Survival In Primary Myelofibrosis Research Articles

MPN-541 Estimated Plasma Volume Status in Patients With Primary Myelofibrosis and Associated Thrombotic and Mortality Risks.

Blood plasma experiences substantial changes in both volume and composition in patients with chronic myeloproliferative neoplasms (MPN) and represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has recently been shown to correlate with increased thrombotic risk in polycythemia vera patients. To estimate clinical and prognostic associations of ePVS in patients with myelofibrosis. Retrospective cohort study. 6 hematology centers. 238 myelofibrosis patients, 168 with PMF, 34 with post-PV SMF and 36 with post-ET SMF. ePVS was calculated using the Strauss derived Duarte formula: (100-hematocrit (%)/hemoglobin (g/dL) and expressed as dl/g. Overall survival (OS) and time to thrombosis (TTT). Median ePVS was 5.8 dl/g and it did not significantly differ between PMF and SMF patients. Among other associations, higher ePVS was significantly associated with higher degree of bone-marrow fibrosis, absence of JAK2-mutation, lower white blood cells (WBC), platelets and hemoglobin, presence of circulatory blasts, higher C-reactive protein, higher lactate dehydrogenase, lower albumin and higher Charlson comorbidity index in an overall cohort, as well as with more pronounced splenomegaly and higher Dynamic International Prognostic Scoring System (DIPSS) risk in primary myelofibrosis (PMF) and higher Mysec-PM risk in secondary myelofibrosis (SMF) patients (P<0.05 for all analyses). Higher ePVS (>5.6 dl/g) was associated with shorter overall-survival (OS) in PMF (HR=2.8, P<0.001) and SMF (HR=2.55, P=0.025) and with shorter time-to-thrombosis in PMF (>7 dl/g, HR=4.1, P=0.009) patients. Associations with overall survival diminished in multivariate analyses after adjustments for DIPSS and Mysec-PM, respectively. Association with TTT remained significant independently of JAK2, WBC and chronic kidney disease. Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.

Clinical Features, Gene Alterations, and Outcomes in Prefibrotic and Overt Primary and Secondary Myelofibrotic Patients.

Simple SummaryThe final stages of myeloproliferative neoplasms (MPNs) are related to myelofibrosis (MF). This study aimed to compare secondary myelofibrosis (SMF), overt (PMF), and prefibrotic primary myelofibrosis (pre-PMF) and determine prognostic factors in clinical and genetic features. This study included 229 patients; 67 (29%), 122 (53%), and 40 (18%) cases were confirmed as SMF, overt PMF, and pre-PMF, respectively. We compare MFs, including pre-PMF, using six scoring stratifications associated with PMF and one scoring system with SMF. We also evaluated the impact of the genetic groups with clustering methods and previously reported genomic groups. We determined the clinical and genetic features associated with disease progression in SMF, overt PMF, and pre-PMF groups.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.

Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.

All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia.

Survival in Primary Myelofibrosis: A Population-based Analysis in the Netherlands

Survival in Primary Myelofibrosis: A Population-based Analysis in the Netherlands

Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations. Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. Bone marrow morphology is the primary basis for diagnosis. Presence of JAK2, CALR, or MPL mutation, expected in around 90% of the patients, is supportive but not essential for diagnosis; these mutations are also prevalent in the closely related MPNs, namely polycythemia vera (PV) and essential thrombocythemia (ET). The 2016 World Health Organization classification system distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic ET in its presentation. Furthermore, approximately 15% of patients with ET or PV might progress into a PMF-like phenotype (post-ET/PV MF) during their clinical course. SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors. RAS/CBL mutations predicted resistance to ruxolitinib therapy. Very high risk abnormalities include -7, inv (3), i(17q), +21, +19, 12p-, and 11q-. Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation- and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSSv2 includes, in addition, clinical risk factors. GIPSS features four and MIPSSv2 five risk categories. Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment for "very high" and "high" risk disease (estimated 10-year survival 0%-13%); treatment-requiring patients with intermediate-risk disease (estimated 10-year survival 30%) are best served by participating in clinical trials. In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures. Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for non-hepatosplenic EMH and extremity bone pain. A number of new agents, alone or in combination with ruxolitinib, are currently under investigation for MF treatment (ClinicalTrials.gov); preliminary results from some of these clinical trials were presented at the 2020 ASH annual meeting and highlighted in the current document.

Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data.

Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by an increased risk of thrombosis and progression to acute myeloid leukemia. MPN are associated with driver mutations in JAK2, CALR and MPL which are crucial for the diagnosis and lead to a constitutive activation of the JAK-STAT signaling, independent of cytokine regulation. Moreover, most patients have concomitant mutations in genes involved in DNA methylation, chromatin modification, messenger RNA splicing, transcription regulation and signal transduction. These additional mutations may arise before, in the context of clonal hematopoiesis of indeterminate potential (CHIP), or after the acquisition of the driver mutation. The clinical phenotype of MPN results from complex interactions between mutations and host factors. The increased application of next-generation sequencing (NGS) techniques to a large series of patients with MPN has expanded the knowledge of mutational landscape and contributed to define the clinical significance of mutations. This molecular information is being increasingly used to refine diagnosis, risk stratification, monitoring of residual disease and response to treatment. ASXL1, SRSF2, EZH2, IDH1/IDH2 and U2AF1 mutations are associated with a more advanced disease and reduced overall survival in primary myelofibrosis (PMF), whereas spliceosome mutations in Polycythemia vera (PV) and essential thrombocythemia (ET) adversely affect both overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival. This review discusses current knowledge of the molecular landscape of MPN, and how the availability of those molecular information may impact patient management.

Significance of cytogenetic-risk categories and refined international prognostic scoring system for overall survival in primary myelofibrosis: A single-center experience

Abstract Background/Aim. Primary myelofibrosis (PMF) is a chronic, malignant hematological disease characterized by a leucoerythroblastic blood picture, anisopoikilocytosis teardrop- shaped erythrocytes, different degrees of bone marrow fibrosis and hepatosplenomegaly due to extramedullary hematopoiesis. Among genetic specificities of the disease, those that stand out are chromosomal aberrations in pathological, myeloid blood cells. The aim of this study was to examine the prognostic significance of clinical, hematologic and cytogenetic parameters in PMF. Methods. A retrospective study included 144 patients with PMF. Karyotypes were analyzed using conventional cytogenetic methods. Results. The chromosome examinations were successful in 126 (88%) patients and failed in the remainder ones (12%). Karyotype was abnormal in 36/126 (29%) subjects at presentation. The most frequent changes included +9, 13q- and 20q- (28%). Other abnormalities were: aberrations of chromosome 18 and 16, deletions (9q-, 12p-, 7q-, 5q-, 6q-, 8q-), trisomies (+1q, +8, +10, +21), monosomies (-7, -11), 3q inversion and loss of Y chromosome. We detected four novel balanced translocations in PMF: t(17;22)(q11;q13), t(15;17)(q22;q25), t(9;12)(q22;q24) and t(2;4)(q21;p16), one constitutional translocation-rob(13;14)(q10;q10) and some new karyotype anomalies ? deletion of both homologues, hyperdiploidy and the coexistence of unrelated pathological clones. Conclusion. Chromosomal aberrations had a significant influence on overall survival of patients with PMF according to the refined cytogenetic-risk of the International Prognostic Scoring System (Refined CIPSS) (p = 0.004). Our patients matched the pattern of chromosome aberrations usually observed in PMF but some newly registered, balanced translocations and other rare karyotype anomalies were recorded as well.

The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly-annotated patients with primary myelofibrosis.

JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple-negative (P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P = .48) or triple-negative cases (P = .27). Multivariable analysis that included karyotype, driver mutational status and high-molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P = .02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically-inspired GIPSS risk model (P = .04), but not in the context of the integrated genetics-clinical MIPSS70+ version 2.0 model (P = .4). Leukemia-free survival was not affected by the 46/1 haplotype (P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2-mutated PMF.

20+ Years and alive with primary myelofibrosis: Phenotypic signature of very long-lived patients.

