%); malaise (grade 1-2, N=29, 40.8%; grade 3-4, N=1, 1.4%), and hair loss (grade 1-2, N=24, 33.8%). The most common hematologic AEs were anemia (grade 1-2, N=15, 21.1%; grade 3-4, N=6, 8.5%), neutropenia (grade 1-2, N=15, 21.1%; grade 3-4, N=4, 5.6%) and thrombocytopenia (grade 1-2, N=8, 11.2%; grade 3-4, N=3, 4.2%). Thrombohemorrhagic events or progression to blast-phase MF was not observed during the study. Conclusions: Ropeg-IFN-α2b was well-tolerated and induced clinical, hematologic and molecular responses in patients with pre-PMF and low/intermediate-1-risk MF. Clinical trial information: NCT04988815 .
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Barosi, Giovanni, Francisco Cervantes, Dina Ben-Yehuda, et al. "A Ruxolitinib Individual Supply Program for Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis." Blood 118, no. 21 (2011): 5170. http://dx.doi.org/10.1182/blood.v118.21.5170.5170.
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Abstract Abstract 5170 Background: There are currently no approved, effective drug therapies for myelofibrosis (MF). Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has recently demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life in 2 phase 3 studies in patients with MF. Both studies met their primary endpoint of the proportion of patients with ≥35% reduction in spleen volume at 24 weeks (COMFORT-I) and at 48 weeks (COMFORT-II): 41.9% vs 0.7% (ruxolitinib vs placebo, P <.0001) and 28.5% vs 0% (ruxolitinib vs best available therapy, P <.0001), respectively. The most common grade ≥3 hematologic adverse events (AEs) were thrombocytopenia and anemia, which were manageable and rarely led to discontinuation (COMFORT-I: n=1 each; COMFORT-II: thrombocytopenia, n=1; anemia, n=0). Because of the limited available treatment options and medical need, ruxolitinib has been made available through an individual supply program (ISP) outside the United States. Methods: Patients with PMF, PPV-MF or PET-MF who are determined by their physicians to be in need of treatment are considered for eligibility, irrespective of JAK2 mutation status. As in the COMFORT studies, the starting dose of ruxolitinib is determined on the basis of baseline platelet count and can be adjusted for efficacy and safety. Dose changes during treatment are registered, and AEs and serious AEs (SAEs) are monitored throughout the study. Results: To date, 231 patients have been screened at more than 150 study sites in 28 countries, including Canada, Australia, and locations in Europe, Latin America, the Middle East, and Asia. The baseline characteristics for patients whose requests for access were approved/enrolled (n=200) and denied/pending (n=31) are shown below (Table). The patient characteristics are generally similar to those expected in the overall MF patient population. To date, the proportion of patients with the JAK2V617F mutation enrolled in this ISP (68.5%) is higher than that for the general MF population (50–60%) and may reflect the tendency of physicians to include more JAK2V617F-positive patients in the ISP, even though ruxolitinib has demonstrated comparable efficacy in both patient types (Verstovsek S, et al. N Engl J Med. 2010;363(12):1117–1127). Thrombocytopenia and herpes zoster were each reported as an AE in 1 patient, and no SAEs have been reported. Conclusions: Ruxolitinib is currently the only drug to have completed phase 3 studies for the treatment of MF and has garnered a substantial number of requests for access through the individual supply program. Disclosures: Barosi: Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Panagiotidis:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding; GSK: Honoraria. Perez:Novartis: Employment. Orlando-Harper:Novartis: Employment. Martin:Novartis Pharma AG: Employment. Willenbacher:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AESCA: Honoraria, Research Funding. Ojeda:Novartis: Consultancy. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Knoops:Novartis: Consultancy.
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Daver, Naval, and Rita Assi. "An Exciting New Era in the Treatment of Myeloproliferative Neoplasms." Oncology & Hematology Review (US) 12, no. 02 (2016): 71. http://dx.doi.org/10.17925/ohr.2016.12.02.71.
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Myeloproliferative neoplasms (MPNs), including primary myelofibrosis and myelofibrosis (MF) evolving from a pre-existing MPN (post polycythemia vera- and post essential thrombocythemia-myelofibrosis) are clonal hematopoietic stem cell disorders with heterogeneous symptoms, mutational profile, transformation risk and prognosis. Given the potentially chronic disease course, the goal of therapy in MF is to alleviate associated signs and symptoms, including reduction in spleen size, weight gain, improved performance status, and control of constitutional symptoms, leading to a prolonged survival and reduced transformation to leukemia.
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Nazha, Aziz, Zeev Estrov, Jorge E. Cortes, Sherry Pierce, Hagop M. Kantarjian, and Srdan Verstovsek. "Prognostic Implications and Clinical Characteristics Associated with Bone Marrow Fibrosis in Patients with Myelofibrosis." Blood 118, no. 21 (2011): 2824. http://dx.doi.org/10.1182/blood.v118.21.2824.2824.
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Abstract Abstract 2824 Background: Myelofibrosis (MF) is a heterogeneous, hematopoietic stem cell malignancy characterized by abnormal proliferation of myeloid cells with varying maturity and function. Bone marrow fibrosis (BMF), which results from abnormal deposition of stromal reticulin and collagen fibers, plays a major role in the pathophysiology of MF. Objectives: To investigate the characteristics associated with the extent of BMF and its implications on the clinical manifestation, overall survival (OS), event-free survival (EFS), and transformation to acute leukemia in patients with primary or secondary myelofibrosis. Methods: We conducted a retrospective chart review analysis of 514 patients who were diagnosed with myelofibrosis according to World Health Organization criteria (353 patients with primary myelofibrosis, 82 with post polycythemia vera [Post-PV] MF, and 79 with post essential thrombocythemia [Post-ET] MF) and were referred to MD Anderson Cancer Center between February 2005 and December 2009. Results of the first bone marrow biopsy done at MD Anderson were reviewed. BMF was documented according to the European consensus grading system (MF 0–3), in which MF-3 is the most severe grade of fibrosis. Result: Of 514 patients, 7 (1%) had MF-0, 44 (9%) had MF-1, 171 (33%) had MF-2, and 292 (57%) had MF-3. Table 1 summarizes patient characteristics and outcomes by grade. Conclusion: Severe bone marrow fibrosis was associated with lower Hgb, lower WBC count, larger spleen and abnormal cytogenetics. There was no association between JAK2 mutation and the severity of BMF. The OS, EFS and transformation to leukemia were similar among patients with various degrees of fibrosis. Similar results were achieved in patients with primary, post-PV MF, and post-ET MF. This might explain the heterogeneity of the disease course and its prognosis. Longer follow-up is needed to further investigate the impact of BMF on OS, EFS and PFS. Disclosures: No relevant conflicts of interest to declare.
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Odenike, Olatoyosi. "Beyond JAK inhibitor therapy in myelofibrosis." Hematology 2013, no. 1 (2013): 545–52. http://dx.doi.org/10.1182/asheducation-2013.1.545.
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Abstract Myelofibrosis (MF), including primary MF, postpolycythemia vera MF, and postessential thrombocythemia MF, is a clonal stem cell disorder characterized by BM fibrosis, extramedullary hematopoiesis, and a variable propensity to transform into acute leukemia. Allogeneic stem cell transplantation is the only known cure for MF, but its applicability is limited by the advanced age of most patients and by comorbid conditions. In the past decade, there has been an explosion of information on the molecular-genetic features associated with these diseases, fueled recently by the discovery of the JAK2V617F mutation. The development of JAK inhibitors has represented a significant therapeutic advance for these diseases; however, their use in MF has not yet been associated with eradication or a significant suppression of the malignant clone. In this era, much remains to be understood about MF, but it is likely that the identification of key pathogenetic drivers of the disease, coupled with the availability of novel molecularly targeted agents, will result in the discovery of new agents that significantly alter the natural history of the disease. This review focuses on recent and ongoing efforts in the development of novel agents in MF that go beyond the field of JAK inhibitors.
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Vargas, Pablo, Roberto Ovilla, Martha Alvarado, et al. "Compassionate Use Program (CUP) with Ruxolitinib in Mexican Patients with Primary Myelofibrosis (PMF), Post – Polycythemia, Vera Myelofibrosis (PPV – MF), and Post–Essential Thrombocythemia Myelofibrosis (PET – MF)." Blood 120, no. 21 (2012): 5067. http://dx.doi.org/10.1182/blood.v120.21.5067.5067.
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Abstract Abstract 5067 Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) that is characterized by ineffective hematopoiesis and symptomatic burden such as cytopenias, and splenomegaly. The prevalence of MF symptoms is relatively uniform across the 3 main subtypes: primary MF (PMF), post – polycythemia vera MF (PPV MF), and post – essential thrombocythemia MF (PET MF). Available therapies (AT) in Mexico, includes hydroxyurea (HU), interferon (IFN), for ET, besides phlebotomy for PV, as well as androgens, steroids, chemotherapy, IFN, thalidomide, EPO and radiotherapy for PMF. The only potentially curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT) but treatment-related mortality remains high. Recently ruxolitinib an oral Janus kinase–2 inhibitor (JAK-2) has been approved to treat patients with MF. The safety and efficacy of Ruxolitinib has been evaluated 528 patients from COMFORT I and COMFORT II trials. Objective To report the first clinical experience in a CUP with an oral JAK–2 Inhibitor (ruxolitinib) in 40 MF patients refractory to AT in Mexico. Patients and Methods PMF patients and PPV/PET MF eligible for the ruxolitinib CUP, were diagnosed according to the 2008 WHO criteria, irrespective of JAK2 mutation status; classified as high risk; intermediate risk level 2; or, intermediate risk level 1 with an enlarged spleen; with a peripheral blood blast count of < 10%; adequate renal and liver function, platelet count >100×109/L, all of them were treated with best available therapies in Mexico. Therapy with ruxolitinib was administered to all patients. Doses were adjusted according to the platelet counts. Clinical and demographic characteristics were assessed at baseline and during the follow-up. The analyzed characteristics were: Demographic: age, gender; Clinical: Risk group, Bone marrow fibrosis grade, spleen size, ECOG, MPN subtype, JAK mutation, CBC counts;Spleen size at baseline and at week 20 of treatment. Results The median age was 64. 2 (Interval 41 – 75). Gender distribution was 46% female and 54% male. Patients according to the International Prognostic Scoring System (IPSS) were distributed in the following risk category: 10% low risk; 53. 3% intermediate – 1 risk; 26. 7 % intermediate – 2 risk; and 20% high risk. Bone marrow fibrosis grade distribution was: Grade I 46. 15%; Grade II 23. 07%; Grade III 30. 76%. Spleen length below costal margin: <10 cm, 80. 7%; 10 to <20 cm, 11. 5% and > 20 cm, 7. 7% of patients. Spleen Average size was 9. 58 cm below costal margin at the beginning of treatment. ECOG 0 was present in 15% of patients; ECOG 1, 73%; and ECOG 2, 12% of patients. The disease subtype distribution was: PMF 45%; PPV-MF 36% and PET-MF 46%. JAK mutation was positive for 19% of patients, 46% were negative, and 35% did not have mutation analysis. The findings from the baseline to week 20 were: Splenomegaly decreased from 9. 58 cm (avg) to 4. 5 cm (avg) (53. 02% of reduction); Median Hemoglobin level was 13. 2 gr/dL at baseline versus 10. 24 gr/dL (22. 42% of decrease). Median Platelet count was 437, 000/mm3 at baseline versus 341, 503/mm3 at week 20 of treatment (21. 85% of decrease). Median time of treatment is 20. 1 weeks. Hematologic adverse events presented: Hemoglobin level decrease events (CTCAE grade 2 and 3) resolved with transfusion support. Platelet count decreases (CTCAE grade 2) were transitory and resolved after two weeks of treatment interruption. Conclusion Data showed demonstrate principal characteristics of this MF cohort. Until recently, most treatments provided only palliative care with no single treatment addressing all of the complications and symptoms of the MF. Ruxolitinib showed a primary therapeutic benefit as reduction in splenomegaly and significant improvement in MF-related symptoms in this cohort of Mexican patients with myelofibrosis. Disclosures: No relevant conflicts of interest to declare.
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Mullally, Ann, John Hood, Claire Harrison, and Ruben Mesa. "Fedratinib in myelofibrosis." Blood Advances 4, no. 8 (2020): 1792–800. http://dx.doi.org/10.1182/bloodadvances.2019000954.
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Abstract Following the discovery of the JAK2V617F mutation in myeloproliferative neoplasms in 2005, fedratinib was developed as a small molecular inhibitor of JAK2. It was optimized to yield low-nanomolar activity against JAK2 (50% inhibitory concentration = 3 nM) and was identified to be selective for JAK2 relative to other JAK family members (eg, JAK1, JAK3, and TYK2). It quickly moved into clinical development with a phase 1 clinical trial opening in 2008, where a favorable impact on spleen and myelofibrosis (MF) symptom responses was reported. A phase 3 trial in JAK2 inhibitor treatment-naive MF patients followed in 2011 (JAKARTA); a phase 2 trial in MF patients resistant or intolerant to ruxolitinib followed in 2012 (JAKARTA-2). Clinical development suffered a major setback between 2013 and 2017 when the US Food and Drug Administration (FDA) placed fedratinib on clinical hold due to the development of symptoms concerning for Wernicke encephalopathy (WE) in 8 of 608 subjects (1.3%) who had received the drug. It was ultimately concluded that there was no evidence that fedratinib directly induces WE, but clear risk factors (eg, poor nutrition, uncontrolled gastrointestinal toxicity) were identified. In August 2019, the FDA approved fedratinib for the treatment of adults with intermediate-2 or high-risk MF. Notably, approval includes a “black box warning” on the risk of serious and fatal encephalopathy, including WE. FDA approval was granted on the basis of the JAKARTA studies in which the primary end points (ie, spleen and MF symptom responses) were met in ∼35% to 40% of patients (JAKARTA) and 25% to 30% of patients (JAKARTA-2), respectively.
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Vannucchi, Alessandro M. "Management of Myelofibrosis." Hematology 2011, no. 1 (2011): 222–30. http://dx.doi.org/10.1182/asheducation-2011.1.222.
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Abstract Myelofibrosis (MF), either primary or arising from previous polycythemia vera (PV) or essential thrombocythemia (ET), is the worst among the chronic myeloproliferative neoplasms in terms of survival and quality of life. Patients with MF have to face several clinical issues that, because of the poor effectiveness of medical therapy, surgery or radiotherapy, represent largely unmet clinical needs. Powerful risk stratification systems, applicable either at diagnosis using the International Prognostic Scoring System (IPSS) or during the variable course of illness using the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus, allow recognition of categories of patients with survival times ranging from decades to < 2 years. These scores are especially important for therapeutic decisions that include allogeneic stem cell transplantation (allogeneic SCT), the only curative approach that still carries a nonnegligible risk of morbidity and mortality even with newest reduced intensity conditioning (RIC) regimens. Discovery of JAK2V617F mutation prompted the development of clinical trials using JAK2 inhibitors; these agents overall have resulted in meaningful symptomatic improvement and reduction of splenomegaly that were otherwise not achievable with conventional therapy. Intriguing differences in the efficacy and tolerability of JAK2 inhibitors are being recognized, which could lead to a nonoverlapping spectrum of activity/safety. Other agents that do not directly target JAK2 and have shown symptomatic efficacy in MF are represented by inhibitors of the mammalian target of rapamycin (mTOR) and histone deacetylases (HDACs). Pomalidomide appears to be particularly active against MF-associated anemia. However, because these agents are all poorly effective in reducing the burden of mutated cells, further advancements are needed to move from enhancing our ability to palliate the disease to arriving at an actual cure for MF.
