Treatment Of Primary Myelofibrosis Research Articles

Abstract 3628: Combined mek and jak inhibition in vitro is an effective strategy in overcoming jak inhibitor resistance in primary myelofibrosis (PMF)

Abstract Introduction Primary myelofibrosis (PMF) is a myeloproliferative neoplasm arising from various mutations in myeloid-committed hematopoietic progenitor cells. Treatment of PMF is challenging as Jak inhibitor resistance is common, making the expansion of molecular characterization and novel therapeutic target identification in PMF essential. The main goals of this study are to determine both the presence of Ras activity in PMF and the impact on Ras/MAP Kinase pathway targeting in the disease. Methods Integrated genomic-transcriptomic sequencing analyses were performed on peripheral blood mononuclear cells (PBMCs) purified from 27 patients with PMF at a single institution; protein was then obtained from whole cell lysates. Ras activity was then assessed by applying Ras binding domain (RBD) to sample in an ELISA and was compared between patients with PMF, essential thrombocythemia (ET), polycythemia vera (PV) and healthy donors. Statistical analyses were conducted using two-way unpaired t-tests. The next set of in vitro studies aimed to evaluate the effects of MEK inhibition in PMF. Cell viability studies were first performed on human erythroleukemia (HEL) cells to identify IC50 values. Colony forming assays in methylcellulose-enriched media formulated for the growth of CD34+ cells were then performed in 4 conditions: Ruxolitinib and Cobimetinib monotherapy, combined therapies and untreated sample. Results As previously reported in our initial study, Ras activity in 21 patients with MF was 1.74 fold higher than healthy donors (13 volunteers, p=0.0304) and 1.64 fold higher than in PV/ET (12 patients, p=0.0462). We also reported previously on Ras activity from differential enrichment of myeloid and lymphoid cells from PBMC samples, where a key observation was that myeloid contribution to Ras activity in PMF patients with RAS/MAP Kinase pathway mutations was 3.8 times higher in Ras/MAP Kinase WT patients (p=0.0012), potentially suggesting that RAS pathway mutations have a predominance in myeloid cells. In HEL cell viability assays, cobimetinib and ruxolitinib, when utilized in tandem, resulted in more cell growth inhibition than either agent individually. This same finding was recapitulated in colony forming assays in 4 different patients with varying levels of sensitivity to Jak inhibitors, in all of whom ruxolitinib and cobimetinib lead to a greater reduction in colony formation than ruxolitinib monotherapy. Discussion Data from colony forming assays of bone marrow from patients with PMF identifies at least an additive effect of combined Jak and Ras/MAP Kinase (specifically Mek) inhibition on CD34+ colony formation. The specific observation that Ras pathway inhibition may be utilized as a means of overcoming Jak inhibitor resistance in PMF is a novel finding in this field and may be a valuable avenue for future early-phase clinical trials. Citation Format: Samuel Benjamin Reynolds, Sho Matono, Malathi Kandarpa, Kristen Pettit, Mark Ribick, Moshe Talpaz, Qing Li. Combined mek and jak inhibition in vitro is an effective strategy in overcoming jak inhibitor resistance in primary myelofibrosis (PMF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3628.