In the last decade, several prognostic models for primary myelofibrosis (PMF) have been introduced and shown to be effective in predicting overall survival. The main objective for this study was to identify clinical and genetic markers of very long (20+ years) survival in PMF. A total of 1282 patients with PMF were considered (median age 65 years, range 19-92; 63% males); 26 (2%) patients (median age 51 years, range 28-71; 38% males) survived their disease for at least 20 years (long-lived patients) and 626 (49%) patients (median age 68 years, range 27-92; 66% males) died within 5 years of their diagnosis (short-lived patients). Multivariable logistic regression analysis identified 7 variables that were associated with survival beyond 20 years: age ≤ 70 years (P = .002); female sex (P = .03); hemoglobin level ≥ 10 g/dL for women and ≥ 11 g/dL for men (P = .03), leukocyte count ≤25 × 109 /L (P = .009), platelet count ≥100 × 109 /L (P = .002), circulating blasts <2% (P = .03) and absence of constitutional symptoms (P = .04). Five-year mortality was independently predicted by high-molecular risk mutations (P < .001); unfavorable or very high risk karyotype (P < .001); absence of type 1/like CALR mutation (P < .001); age > 70 years (P < .001); constitutional symptoms (P < .001); hemoglobin level < 10 g/dL for women and < 11 g/dL for men (P < .001); leukocyte count >25 × 109 /L (P = .004); and circulating blasts ≥2% (P = .001). This study suggests that genetic risk factors in PMF are associated with early mortality while survival beyond 20 years could be predicted by easily accessible clinical variables, including age, sex, blood counts, and symptoms.

The Germline JAK2 GGCC (46/1) Haplotype and Survival Among 414 Molecularly-Annotated Patients with Primary Myelofibrosis

Background:We have long introduced the concept of host genetic variations in the phenotypic diversity of myeloproliferative neoplasms (MPN) (Blood 2008;111:2785). Previous studies have established an association between JAK2 mutations in myeloproliferative neoplasms (MPN) and the germline GGCC (46/1) haplotype, which constitutes a string of single nucleotide polymorphisms (SNPs) near the JAK2 gene that are inherited together on chromosome 9p (reviewed recently;Int J Mol Sci. 2018; 19: 1152). In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype (Leukemia 2010; 24:105), although our findings were not confirmed in another study (Leukemia 2010; 24:1533). Others have reported an association with splanchnic vein thrombosis, that was not accounted for by JAK2 mutations (Ann Hematol 2014;93:1845). In the current study, we have increased the number of informative cases to 414 (from 130 reported in 2010), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF.Methods:Study patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses PMF and its leukemic transformation were confirmed by both clinical and bone marrow examinations, in line with the 2016 World Health Organization criteria (Blood. 2016;127:2391). Screening for the JAK2 46/1 haplotype included rs12343867 SNP genotyping, as previously detailed (Leukemia 2010; 24:105), and using a commercially available TaqMan SNP genotyping assay (Applied Biosystems Inc., Foster City, CA, USA). Statistical analyses considered clinical and laboratory data collected at the time of initial PMF diagnosis or Mayo Clinic referral point. Conventional statistics was used for confirming phenotypic associations and calculation of overall (OS) and leukemia-free (LFS) survival. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations.Results:414 patients with PMF (median age 63 years; 63% males) were included in the current study; among 324 evaluable cases, MIPSS70+ version 2.0 risk distribution was 18% very high risk, 41% high risk, 19% intermediate risk, 18% low risk and 4% very low risk. Driver mutation distribution was 63% JAK2, 17% type 1-like CALR, 3% type 2-like CALR, 7% MPL and 10% triple-negative. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL and 6%/10%/14% triple-negative (p=0.02). The three 46/1 haplotype groups were phenotypically mostly similar, with the exception of platelet count (p=0.02) and leukocyte count (p=0.003), which were both higher with homozygous 46/1 haplotype.In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9; figure 1a); this survival effect was most pronounced in JAK2 mutated cases (figure 1b; p<0.001), as opposed to CALR/MPL mutated cases (figure 1c; p=0.48) or triple-negative cases (figure 1d; p=0.27). Multivariable analysis that included age and other genetic risk factors, including karyotype, driver mutational status and presence of high molecular risk mutations, such as ASXL1 and SRSF2, confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (p=0.02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the recently unveiled genetics-based prognostic model, GIPSS (genetically-inspired prognostic scoring system) (p=0.04) (Leukemia.2018 doi: 10.1038/s41375-018-0107-z), but not in the context of MIPSS70+ version 2.0 (karyotype and mutation-enhanced international prognostic scoring system for transplant-age patients) (p=0.4). (JClinOncol.2018 doi: 10.1200/JCO.2018.78.9867). Leukemia-free survival was not affected by the 46/1 haplotype (p=0.6).Conclusions:The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in PMF, primarily in JAK2-mutated cases; the observed survival effect was independent of currently acknowledged genetic risk factors, including karyotype and high molecular risk mutations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of Ropeginterferon Alfa-2b in Prefibrotic Primary Myelofibrosis