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Vinogradova, O. Yu, L. B. Egoryan, D. I. Shikhbabaeva, A. L. Neverova, M. M. Pankrashkina, and L. K. Moshetova. "Primary and secondary myelofibrosis: ophthalmological manifestations at onset and during therapy." Oncohematology 20, no. 1 (2025): 95–113. https://doi.org/10.17650/1818-8346-2025-20-1-95-113.
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Background. There is little information about ophthalmological manifestations of myelofibrosis (MF), their dependence on hematological, morphological, genetic parameters, and eye damage during therapy, and there are no publications on eye changes during targeted therapy. Aim. To study the spectrum and frequency of ophthalmological manifestations of primary, post‑polycythemic, post‑thrombocythemic MF at the diagnosis and during therapy. Materials and methods. A prospective single‑center controlled study included 128 people: 98 patients with primary, post‑polycythemic, post‑thrombocythemic MF in the chronic phase (17 at onset, 30 long‑term receiving hydroxycarbamide, 51 long‑term receiving ruxolitinib), observed at the botkin Hospital and 30 healthy participants of the control group. Ophthalmological and genetic studies were conducted. Results. It has been established that ophthalmologic manifestations accompany MF already at the onset of the disease: significantly higher frequency of retinal angiopathy and angioretinopathy, decreased retinal sensitivity in the macular area, remodeling of the foveolar avascular zone (increased perimeter, decreased circumference index), low vascular and perfusion density of the retina, choroid and optic disc, decreased thickness of the subfoveolar choroid compared with the control group. Ruxolitinib MF therapy is safe for the visual organ according to the assessed parameters and has a positive therapeutic effect compared with MF onset and hydroxycarbamide therapy: such patients demonstrated smaller perimeter of the foveolar avascular zone, higher vascular and perfusion density of the retina, choroid and optic disc. There was a statistically significant association between an increased frequency of retinal angiopathy and angioritinopathy with a platelet count less than 100 × 109 / L, erythrocytes less than 3.7 × 1012 / L, hemoglobin level less than 100 g / L, high degree of fibrosis (MF‑3), presence of the JAK2 v617F mutation; the increased frequency of angiopathy associated with the leukocyte count less than 4.0 × 109 / L and more than 9.0 × 109 / L, erythrocytes more than 5.1 × 1012 / L, high risk according to DIPSS (Dynamic International Prognostic Scoring System). Vascular and perfusion density of the choriocapillary layer in patients at the onset of primary MF significantly correlated with the level of platelets and hemoglobin. Conclusion. The conducted search for ophthalmological manifestations on a large cohort of MF patients at the onset and during therapy is largely innovative and requires further research, and also confirms the need to include a consultation with an ophthalmologist in the examination algorithm for MF patients.
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Feng, Qiutian, and Jian Huang. "Cytogenetic Abnormalities Lead to Poor Prognosis in Patients with Myelofibrosis, Especially Postessential Thrombocythemia Myelofibrosis and Postpolycythemia Vera Myelofibrosis: A Multicenter Retrospective Study." Blood 144, Supplement 1 (2024): 6638. https://doi.org/10.1182/blood-2024-205559.
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For patients with myelofibrosis (MF), personalized treatment planning based on disease risk stratification and symptom assessment is typically carried out. Some prognostic scoring systems applicable to overt Primary myelofibrosis(overt PMF) patients may not accurately categorize the prognosis of postessential thrombocythemia myelofibrosis (post-ET MF) and postpolycythemia vera myelofibrosis (post-PV MF) patients. Currently, the prognostic model for myelofibrosis secondary to postpolycythemia vera(PV) and thrombocythemia(ET) (MYSEC-PM) involves only clinical features and driver gene mutations, without stratified assessment of their cellular genetic characteristics. Here, we conducted a retrospective study of 338 MF patients in 6 hematooncology centers between 01 October 2013 and 30 November 2023. By analyzing the correlation and differences between the cellular genetic characteristics of patients with different types of MF and clinical factors, gene mutations, and survival prognosis, we aimed to provide guidance for clinical diagnosis, treatment, and prognosis assessment of different types of MF, especially post-ET MF and post-PV MF. Chromosomal results for 338 MF patients revealed 253 patients with a normal karyotype (74.9%) and 85 patients with an abnormal karyotype (25.1%). When comparing the distribution of abnormal karyotypes among the different types of MF, the most common abnormal karyotypes in overt PMF patients were +8 (4.2%) and -20/20q- (4.2%), followed by -13/13q- (3.8%). The most common abnormal karyotype in post-ET MF patients was trisomy 1 (8.1%), followed by +8 (4.8%). In post-PV MF patients, the most common abnormal karyotypes were -17 (5.0%) and -5/5q- (5.0%). We analyzed the impact of abnormal karyotypes on the survival prognosis of MF patients. In MF patients (including those with overt PMF, post-ET MF, and post-PV MF), abnormal karyotypes were associated with significantly shortened overall survival (OS) compared to normal karyotypes (P&lt;0.0001, P=0.0483, P&lt;0.0001). In overt PMF and post-ET MF patients, both monosomal karyotypes and complex karyotypes were associated with significantly shortened OS compared to normal karyotypes (P&lt;0.0001, P&lt;0.0001). In overt PMF patients, the isolated +8 karyotype was associated with shortened OS compared to normal karyotypes (P=0.0001). In post-ET MF patients with the +8 karyotype (3 cases), all with additional abnormal karyotypes, OS was significantly shortened compared to those with normal karyotypes (P=0.0010). In overt PMF patients with the 1q+ karyotype (7 cases), all with additional abnormal karyotypes, OS was significantly shortened compared to those with normal karyotypes (P=0.0002). In post-ET MF patients with an isolated 1q+ karyotype, OS was significantly shortened compared to those with normal karyotypes (P=0.0007). Analysis of the impact of other common abnormal karyotypes on the survival prognosis of overt PMF patients revealed that -13/13q-, -7/7q-, -11/11q-, +9, -12/12q-, -17, der(6), -5/5q-, and +19 abnormal karyotypes were associated with significantly shortened OS compared to normal karyotypes (P=0.0191, P＜0.0001, P=0.0030, P=0.0102, P=0.0014, P＜0.0001, P=0.0023, P＜0.0001, P=0.0021). In conclusion, abnormal karyotypes, complex karyotypes, and monosomal karyotypes were adverse prognostic factors in MF patients. Aberrations such as +8, -13/13q-, -7/7q-, -11/11q-, +9, -12/12q-, -17, der(6), -5/5q-, and +19 all indicated poor prognosis in overt PMF patients, and translocations/duplications of chromosomes 1 and +8 were associated with poor prognosis in post-ET MF patients. Acknowledgement: This research was funded by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; Zhejiang Medical Association Clinical Medical Research special fund project, No. 2022ZYC-D09. *Correspondence to: Jian Huang, M.D., Ph.D., Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China. E-mail: househuang@zju.edu.cn
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Lu, Min, Lijuan Xia, Yen-Chun Liu, et al. "The Effects of Lipocalin (LCN2) on Hematopoiesis in Primary Myelofibrosis." Blood 124, no. 21 (2014): 1878. http://dx.doi.org/10.1182/blood.v124.21.1878.1878.
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Abstract Myelofibrosis (MF) is characterized by anemia, thrombocytopenia and marrow fibrosis. Malignant rather than normal hematopoietic progenitor cells (HPC) preferentially proliferate. A form of MF can also occur in patients with a prior history of PV or ET which is referred to as PV or ET related MF (PV-MF and ET-MF). In MF, excessive proliferation of marrow stromal cells occurs in response to cytokines elaborated by the malignant clone. Previously, we found that lipocalin-2 (LCN2) levels were elevated in patient plasmas with MPN, and a greatest degree of elevation was observed in the PMF plasma and PMF conditioned medium. We also found that LCN2 increased PMF HPC proliferation and increased numbers of JAK2V617F homozygous HPCs, but depressed normal BM HPC (Lu. et al, 2013 ASH meeting). In this study, a series of experiments were performed to further explore the effects of LCN2 on MF pathogenesis. ELISA data showed that plasma LCN2 levels not only were higher in all MF patients, plasma LCN2 levels in PV-MF as well as ET- MF were significantly greater than that in PV or ET plasma (p=0.0002 and p=0.0175, respectively). Importantly, in MPN patients, a non-parametric spearman correlation coefficient analysis suggested an inverse relationship between the patients’ hemoglobin levels and LCN2 levels (coefficient=-0.35, p<0.0001) and between platelet counts and LNC2 levels (coefficient=-0.26, p=0.0044). Immunofluorescence staining showed a greater proportion of PMF MNCs expressed LCN2. And immunohistochemical results revealed that LCN2 expressing cells were present in the PMF bone marrow and spleens samples and the LCN2 expression was restricted to cells belonging to the myeloid lineage rather than erythroid precursors or megakaryocytes. These data strongly confirmed that a higher level of LCN2 was expressed in MF patients. We then found that LCN2 significantly increased the generation of ROS (reactive oxygen species) in normal BM CD34+ cells but not PMF CD34+ cells (p<0.05). Furthermore, exposure of normal marrow to the LCN2 dramatically increased the CD34+/annexin V+ cell population in a dose dependent fashion. These apoptotic effects were blocked by addition of N-Acetyl-Cysteine (NAC), a ROS scavenger. By contrast, LCN2 did not increase the degree of apoptosis of PMF CD34+ cells when added at similar doses. These data indicate that LCN2 selectively promotes the survival of PMF CD34+ cells but leads to the apoptosis of normal BM CD34+ cells by increasing ROS. With 6 different individual BM samples, we demonstrated that PMF MNC cells that produce high levels of LCN2 as well as a recombinant form of LCN2 strongly promoted BM marrow adherent cells (MAC) proliferation. Similarly, LCN2 added to semisolid cultures of normal marrow cells resulted in the appearance of increased numbers of fibroblast-like cells. In addition, the ability of LCN2 to promote MAC proliferation was blocked by addition of NAC. These results suggest that LCN2 related generation of ROS induces MAC proliferation. The MAC in both control and LCN2 containing conditions expressed vimentin, Von Willebrand factor (VWF) and α-smooth muscle actin (a-SMA), while in LCN2 cultures expressed higher levels of CD105 (Endoglin) and CD106 (VCAM-1). These MAC therefore expressed features characteristic of mesenchymal stem cells, fibroblasts and endothelial cells. The MAC under control conditions expressed CD90+ on their cell surface, while incubation with LCN2 resulted in diminished cell surface CD90 expression, and its localization to the nucleus. We propose that LCN2 acts in an autocrine fashion to promote malignant PMF hematopoiesis as documented by its ability to preferentially favor the appearance of JAK2V617F homozygous hematopoietic colonies in vitro, but also acts in a paracrine fashion to suppress the proliferation of normal HPC and to affect the marrow microenvironment by promoting stromal cell proliferation. Our findings indicate that LCN2 affects these numerous biological effects by promoting the generation of ROS. We also propose that therapeutic strategies that can impair the actions of LCN2 or inactivate ROS are likely to be beneficial to MPN patients since they improve disease related cytopenias as well as impede the development of progressive marrow fibrosis. Such agents affecting this alternative therapeutic target might potentially be used alone or in combination with other presently available therapeutic modalities. Disclosures No relevant conflicts of interest to declare.
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Rajabi-Moghaddam, Mahdieh, Gholamali Sarparast, and Hamid Abbaszadeh. "Bicytopenia Secondary to Autoimmune Myelofibrosis as the First Presentation of an Undiagnosed Systemic Lupus Erythematosus: A Rare Case Report." Journal of Advances in Medical and Biomedical Research 30, no. 139 (2022): 190–95. https://doi.org/10.30699/jambs.30.139.190.
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<strong>Abstract:</strong> Autoimmune myelofibrosis (AIMF) is considered as an infrequent cause of bone marrow fibrosis (BMF) and a rare complication of systemic lupus erythematosus (SLE). Due to its rarity, it is mistakenly diagnosed as primary myelofibrosis (MF). We describe the clinicopathologic features of a secondary form of AIMF in a 33- year- old female patient with an undiagnosed SLE which presented with acute bicytopenia. Absence of splenomegaly, leukopenia, anemia, BMF (grade MF-1), and presence of autoantibodies were some of noticeable features. Treatment with corticosteroid led to complete regeneration of the bone marrow and subsequently to an improved hematological status. Six- month follow-up showed that the patient was in good clinical condition. Identification of AIMF is a diagnostic challenge and pitfall and it is actually a diagnosis of exclusion. It could be the first and only presenting feature of SLE and results in hematologic disturbances. So, we should consider SLE-associated AIMF in the differential diagnosis of pancytopenia. <strong>Keywords: </strong>Autoimmune diseases, Primary Myelofibrosis, Fibrosis, Lupus Erythematosus, Systemic
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le Coutre, Philipp D., Heinz Gisslinger, Pierre Zachee, et al. "An open-label, multicenter, expanded access study assessing the safety and efficacy of oral ruxolitinib administered to patients with primary myelofibrosis (PMF), post-polycythemia myelofibrosis (PPV MF) or post-essential thrombocythemia myelofibrosis (PET-MF)." Journal of Clinical Oncology 30, no. 15_suppl (2012): TPS6640. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps6640.
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TPS6640 Background: Myelofibrosis (MF) can be primary in origin or can progress from polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). MF is characterized by cytopenias, reactive bone marrow fibrosis, splenomegaly, and constitutional symptoms including weight loss, fever, and night sweats. MF is associated with dysregulation of the Janus kinase pathway, irrespective of JAK2V617F mutation status. Recently, ruxolitinib (INCB018424) was approved for the treatment of MF on the basis of results from 2 phase 3 trials (COMFORT-I and -II). These trials demonstrated marked reductions in splenomegaly and symptom burden, and improvements in health-related quality of life (QoL) measures. Methods: JAK Inhibitor rUxolitinib in Myelofibrosis Patients (JUMP) is a global, phase 3b expanded access trial (NCT01493414) designed to assess the safety and efficacy of ruxolitinib in adult pts with PMF, PPV-MF or PET-MF who are treatment naïve, and are intolerant of, or had progressed on any prior therapy. Inclusion criteria: peripheral blast count of <10%, adequate liver and renal function and intermediate-2 or high risk MF according to IPSS criteria or intermediate-1 risk MF with palpable spleen length ≥ 5 cm. The primary endpoint is to assess the safety of ruxolitinib. Additional endpoints include the proportion of pts with a > 50% reduction in palpable spleen length, % change in white blood cell and platelet counts from baseline (BL), and change in packed red blood cell transfusion requirements. Changes from BL in QoL scores will be assessed using validated ECOG PS, FACT-Lymphoma, and FACIT instruments. Pts with a BL platelet count > 200,000/μL will receive oral ruxolitinib 20 mg BID; pts with a BL platelet count of 100,000/μL to 200,000/μL will receive 15 mg BID; dose modifications are permitted for safety and efficacy. Global enrollment is open and currently includes 277 pts. This is planned to be the largest study ever conducted in pts with MF. [Table: see text]
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Gul, Zartash, Naomi Galili, Nishant Tageja, and Azra Raza. "MD." Blood 114, no. 22 (2009): 4863. http://dx.doi.org/10.1182/blood.v114.22.4863.4863.