Targeting the JAK2V617F Hematopoietic Stem Cell through Beta1 Integrin

The major barrier to progress in treatment of primary myelofibrosis (PMF) is the lack of effective therapies targeting the malignant JAK2 V617F hematopoietic stem cell (HSC), the source of disease progression and relapse. Expression of JAK2 V617F induces abnormal proliferation and differentiation of HSC, affecting all blood lineages but most prominently the erythro-megakaryocytic lineage, leading to clonal megakaryocyte proliferation, erythrocytosis and thrombocytosis. In our previously published work ( Matsuura et al, Blood 2020) we identified elevated expression of the α5 subunit of the α5β1 integrin receptor as a driver of JAK2 V617F megakaryocyte proliferation. Expression of β1 integrin subunit was similar in wild-type (WT) and JAK2 V617F megakaryocytes, but activation of β1 integrin, detected by the conformation-specific 9EG7 antibody, was elevated in JAK2 V617F megakaryocytes. Following up on those findings, we detected elevated β1 integrin activation in long-term hematopoietic stem cells (HSC LT, LSKCD48-CD150+) from JAK2 V617F transgenic mice ( Xing et al, Blood 2008) when compared to WT controls. To determine whether inhibition of β1 integrin in vivo reduces the number of HSC LT in JAK2 V617F transgenic mice, we examined HSC LT 24 hours after intravenous administration of 2mg/Kg of anti-β1 integrin inhibitory antibody HMβ1-1. This regimen led to a sharp reduction in number and percentage of HSC LT in JAK2 V617F transgenic mice, to 45% of control antibody-treated animals. The effect on WT HSC LT was negligible. HSC ST (LSKCD48-CD150-) and MPP2 (LSKCD48+CD150+) were also reduced, but the reduction was not statistically significant. MPP3/4 (LSKCD48+CD150-) and LSK were not affected. Megakaryocyte progenitors (LKCD41+CD150+) were significantly reduced. Inhibition of β1 integrin also sharply reduced peripheral blood platelet numbers in WT animals. The reduction in JAK2 V617F transgenic mice was not statistically significant. A longer observation time of 7 days demonstrated that while WT animals were able to mount a robust regenerative response with slight but significant increases in HSC LT and normalization of platelet numbers, in JAK2 V617F transgenic mice the number of HSC LT remained depressed, as did downstream stem/progenitor populations at various significance levels. To gain insight into the mechanisms that lead to reduction in HSC LT, we examined apoptosis, cell cycle and HSC mobilization, all processes known to be affected by β1 integrin. Although basal expression of the apoptotic marker annexin V was decreased in JAK2 V617F HSC LT compared to WT, no differences were detected upon administration of HMβ1-1 in both genotypes at 4 hours post-administration. Similarly, peripheral blood colony assays revealed a basally higher level of stem/progenitor mobilization in JAK2 V617F, which did not significantly increase upon HMβ1-1 administration. In contrast, the cell cycle profile, examined at 4 hours post-administration to account for the earliest effects, demonstrated a decrease in G0 phase cells and increase in S/G2/M cells indicating cell cycle induction and exit from quiescence in both WT and JAK2 V617F HSC LT. The results indicate that inhibition of β1 integrin disrupts the adhesion-mediated cell cycle suppression in both WT and JAK2 V617F HSC LT leading to exit from quiescence. However, the downstream consequences of cell division in HSC LT differ significantly, with an apparent loss of regenerative potential in JAK2 V617F HSC LT, at least at the observed timepoints. Longer observation times are required to determine whether continuous β1 integrin inhibition can lead to JAK2 V617F HSC LT exhaustion. More sensitive assays to monitor mobilization are warranted to quantify possible minute amounts of mobilized HSC LT. Our preclinical studies indicate that β1 integrin is an attractive target to specifically reduce the number of JAK2 V617F HSC LTin vivo. The role of β1 integrin in HSC LT has not been thoroughly studied due to lack of phenotype in β1 integrin-deficient HSC ( Brakebush et al, Immunity 2002). Our studies using the anti-β1 integrin antibody in WT HSC LT confirm previous findings. However, β1 integrin seems to be critical for maintenance of JAK2 V617F HSC LT, offering a possible therapeutic window. Understanding how β1 integrin supports quiescence in HSC LT will bring us a step closer to understanding the mechanisms that drive malignancy and fitness in JAK2 V617F HSC LT.

Advances in management of primary myelofibrosis and polycythaemia vera: Implications in clinical practice.

Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare BCR-ABL1-negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.