Primary myelofibrosis (PMF) is a clonal stem cell disorder currently classified as myeloproliferative neoplasm (MPN). Median survival in PMF is estimated with 6 years, but can range from few months to several decades in early pre-fibrotic PMF. The disease course is almost always complicated by progressive anemia, symptomatic splenomegaly and severe constitutional symptoms. Causes of death include leukemic transformation with marrow failure and complications from bleeding, thrombosis, portal hypertension or infections. While PMF patients in advanced stages benefit from a JAK2 inhibitor therapy, there is no evidence for prevention of disease progression to overt MF by an early therapeutic intervention. Interferon alpha has been shown to reduce white cell counts, elevated platelet counts and improve splenomegaly and there are some observations of its disease modifying capability in the earlier phase of PMF.The aim of the present phase II study was to test the capability of a novel pegylated interferon compound (Ropeginterferon-alfa-2b) to improve hematologic parameters, splenomegaly and to monitor the course of the disease concerning clinical symptoms in a homogeneous cohort of early pre-fibrotic PMF patients. The endpoints of the study were hematological response, maintenance or improvement of quality of life and the symptom scales during a period of 2 years interferon treatment, and interferon tolerability.Twenty-five patients were included in the study. Nine patients were pretreated with pegylated interferon alfa 2b (PegIntron or Pegasys) during at least 3 years and 16 patients were interferon naïve. At start of therapy the median red blood cell count was 4.3 T/l (3.3 - 5.2); median hemoglobin level was 12.5 g/dl (9.6 - 14.7 g/dl), median WBC count was 7.7 G/l (2.44 - 27.55 G/l) and the median platelet count was 435 G/l (124 - 1161 G/l). Median LDH-level was 263.5 U/l (163 - 538 U/l) and the median spleen size was 11.2 cm (8 - 22 cm). 13 patients were JAK2 positive, and 12 patients were CALR positive. Detailed patient characteristics in 6-month intervals for pretreated and interferon naïve patients are given in Table 1.At study entry, 12 patients presented with anemia, 12 with thrombocytosis, 9 with leukocytosis, 14 with elevated LDH levels and 7 with splenomegaly. After 24 months of treatment, 6 patients improved their anemia (N=2 pretreated, 4 treatment-naïve), 6 their thrombocytosis (N=6 treatment-naïve), 7 their leukocytosis (N=7 treatment-naïve), 6 normalized LDH levels (N=1 pretreated, 5 treatment-naïve) but none showed response in the form of significant spleen size reduction. The fact that no patient showed disease progression in any single parameter after 2 years of treatment can already be considered a success.The most common side effects observed during this study include flu-like symptoms (N=7 pretreated, 15 treatment-naïve), lack of concentration (N=3 pretreated, 8 treatment-naïve), pruritus (N=2 pretreated, 7 treatment-naïve), infections (N=2 pretreated, 5 treatment-naïve) and bleeding (N=2 pretreated, 4 treatment-naïve). Generally, pretreated patients suffered from fewer side effects than treatment-naïve patients in every category. This may be due to the fact that those patients had already been exposed to an interferon in previous treatment regimen. Two patients had to be withdrawn from the study after approximately 12 months due to psychological side effects, both from the treatment-naïve group.Additionally to conventional symptom screening, the EORTC-QLQ-C30 questionnaire was used to assess therapy-response. With this tool, function scales, symptom scales and quality-of-life were recorded. After 24 months of treatment, almost every category showed improvement for both pretreated and treatment-naïve patients. Detailed results about symptom scales are shown in Figure 1.In conclusion, the data demonstrate that Ropeginterferon-alfa-2b is able not only to induce hematologic responses but also to improve constitutional symptoms and overall quality of life in prefibrotic PMF. Thus ropeginterferon-alfa-2b warrant further investigation as a treatment option in prefibrotic PMF, where only very limited alternatives exist. [Display omitted] DisclosuresGisslinger:Shire: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding. Krejcy:AOP Orphan Pharmaceuticals: Employment. Widmann:AOP Orphan Pharmaceuticals: Employment. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Krauth:Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Development of a prognostically relevant cachexia index in primary myelofibrosis using serum albumin and cholesterol levels