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Abstract Abstract 4863 THE SECONDARY TRANSFORMATION OF MDS INTO MYELOFIBROSIS IS INDEPENDENT OF THE JAK2 MUTATION Introduction The exact significance of the JAK2 V617F mutation in MDS is unclear. It has previously been suggested that MF could be associated with MDS as one phenotype of myeloproliferative disorders. Ohyashiki et al in 2005 showed that two of six patients with MDS terminating in MF had the mutation at the time of MF, while no MDS patient without MF had the JAK2 V617F mutation, suggesting that MDS patients with the JAK2 V617F mutation may be responsible for secondary MF in MDS patients. We conducted the following experiments to further probe the role of JAK2 mutation in the pathology of MDS with myelofibrosis at our institution. Methods DNA samples of 8 patients in our institution who had MDS with subsequent myelofibrosis were isolated. Genomic DNA isolated using DN easy tissue kit(Qiagen) was amplified by PCR. After confirmation of DNA presence on 1 % agarose gel and purification using QIA quick PCR purification kit (Qiagen), gene sequencing was done. This sequencing was then analyzed for G to T mutation V617F in JAK2. Results We found no evidence of the JAK2 mutation in any of the eight samples. Discussion Given the fact that nearly half the patients with myelofibrosis carry the JAK2 V617F mutation, the possibility of an association between those patients who have myelodysplasia and subsequent myelofibrosis needs to researched. Our cohort which consisted of 8 patients showed no evidence for any such correlation. This evidence confirms the presence of different pathophysiological mechanisms for phenotypic expression of MDS and primary MF and also leads us to suggest that the expression of JAK2 is not the driving mutation in the pathogenesis of MDS progression to myelofibrosis. Disclosures No relevant conflicts of interest to declare.
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Zhang, Liqiang, Kathryn McGinnis, Paul Gonzales, et al. "A Dual-Specific Inhibitor of Rock/Aurk, RR-1752, for Primary Myelofibrosis." Blood 142, Supplement 1 (2023): 4529. http://dx.doi.org/10.1182/blood-2023-182046.
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Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized by driver mutations in JAK2, CALR, and MPL resulting in constitutive activation of JAK-STAT signaling. Abnormalities in megakaryocyte (MK) numbers and morphology are a common feature of MF where abnormal MKs are associated with bone marrow fibrosis and pro-inflammatory cytokine release. Therapies that target constitutive JAK-STAT signaling and atypical megakaryocytes could provide clinical benefit for patients with MF. ROCK and Aurora kinase (AURK) are overexpressed in MPN and linked to dysregulated MKs of patients with MPN. We therefore tested the activity of RR-1752, a dual-specific inhibitor of ROCK and AURK, in preclinical models of MF. RR-1752 acted as an inhibitor of pSTAT3 in IL-2 stimulated human PBMC 1h post stimulation and significantly inhibited phosphorylated myosin light chain 2 (pMLC2) in two human MPN cell lines, HEL-92.1.7 and UKE-1, confirming an on-target action. RR-1752 inhibited colony formation by HEL-92.1.7 and UKE-1, (IC 50 = 25.2 nM and 54.6 nM respectively). RR-1752 also induced cell cycle arrest in HEL-92.1.7 and UKE-1 specifically at the G2/M checkpoint. RR-1752 was also tested in a hematopoietic colony formation assays of MF patient derived CD34 + cells. RR-1752 led to concentration specific inhibition of MF patient derived CD34 + cell colony formation between 100-190 nM demonstrating relevant activity against patient-derived MF samples (51% inhibition at 190 nM as compared to vehicle control). These data were in line with flow cytometrically determined cell viability data of MF CD34 + cells cultured in the presence of varying concentrations of RR-1752 in liquid culture. The in vivo activity of RR-1752, was examined using the human HEL- 92.1.7 cell line, homozygous for both JAK2 V617F and p53 M133K in a mouse xenograft model. The effects of RR-1752 alone and in combination with ruxolitinib were compared to single agent ruxolitinib. The administration of RR-1752, 25 mg/kg PO daily resulted in a significant (p&lt;0.01) improvement in median survival (31 days) compared to ruxolitinib alone, 45 mg/kg PO daily (21 days). RR-1752 5.0 mg/kg PO QD plus ruxolitinib 45 mg/kg PO QD also resulted in a significant improvement in survival (p&lt;0.05) compared to single agent ruxolitinib but was inferior to single agent RR-1752 at 25mg/kg. The demonstrated activity in MF patient derived CD34 + cells combined with the significant improvement in survival compared to the approved drug ruxolitinib in an aggressive, JAK2/p53 mutant MF xenograft model provides a compelling case for its evaluation as a therapeutic modality in MF patients. Dose optimization of RR-1752 alone and in combination with ruxolitinib in the HEL-92.1.7 IV dissemination model as well as testing in the hMPL-W515L-evoked myelofibrosis model is ongoing. Conventional treatments for MF have largely focused on symptom management but RR-1752 treatment could result not only in beneficial symptom improvement but also important disease modifying potential by inhibiting JAK-STAT signaling, cell cycle progression and targeting dysregulated MKs.
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Lee, Byung-Hyun, Hyemi Moon, Ka-Won Kang, Byung Soo Kim, and Yong Park. "Clinical Efficacy of Ruxolitinib in Patients with Myelofibrosis: A Nationwide Population-Based Study in Korea." Blood 134, Supplement_1 (2019): 2951. http://dx.doi.org/10.1182/blood-2019-122156.
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Background: The survival benefit of ruxolitinib, approved for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera (PV) MF, and post-essential thrombocythemia (ET) MF, has been reported in phase-3 studies. However, population-based comparison data of its efficacy in primary and secondary MF are limited. We analyzed the effects of ruxolitinib in MF patients from a real-world population using National Health Insurance Research Database of Korea. Methods: A total of 1171 patients who diagnosed MF (ICD-10 code D47.4) from January 1, 2011 to December 31, 2017 were identified. Of these, 291 patients previously diagnosed with leukemia, myelodysplastic syndromes, or lymphoma were excluded. The remaining 880 patients (361 patients with primary MF and 519 with secondary MF) were included in the study and divided into 2 group according to ruxolitinib treatment. Patients who received ruxolitinib (n = 276) were matched with those who did not receive ruxolitinib (n = 604) using the 1:1 greedy matching algorithm. Propensity scores were formulated using six variables: age, sex, previous history of arterial/venous thrombosis, red blood cell (RBC) or platelet (PLT) transfusion dependence, and previous hydroxyurea treatment. Overall survival (OS) and occurrence of acute leukemia and thrombotic complications were evaluated using stratified Cox-regression analysis between patients who received ruxolitinib and those who did not. Among the former, we evaluated the risk factors for OS as the primary outcome and occurrence of acute leukemia, thrombotic complications, and RBC and PLT transfusion response as secondary outcomes using multivariable Cox-regression analysis. Primary MF was defined as MF without a prior diagnosis of PV (ICD-10 code D45), ET (ICD-10 code D47.3), and chronic myeloproliferative disease (ICD-10 code D47.1). Secondary MF was defined as MF, which was not included in primary MF. Results: In the Cox-regression analysis for OS, non-ruxolitinib treatment (adjusted hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.22-2.10; P <0.001) was a significant prognostic factor for shorter survival. In the subgroup analysis, non-ruxolitinib treatment was a significant prognostic factor for poor survival in patients with secondary MF (adjusted HR, 1.78; 95% CI, 1.28-2.48; P <0.001). Contrastingly, no significant difference was observed in patients with primary MF (adjusted HR, 1.00; 95% CI, 0.73-1.94; P = 0.478). Ruxolitinib treatment did not affect the occurrence of leukemia and thrombotic complications in patients with both primary and secondary MF. In the multivariable Cox-regression analysis for OS in patients treated with ruxolitinib, older age (adjusted HR, 1.06; P <0.001), RBC (adjusted HR, 2.91; P <0.001), and PLT (adjusted HR, 9.65; P <0.001) transfusion dependence were significantly associated with poor survival, although MF type did not significantly affect survival. In the multivariable analysis for secondary outcomes, PLT transfusion dependency was the only significant risk factor for the occurrence of acute leukemia (adjusted HR, 4.78; P = 0.046) and thrombotic complications (adjusted HR, 14.16; P = 0.002). Older age (adjusted HR, 1.05; P <0.001) and previous hydroxyurea treatment (adjusted HR, 0.41; P = 0.005) significantly affected the response to RBC transfusion. Patients with secondary MF who received ruxolitinib showed a better RBC transfusion response than those with primary MF (adjusted HR, 0.51; P = 0.055). Conclusions: Ruxolitinib treatment led to better survival in patients with MF and might be more beneficial in secondary MF. Moreover, ruxolitinib was more efficacious in reducing RBC transfusion requirement in secondary MF than in primary MF. Further studies on the efficacy of ruxolitinib in other populations are needed. Disclosures No relevant conflicts of interest to declare.
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Medeiros, Jessie J. F., Amanda Mitchell, Aaron Trotman-Grant, et al. "Myelofibrosis Is Initiated and Sustained By Rare Multipotent Stem Cells." Blood 132, Supplement 1 (2018): 1790. http://dx.doi.org/10.1182/blood-2018-99-119088.
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Abstract Background: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by marked bone marrow fibrosis, extramedullary hematopoiesis and significant risk for leukemic transformation. Most patients carry recurrent MPN driver mutations in JAK2, CALR and MPL and many carry additional mutations in epigenetic regulators, splicing and signaling pathways. MF pathophysiology remains poorly understood, particularly with respect to the cellular identity of the MF clone(s) bearing mutations that initiate and maintain the disease. Therefore, here we tracked somatic mutations from nine MF patients in sorted hematopoietic cell populations from serial time-points as well as patient-derived xenografts (PDXs), to identify clinically relevant MF cell populations for future targeted therapies. Methods: Genomic DNA was isolated from the peripheral blood mononuclear cells (PBMCs) of nine chronic-phase MF patients (5 JAK2+ and 4 CALR+) and sequenced using the 54-gene TruSight Myeloid targeted panel. PBMCs from the same patients at serial time-points (if available) were sorted into hematopoietic stem and progenitor cell (HSPC) and mature cell populations. In addition, PDXs were generated following injection of CD34+ peripheral blood cells into sub-lethally irradiated NSG and/or NSG-SGM3 mice. Human myeloid (CD45+33+) and B (CD45+19+) cells were isolated from PDXs after 8-16 weeks. Digital droplet PCR was used to interrogate known oncogenic variants, identified from the targeted sequencing, in all sorted primary and PDX cell fractions. Results: We reveal that the vast majority of genetic lesions used to interrogate the hierarchy were acquired at the level of immunophenotypically defined hematopoietic stem/multipotent progenitor cells (HSC/MPP) (CD45+34+38-RA-, termed MF-HSC). MF-HSC variants were generally shared with most HSPC, differentiated myeloid (CD33+) and lymphoid (B and/or T cell) populations sorted from primary patient samples. In our cohort, MPN driver mutations were invariably acquired in MF-HSC and consistently maintained over longitudinal clinical follow-up (median of 17 months) in both MF-HSCs and differentiated myeloid cells (CD33+). Interestingly however, in 2 cases (1 CALR+ and 1 JAK2+ MF), ASXL1 mutations in MF-HSCs were observed at the first time-point but restricted to the CD33+ compartment at a later time-point. Further, in one patient, SF3B1 mutation was restricted to the CD33+ fraction at the first time-point and was completely absent at the second time-point. Thus, certain mutations, like ASXL1, may be required for MF initiation but not necessarily disease maintenance; or alternatively, independent MF-HSC clones may outcompete others over time. Additionally, some acquired downstream mutations may be transient in nature and not clinically relevant. Together these data suggest that MF-HSCs are essential for MF clonal maintenance. To complement our genetic interrogation of the hematopoietic hierarchy in MF, we demonstrate that CD34+ HSPCs generate multi-lineage grafts in xenotransplanted mice bearing mutations identified in MF-HSCs. CALR+ samples invariably demonstrate multi-lineage potential and clonal dynamics in PDXs suggest that CALR mutations are likely the first genetic lesion acquired in multipotent MF-HSCs. JAK2+ samples generated more variable data, but by combining the genetic data of both PDXs and lymphoid cells sorted from primary patient samples, we show that JAK2+ MF-HSCs may also be multipotent. Taken together, these data suggest that MF-HSCs are multipotent, functionally relevant MF-initiating cells capable of propagating downstream HSPC populations and the CD33+ MF-disease clone that harbors all interrogated mutations. Thus, rare MF-HSCs are both disease-initiating and disease-maintaining cells. Conclusions: Our approach combining high-resolution cell sorting and xenograft assays with genomic interrogation demonstrates that MF is initiated and maintained by rare multipotent MF-HSCs. Our study underscores the complex evolutionary events that occur in the stem cell compartment during disease progression and identifies MF-HSCs as the relevant cellular target for future therapeutic intervention. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding.
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Barosi, Giovanni, Vittorio Rosti, Rita Campanelli, et al. "Prefibrotic Myelofibrosis (PreMF) Belongs to a Continuum of Epidemiological, Clinical and Histological Characteristics Featuring Primary Myelofibrosis (PMF)." Blood 118, no. 21 (2011): 1743. http://dx.doi.org/10.1182/blood.v118.21.1743.1743.
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Abstract Abstract 1743 Background: WHO diagnostic criteria of myeloproliferative neoplasms (MPNs) identify a preMF variant including patients having absence or early grade fibrosis, dual myeloid and megakaryocytic dominance, and clusters of atypical, ectopic, variable in size megakaryocytes in the bone marrow (BM). Many issues on the variant are critical, such as its distinction from essential thrombocythemia, recognisability, biological identity and true place among MPNs. Here we describe the clinical presentation of patients with preMF collected among a large cohort of patients diagnosed with PMF according WHO and for whom long-term follow-up data were available. The aim is to investigate whether there is an underlying structure of the patients' characteristics that allows to assign them to a distinct variant of MPNs or to align them along a continuum in the realm of PMF. Methods: We included in this study patients with PMF who were referred to the Center for the Study of Myelofibrosis of IRCCS Policlinico S. Matteo Foundation, Italy from 1990 to 2011. In all patients the BM biopsy taken at diagnosis was reviewed (pathologist: UM) and the diagnosis of preMF was established adopting the stringent criterion that, besides typical BM cellularity and megakaryocyte morphology, BM had less than grade 1 reticulin fibrosis (EUMNET criteria). Results: Of the 659 patients with PMF, 126 fulfilled the criteria we established for the diagnosis of preMF, thus accounting for 19.1% of the cohort. Female sex accounted for 59.5% of the preMF cohort while it accounted for 33.8% of PMF fibrotic type (P<0.0000). The mean age at diagnosis of patients with preMF was 39.2 years (range, 6 to 78 years), while it was 54.6, range 6 to 90 years (P<0.0000) in patients with PMF fibrosis type. Patients with preMF showed higher hemoglobin (14.0 vs. 11.9 g/dL; P=0.0004), higher platelet count (647 vs. 435 × 109/L; P<0.0000), lower WBC count (9.0 vs. 10.7 x109/L; P=0.02) and smaller spleen index (120 vs. 182; P<0.0000) than patients with MF fibrotic type. As a consequence, preMF displayed a greater frequency of patients with grade 0 IWG prognostic score ( 88.7% vs. 56.9%, P<0.0000). PreMF patients displayed a higher frequency of thrombotic events at the time of the diagnosis or in the year preceding the diagnosis (30.1% vs. 6.4%; P<0.0000). Both in prefibrotic and fibrotic type MF, the great majority of the thrombotic episodes were portal vein thrombosis or Budd-Chiari syndrome (89.4% in preMF and 79.4% in PMF fibrotic type). The proportion of JAK2 V617F mutated patients was not significantly different in the two categories of patients (65.2% vs. 62.1%; P=NS). In order to assign patients with PMF to groups with different degrees of BM fibrosis, we further categorized MF fibrotic type into early MF (BM fibrosis grade 1) and advanced MF (BM fibrosis grade 2 or 3). Female frequency steadily varied from 59.5% to 43.2% and 25.6% in the 3 categories of BM fibrosis, respectively. Age varied from 39.2, 50.4, 57.0 years, respectively. Hemoglobin and platelet count steadily decreased (Hb=14.0, 13.3, 11.2 g/dL, respectively; platelet count=647, 554, 346 x109/L, respectively). Spleen size steadily increased along with increasing of BM fibrosis (spleen index=120, 152, 200). All these parameters exhibited a statistically significant trend along the continuum of BM fibrosis grade (ANOVA, P<0.0001). During 993 cumulative person-years of follow-up, 4% of patients with preMF died. During 1372 cumulative person-years of follow-up, 15.4% of patients with early MF died. During 1446 cumulative person-years of follow-up, 24.5% of patients with advanced MF died. The cause of death was blast transformation in 80, 53 and 41.7% of cases, respectively. 94%, 80% and 54% of patients with preMF, early MF and advanced MF were alive at 10 years from the diagnosis. Overall, these results speak in favour to preMF belonging to a continuum of epidemiological, clinical and histological phenotypes in the realm of PMF. Splanchnic vein thrombosis, on the contrary, clusters in the category of preMF, suggesting that young age, female sex and a very indolent hematological phenotype are associated with biological characteristics that predispose to thrombosis. Conclusions: The BM picture of preMF identifies a group of patients with PMF associated with a very indolent hematologic phenotype, female dominance and very young age at presentation characterized by high incidence of splanchnic vein thrombosis. Disclosures: Barosi: Novartis: Membership on an entity's Board of Directors or advisory committees.