Next-Generation Sequencing Mutational Landscape and Clinical Features of Chinese Adults with Myeloproliferative Neoplasms

▪Myeloproliferative neoplasms (MPNs) include three classical subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Since prefibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity in the 2016 revised classification of MPN, it has been a subject of debate among experts due to its indefinite diagnosis. However, pre-PMF usually has a distinct outcome compared with either ET or overt PMF. We conducted a retrospective study of MPN patients from October 2014 to June 2020 in the Fourth Affiliated Hospital of Zhejiang University. Patients who were diagnosed with ET, pre-PMF or overt-MF according to the 2016 WHO Classification were included. We reviewed the clinical parameters, haematologic information, and genetic mutations of patients using next-generation sequencing (NGS).Mutation screening was performed in 44 patients by next‐generation sequencing techniques, 84 genes and 258 mutations were detected. JAK2 was the most frequently mutated gene (25/44, 56.82%), followed by TET2 (14/44, 31.82%), KMT2C (13/44, 29.55%), and ASXL1 (10/44, 23.73%) in MPN (Figure 1-A). The VAFs of all studied genes with mutation frequencies >10% are shown in Figure 1-B. Of the 20 patients with ET, 9 (45%) were positive for the JAK2 mutation, 5 (25%) carried FAT1, 5 (25%) carried KMT2C, and 4 (20%) carried CALR. Of the 5 patients with pre-PMF, 4 (80%) carried JAK2, 3 (60%) carried EP300, and 2 (40%) carried TET2. Of the 19 patients with overt PMF, 12 (63%) carried JAK2, 10 (53%) carried TET2, 7 (37%) carried ASXL1, and 6 (32%) carried KMT2C, as reported in Figure 2. The median follow-up was 36 months for ET, 42 months for pre-PMF, and 53 months for overt PMF. Overall survival between pre-PMF, overt PMF, and ET was significantly different (P<0.001), as shown in Figure 3. During the follow-up time, only one death of ET was registered, so we analysed the impact of clinical parameters and mutational status at diagnosis on outcome in PMF, including pre-PMF and overt PMF. We performed Kaplan-Meier curves to examine the relationships between the clinical parameters and patient survival. We found that male sex (P=0.0107), MPN10 symptoms (P=0.0354), anaemia (haemoglobin<120g/L, P=0.0239), and thrombocytopenia (platelet count <100 ×10 9/L, P=0.0002) were significantly related to inferior OS (Figure 4). Pre-PMF patients exhibited higher leukocyte counts, higher LDH values, a higher frequency of splenomegaly, and a higher incidence of hypertension than ET patients. On the other hand, pre-PMF patients had higher platelet counts and haemoglobin levels than overt PMF patients. Molecular analysis revealed that the frequency of EP300 mutations was significantly increased in pre-PMF patients compared with ET and overt PMF patients. In terms of outcome, male sex, along with symptoms including MPN10, anaemia, thrombocytopenia, and KMT2A and CUX1 mutations, indicated a poor prognosis for PMF patients.In conclusion, we identified differences in the clinical, haematologic, and molecular presentations of ET, pre-PMF, and overt PMF patients, indicating that comprehensive evaluation of not only BM features but also clinical, haematologic, and molecular profiles is needed for accurate diagnosis and treatment of these three disease entities. The molecular analysis revealed that pre-PMF might be relevant to EP300 mutation, demonstrating the value of molecular examination. The results of this study indicated that comprehensive evaluation of BM features, clinical phenotypes, haematologic parameters, and molecular profiles is needed for the accurate diagnosis and treatment of ET, pre-PMF, and overt PMF patients.Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnostic and Therapeutic MicroRNAs in Primary Myelofibrosis