Key PointsSerum albumin and cholesterol levels predict survival in primary myelofibrosis, independent of each other and contemporary risk models. The cachexia index, determined by serum albumin and cholesterol levels, might further refine current prognostic models in myelofibrosis.

Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients.

The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9-3.5), type 2/like CALR (HR 2.5, 95% CI 1.4-4.5), MPL (HR 1.8, 95% CI 1.1-2.9) and triple-negative mutational status (HR 2.4, 95% CI 1.6-3.6), but otherwise similar between the non-type 1/like CALR mutational states (P = .41). In multivariable analysis, the absence of type 1/like CALR (P < .001; HR 2, 95% CI 1.4-2.7), presence of ASXL1/SRSF2 mutations (P < .001; HR 1.9, 95% CI 1.5-2.4) and DIPSS-plus (P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple-negative status did not disclose additional prognostic information for overall or leukemia-free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.

Monocytosis Is a Powerful and Independent Predictor of Shortened Overall and Leukemia-Free Survival in Primary Myelofibrosis

BackgroundThe Dynamic International Prognostic Scoring System (DIPSS)-plus currently provides the most comprehensive prognostic model for primary myelofibrosis (PMF) (JCO 2011;29:392). DIPSS-pluse uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocyte count >25 x 109/L, circulating blasts ³1%, constitutional symptoms, unfavorable karyotype, red cell transfusion need and platelet count <100 x 109/L. More recently, type 1/type 1-like CALR driver mutational status and ASXL1 andSRSF2 mutations were identified as additional DIPSS-plus-independent risk factors for survival in PMF (JAMA Oncol. 2015;1:97). Based on our earlier preliminary observation (Leuk Res. 2007;31:1503), we conducted the current study to fully examine the additional prognostic relevance of monocytosis (absolute monocyte count ≥1 x 10(9)/L) in PMF.MethodsStudy patients fulfilled the 2016 WHO criteria for the diagnosis of PMF, including both pre-PMF and overt PMF (Blood. 2016;127:2391). Additional selection criteria included the availability of absolute monocyte count (AMC) and percentage at time of referral. Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Blood 2015 126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of initial referral to the Mayo Clinic.ResultsPatient characteristics:The study population included 454 patients (median age 64 years; 62% males); 293 (64%) patients harbored JAK2 mutations, 74 (16%) type 1/like CALR, 16 (3%) type 2/like CALR, 24 (5%) MPL and 47 (10%) were "triple-negative". DIPSS-plus risk distribution was 29% high, 38% intermediate-2, 17% intermediate-1 and 15% low; 27% displayed red cell transfusion-dependency, 29% constitutional symptoms, 70% palpable splenomegaly and 36% abnormal karyotype, including 13% with unfavorable karyotype. 301 patients were screened for ASXL1 mutations with 39% mutated, 297 for SRSF2 mutations with 15% mutated, 286 for U2AF1 with 18% mutated, 253 for SF3B1 with 6% mutated, 229 for EZH2 with 5% mutated and 110 for IDH1/2 with 7% mutated.Clinical, cytogenetic and molecular comparisons between PMF patients with and without monocytosis:Among all study patients, 376 (83%) displayed AMC <1 x 10(9)/L; the remaining had either moderate (AMC between 1 and 3 x 10(9)/L; n=65) or marked (AMC >3 x 10(9)/L; n=13) monocytosis. Comparison of these three groups revealed that monocytosis was significantly associated with older age (p=0.0001), higher leukocyte count (p<0.0001), lower platelet count (p=0.01), higher circulating blast percentage (p=0.0002) and higher DIPSS-plus risk distribution (p=0.01). There were no significant differences in the distribution of driver mutations, ASXL1, SRSF2, U2AF, SF3B1, EZH2 or IDH1/2 mutations or incidence of unfavorable karyotype.Survival analysis:After a median follow up of 3.2 years, 265 (58%) deaths and 38 (8%) leukemic transformations were documented. In univariate analysis, all 8 variables included in DIPSS-plus were significantly associated with shortened survival (p<0.001 in all instances). Significant risk factors in univariate analysis also included AMC >3 x 10(9)/L (p<0.0001; HR 5.6, 95% CI 3.1-10.0), AMC 1 to 3 x 10(9)/L (p<0.0001; HR 2.1, 95% CI 1.5-2.9), absence of CALR type 1/type 1-like (p<0.0001) and presence of ASXL1 (p<0.0001) or SRSF2 (p<0.0001) mutations. The significant difference in survival between the three AMC categories (i.e. <1, 1-3 and >3 x 10(9)L) was independent of each one of the eight DIPSS-plus variables, DIPSS-plus, driver mutational status, ASXL1 and SRSF2 mutations (p<0.0001 in all instances). The survival difference between patients with and without monocytosis was evident in both high/intermediate-2 and low/intermediate-1 DIPSS-plus risk groups (Figure). Patients with monocytosis were also more likely to undergo leukemic transformation (HR 3.0, 95% CI 1.4-6.5) and this effect was also independent of karyotype, driver mutational status, ASXL1 or SRSF2 mutations.ConclusionThe current study identifies monocytosis as a powerful risk factor for both overall and leukemia-free survival in PMF and the effect was independent of currently established prognostic models and genetic risk factors. It was particularly noteworthy to document similar distribution of driver mutations among the three monocyte categories. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms.