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Mesa, Ruben A. "How I treat symptomatic splenomegaly in patients with myelofibrosis." Blood 113, no. 22 (2009): 5394–400. http://dx.doi.org/10.1182/blood-2009-02-195974.
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Managing patients with myelofibrosis (MF), either those with primary MF or those whose MF has evolved from antecedent polycythemia vera or essential thrombocythemia, presents many challenges to the hematologist. MF patients have a range of debilitating disease manifestations (eg, massive splenomegaly, cytopenias, constitutional symptoms, and transformation to a treatment-refractory blast phase). Cure is potentially achievable through allogeneic stem cell transplantation; however, this therapy is either inappropriate or not feasible for the majority of patients. Therefore, remaining therapies are palliative but can be of significant value to some MF patients. In particular, management of symptomatic splenomegaly remains one of the most perplexing aspects of MF clinical care. Using medications is the simplest approach for reducing splenomegaly, yet achieving symptomatic response without undue myelosuppression is challenging. Splenectomy or radiotherapy offers benefit, but careful patient selection and close monitoring are required because both have the potential for dangerous adverse effects. Experimental medical therapies, such as JAK2 inhibitors, show promise and may soon play an important role in the management of symptomatic splenomegaly in MF patients. Future care of MF patients, including splenomegaly management, will continue to require the hematologist to select therapeutic options carefully in the context of realistic, achievable goals.
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Tefferi, Ayalew. "How I treat myelofibrosis." Blood 117, no. 13 (2011): 3494–504. http://dx.doi.org/10.1182/blood-2010-11-315614.
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Abstract It is currently assumed that myelofibrosis (MF) originates from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling, clonal myeloproliferation, and abnormal cytokine expression. These pathogenetic processes are interdependent and also individually contributory to disease phenotype–bone marrow stromal changes, extramedullary hematopoiesis, ineffective erythropoiesis, and constitutional symptoms. Molecular pathogenesis of MF is poorly understood despite a growing list of resident somatic mutations that are either functionally linked to Janus kinase (JAK)–signal transducer and activator of transcription hyperactivation (eg JAK2, MPL, and LNK mutations) or possibly involved in epigenetic dysregulation of transcription (TET2, ASXL1, or EZH2 mutations). Current prognostication in primary MF is based on the Dynamic International Prognostic Scoring System-plus model, which uses 8 independent predictors of inferior survival to classify patients into low, intermediate 1, intermediate 2, and high-risk disease groups; corresponding median survivals are estimated at 15.4, 6.5, 2.9, and 1.3 years. Such information is used to plan a risk-adapted treatment strategy for the individual patient, which might include observation alone, conventional or investigational (eg, JAK inhibitors, pomalidomide) drug therapy, allogenic stem cell transplantation with reduced- or conventional-intensity conditioning, splenectomy, or radiotherapy. I discuss these treatment approaches in the context of who should get what and when.
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Shakil, Shams A., Chi Chen, Ali Surahio, et al. "T Regulator Cells (Treg) In Patients with Myelofibrosis." Blood 116, no. 21 (2010): 5051. http://dx.doi.org/10.1182/blood.v116.21.5051.5051.
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Abstract Abstract 5051 Primary myelofibrosis (PMF) and myelofibrosis post essential thrombocytosis (MF-ET) or myelofibrosis post polycythemia vera (MF-PV) have been reported to be associated with autoimmune phenomenon, such as Coomb positive anemia, lupus anticoagulant, positive ANA and the presence of circulating immune complex etc. Regulatory T cells (Treg) also have known to play important roles in modulating immune responses. Therefore we studied Treg cells in 25 patients with MF including PMF (12), MF-ET (8), MF-PV (5) and compared with other MPD including ET (7), PV (8), and normal volunteer controls (17). Mononuclear cells (MNC) were separated from peripheral blood. 106 MNCs were stained for flow cytometry analysis using Treg Detection Kit from Miltenyi Biotec Inc (Auburn, CA). The numbers of Treg was calculated as the percentage of positive CD4+ CD25+ FoxP3+ T cells (Treg) from the numbers of gated CD4+ cells. Treg function was evaluated by XTT cell proliferation assay (Invitrogen) with ratios of Treg vs. T-effector cells (CD4+ CD25-) at 1:1, 1:2, 1:4, and 0:1 in the presence of anti-CD3 CD28 microbeads (Invitrogen). The results (mean ± SE) showed numbers of Treg cells in MF were 0.73 + 0.08, other MPD were 1.37 ± 0.22, and normal controls were 0.96 ± 0.27 (p=NS). Treg function was evaluated in 12 patients with MF and 6 normal volunteer controls. Four MF patients were found to have significant lower values than controls. We concluded that in MF, quantitatively Treg were not different from other MPD or normal controls but Treg dysfunction was observed in 30–40 % of MF patients. This could explain why some patients with MF are prone to develop autoimmune phenomenon. Further studies with more patients are in progress. Disclosures: No relevant conflicts of interest to declare.
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Palmer, Jeanne, and Ruben Mesa. "The role of fedratinib for the treatment of patients with primary or secondary myelofibrosis." Therapeutic Advances in Hematology 11 (January 2020): 204062072092520. http://dx.doi.org/10.1177/2040620720925201.
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Myelofibrosis (MF) is a chronic myeloid neoplasm characterized by either primary myelofibrosis, or secondary MF following essential thrombocythemia or polycythemia vera. Historically, therapy has been symptom directed; however, in 2011, the first janus kinase inhibitor (JAK-i) – ruxolitinib – was approved for treatment. This medication was found to be effective in reduction of symptom burden and spleen size; however, the median duration of response is about 3 years. In addition, many patients are intolerant or develop toxicities to ruxolitinib, including patients with anemia, as well as thrombocytopenia. Therefore, there is a critical need for alternate therapeutic options for patients with MF. Additional JAK-i have been developed over the last 8 years, including fedratinib, momelotinib, and pacritinib. Fedratinib recently received approval for treatment of MF both in the first-line and second-line setting. It has shown efficacy in the first-line setting, as well as in 30% of patients who are refractory/intolerant of ruxolitinib. This review covers the trials that have led to the approval of ruxolitinib as well as fedratinib, as well as reviews of two JAK inhibitors that are still under clinical investigation: momelotinib and pacritinib.
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Takagi, Shinsuke, Shigesaburo Miyakoshi, Yasunori Oota, et al. "Reduced-Intensity Unrelated Cord Blood Transplantation (RICBT) for Myelofibrosis (MF)." Blood 106, no. 11 (2005): 5437. http://dx.doi.org/10.1182/blood.v106.11.5437.5437.
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Abstract Introduction: Although allogeneic hematopoietic stem cell transpslantation is the only curative treatment for patients with MF, the potential role of cord blood transplantation remains still unclear. We report the results of RICBT for hematological diseases with primary and secondary MF. Patients and Methods: We reviewed medical records of 179 patients with advanced hematological diseases who received RICBT between March 2002 and June 2005 at our institution. Of 179 patients, pre-transplant bone marrow specimens were available for 82 patients. We evaluated bone marrow specimens by aspiration and trephine biopsy. Aspiration may be not enough to evaluate marrow fibrosis, but could reflect fibrotic change in bone marrow (Am J Clin Pathol1971; 56: 25). One patient had primary MF and 47 had secondary. Underlying diseases for secondary MF included AML/MDS (35), ALL (6), CML (1), severe aplastic anemia (2), malignant lymphoma (2), essential thrombocythemia (1). For staging of MF, we used pathological criteria by Michiels (Int J Hematol2000; 76: 133). MF0: no reticulin fibrosis (n=35), MF1: slight reticulin fibrosis (n=38), MF2: marked increase in reticulin and slight to moderate collagen fibrosis (n=8), MF3: advanced collagen fibrosis-osteosclerosis (endophytic bone formation) (n=1). Median age of the patients was 55 years (17–71). Most of the conditioning regimens were fludarabine 125 mg/m2, melphalan 80 mg/m2 and TBI 4 Gy. GVHD prophylaxis was cyclosporine (n=35) or tacrolimus (n=47). The median number of infused nucleated cells: 2.66 x 10e7 cells (1.67_5.24 x 10e7); CD34 positive cells: 0.69 x 10e5 cells (0.11_3.90 x 10e5); HLA disparity: 6/6 (n=4), 5/6 (n=14), 4/6 (n=60), 3/6 (n=4). Results: Neutrophil engraftment at day 50 was observed in 70.8 % with MF (median 22 days) and 73.7 % without MF (median 22 days). Platelet engraftment at day 100 was observed in 40.0 % with MF (median 42 days) and 60.0 % without MF (median 40 days). There was no statistical significance in neutrophil and platelet engraftment between patients with MF and without MF. Of 48 patients, 6 showed biopsy-proven MF greater than stage 1. Their neutophil and platelet engraftment was observed in 100 % (median 22 days) and 66.7 % (median 48 days), respectively. Cumulative incidence of acute GVHD (II–IV) was 17 % with MF and 28 % without MF. There was no statistical significance. The estimated OS was 25 % with MF and 52 % without MF (p=0.03) (Figure 1). Most cause of death with MF was relapse. Conclusion: Despite of marrow fibrosis, neutophil and platelet engraftment was not influenced. These results have suggested that RICBT is feasible for MF. However, the existence of MF could be poor prognostic factor of RICBT for hematological diseases due to relapse. Figure Figure
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Liu, Enli, Adaani E. Frost, Uday R. Popat, and Josef T. Prchal. "Dysregulation of BMPR2, Arginase II and HMGA2 Expression in Idiopathic Myelofibrosis and Secondary Myelofibrosis." Blood 104, no. 11 (2004): 792. http://dx.doi.org/10.1182/blood.v104.11.792.792.
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Abstract Idiopathic myelofibrosis (IMF) is a fatal clonal myeloproliferative disorder, characterized by variable pancytopenia, splenomegaly, leukoerythroblastic blood smear, marrow fibrosis (MF), and myeloid metaplasia. Like all myeloproliferative disorders, it is due to an acquired somatic mutation of a single hematopoietic progenitor. MF has also been reported in systemic lupus and metastatic malignancies involving bone marrow. We have recently demonstrated the occurrence of MF in 85% patients with pulmonary hypertension (PH), which (unlike IMF) is associated with polyclonal hematopoiesis and normal number of circulating CD34+ cells. The pathophysiological mechanisms resulting in IMF and secondary MF (SMF) in PH remain still unclear. To date, 52 heterozygous germline mutations in the gene (BMPR2) encoding the bone morphogenetic protein type II receptor (BMPR-II) have been found to characterize many cases of familial (Lane, 2000) and sporadic primary PH (PPH) (Thomson, 2000). Recently, increased activity of arginase in pulmonary tissue of patients with PH was found. This may contribute to the pathogenesis of pulmonary hypertension by decreasing the substrate for NO synthesis. We examined BMPR2 and Arginase II mRNA levels by quantitative real-time RT-PCR in mononuclear cells (MNC), platelets (PLT) and granulocytes (GNC) from IMF patients and PH patients with secondary MF. We show for the first time that the mRNA level of BMPR2 is increased in PLT and GNC of IMF compared with normal controls. Arginase II mRNA was significantly increased in GNC of IMF as well as PH patients with SMF. Rearrangement and over expression of high-mobility group AT-hook2 (HMGA2) gene in myeloid progenitors in two patients with IMF was recently reported. This gene is known to play a major role in fetal growth and development, and is expressed in trace amount in adult lung, kidney, and synovia. We found significantly increased HMGA2 mRNA expression in MNC of IMF patients. In summary, the biomarkers studied here can be abnormal in both IMF and PH with secondary MF and may not be useful to discriminate between the two types of MF. Dysregulation of BMPR2, Arginase II and HMGA2 expression may play a pathophysiological role in MF of both IMF and PH. Expression of BMPR2 , Arginase II and HMGA2 in Blood Cells of IMF and SMF Gene Cells Control (ΔCT) Idiopathic MF (ΔCT) Secondary MF (ΔCT) *The P value represents a significant difference of gene expression in IMF or SMF compared with normal controls. A lower ΔCT indicates a higher gene expression. BMPR2 PLT 18.5±1.2 16.7±1.4 (p=0.038) * 18.4±2.2 (p=0.881) GNC 19.2±1.0 18.3±1.3 (p=0.009) * 19.1±1.2 (p=0.893) MNC 18.3±1.2 19.2±1.8 (p=0.059) 19.0±2.7 (p=0.554) Arginase II GNC 24.5±0.6 21.9±1.7 (p=0.000) * 22.6±1.2 (p=0.004) * MNC 24.4±3.5 24.4±3.9 (p=0.965) 22.5±2.4 (p=0.222) HMGA2 MNC 32.4±1.6 29.3±1.7 (p=0.000) * 30.8±1.8 (p=0.085)
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Mead, Adam J., Nauman M. Butt, Waseem Nagi, et al. "A retrospective real-world study of the current treatment pathways for myelofibrosis in the United Kingdom: the REALISM UK study." Therapeutic Advances in Hematology 13 (January 2022): 204062072210844. http://dx.doi.org/10.1177/20406207221084487.