Primary myelofibrosis (PMF) is a pluripotent hematopoietic stem cell-derived malignancy, included in the heterogeneous group of myeloproliferative neoplasms (MPNs). PMF diagnosis is based on a composite assessment of clinical and laboratory data. The three major diagnostic criteria are: screening for driver mutations, exclusion of other conditions that can cause myelofibrosis, and bone marrow biopsy displaying megakaryocyte changes and fibrosis. PMF treatment options are only partially disease-modifying and consist mainly of symptom control. Recently, a new targeted therapy was introduced for PMF patients, JAK-STAT inhibitors (i.e. ruxolitinib). However, specific subgroups of patients do not benefit from the JAK-STAT inhibitors: (1) those who are carrying JAK2 mutations, but ruxolitinib does not reduce the spleen size; (2) triple negative patients (no JAK2, CALR, or MPL mutations); and (3) those who discontinue JAK-STAT therapy because of side effects. These subgroups are in need of new therapeutic approaches. Mature microRNAs (miRNAs) range from 16 to 28 nucleotides (nt) in length and regulate specific messenger RNAs at the post-transcriptional level. Numerous in vitro and in vivo studies have reported specific miRNAs, as well as complex miRNA networks, to be dysregulated in PMF. Several of these miRNAs were shown to be implicated in essential events of PMF pathophysiology: increase of bone marrow fibrosis, progression to acute myeloid leukemia, resistance to JAK-STAT inhibitors, and activation of differentiation of hematopoietic stem/progenitor cells into megakaryocytes. Hence, we propose miRNAs as a potential minimally invasive diagnostic tool for PMF and as therapeutic targets that could address the unmet medical needs of these patients.

Risk of Mortality and Leukemic Transformation in Primary Myelofibrosis before and after Ruxolitinib Approval

Background: Primary myelofibrosis (PMF) has the worst prognosis of the classical BCR-ABL1 negative myeloproliferative neoplasms, with a median overall survival of six years. Factors affecting survival include age, symptom burden, cytopenias, mutation profile, and development of second malignancies including transformation to acute myeloid leukemia (AML). Ruxolitinib, a selective JAK1 and JAK2 inhibitor, was granted approval by the United States (US) Food and Drug Administration for treatment of intermediate and high-risk PMF in November 2011 based on reduction in spleen volume and demonstration of symptom improvement. The impact of ruxolitinib on PMF survival is unknown. In this study, we aimed to evaluate whether there has been a change in survival and patterns of second primary malignancies (SPMs) including AML transformation among PMF population in US after ruxolitinib approval. Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 survival and Multiple Primary Standardized Incidence Ratio (MP-SIR) registries, we conducted a retrospective study with patients diagnosed with PMF between the years of 2007 and 2016. We divided these patients into two five-year cohorts, pre-ruxolitinib approval (2007-2011) and post-ruxolitinib approval (2012-2016), and compared relative survival rates (RSRs) and standardized incidence ratios (SIRs) of SPMs between the cohorts. SIRs were calculated as the ratio of observed to expected malignancy cases over the specified time periods. Median follow-up duration was five years for each cohort. RSRs and SIRs were compared between cohorts using two-proportion Z-tests. Results: We included 2164 patients diagnosed with PMF between 2007 and 2016 with data available in the SEER-18 survival and MP-SIR registries. Of these, 1051 (49%) patients were included in the pre-ruxolitinib cohort and 1113 (51%) patients were included in the post-ruxolitinib cohort. There was no significant difference in the four-year RSRs between the pre-ruxolitinib and post-ruxolitinib cohorts (55% vs. 56%, p = 0.719). A higher proportion of SPMs occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (60% vs. 40%, p &amp;lt; 0.001). Hematologic malignancies comprised a majority of all SPMs (AML 39% and non-Hodgkin lymphoma 16%). A higher incidence of AML transformation occurred in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 121.48 vs. 72.22, p = 0.037). Non-hematologic malignancies were also more common in the post-ruxolitinib cohort when compared with the pre-ruxolitinib cohort (SIR 1.09 vs. 0.94, p &amp;lt; 0.001). The most common non-hematologic malignancies were cancers of the respiratory tract, urinary tract, and prostate gland, though their SIRs were not significant in either cohort. Conclusions: Our study results suggest that despite improvements in prognostication and the approval of ruxolitinib, the prognosis of PMF remains poor in the US. These results may be due to low uptake of ruxolitinib in practice or a lack of benefit from the drug itself. Additionally, for reasons that are unclear, SPM incidence has increased in the five years following the approval of this drug. Further studies should be conducted to determine the cause of these findings. Figure Disclosures Shah: Dren Bio: Consultancy. Vachhani:astellas: Speakers Bureau; agios, blueprint medicines, jazz pharmaceuticals, daiichi sankyo: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Leczenie ruksolitynibem u chorego na pierwotne włóknienie szpiku oraz małopłytkowość