BackgroundDespite insights into the genetic basis of Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs), a significant proportion of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients present with no known MPN disease alleles. There were no previous studies investigating the impact of ASXL1 mutations in Ph-negative MPNs in Turkey. In the current study, we investigated the prognostic significance of ASXL1 mutations in Turkish MPN patients. We also aimed to determine the prognostic significance of JAK2V617F allele burden and the relationship of JAK2V617F mutation with ASXL1 mutations in Ph-negative MPNs.MethodsAbout 184 patients from a single center diagnosed with Ph-negative MPNs were screened for ASXL1, JAK2V617F mutations, and JAK2V617F allele burden: 107 ET and 77 PMF.ResultsA total of 29 ASXL1 mutations were detected in 24.7% of PMF and 8.4% of ET patients. ASXL1-mutated ET patients showed a trend toward an increase in the incidence of cerebrovascular events and higher total leukocyte counts. ASXL1-mutation in PMF was associated with older age and a higher prevalence of bleeding complications. In univariate analysis, overall survival (OS) was significantly reduced in ASXL1-mutated PMF patients. In multivariate analysis, Dynamic International Prognostic Scoring System-plus high-risk category and ASXL1 mutation status were independently associated with shorter survival in PMF. In PMF, mutational status and allele burden of JAK2V617F showed no difference in terms of OS and leukemia-free survival.ConclusionWe conclude that ASXL1 mutations are molecular predictors of short OS in PMF.

Impact of Mutation Status of ASXL1, EZH2, SRSF2, IDH1/2 on Clinical Phenotype and Prognosis in Patients with Post-Polycythemia and Post-Essential Thrombocythemia Myelofibrosis: An AGIMM Study