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Background: Myelofibrosis (MF) is a blood cancer associated with splenomegaly, blood count abnormalities, reduced life expectancy and high prevalence of disease-associated symptoms. Current treatment options for MF are diverse, with limited data on management strategies in real-world practice in the United Kingdom. Methods: The REALISM UK study was a multi-center, retrospective, non-interventional study, which documented the early management of patients with MF. The primary endpoint was the time from diagnosis to active treatment. Discussion: Two hundred patients were included (63% [ n = 126/200] with primary MF; 37% [ n = 74/200] with secondary MF). Symptoms and prognostic scores at diagnosis were poorly documented, with infrequent use of patient reported outcome measures. ‘Watch and wait’ was the first management strategy for 53.5% ( n = 107/200) of patients, while the most commonly used active treatments were hydroxycarbamide and ruxolitinib. Only 5% of patients proceeded to allogeneic transplant. The median (IQR) time to first active treatment was 46 days (0–350); patients with higher risk disease were prescribed active treatment sooner. Conclusion: These results provide insight into real-world clinical practice for patients with MF in the United Kingdom. Despite the known high prevalence of disease-associated symptoms in MF, symptoms were poorly documented. Most patients were initially observed or received hydroxycarbamide, and ruxolitinib was used as first-line management strategy in only a minority of patients. Plain Language Summary Background: Myelofibrosis is a rare blood cancer associated with symptoms that can seriously affect a patient’s daily life, such as enlarged spleen and decreased white and red blood cells. Although several treatments are available for patients with myelofibrosis, it is not clear which ones clinicians use most frequently. Methods: We aimed to review which treatments are usually given to patients with myelofibrosis in the UK, by collecting information from the medical records of 200 patients with myelofibrosis treated in different centres across the UK. Results: The results showed that the symptoms patients experienced were not always written down in the medical records. Similarly, clinical scores based on patient characteristics (which clinicians use to try to predict if a patient will respond to treatment well or not) were also missing from the medical records. Clinicians also rarely asked patients to complete questionnaires that try to measure the impact of myelofibrosis and its treatment on their health. The most common approach for patients with myelofibrosis in the UK was ‘watch and wait’, which over half of patients received. The most common drugs used for treatment were hydroxycarbamide and ruxolitinib; only a very small proportion of patients received a bone marrow transplant. On average, patients waited for 46 days before receiving a treatment, although patients considered to have a more aggressive type of disease received treatment sooner. Conclusion: The results of this study suggest that medical records can be missing key information, which is needed to decide which is the best way to treat a patient with myelofibrosis. They also suggest that clinicians in the UK prefer observation to treatment for a large number of patients with myelofibrosis. This could mean that the approach used for many patients with myelofibrosis does not help them to control symptoms that have an impact on their daily lives.
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Hu, Shiwei, Xiudi Yang, Hongyan Tong, Jie Jin, and Jian Huang. "Efficacy and safety of ruxolitinib in patients with lower risk myelofibrosis: A single-arm, exploratory and prospective study." Journal of Clinical Oncology 42, no. 16_suppl (2024): 6573. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.6573.
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6573 Background: The COMFORT studies assessed the efficacy and safety of ruxolitinib in patients with intermediate-2 and high risk myelofibrosis (MF), and JUMP study has broadened the investigation including patients with intermediate-1 MF in the classification of DIPSS. However, there have been limited prospective studies evaluating the efficacy and safety of patients with low risk MF in the classification of more comprehensive scoring system. Here we present a single-arm, exploratory and prospective study to assess the efficacy and safety of ruxolitinib in patients with lower risk MF in China. Methods: Lower risk was defined as MIPSS-70 ≤ 3, MIPSS+V2.0 ≤ 3, DIPSS-Plus ≤ 1, DIPSS ≤ 2 or MYSEC-PM < 14 according to the expert guidelines. Patients aged ≥ 18 with overt primary myelofibrosis (overt-PMF), prefibrotic primary myelofibrosis (pre-PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF), classified as lower risk were enrolled. The primary endpoint was the proportion of patients with a spleen length reduction of ≥ 50% from baseline at week 48. Secondary endpoints included the best spleen response, the proportion of patients with a ≥ 50% reduction in Total Symptom Score (TSS50) and safety. Results: A total of 40 patients were enrolled in the lower risk group, including 7 pre-PMF, 17 overt-PMF, 8 PPV-MF, and 8 PET-MF patients. The median age was 62.0 years. 32 (80%) were JAK2V617F positive. 16 patients had next generation sequencing (NGS), the most frequent non-driver mutation was in TET2 (43.8%), followed by BCOR (12.5%). By week 48, 26 (65.0%) patients achieved a ≥ 50% decrease in palpable spleen length. 32 (80.0%) patients achieved a ≥ 50% reduction from baseline at any time. The median time to a spleen response was 4.3 weeks. The TSS50 rates at week 48 was 25%. No patients required red blood cell transfusion at baseline. And only 1 patient had a baseline hemoglobin (HB) <100 g/L, which remained stable during the follow-up process. The most common grade ≥ 3 hematological treatment emergent adverse events (TEAEs) were anemia (10.0%) and thrombocytopenia (2.5%). 6 (15.0%) and 15 (37.5%) patients experienced grade 1 or 2 anemia and thrombocytopenia, respectively. The mostly common non-hematological TEAEs was infection (12.5), including upper respiratory tract infection (7.5%), urinary infection (2.5%), fever (2.5%), predominantly of grade 1 or 2. Of note, 1 patient developed staphylococcal sepsis and 1 patient experienced acute renal failure. No one discontinued ruxolitinib treatment due to TEAEs. Conclusions: Ruxolitinib is an effective treatment for patients with intermediate-1 and low risk MF, resulting in improved spleen and symptom responses, along with fewer hematological and non-hematological TEAEs. This trial was registered as ChiCTR2200064250 at ClinicalTrials.gov . Clinical trial information: ChiCTR2200064250.
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Guglielmelli, Paola, Giovanni Barosi, Alessandro Pancrazzi, et al. "Clinical Relevance of JAK2V617F Allele Burden in Primary and Post-Polycythemic/Post-Thrombocythemic Myelofibrosis." Blood 112, no. 11 (2008): 2799. http://dx.doi.org/10.1182/blood.v112.11.2799.2799.
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Abstract The JAK2V617F mutation is found in 60% of patients (pts) with primary myelofibrosis (PMF) and &gt;90% with post-polycythemia vera MF (PPV-MF); few pts with post-essential thrombocythemia MF (PET-MF) have been reported. There are conflicting results about clinical relevance of V617F mutational status and/or burden in PMF, while no study specifically addressed this point yet in PPV/PET-MF. An association of mutation with poorer survival in PMF has been reported (Campbell P et al, Blood, 2006), while Tefferi A et al (Leukemia, 2008) found a reduced survival only for pts with lowest allele burden. Barosi G et al (Blood, 2007) found that JAK2V617F mutation independently predicted evolution towards large splenomegaly, splenectomy and leukemic transformation. We separately evaluated 2 groups of pts, 240 pts with PMF and 65 pts with secondary forms of MF (PPV-MF n=43, PET-MF n=22); the V617F allele burden was measured in granulocytes by RT-PCR. Diagnosis of PMF satisfied the 2008 WHO criteria, and that of PPV- or PET-MF the IWG-MRT criteria. PMF: 150 pts (63%) were JAK2V617F-pos, median V617F allele burden 45% (range, 1–100%); percentage of pts in the four allele quartiles was 16%, 50%, 15%, and 19%. Median interval from diagnosis to genotyping was 21 months. In multivariate analysis, JAK2V617F mutated patients had significantly higher leukocyte count (P=.02) and hemoglobin level (P&lt;.0001), that were both positively correlated with V617F burden (P= .03 and P=.01, respectively). Pts with Hb &lt;10g/dL were significantly less among JAK2V617-pos (12% vs 26%; P&lt;.007), accounting for a significantly greater proportion of mutated pts in the Lille low risk category (P=.04). Nor a mutated JAK2 genotype nor the V617F burden had any influence on presence or degree of palpable splenomegaly, thrombosis, hemorrhage, AML evolution, or cytoreductive treatment. 29 pts died (12.0%); survival was independent of JAK2 genotype, and was associated (multivariate analysis) only with age (95% CI, 1.07–1.18) and leukocyte count (95% CI, 1.02–1.10). Since we previously observed a time-dependent accumulation of mutated alleles in PMF, we performed a sub-group analysis in 90 pts in whom quantitation of V617F burden was performed within six months from diagnosis: 56 pts (62%) were mutated, median V617F burden was 36% (range, 10–100%); percentage of pts in the four allele quartiles was 27%, 50%, 16%, and 7%. Similar to the whole pts series, the only parameters significantly associated with allele burden were hemoglobin level, (P=.03), leukocyte count (P=.04) and low Lille score (P=.04). However, we found a statistically significant association (multivariate analysis) of lowest V617F burden quartile with shortened survival compared to patients having greater than 25% V617F allele or to JAK2V671F unmutated patients, corroborating finding from Tefferi et al (Leukemia, 2008). Using Cox analysis, reduced survival was associated with low V617F burden (P=.008), leukocytosis (P=−003) and age (P=.03). These findings indicate that a low V617F burden, measured at the time of diagnosis, has a negative impact on survival, and might represent a novel criterion for risk stratification in PMF. PPV/PET-MF: 49 pts (75.3%) were JAK2V617F mutated, median V617F allele burden 73% (10–100%). All 43 PPV-MF were mutated compared to 6/22 (27%) of PET-MF (P&lt;.01). Median V617F burden was significantly greater in PPV-MF than in 173 control PV pts (72% vs 52%; P&lt;.01), as well as in PET-MF (57% vs 26% in 200 control ET pts; P&lt;.001), supporting that accumulation of V617F alleles is a mechanism of evolution toward MF in JAK2V617F-positive PV or ET pts. However, since JAK2V617F mutation frequency was significantly lower in PET-MF pts (27.2%) than in ET pts (63.4%; P&lt;.01), genetic mechanisms other than JAK2V617F may have a dominant role in MF transformation of ET. A part for lower platelet count (P=.04) in JAK2V617F-pos PPV/PET-MF pts no other difference with unmutated pts was found. In the analysis of quartiles, we found a correlation of allele burden with age, leukocyte count and circulating CD34+ cell count (all P&lt;.05), while there was no impact on clinical characteristics including spleen size, thrombosis, hemorrhage, AML transformation or overall survival (median follow-up, 40 months). Therefore, both presence and burden of JAK2V617F seem to have little influence on disease phenotype in pts with PPV- or PET-MF, although larger series and longer follow-up might be warranted.
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Kim, Tong-Yoon, Daehun Kwag, Jong-Hyuk Lee, et al. "Clinical Features, Gene Alterations, and Outcomes in Prefibrotic and Overt Primary and Secondary Myelofibrotic Patients." Cancers 14, no. 18 (2022): 4485. http://dx.doi.org/10.3390/cancers14184485.
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The Philadelphia-negative myeloproliferative neoplasms (MPNs) are divided in three major groups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 WHO classification incorporates also prefibrotic PMF (pre-PMF) and overt PMF. This study aimed to discriminate the clinical features, genetic alterations, and outcomes in patients with prefibrotic, overt PMF, and secondary MF (SMF). This study included 229 patients with diagnosed myelofibrosis (MF). Among 229 patients, 67 (29%), 122 (53%), and 40 (18%) were confirmed as SMF, overt PMF, and pre-PMF, respectively. The JAK2 V617F mutation was differentially distributed in SMF and PMF, contradictory to CALR and MPL mutations. Regarding nondriver mutations, the occurrence of ASXL1 mutations differed between PMF and SMF or pre-PMF. The three-year overall survival was 91.5%, 85.3%, and 94.8% in SMF, overt PMF, and pre-PMF groups. Various scoring systems could discriminate the overall survival in PMF but not in SMF and pre-PMF. Still, clinical features including anemia and thrombocytopenia were poor prognostic factors throughout the myelofibrosis, whereas mutations contributed differently. Molecular grouping by wild-type SF3B1 and SRSF2/RUNX1/U2AF1/ASXL1/TP53 mutations showed inferior progression-free survival (PFS) in PMF, SMF, and pre-PMF. We determined the clinical and genetic features related to poor prognosis in myelofibrosis.
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Masarova, Lucia, Prithviraj Bose, Naval G. Daver, et al. "Cytogenetic Risk Stratification in Primary Versus Post-Essential Thrombocythemia / Post-Polycythemia Vera Myelofibrosis." Blood 128, no. 22 (2016): 4250. http://dx.doi.org/10.1182/blood.v128.22.4250.4250.
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Abstract Introduction: The Dynamic International Prognostic Scoring System-Plus (DIPPS-Plus) for primary myelofibrosis (PMF) categorizes cytogenetic abnormalities as "favorable" and "unfavorable." Abnormalities (Abn) -7/7q-; -5/5q-; i(17q), +8; inv(3); 12p-; 11q23; and complex karyotype (CK; >3 Abn) are considered unfavorable. More recently monosomal karyotype (MK), defined as 2 autosomal monosomies or a single monosomy with at least one additional structural Abn, was also recognized as unfavorable (Vaidya, Blood 2011). While the prognostic impact of cytogenetic Abn has been studied in patients with PMF, almost no data exist in patients with post-essential thrombocythemia/polycythemia vera myelofibrosis (PET/PV-MF). Objective: To identify the impact of cytogenetic Abn on prognosis in patients with PMF and PET/PPV-MF referred to our center between 1984 and 2013. Methods: We retrospectively reviewed the charts of 1100 patients with MF. Cytogenetic analysis performed at the time of referral to our institution was reported according to the International System for Human Cytogenetic Nomenclature. Overall survival (OS) was calculated and compared using the Kaplan-Meier method with the log rank test. The impact of each cytogenetic Abn on OS was measured by stepwise Cox regression model by comparing them against patients with diploid karyotype. Analyses were conducted separately for patients with PMF and PET/PPV-MF. Results: Cytogenetic data (≥ 10 metaphases) were available in 981 patients (660 with PMF and 321 with PET/PPV-MF). Median age was similar in both groups (66 years; range, 27-90), and 61% of patients were male. The distribution of DIPSS scores were similar in both groups (overall 7% low, 37% int-1, 41% int-2 and 15% high). OS in each DIPSS category were 134, 65, 33, 19 months in patients with PMF; and 160, 73, 48, 36 in patients with PET/PPV-MF (in both groups P<0.001). The JAK2 mutation was present in 65% of patients in both groups. Overall, 621 (63%) patients had diploid karyotype (DK), 17% had CK (n=62), and 7% had MK (n=26). Abnormal karyotypes present in >10% of patients were single 20q- (n=75, 21%), single 13q- (n=38, 11%), and CK (n=62, 17%). Others Abn (single +8, +9, single -7/7q-, -5/5q-, or various combinations of the two Abn) occurred less frequently. Importantly, Abn of chromosome (chr) 17 occurred only in patients with PMF, while all other Abn were similarly distributed among PMF and PET/PPV-MF. Ninety nine patients (10%) developed AML, 44% of whom had cytogenetic Abn, similar in PMF and PET/PPV-MF. After a median follow-up of 31 months (range, 0.5-251), 548 (56%) of patients have died, with similar rates in both groups. Impact of different cytogenetic Abn on OS is presented in Table 1 and Graph 1 for PMF, and Graph 2 for PET/PPV-MF. We have identified 4 different risk categories in PMF patients with respective median OS of 86, 46, 14 and 6 months (P<0.001, Graph 1A). Only 2 different categories were identified in patients with PET/PPV-MF, with the corresponding OS of 70 and 14 months (P<0.001, Graph 1B); further separation of these patients was not possible due to smaller number of patients with specific Abn. Conclusions: Results from our cohort of 691 PMF and 321 PET/PPV-MF patients differ from those described in DIPSS-Plus. First, we showed that OS in patients with PMF and single +8 Abn, and 1-3 abnormalities (excluding chromosomes 5, 7, 12p and MK) is no different than in those with normal karyotype. Second, OS was the best in patients with single 20q- Abn, which was significantly better than in patients with normal karyotype. Third, we report cytogenetic stratification on the largest cohort of PET/PPV-MF patients, with findings different than in PMF (Table 1). Further validation in larger multicenter studies is warranted. Table Table. Figure Overall survival in PMF [1A] and PET/PPV-MF [1B] patients stratified by cytogenetic groups. Figure. Overall survival in PMF [1A] and PET/PPV-MF [1B] patients stratified by cytogenetic groups. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.