46-years old male diagnosed with primary myelofibrosis (PMF) was included into therapeutic program of treatment with ruxolitinib. Due to initial thrombocytopenia with basal platelets [PLT] range below 100 G/l, initial dosage of the treatment was reduced according to characteristics of drug. No treatment-related toxicity was noted, the dosage was gradually increased reaching the dose 20 mg twice a day at twelfth week of therapy. Although alleviation of systemic symptoms was reached, lack of diminishment of spleen size demanded by therapeutic program led to cessation of treatment. In group of patients with PMF and secondary thrombocytopenia treatment with ruxolitinib may lead to improvement of patient condition.

Assessment of Clinical Outcome of Patients With Primary Myelofibrosis Treated ‎With Ruxolitinib in the Real-World Practice

BACKGROUND: Primary myelofibrosis (PMF) is a disease that characterized by bone &amp;lrm;marrow fibrosis which &amp;lrm;may &amp;lrm;result sometime in cytopenias and extramedullary &amp;lrm;hematopoiesis causing massive &amp;lrm;splenomegaly. Ruxolitinib (Rux) therapy that targeted &amp;lrm;Janus Kinase-2 receptor and approved &amp;lrm;for treatment of primary myelofibrosis. &amp;lrm;&#x0D; &#x0D; OBJECTIVE: evaluate the clinical &amp;lrm;outcome of patients with &amp;lrm;primary myelofibrosis &amp;lrm;receiving Ruxolitinib treatment as &amp;lrm;a compassionate use program &amp;lrm;and compare this treatment with the best &amp;lrm;available treatment (BAT).&amp;lrm; &#x0D; &#x0D; METHODS: &amp;lrm;This is a retrospective case series conducted at the national &amp;lrm;center of hematology /&amp;lrm;&amp;lrm;Mustansiriyah University. The enrollment of patients started &amp;lrm;in May 2014 and ended in May &amp;lrm;&amp;lrm;2017. There were &amp;lrm;&amp;lrm;22 patients diagnosed with PMF (7 on &amp;lrm;the Ruxolitinib arm and 15 on best &amp;lrm;available treatment arm). The &amp;lrm;treatment response &amp;lrm;was evaluated according to consensus criteria &amp;lrm;of IWG-MRT 2013 in primary &amp;lrm;&amp;lrm;myelofibrosis.&#x0D; &#x0D; RESULTS: In this study 3 out of 7 patients on Ruxolitinib arm showed reduction in spleen size and reduction in anemia. In addition to &amp;lrm;that 4 patients &amp;lrm;showed clinical response specifically in spleen &amp;lrm;size (with 65% reduction from baseline during the first three months of treatment). &#x0D; &#x0D; CONCLUSION: Rux is effective and safe to treating &amp;lrm;primary myelofibrosis with &amp;lrm;symptomatic splenomegaly.

Orphan designation: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt, Treatment of primary myelofibrosis

Orphan designation: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt, Treatment of primary myelofibrosis

Orphan designation: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt, Treatment of primary myelofibrosis

Orphan designation: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide, dihydrochloride salt, Treatment of primary myelofibrosis

Chinese guideline on the diagnosis and treatment of primary myelofibrosis (2019)

Chinese guideline on the diagnosis and treatment of primary myelofibrosis (2019)