Background: We reported that mutations in ASXL1, EZH2, IDH1/2 and SRSF2 are negative prognostic variables for survival in primary myelofibrosis (PMF). Patients harboring any one of these mutations comprise IPSS and DIPSS-plus independent high molecular risk (HMR) category. Conversely, prognostic variables in secondary myelofibrosis (sMF), including post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF are not defined.Aims: The aim was to evaluate the correlations of HMR mutational status with hematologic characteristics and clinical presentation, and the role for outcome predition, in PPV- and PET-MF.Methods: PPV- and PET-MF were diagnosed by IWG-MRT criteria; all pts provided informed consent. Previously published methods were used to screen mutations involving JAK2,MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. The prognostic value of the molecular variables with regard to OS was estimated by the Kaplan-Meier method and Cox regression.Results: A series of 200 sMF pts from 3 Italian centres was collected: 108 were PPV-MF (54%), 92 PET-MF (46%). PPV-MF cohort: Median age was 65y. Median follow up from PPV-MF diagnosis 4.7y (0.2-25.9y) and median time from PV to PPV-MF 10y (1.08-30.7y). Death occurred in 34 pts (31.8%), 7 pts (6.5%) developed leukemia. Median OS from PPV-MF diagnosis was 9.5y (7.1-11.9y). Frequency of mutations was: JAK2V617F 100% (median allele burden 77%, range 23-100), ASXL1 17.8%, EZH2 3.7%, IDH 5.6%, SRSF2 1%; 29 patients (26.9%) were classified as HMR cases. Hematologic characteristics: median leucocytes 13.0x109/L, hemoglobin 13.3g/dL, platelets 328x109/L, blasts ≥1% 23.4%. Constitutional symptoms in 45.8%, splenomegaly 94.1% (43.3% >10cm from LCM), pruritus 49%; median percentage of BM cellularity was 90% (25-100%) and grade 3 fibrosis in 16.8%. Overall 73 patients were evaluable for karyotype and abnormalities were detected in 42.5%. We did not find significant correlations between individual mutations or HMR category and hematologic and clinical characteristics. PET-MF cohort: Median age was 63.6y. Median follow up from the PET diagnosis 3.3y (0.2-14.5y), median time from ET to PET-MF 11.8y (0.9-30.6y). Death occurred in 30 pts (32.6%), 11 pts (12.0%) developed leukemia. Median OS from PET-MF diagnosis was 9.2y (4.9-13.6y). Frequency of mutations was: JAK2V617F 48.9% (median allele burden 49%, range 0-100), CALR 40.2%, MPL 4.3% and triple negativity (TN) 6.5%; ASXL1 29.3%, EZH2 6.5%, IDH 1.1%, SRSF2 3.3%; 33 pts (35.9%) were HMR. Hematologic characteristics: median leucokytes 8.0x109/L, hemoglobin 10.9 g/dL, platelets 375x109/L, blasts ≥1% 26.4%. Constitutional symptoms 35.4% of pts, splenomegaly 82% (18.2% >10cm from LCM), pruritus i31%; median percentage of BM cellularity was 70% (15-90%) and grade 3 fibrosis was found in 31.7%. Overall 56 patients were evaluable for karyotype and abnormalities were detected in 25.0%. By correlating hematologic and clinical characteristics with unique mutations and HMR category, we found that HMR mutated pts presented greater leukocytosis (P=0.04) and higher JAK2V617F allele burden (P=0.017) than pts in the low-molecular risk –LMR- category (ie, wild-type for ASXL1, EZH2, SRSF2, IDH1/2).Comparison of PPV-MF and PET-MF: a comparison of hematologic and clinical characteristics according to the diagnosis sMF disclosed that PPV-MF pts presented more frequently splenomegaly (P=0.008; for >10cm from LCM P<0.001), pruritus (P=0.009), abnormal karyotype (P=0.009), increased leukocytes (P<0.001), higher hemoglobin (P<0.001) and BM cellularity (P<0.001) compared with PET-MF. Conversely, PET-MF pts presented higher incidence of grade 3 of BM fibrosis (P=0.04). The median JAK2 allele burden (P<0.001) was higher in PPV-MF pts, while PET-MF pts showed more frequent mutations of ASXL1 (29.3% vs 17.8%; P=0.03).Univariate analysis disclosed significant correlations between shortened survival and mutated ASXL1 (P=0.02, HR 2.2 95% CI, 1.02-4.8) or EZH2 (P=0.05, HR 5.0 95% CI, 1.0-40.7) in PPV-MF. A HMR category was associated with reduced survival in PPV-MF: median survival 6.1y versus 9.5yr LMR (HR 1.07, 95%CI 1.0-4.4; P=0.04). In PET-MF survival was 4.8y in HMR versus 10.9y in LMR (HR1.6, 95%CI 0.8-3.4; P=0.2).Conclusion: We conclude that a HMR status is associated with shorter survival in sMF, but the overal impact is narrower than in primary MF, even though the rate of mutations is similar (Table1). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ph-Negative Chronic Myeloproliferative Neoplasms – Population Analysis, a Single Center 10-years’ Experience