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Gill, Harinder, Garret M. K. Leung, and Yok-Lam Kwong. "Evolving landscape of JAK inhibition in myelofibrosis: monotherapy and combinations." Hematology 2023, no. 1 (2023): 667–75. http://dx.doi.org/10.1182/hematology.2023000452.
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Abstract Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post–polycythemia vera MF, and post–essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor–based combinations.
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Ianotto, Jean-Christophe, Françoise Boyer-Perrard, Jean-Loup Demory та ін. "Efficacy and Safety of Peg-Interferon-α2a In Myelofibrosis: a Study of the FIM and GEM French Cooperative Groups". Blood 116, № 21 (2010): 4103. http://dx.doi.org/10.1182/blood.v116.21.4103.4103.
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Abstract Abstract 4103 Background: The moderate effect of most palliative treatments in primary and secondary myelofibrosis (MF), in addition to the limited possibilities of allogeneic stem cell transplantation, has incited physicians to look for alternative treatments. Since 1987, several studies have suggested that interferon may be beneficial in the treatment of MF. However, important hematological and general limiting toxicities frequently occur in MF patients (pts), leading to rapid treatment discontinuation in more than 50% of pts. Better results were recently reported in a small series of 13 MF pts treated with Peg-Interferon-α2a (Ianotto et al., Br J Haematol, 2009). The present study aimed to collect data of pts with primary and secondary MF treated with Peg-Interferon-α2a in French centers members of the FIM (French Intergroup of Myeloproliferative disorders) and GEM (Groupe d'Etudes des Myelofibroses) groups, to better assess tolerance and efficacy of this form of interferon in MF. Patients and Methods: Between Dec 2006 and Feb 2010, 39 MF pts treated with Peg-Interferon-α2a were registered from 10 different French centers affiliated to FIM and GEM groups. Age of pts ranged from 41 to 81 years, 21 were men and 18 women. Sixteen pts had primary MF, 13 had post-PV and 10 post-ET MF, respectively. Twenty-five patients (64%) were JAK2V617F positive. Twenty-eight patients had previously received other cytoreductive treatment. Clinical and biological parameters were collected at diagnosis and every 3 months. Responses were assessed according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Analyses were performed in July 2010, after a median follow-up of 18 months (range: 3 – 42 months). Results: Among the 28 patients with splenomegaly, we observed 10 responses (36%) including 7 complete and 3 partial responses. Fourteen patients had constitutional symptoms which resolved in 8 of them (57%). Seven of 15 patients (47%) with an initial hemoglobin level below 100 g/L achieved complete response (CR). Three of 8 (37%) transfused pts became transfusion-independent. Twenty-two patients had abnormal WBC count which normalized in 13 of them (59%). Platelet count was abnormal in 27 patients, and 14 (52%) achieved CR with Peg-Interferon-α2a treatment. The evolution of the JAK2V617F allele burden is currently under investigation and will be presented at the meeting. The initial median dose of Peg-Interferon-α2a effectively received was 103 μ g/wk, further decreased to a median of 85 μ g/wk after one year. At time of analysis, treatment was stopped in 11/39 (28%) pts due to side effects, inefficacy or hematologic evolution. Conclusion: In this observational study, we found higher efficacy and better tolerance of interferon than previously reported in patients with primary or secondary MF. Such results were possibly due to a better tolerance of the pegylated form used, and to the low-dose schedule applied by the physicians. Our results suggest at least that Peg-Interferon-α2a should be considered as a possible therapeutic option in selected MF patients. Future clinical trials in MF will hopefully involve combinations of low dose Peg-Interferon-α2a with JAK2-inhibitors or immunomodulatory agents in order to improve tolerability and increase efficacy. Disclosures: Off Label Use: This is an observational study of the off-label use of peg-Interferon-alfa2a in myelofibrosis.
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Guglielmelli, Paola, Giada Rotunno, Annalisa Pacilli, et al. "Prognostic Impact of Bone Marrow Fibrosis in Primary Myelofibrosis: A Study of Agimm Group on 540 Patients." Blood 126, no. 23 (2015): 351. http://dx.doi.org/10.1182/blood.v126.23.351.351.
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Abstract Background. The prognostic significance of bone marrow (BM) fibrosis grade in pts with primary myelofibrosis (PMF) is debated. A fibrosis grade greater than 1 was associated with a 2-fold higher risk of death compared with pts with early/prefibrotic MF (grade 0) [Thiele J, Ann Hematol 2006]. Recent data suggest that more accurate prediction of survival is achieved when fibrosis grade is added to IPSS [Verner C, Blood 2008; Giannelli U, Mod Pathol 2012]. Aim. To analyze the prognostic impact of fibrosis in diagnostic BM samples of 540 WHO-2008 diagnosed PMF pts with extensive clinical and molecular information collected in 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). Methods. The clinical variables assessed were those previously identified as prognostically relevant in the IPSS score. Published methods were used to screen mutations of JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. European consensus scoring system was used to grade fibrosis (on a scale of MF-0 to MF-3). The prognostic value of fibrosis with regard to overall survival (OS) was estimated by Kaplan-Meier method and Cox regression. Results. Pts' median age was 61y; median follow-up 3.7y; median OS 10.5y; 184 pts (34.1%) died. IPSS risk category: low 33.7%, Int-1 27.7%, Int-2 19.1%, High-risk 19.5%. Mutational rate: JAK2 V617F 62.6%, CALR 20.7% (type-1/1-like 77.7%, type2/2-like-2 21.4%), MPL W515 5.9%; 62 (11.5%) were triple negative (TN). 171 pts (31.7%) were High-Molecular Risk (HMR) category (Vannucchi AM, Leukemia 2013); mutation rate: EZH2 7.2%, ASXL1 22.2%, IDH1-2 2.4%, SRSF2 8.3%. According to fibrosis grading, 50 pts were MF-0 (9.3%), 180 MF-1 (33.3%), 196 MF-2 (36.3%), 114 MF-3 (21.1%). Compared with both MF-0 and MF-1, MF-2 and MF-3 pts presented more frequently constitutional symptoms (P<.0001), larger splenomegaly (P<.0001), greater risk of developing anemia (P<.0001) or thrombocytopenia (P=.003). We found a significant association (P<.0001) between IPSS higher/Int-2 risk categories and MF-2 and -3 (20.5% and 37.8%, respectively, vs 14.8% and 6.0% for MF-0 and -1). There was no correlation between fibrosis grade and phenotypic driver mutations; in particular, TN pts were equally distributed among MF fibrosis grades (10%, 10.6%, 14.3% and 8.8% from MF-0 to -3, respectively). Conversely, the frequency of HMR pts increased progressively according to fibrosis grade: 8 pts MF-0 (16%), 46 MF-1 (25.6%), 66 MF-2 (33.7%) and 51 MF-3 (44.7%) (P<.0001). In particular, we found a significant association between fibrosis grade and ASXL1 (12%, 15%, 23.5% and 36% from MF-0 to -3; P<.0001) and EZH2 (2%, 3.9%, 8.2%, 13.2%; P=.01) mutations. Also, pts with 2 or more HMR mutated genes were preferentially MF-2 or -3 ( 0%, 4.4% 10.2% and 10.5% from MF-0 to -3; P=.001). Median OS was significantly shorter in pts with MF-2 (OS 6.7y, HR 7.3, IC95% 2.7-20.0; P<.0001) and MF-3 (OS 7.2y, HR 8.7, IC95% 3.1-24.2; P<.0001) compared with MF-1 (14.7y; HR 3.9, IC95% 1.4-10.9, P=.008) and MF-0 (P<.0001) used as reference group (OS not reached) (Figure). Excluding MF-0, MF-2 and -3 maintained negative prognostic impact with HR 1.9 (1.3-2.6; P=.001) and 2.2 (1.5-3.3; P<.0001) respectively vs MF-1. The impact of fibrosis on OS was maintained when analysis was restricted to younger (≤65y) pts. In multivariate analysis using the individual IPSS variables, grade MF-2 and -3 were independently predictive of survival (HR 3.9 (1.4-10.8), and HR 4.2 (1.5-12.0), respectively, P=.008 for both). The negative impact on survival of MF-2/-3 was maintained regardless of IPSS category, HMR status, number of HMR mutated genes and driver mutations, included as covariates (Table). In low, Int-1 and Int-2, but not high-risk IPSS categories, MF-2/-3 associated with reduced survival (P<.03). Conclusions. Overall, these results indicate that higher grades (MF-2 and MF-3) of fibrosis correlate with defined clinical and molecular variables and independently negatively impact on OS in PMF, suggesting the opportunity to explore its value in the setting of clinical and molecular prognostic scores for PMF. Table. Multivariate Analysis Variables HR 95% CI P value HMR status 2.4 1.5-3.7 <.0001 HMR≥2mutations 4.3 2.8-6.4 .009 IPSS scoring Int1 2.9 1.6-5.1 <.0001 Int2 10.0 5.6-17.7 <.0001 High 9.7 5.5-17.2 <.0001 Driver mutations CALR type2 3.4 1.3-8.6 .010 JAK2/MPL 2.4 1.4-4.3 .003 TN 4.5 2.3-8.8 <.0001 Fibrosis MF-2/MF-3 3.8 1.4-10.6 .010 Figure 1. Figure 1. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Ohyashiki, Kazuma, Yasuo Aota, Akihiko Gotoh, Keisuke Miyazawa, Yukihiko Kimura, and Junko H. Ohyashiki. "Myelodysplastic Syndromes with Myelofibrosis May Be a Target for the JAK2 V617F Tyrosine Kinase Mutation." Blood 106, no. 11 (2005): 4895. http://dx.doi.org/10.1182/blood.v106.11.4895.4895.
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Abstract The JAK V617F tyrosine kinase mutation is responsible for development of the disease in chronic myeloproliferative disorders, including myelofibrosis (MF). Since MF is associated with various hematologic diseases as a terminal hematologic condition and is an important issue in managing patients, we searched for the V617F mutation in primary and secondary MF in various hematologic diseases using the sequence-specific primer-single molecule fluorescence detection assay (SSP-SMFD). Of the MF patients associated with acute myeloid leukemia and (n = 3), lymphoma (n = 3), and chronic myeloid leukemia (n = 3), none of them showed the mutation at the time of the diagnosis of MF. Approximately 40% of essential thrombocythemia (ET: n = 16) and primary MF (n = 4) showed the JAK2 V617F mutation, whereas 6 of 8 patients with polycythemia vera showed the mutation. Of note is that 2 of 6 patients with myelodysplastic syndromes (MDS) terminating in MF showed the mutation, while no MDS patient without MF (MDS: n = 3) had the JAK2 V617F mutation. Our study clearly demonstrated that MF in MDS patients is sometimes associated with JAK2 V617F mutation, while other underlying diseases developing MF may involve other pathways. Moreover, it permits speculation that clonal evolution in some MDS patients with the JAK2 V617F tyrosine kinase mutation may be responsible for secondary MF.
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Braish, Julie, Prithviraj Bose, Naveen Pemmaraju, et al. "Deeper Insight into Splicing Mutations in Myelofibrosis." Blood 142, Supplement 1 (2023): 4580. http://dx.doi.org/10.1182/blood-2023-189168.
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Introduction: Prognostically adverse mutations in patients with primary myelofibrosis (MF) include ASXL1, EZH2 IDH1, IDH2, and two types of splicing mutations U2AF1 Q157 and SRSF2 (as in MIPSS70.v2 score). The other splicing mutations (SPM), such as SF3B1 or ZRSR2, do not appear to have impact on prognosis. In patients with MF secondary to polycythemia vera or essential thrombocytopenia (PPV-MF, PET-MF), the role of SPM is less known, and they are not included in the MYSEC-PM score. Objective: We aimed to evaluate the role of SPM on the outcome of patients with PPV/PET-MF, and their interplay with other HMR on prognosis of all MF patients from our center. Methods: We retrospectively reviewed medical charts of 114 patients with MF from our institution who had SPM on next generation sequencing (51+ gene myeloid panel). We assessed impact of high-risk SPM (HR_spl: U2AF1 Q157; SRSF2) and remaining SPM (low risk, LR_spl: SF3B1, PRPF40B, U2AF2, ZRSR2) on the outcome of MF patients. Separate analysis was carried per disease phenotype (MF vs PET/PPV-MF), and presence of the other high-risk molecular mutations (HMR: ASXL1, IDH1/2, EZH2). Descriptive statistics was used for demographic variables; Kaplan-Meier curve with log-rank test was used for overall survival (OS), calculated from the time of presentation. Results: Table summarizes clinical characteristics of all patients. The most common SPM were SRSF2 and SF3B1 (41% each), followed by U2AF1 (17.5%) and ZRSR2 (11%). 6 patients had more than one SPM. The distribution of SPM types did not statistically differ between PMF and PET/PPV-MF patients, albeit numerically, more patients with PMF had SRSF2 and PET/PPV-MF had SF3B1 (table). 77% of all patients had higher DIPSS score; 85% of PMF patients had higher MIPSS70.v2 score and 36% of PET/PPV-MF had higher MYSEC-PM. HMR mutations were detected in 77 (68%) patients: ASXL1 (65%), EZH2 (19%), IDH1/2 (16%). ASXL1 co-occurred more frequently with SF3B1 in PET/PPV-MF patients (75% vs 25%), and with SRSF2 (62% vs 38%) and U2AF1 (89% vs 11%) in PMF patients. The median OS (months [95% CI]) according to SPM: SRSF2, U2AF1, SF3B1 and others (U2AF2 in 2 patients, PRPF40B in 1 patient and ZRSR2 in 13 patients) was as follows: 46 [23-70], not reached, 130 [104-156], unreached, respectively. The median OS (months [95% CI]) per HR_spl (n = 61) and LR_spl (n = 67) was 51 [26-76] vs 130 [101-159], p &lt; 0.01, HR 0.31, 95% CI 0.13-0.74. Sub-analysis for PMF (n = 86) and PET/PPV-MF (n = 28) showed comparable results, median OS for HR_spl and LR_spl in PMF of 51 vs 109 months and for PET/PPV-MF of 46 and 130 months, respectively. The median OS (months [95% CI] of HR_spl with and without HMR and LR_spl with and without HMR as shown in Figure was 46 [20-72] and 51 [21-81] vs 109 [0.5-221] and 130 [95-165], respectively. Two years survival for patients with HR_spl and LR_spl with and without HMR was at 69% vs 85% and 87% vs 95%, respectively. Median OS (months; 95% CI]) of each individual SPM without and with HMR was 51 [not estimated] and 46 [11-82] for SRSF2; unreached for all groups in U2AF1 and ZRSR2, respectively; 130 [98-161] and 109 [10-220] for SF3B1. Conclusions: Various SPM seem to have similar effect on survival of PET/PPV-MF and PMF patients. PET/PPV-MF patients have more low risk SPM (SF3B1) and the co-occurrence of HMR does not appear to impact the outcome. Among the high-risk SPM, SRSF2 has the worst prognostic role irrespective of concurrent HMR. Further validation of our data, including association with received therapy, is ongoing and will be presented at the conference.