New Insight into the Treatment of Primary Myelofibrosis

New Insight into the Treatment of Primary Myelofibrosis

Progress of treatment of primary myelofibrosis

Primary myelofibrosis (PMF) is a type of myeloproliferative neoplasms (MPN) with the worst prognosis in MPN. Immunomodulators, erythropoiesis-stimulating agents, cytoreductive drugs, splenectomy, etc. can significantly reduce the symptoms of patients, but can not improve the prognosis of patients. Allogeneic hematopoietic stem cell transplantation remains the only method that may cure PMF. The marketed JAK kinase inhibitor ruxolitinib and the hypomethylating agents, anti-fibrosis agents and telomerase inhibitor provide new ideas for the treatment of PMF, made it possible to reverse the natural course of myelofibrosis. This paper reviews the progress of PMF therapy. Key words: Primary myelofibrosis; Ruxolitinib; Treatment

Identification of potential therapeutic target genes and miRNAs for primary myelofibrosis with microarray analysis

The aim of the present study was to identify potential therapeutic target genes and miRNAs for primary myelofibrosis (PMF). The dataset GSE53482 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) of peripheral blood (PB) cluster of differentiation (CD)34+ cells from PMF patients (PB-PMF group) and peripheral blood CD34+ cells from healthy individuals (PB-control group) were analyzed using the Linear Models for Microarray Data package in R. The Kyoto Encyclopedia of Genes and Genomes was used for pathway enrichment analysis. MiRNA-gene joint enrichment analysis was performed by ENViz and a miRNAs-gene regulatory network was constructed. A total of 1,182 DEGs (773 upregulated and 109 downregulated) and 48 DEMs (28 upregulated and 20 downregulated) were identified. According to the pathway enrichment analysis, a number of DEGs were enriched in metabolic pathways, including IDH1 and DNMT1. Other DEGs were enriched in the citrate cycle (tricarboxylic acid cycle; IDH1 and IDH3A) and certain DEGs were enriched in pyrimidine metabolism, including CARD8. For downregulated genes, certain DEGs were enriched in the spliceosome, including SF3B1 and CDC40. Furthermore, hsa-miR-127-3p, hsa-miR-140-3p and hsa-miR345 were associated with cell cycle-related biological processes, signal transduction and cell surface receptor signaling pathway. The DEM-DEG regulatory network indicated that hsa-miR-543 regulated 113 genes, including CARD8 and TIFA. The present study identified a number of genes, including IDH1, DNMT1, SF3B1 and CARD8, and miRNAs, including hsa-miR-127-3p and hsa-miR-140-3p, which may be therapeutic targets in the treatment of PMF.

'JAK-ing' up the treatment of primary myelofibrosis: building better combination strategies.

The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting. Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK-inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up. Emerging data have revealed the complex molecular architecture of myelofibrosis with clonal evolution playing a central role in disease progression or transformation. These molecular pathways may explain the heterogeneous benefits obtained by JAK-inhibitors in patients with myelofibrosis. In addition, the genetic and epigenetic mutations appear to work in concert with overactive JAK/STAT signaling and contribute to myelofibrosis pathogenesis and prognosis, suggesting a potential to exploit them as potential therapeutic targets. Combining JAK-inhibitors with agents that target parallel prosurvival pathways or agents that enhance hematopoiesis may enhance efficacy and/or mitigate on-target myelosuppression, thereby extending the therapeutic benefits observed with JAK-inhibitors alone.

Ruxolitinib in myelofibrosis: to be or not to be an immune disruptor

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm classified according to the 2016 revision of World Health Organization Classification of Tumors and Haematopoietic and Lymphoid Tissue. Ruxolitinib is an oral inhibitor of Janus kinase approved in the USA for the treatment of intermediate or high-risk PMF and approved in Europe for the treatment of splenomegaly and constitutional symptoms of the disease. More recently, case reports described serious opportunistic infections in this neoplasm treated with ruxolitinib. Research studies demonstrated the immunological derangement of this compound mainly based on T, dendritic, and natural killer cell defects. The purpose of this review of the literature was to analyze the relationship among ruxolitinib, immune system and bacterial, viral, fungal, and protozoan infections. A literature search was conducted using PubMed articles published between January 2010 and November 2016. The efficacy of drug in patients with PMF was demonstrated in two phase III studies, Controlled MyeloFibrosis Study with ORal Jak inhibitor Treatment (COMFORT-I and COMFORT-II). Grade 3 and 4 neutropenia were recognized in 7.1% and 2% of patients in the ruxolitinib and placebo arm of COMFORT-I. Grade 3 or 4 neutropenia or leukopenia were observed in 8.9% and 6.3% of ruxolitinib treated patients of 5-year follow-up of COMFORT-II. In addition, leukocyte subpopulations, lymphocyte functions, or antibody deficiency were not documented in either of the studies. The complex interactions between ruxolitinib, bone marrow, immune system, and infections in PMF need further investigation, robust data from a randomized clinical trial, registry, or large case-series.