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Siordiya, Nadiya, Ekaterina Lisina, Pavel Butylin, et al. "Incidence of Elevated Expression of wt1 in Primary Myelofibrosis (pmf) and Postpv-, Postet Myelofibrosis and Its Dynamics during Ruxolitinib Treatmeny." Blood 128, no. 22 (2016): 5498. http://dx.doi.org/10.1182/blood.v128.22.5498.5498.
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Abstract Background. Wt1 expression is thoroughly studied in acute myeloblastic leukemia and widely used for disease response monitoring.Its role in MPN is less known. Aim. The aim of the study was to reveal the incidence of elevated Wt1 expression in PMF and secondary MF, as well as to find out clinical significance during ruxolitinib therapy. Patients and methods. 38 pts were included ( Primary Mf-31, post PV- and post ET Mf- 8, males - 12, females- 26). Wt1 expression in peripheral blood was studied by qPCR at diagnosis and during ruxolitinib treatment using Quiagen kit. Dynamics of Wt1 expression was studied in 20 pts treated by ruxolininib. Spleen size was measured in cm below costal margin. Results. Wt1 increased expression was found in 35/38 pts. Correlation of Wt1 expression and DIPSS was not found. The relation between blast cell and Wt1 expression was studied by dividing pts in 3 subgroups according to the number of blast cells in peripheral blood- 0, 1-2, >2. Wt1 expression was lowest in the 1st group, and the highest in the 3rd group((p<.05). Ruxolitinib treatment resulted in the decrease of spleen size and parallel decrease of Wt1 level( p<.05 -Fig1).Pts with transformation to acute leukemia(5) had higher level of Wt1 than before transformation. Conclusion. Wt1 expression is elevated in the majority of pts with PMF as well as in secondary MF. Correlation was found with blast level and spleen size. Wt1 could be used for monitoring efficacy of ruxolitinib therapy Disclosures Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.
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Hossain, Homayra Tahseen, Arfa Rahman, Md Maksudul Islam Mazumder, Mahbub Mayukh Rishad, Quazi Tarikul Islam, and Mohammad Zahiruddin. "Primary Myelofibrosis in a Young Girl- A Case Report." Journal of Bangladesh College of Physicians and Surgeons 41, no. 3 (2023): 239–43. http://dx.doi.org/10.3329/jbcps.v41i3.66913.
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Myelofibrosis (MF) is a rare disorder that is classified as one of the myeloproliferative disorders. It is a BCR-ABL1- negative myeloproliferative neoplasm characterized by abnormal proliferation of hemopoietic stem cells within the bone marrow, which leads to overproduction of fibrous tissue. Our patient a young girl of 17 year old presented with lump in left upper abdomen, shortness of breath & generalized swelling. The diagnosis was made based on severe anaemia, pancytopenia in peripheral blood film. Bone marrow trephine biopsy from the tibia revealed myelofibrosis. Splenectomy was done in an attempt to reduce the total volume of malignant cells and improve the features of hypersplenism. Myelofibrosis with hypersplenism in a 17- year- old girl is reported rarely. However, when it does, it usually runs rapid and fatal course. J Bangladesh Coll Phys Surg 2023; 41: 239-243
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Bahadur, Laila, Humaira Taj Niazi, Kulsoom Bahadur, Ansa Kulsoom Rehman, Saliha Syed, and Sidra Humayun. "ASXL1 MUTATIONAL ANALYSIS IN MYELOFIBROSIS PATIENTS IN KHYBER PAKHTUNKHWA." Khyber Journal of Medical Sciences 18, no. 1 (2025): 58–64. https://doi.org/10.70520/kjms.v18i1.632.
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Objectives: To determine the patients with MPNs for JAK2 mutations and to Identify ASXL1 mutation in JAK2 positive and JAK2 negative patients. Methodology: This descriptive cross-sectional study consists of two consecutive phases. In the first phase, patients with myelofibrosis (MF) were identified. Both previously diagnosed and newly diagnosed MF cases were included. Data collection involved a comprehensive questionnaire including demographic details, clinical history, and physical examination findings. Blood samples were collected from participants for routine investigations and DNA extraction. The second phase consisted of genomic DNA extraction, and conventional PCR was performed to determine JAK-2 mutational status. Additionally, direct Sanger sequencing of ASXL1 was carried out for all patients. Results: The study included 50 myelofibrosis (MF) patients diagnosed based on bone marrow biopsy and reticulin staining. The cohort comprised primary and secondary MF cases, including male and female participants. JAK2 mutation analysis revealed that 48 (96%) patients were JAK2-positive, while only 2 (4%) patients were JAK2-negative. Direct Sanger Sequencing analysis of ASXL1 Exon 12 identified missense variations in 2 (4%) out of 50 patients. Conclusion: The high prevalence of JAK2 mutations (96%) among MF patients underscores its significance in disease pathogenesis and diagnosis.
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Barosi, Giovanni, Elisa Bonetti, Paolo Catarsi, et al. "Somatic and Germ-Line Molecular Characteristics Of Prefibrotic Myelofibrosis." Blood 122, no. 21 (2013): 4058. http://dx.doi.org/10.1182/blood.v122.21.4058.4058.
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Abstract Prefibrotic myelofibrosis (pre-MF) is a prodromic variant of primary myelofibrosis (PMF) characterized by prevalence of female sex, young age, high frequency of splanchnic vein thrombosis and indolent disease course (Barosi et al, PLoS One. 2012;7(4):e35631). Here we report the molecular characteristics at diagnosis of 177 consecutive pre-MF patients included in the institutional data-base of PMF patients at the Center for the Study of Myelofibrosis in Pavia from January 2001 through July 2013. As compared with patients with fibrotic type-MF (bone marrow (BM) fibrosis= 1 to 3), the frequency of JAK2V617F mutation in pre-MF patients (BM fibrosis=0) was higher (69.2% vs. 60.9%; P=0.02) but the JAK2V617F allele burden was lower (39% vs. 50.6%; P=<0.001). Patients with pre-MF displayed MPL, EZH2 or ASXL1 mutation at a frequency of 2.6%, 0% and 0% respectively, lower than in fibrotic type-MF (frequency: 7.6%, 4%, 17.4%, respectively). Both 45/1 haplotype of the JAK2 gene (rs12343867), and A3669G polymorphism of the glucocorticoid receptor (GR)- rs6198, known susceptibility alleles for PMF, were over-represented in pre-MF with respect to the normal control population (minor allele frequency, 43.3% vs. 24%, and 22.5% vs. 18.2%, respectively; P<0.001 and P= 0.04, respectively). However, the frequency of the variants were not significantly different in pre-MF with respect to fibrotic type-MF (minor allele frequency, 43.4% vs. 46.9%, and 22.5% vs. 27.1%). In pre-MF JAK2V617F mutated patients, a significant correlation between the burden of the V67F allele and the frequency of 46/1 haplotype (rs 12343867) was documented. By dividing JAK2V617F mutated patients in quartiles of allele burden, the frequency of the minor C allele increased progressively from 0.29% to 0.71% (P<0.001, X2 test for trend). No association was ascertained between the burden of the V617F allele and G allele of CR A3669G polymorphism. In conclusion, pre-MF patients segregated preferentially with JAK2V617F mutated genotype with low allele burden. Pre-MF patients were characterized by an almost complete absence of the acquired somatic mutations (EZH2 and ASXL1) that complement the JAK2V617F mutation in the fibrotic type-MF, and that are known to be associated to poor survival and propensity to blast transformation. Pre-MF patients were associated with susceptibility alleles 46/1 and GR A3669G, and the strength of association was not different from that of the fibrotic type-MF patients. Disclosures: No relevant conflicts of interest to declare.
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Bose, Prithviraj, Jayastu Senapati, Lucia Masarova, et al. "Impact of SF3B1 mutation on outcomes in myelofibrosis." Journal of Clinical Oncology 40, no. 16_suppl (2022): e19080-e19080. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e19080.
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e19080 Background: Splicing factor 3B subunit 1 ( SF3B1) mutations have been shown to confer a unique phenotype in MDS and MDS/MPN overlap syndromes, with ring sideroblasts, thrombocytosis and favorable prognosis. In myelofibrosis (MF) the frequency of SF3B1 mutation is <10% and may play a less important role in disease outcomes (Lasho et. al, Leukemia, 2011). Methods: We retrospectively analyzed all patients (pts) with WHO-defined MF (primary, including pre-fibrotic MF, or progressed from PV or ET) seen at our center from Jan. 2017 through Jul. 2021. We compared disease phenotypes, MPN driver and co-occurring mutations, cytogenetics, dynamic IPSS (DIPSS) score, transfusion requirements, treatment characteristics and survival outcomes between patients with SF3B1-mutated ( SF3B1+) and -wild type ( SF3B1-) MF. Results: A total of 381 pts were identified, 29 (8%) of whom were SF3B1+. There were similar frequencies of JAK2, CALR, MPL mutations and “triple negative” MF in the 2 groups (Table). The median number of SF3B1 mutations was 1 (range, 1-2); K666N being the most common (52%). The 2 groups were similar in regard to their baseline hemoglobin, white blood cell counts, platelets, co-occurring mutations, symptom burden and DIPSS but more SF3B1+ pts were PRBC transfusion-dependent at presentation than SF3B1- pts (38% vs. 15%, p=0.003). At a median follow up of 17.2 months for the entire cohort (range, 0.1- 52.2 mos., 22.6 mos. for SF3B1+ and 16.8 mos. for SF3B1-), 41 pts had died [14% SF3B1+ and 10% SF3B1-, p=0.5] and 7 pts (1 SF3B1+ and 6 SF3B1-) had leukemic transformation. The median estimated OS was 230 months for SF3B1- vs. not reached for SF3B1+ pts (p = 0.6). Conclusions: SF3B1 mutation is an uncommon event in MF and does not substantially affect disease phenotype and outcomes. MF pts with SF3B1 mutation are more likely to be PRBC transfusion dependent.[Table: see text]
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Mesa, Ruben A. "Assessing New Therapies and Their Overall Impact in Myelofibrosis." Hematology 2010, no. 1 (2010): 115–21. http://dx.doi.org/10.1182/asheducation-2010.1.115.
Full textAbstract:
Abstract Clinical management of myelofibrosis (MF)—whether primary or arising from an antecedent myeloproliferative neoplasm (post-essential thrombocythemia/polycythemia vera MF)—is currently in a period of transition that began with the discovery of the JAK2-V617F mutation 5 years ago. Selective JAK2 inhibitors have been developed, and clinical trials thus far have demonstrated that several of these agents meaningfully reduce MF-associated splenomegaly and constitutional symptoms. JAK2 inhibitors have durable benefits, act across the spectrum of MF subtypes, and provide a level of symptomatic benefit not seen with previous generations of nontargeted therapies. However, the JAK2 inhibitors can cause anemia and/or gastrointestinal disturbance, and their impact on JAK2 allele burden and the natural history is not yet fully defined. Several additional therapies that do not directly target JAK2 (eg, immunomodulatory drugs, histone deacetylase inhibitors, and inhibitors of the mammalian target of rapamycin [mTOR]) may ameliorate MF-associated anemia and morbidity-inducing symptoms. Balancing the potential benefits of these new agents against the risks and benefits of allogeneic stem cell transplantation (which can be curative, but carries a high risk of treatment-associated morbidity and mortality) requires an accurate estimation of the prognosis for an individual patient. Enhanced prognostic modeling systems are helping us to better characterize prognosis in MF patients not only at diagnosis, but also along the dynamic and variable course of the illness. Future advancements in the efficacy of MF-targeted therapy will likely arise from new pathogenetic insights and from combining JAK2 inhibitors with other agents.
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Verstovsek, Srdan, Moshe Talpaz, Ellen K. Ritchie, et al. "Phase 1/2 Study of NS-018, an Oral JAK2 Inhibitor, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF)." Blood 128, no. 22 (2016): 1936. http://dx.doi.org/10.1182/blood.v128.22.1936.1936.
Full textAbstract:
Abstract Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2).In the previously-reported Phase 1 portion, patients with myelofibrosis (MF) who received NS-018 achieved steady-state plasma levels above the IC50 for JAK2 at all doses (75mg QD - 400 mg BID). 300 mg QD was chosen as the recommended dose (RD) for Phase 2 portion of the study. OBJECTIVE: The purpose of this study was to determine the safety, tolerability and efficacy of orally-administered NS-018 in patients with PMF, post-PV MF, or post-ET MF. METHODS: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, post-PV MF, or post-ET MF. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis was evaluated by biopsy, according to standard practice at the sites. Changes from baseline in grade of BM fibrosis were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study is complete. In the ongoing Phase 2 portion, spleen size is being assessed by palpation and by centrally-read MRI, and quality of life evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). RESULTS: 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID) in Phase 1. Patient characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF; median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. The data cutoff for this analysis was June 30, 2016 (median follow-up time of 279.5 [range 5-1806] days from screening), at which time 10 patients remained on treatment. The median number of treatment cycles was 10 (1-65). Reasons for treatment discontinuation were disease progression (PD, n = 13), adverse events (AE, n = 8), physician consideration (n = 6), patient request (n = 4), and protocol non-compliance (n = 1). The 300 mg QD dose was selected as the phase 2 recommended dose (P2RD) in terms of tolerability and efficacy. For the 48 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including patients with priorJAK2 inhibitor treatment. Among 36 splenic-evaluable patients with baseline splenomegaly > 5 cm and treatment for > 1 cycle, 20 (56%) showed > 50% reduction in spleen size (confirmed for > 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement for > 8 weeks, 4 with hemoglobin CI, and 1 with platelet CI. Twenty-nine patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Patient characteristics: 13 PMF, 12 post-PV MF, 4 post-ET MF; median age (range) 67 yrs (48-86). The reason for discontinuation of prior JAK2 inhibitor treatment: AEs (62%) and PD (38%). To date, the median number of treatment cycles is 6 (1-20). The majority of grade 3/4 AEs were hematologic and the most common hematologic toxicities were anemia (21%) and thrombocytopenia (17%). Non-hematologic AEs were mostly grade 1/2, and the other AEs shown in > 10% of patients was nausea (14%). Updated Phase 2 efficacy and safety data will be presented at the meeting. CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided a durable dosing schedule, an acceptable safety profile, splenic size reductions and clinical symptom improvement. Phase 2 is ongoing and includes patients previously treated with a different JAK2 inhibitor. Disclosures Talpaz: Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Ritchie:Pfizer: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Honoraria; Incyte: Speakers Bureau. Odenike:Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jamieson:GlaxoSmithKline: Research Funding; CTI Biopharma: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.
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Barosi, Giovanni, Mohan Agarwal, Sonja Zweegman, et al. "An Individual Patient Supply Program for Ruxolitinib for the Treatment of Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF)." Blood 120, no. 21 (2012): 2844. http://dx.doi.org/10.1182/blood.v120.21.2844.2844.