Role of Allogeneic Stem Cell Transplant in the Treatment of Primary Myelofibrosis.

The only known curative therapy for primary myelofibrosis is allogeneic hematopoietic stem cell transplant. We retrospectively evaluated 11 transplant procedures involving 10 patients (5 men and 5 women) diagnosed with primary myelofibrosis between 2005 and 2014. The median age at the time of transplant was 60.5 years (range, 22-62 years). Stem cell sources were unrelated (n=1) and related (n=11) peripheral blood stem cells. Conditioning regimen was myeloablative for 8 and reduced intensity for 3 transplants. The median number of infused CD34+ cells was 6.8 × 106 cells/kg (range, 3.2-10.4 × 106 cells/kg). Neutrophil and platelet engraftment occurred at median of 22 days (range, 12-31 days) and 19.5 days (range, 13-56 days). Acute and chronic graft-versus-host disease was seen in 4 of 11 allografts. Relapse and nonrelapse mortality rates were 20%. Six patients (60%) were still alive without disease after median follow-up of 68.5 months (range, 17-120 months). Median progression-free survival and overall survival were 61 months (range, 2-120 months) and 65 months (range, 2-120 months). Our results suggest that allogeneic hematopoietic stem cell transplant may provide a curative treatment for primary myelofibrosis patients. A myeloablative regimen seems to be effective and safe, especially for younger primary myelofibrosis patients.

Application of hematopoietic stem cell transplantation in the treatment of primary myelofibrosis

Drugs and symptomatic and supportive treatment are still the main treatment in the primary myelofibrosis (PMF), but they can only improve symptoms without the natural course change of PMF. Hematopoietic stem cell transplantation (HSCT) is the only curable means to PMF, however, serious transplant-related complications limit its extensive application in PMF patients. In this paper, donor selection process, pretreatment, successful transplantation factors and other factors on HSCT in PMF patients will be reviewed. Key words: Primary myelofibrosis; Hematopoietic stem cell transplantation

Chinese expert consensus on the diagnosis and treatment of primary myelofibrosis （2015)

Chinese expert consensus on the diagnosis and treatment of primary myelofibrosis （2015)

Radioterapia en mielofibrosis ganglionar refractaria a la terapia dirigida

Primary myelofibrosis is a disease of the bone marrow characterized by fibrosis, associated with splenomegaly and extramedullary haematopoiesis. In peripheral blood, a pattern of leucoerythroblastosis and tear drop cells, as well as elevated levels of pro-inflammatory and angiogenic cytokines is observed.There are two types: primary myelofibrosis, which is not associated with any bone marrow condition, and secondary disease, which is associated with myeloproliferative syndrome conditions such as essential thrombocytosis or polycythaemia vera.The incidence in the United States ranges from 0.21 to 0.25 cases per 100 thousand inhabitants, it is associated more often with the male gender, and mean age at diagnosis is 67 years.The treatment of primary myelofibrosis can be in different forms, depending on the goal of treatment, with curative or palliative intent. Treatment modalities include surgical procedures with splenectomy, pharmacological treatment with drugs to produce cell inhibition such as hydroxycarbamide, immunomodulators such as thalidomide, or targeted therapy such as ruxolitinib; radiation therapy is generally used to treat medical treatment-refractory splenomegaly or in those patients with any surgical contraindication and, finally, bone marrow transplantation has proven to be the only treatment that modifies survival.