Full textAbstract:
Abstract Abstract 2844 Background: Myeloproliferative neoplasms, including PMF, PET-MF, and PPV-MF, are a group of clonal stem cell–derived diseases characterized by bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies (COMFORT-I and -II). Due to unmet medical need, rux has been made available through an individual patient supply program (IPSP) outside the US. Methods: Patients (pts) with PMF, PPV-MF, or PET-MF requiring treatment (as determined by their physician) and classified as high-, intermediate (int)-2–, or int-1–risk with an enlarged spleen were evaluated for eligibility on an individual basis by the sponsor, irrespective of JAK2 mutation status. The starting dose of rux was determined on the basis of baseline platelet count (15 or 20 mg twice daily for pts with platelet counts of 100–200 × 109/L and > 200 × 109/L, respectively) and can be adjusted for efficacy and safety. Dose changes during treatment, adverse events (AEs), and serious AEs (SAEs) are registered throughout the program. Results: To date, 1339 requests have been received from > 800 physicians in 48 countries, including locations in Europe, Latin America, the Middle East, and Asia. The baseline characteristics are shown in the Table for pts whose requests for access were approved (n = 1240). Drug resupply requests are received every ≈ 3 months. Follow-up information, based on the first resupply request, was available for 381/639 (60%) of the pts who were enrolled in the program prior to February 2012; 303 (80%) remain on rux therapy, 37 (10%) have discontinued, 11 (3%) died, and 30 (8%) did not initiate therapy. Spleen response was available for 247 pts (decreased, n = 201; unchanged, n = 39; increased, n = 7). Changes in constitutional symptoms were available for 203 pts (decreased, n = 151; unchanged, n = 49; increased, n = 3). In pts enrolled in the IPSP undergoing rux treatment, most pts who had a decrease in spleen length also had a decrease in symptoms. Dose-modification information was available for 259 pts, of whom 44 had dose increases and 89 had dose decreases. Reasons for dose modifications included efficacy (n = 28), safety (n = 69), and other reasons (n = 36). Safety information was available for 266 pts; 75 reported significant AEs or SAEs as determined by investigators. Enrolled pt characteristics are generally similar to those expected in the overall MF pt population. Thus far, the proportion of pts enrolled in the IPSP with the JAK2 V617F mutation (73%) is higher than that for the general MF population (50%-60%). This may reflect a misconception that JAK inhibition is primarily effective in pts who have the JAK2 V617F mutation, when in fact rux has demonstrated similar efficacy in both pt types in the phase 1/2 251 study and the two phase 3 COMFORT trials. This may also be reflected in the higher proportion of PPV-MF pts in the IPSP than in the general MF population (28% vs 10%-15%), of whom 95% are JAK2 V617 F–positive. Conclusions: Considerable requests for access to rux have been received through the IPSP, highlighting the need for an effective treatment in pts with a range of IPSS risk-assessment scores. The demographics of the IPSP pts are similar to those expected in the overall MF population. Responses and safety patterns observed in the IPSP appear to be comparable to those from the COMFORT trials. Disclosures: Off Label Use: Jakafi™ (ruxolitinib) is indicated in the United States for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. In Canada, JAKAVI ® is indicated for the treatment of splenomegaly and/or its associated symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. This abstract reports on a clinical study conducted outside the US including patients of all risk categories. All patients have provided written informed consent. Zweegman:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Raymakers:Novartis: Consultancy. Cantoni:CSL Behring Switzerland: Research Funding; Robapharm/Pierre Fabre Oncology Switzerland: Research Funding; Janssen-Cilag Switzerland: Consultancy; Novartis Oncology Switzerland: Consultancy, Research Funding. Modi:Novartis Pharmaceuticals Corporation: Employment. Khan:Novartis: Employment. Perez:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Gisslinger:AOP Orphan Pharmaceuticals AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Lavie:Novartis: Membership on an entity's Board of Directors or advisory committees. Harrison:Sanofi Aventis: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding.
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Theocharides, Alexandre P. A., Rouven Müller, Yasuyuki Saito, Richard A. Flavell, and Markus G. Manz. "Next Generation Humanized Mice Support Engraftment of Myelofibrosis CD34+ Cells." Blood 124, no. 21 (2014): 1880. http://dx.doi.org/10.1182/blood.v124.21.1880.1880.
Full textAbstract:
Abstract Introduction While the key transforming genetic events occur in the developing cancerous cell, this cell is dependent on its environmental context and interaction for competitive outgrowth and subsequent tumor-development. Myelofibrosis (MF) represents a model cancer disease with stepwise development from a chronic state that depends on microenvironmental interactions to a more aggressive disease. Engraftment of primary MF patient cells in murine xenograft models is poor (Wang et al., JCI 2012) and is possibly explained by the lack of supportive microenvironmental factors. Thrombopoietin (TPO) has been implicated in the pathogenesis of MF (Schepers et al., Cell Stem Cell 2013, Dadfarnia et al., Blood 2014, Abdel-Wahab et al., Annu Rev Med 2009). Also, the interaction between human hematopoietic cells and SIRPα expressed on mouse macrophages is critical for human engraftment in xenografts (Takenaka et al., Nature Immunology 2007). We hypothesized that the constitutive expression of human TPO and human SIRPα may promote the development of the human MF clone in mouse xenografts. Methods Purified peripheral blood CD34+ cells were collected from six patients with primary MF or post-PV/ET MF and low to intermediate 2 risk disease according to the dynamic international prognostic scoring system (DIPSS). Four patients carried a JAK2-V617F mutation and two patients carried a calreticulin (CALR) mutation. CD34+ cells were intrahepatically transplanted into sublethally irradiated newborn humanSIRPα-transgenic/humanTPO-knockin Rag2-/- gamma-/- (TPO-SIRPα) mice (Rongvaux et al., Ann Rev. Immunol 2013). NSG mice were used as controls and injected with the same number of CD34+ cells. Two to three mice were injected with ≥1 million CD34+ cells from the same patient sample each. Mice were sacrificed 12-16 weeks after transplantation and human engraftment and hematopoietic cell lineage distribution was assessed by flow cytometry using human specific antibodies. Tissues were collected for immunohistochemistry, assessment of fibrosis and spleen weight. DNA was extracted from whole bone marrow and a qualitative PCR was performed to determine the presence of the JAK2-V617F or CALR-mutations. Results Three out of six samples generated a human graft of ≥20% human CD45+ cells, while the three other samples generated engraftment of 0.1-3%. The human graft was mainly composed of myeloid cells and monocytic differentiation was observed. In 2/2 experiments analysed, a JAK2-V617F and a CALR type 2 mutation were detected in the bone marrow of engrafted mice transplanted with the respective patient sample. Development of fibrosis was not observed three months post-transplantation, presumably due to the short observation time. Spleen weight was significantly increased in mice engrafted with human MF and was the consequence of increased murine extramedullary hematopoiesis. We then aimed to identify factors that could predict human MF engraftment in TPO-SIRPα mice. While neither the DIPSS, nor the presence of myeloid precursors in the peripheral blood (blasts excluded) were predictive of human MF engraftment, the presence of blasts in the peripheral blood significantly correlated with engraftment potential. Importantly, none of the patients developed acute leukemia during follow-up. Finally, preliminary evidence suggests that TPO-SIRPα mice are more supportive of human MF engraftment than NSG mice. Conclusions This is the first xenograft model that supports robust engraftment of human peripheral blood MF cells and further supports a role for TPO in the pathogenesis of MF. In contrast to previous models TPO-SIRPα mice strongly promote myeloid rather than lymphoid engraftment. The tight correlation between the presence of peripheral blood blasts and the human MF engraftment potential suggests that human MF stem cells reside in the blast population. In summary, the xenograft model presented here constitutes a powerful tool to assess heterogeneity regarding MF biology, microenvironmental dependence of the MF clone and likely also therapeutic response of MF in vivo. Disclosures No relevant conflicts of interest to declare.
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Gill, Harinder, Lester Au, Garret Man Kit Leung, et al. "Ropeginterferon Alfa-2b for Pre-Fibrotic Primary Myelofibrosis and DIPSS Low/Intermediate-1 Risk Myelofibrosis: Durable Responses and Evidence of Disease Modification." Blood 142, Supplement 1 (2023): 4562. http://dx.doi.org/10.1182/blood-2023-180922.
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Background Most patients with primary myelofibrosis (PMF) in pre-/early fibrotic stage (pre-PMF) and at low or intermediate-1 risk by the dynamic international prognostic scoring system (DIPSS) will progress to higher risks or overt MF. There is currently no consensus on the optimal treatment for these patients. Ropeginterferon alfa 2b (ropeg) is a next-generation monopegylated interferon alfa-2b developed specifically to treat myeloproliferative neoplasms (MPN). Aims P1101MF is an on-going multicenter phase 2 study of ropeg in patients with pre-PMF and DIPSS low/intermediate-risk PMF. Methods Key eligibility included morphologically confirmed pre-PMF, overt PMF, post-polycythemia vera MF (PPV-MF) or post-essential thrombocythaemia MF (PET-MF), DIPSS low/intermediate-1 risk, and the need for cytoreduction. The primary outcome were responses in haemoglobin (Hb, from 10 g/dL to upper reference range), white blood cell (WBC, &lt; 10 x 10 9/L) and platelet (≤ 400 x 10 9/L) at 24 and 48 weeks. Secondary outcomes included adverse events (AEs), changes in mutant allele frequencies (MAF) of driver and non-driver genes as assessed by droplet digital polymerase chain reaction (ddPCR), quality-of-life (QOL), cytokine profiles and bone marrow morphology. Patients received ropeg at a dose of 250 mcg at week 1, followed by 350 mcg at week 2 and 500 mcg every 2 weeks from week 4 onwards. Results At the data cut-off of 30 June 2023, 37 men and 29 women with a median age of 59 (range: 30-86) years were enrolled. The diagnoses were pre-PMF (=46, 69.6%); overt PMF (N=6, 9.1%); PPV-MF (N=5, 7.5%); and PET-MF (N=9, 13.6%). Mutational profile of driver genes was JAK2V617F (N=46, 69.6%); CALR mutations (type 1/type-1 like, N=13, 19.7%; type 2/type 2-like, N=4, 6.1%); MPL mutation (N=1, 1.5%); and triple-negative (N=3, 4.5%). The median time from diagnosis to treatment was 5.8 (1-271) months. The median baseline parameters were white blood cell count (WBC): 6.49 (3.25-33.95) x 10 9/L; haemoglobin (Hb): 12.5 (7.1-15.9) g/dL; platelet count: 495 (113-1114) x 10 9/L; and lactate dehydrogenase: 277 (136-1146) IU/L. The median follow-up was 69 (4-69) weeks, with 61 patients (92%) and 51 patients (77%) having completed 24 and 48 weeks of treatment respectively. Responses in Hb, WBC and platelet were 75%, 82% and 74% respectively at 24 weeks, and 82%, 80% and 71% respectively at 48 weeks. Reduction of MAF at 24 and 48 weeks was achieved for JAK2V617F in 50% (19/38) of patients (≥50%, N=10, 26%; complete, N=3, 8%) and 79% (22/28) of patients (≥50%, N=6, 21%; complete, N=1, 4%) respectively; and for CALR in 44% (7/16) of patients (≥50%, N=1, 6%) and 50% (5/10) of patients (≥50%, N=1, 10%) respectively. Forty-six patients (69.6%) had bone marrow biopsies serially performed, with 42 patients (91%) having stable/improved marrow fibrosis. Eight patients (17.4%) had resolution of marrow fibrosis by 48 weeks. There were 5 discontinuations (personal reasons, N=1; intractable pruritus, N=1; symptom/spleen size progression, N=3). Disease progression (pre-PMF to overt PMF; development of accelerated/blast phase) was not observed. Non-haematological AEs included transaminitis (grade 1-2, N=34); malaise (grade 1-2, N=27; grade 3-4, N=1) and hair loss (grade 1-2, N=21). The most common haematological AE was anaemia (grade 1-2, N=15; grade 3-4, N=6). Conclusion: Ropeg was well-tolerated, effective in cytoreduction and induced molecular and morphologic responses in patients with pre-PMF and low/intermediate-1-risk MF.
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Szuber, Natasha, Terra L. Lasho, Christy Finke, et al. "Determinants of Long-Term Outcome in Type 1/like Calreticulin-Mutated Myelofibrosis." Blood 132, Supplement 1 (2018): 1767. http://dx.doi.org/10.1182/blood-2018-99-117458.
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Abstract Background: Type 1 calreticulin (CALR) variants comprise ~70% of all CALR mutations in primary myelofibrosis (PMF) and form a distinct phenotypic and prognostic disease subset (Leukemia. 2014;28:1568). Determinants of long-term outcome have not, however, been systematically appraised in this population. The current study documents the natural history, molecular correlates, and independent predictors of overall (OS), leukemia-free (LFS), and thrombosis-free (TFS) survival in CALR type 1/like-mutated myelofibrosis. Methods: Patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses were consistent with World Health Organization (PMF, fibrotic/leukemic transformations) (Blood. 2016;127:2391) and International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria (post-essential thrombocythemia (ET) MF) (Leukemia. 2008;22:437). Laboratory and clinical data were retrospectively abstracted corresponding to time of referral (PMF) or myelofibrotic transformation (post-ET MF). Conventional prognostic scoring was as previously outlined (Blood. 2010;115:1703; J Clin Oncol. 2018;36:1769). Recipients of allogeneic stem cell transplant were censored at the time of transplant. Standard statistical methods were used for all analyses using the JMP® Pro 13.0.0 software package (SAS Institute, Cary, NC, USA). Results: A total of 162 consecutive patients with CALR type 1/like-mutated myelofibrosis were identified: 139 (86%) with PMF and 23 (14%) with post-ET MF with median age 55 years (range 23-85), 62% male. The PMF and post-ET MF cohorts displayed similar phenotypic features with the exception of higher platelet counts (median 443 vs 340 x 109/l; P=0.02) in post-ET MF (Table 1). The most frequent co-existing mutations were ASXL1 (n=47; 37%) and SRSF2 (n=4; 3%), with ASXL1 seen more frequently in PMF (39% vs 11% post-ET MF; P=0.07). Over a median follow-up of 6 years (range 0-25 years), a total of 20 (12%) leukemic transformations and 66 (41%) deaths were recorded, with no significant differences between the PMF and post-ET MF cohorts (P=0.16 and 0.11, respectively). Kaplan-Meier survival estimates revealed comparably favorable median OS in both CALR type 1/like-mutated variants: not yet reached and 13 years in post-ET MF vs PMF, respectively (P=0.7) (Figure 1A). Multivariable analysis disclosed moderate to severe sex-adjusted anemia (P<0.001), ≥2% circulating blasts (P<0.001), very high risk (VHR) karyotype (P<0.001), age >70 years (P=0.006), and constitutional symptoms (P=0.008) to be independent predictors of inferior OS in CALR type 1/like-mutated PMF (Table 2). LFS was significantly shortened in the presence of IDH1 mutations (P=0.01) and platelets <100 x 109/l (P=0.02) while IDH2 mutations (P=0.02), leukocytosis ≥11 x 109/l (P=0.03) and history of arterial thrombosis (P=0.04) were independent predictors of shortened TFS. Importantly, myelofibrosis variant (primary vs post-ET) did not influence survival (P=0.7) or complication rates (P=0.8 for LFS, P=0.09 for TFS) (Table 2). The karyotype- and mutation-enhanced international prognostic scoring system (MIPSS70+ version 2.0), was effective in risk stratifying type 1/like CALR-mutated PMF (P-values 0.01 to <0.0001), with the exception of low vs intermediate (P=0.22) and intermediate vs high risk (P=0.49) (Figure 1C). The detrimental influences of unfavorable/VHR karyotype and ASXL1 mutations were confirmed (Figure 2A-B) while borderline adverse and prognostically neutral effects were seen on OS for U2AF1 (n=116; P=0.05) and SRSF2 (n=120; P=0.98) respectively (Figure 2C-D). Conclusions: The current study documents analogous disease patterns in primary and post-ET CALR type 1/like-mutated MF and provides information on determinants of long-term survival. Disclosures No relevant conflicts of interest to declare.