Objectives and background. Nowadays chronic myeloproliferative neoplasms (MPN) other than chronic myelogenous leukemia undergo renaissance of interest. It results from advances in decryption of molecular mechanisms of pathogenesis and invention of target drugs. Epidemiological information is needed to assess potential effect and additional costs of new diagnostic and therapeutic techniques. The objective of our study was to review experience of MPN diagnostic and treatment in our center for past ten years.Methods. Our institution serves as primary hematological outpatient department for a half of Saint-Petersburg city with about 2 million inhabitants. We reviewed patients’ charts to obtain information about incidence, symptoms, diagnostic test results, treatment options and relationship to prognostic factors. Statistical methods included descriptive statistics, nonparametric ANOVA for frequencies comparisons and Kaplan-Meyer method with log-rank test for survival comparisons in Statistica 7.0 package.Results. Since 2004 to 2013 there were 570 newly diagnosed MPN patients (pts) in our center. This group consisted of primary myelofibrosis (PMF) (203 pts; 126 female, 77 male; median age 63 years, range 16-83 years), essential thrombocythemia (ET) (201 pts; 146 female, 55 male; median age 58 years, range 23-78 years), polycythemia vera (PV) (166 pts; 96 female, 70 male; median age 57 years, range 20-85 years).The incidence rates were stable during study period: PMF incidence varied from 0.65 to 1.35 with mean of 1.01 new patient per 100 000 inhabitants per year; ET had incidence from 0.60 to 2.1 with mean of 1.00 and PV had incidence from 0.5 to 1.15 with mean of 0.83. The most prevalent symptoms of disease were: splenomegaly (65.5%), constitutional symptoms (fever, night sweats, weight loss) (31.0%), anemia (36.3%) thrombosis (24.1%) for PMF; fatigue (33.2%), headache and dizziness (25.6%), arthralgia (21.8%), erythromelalgia (15.8%) for ET; plethora (82.5%), headache and dizziness (52.4%), fatigue (31.3%) for PV. JAK2V617F was detected in 49.7% of PMF pts, 57.8% of ET pts and in 97.7% of PV pts. Thrombosis rates according WHO IPSET-thrombosis system risks‘ groups of ET and PV pts were: low-risk group 3.33% (3/90), intermediate-risk group 11.1% (13/117) and 39.4% (63/160) in high-risk group with highly significant (p<0.0001) differences between risks’ groups. There were 169 lethal outcomes in the analysed group (102 PMF; 31 ET; 36 PV). Ten-years overall survival rates were 49.8% in PMF pts, 84.6% in ET pts and 78.3% in PV pts. (fig.1). Overall survival in PMF was significantly influenced by risk stratification as IPSS, DIPSS and DIPSS+. Survival curves according DIPSS+ groups are presented in fig.1.Conclusions. Patients with MPN are presented in substantial number; therefore need much finance for novel therapy introduction. Risk stratification systems has high predictive value. Innovative drugs treatment results should be evaluated in comparison with historical control. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Normal Karyotype Primary Myelofibrosis (NK-PMF): Clinical and Molecular Prognostication In 690 Patients

BackgroundThe Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight adverse factors to predict survival in primary myelofibrosis (PMF): age >65 years, hemoglobin <10 g/dL, leukocytes >25 x 109/L, circulating blasts 31%, constitutional symptoms, red cell transfusion need, platelets <100 x 109/L and unfavorable karyotype (J Clin Oncol. 2011;29:392). The latter two also predicted leukemic transformation. Most recently, an international study of 879 PMF patients identified ASXL1, SRSF2, EZH2 and IDH1/2 mutations as inter-independent predictors of shortened overall or leukemia-free survival (Leukemia 2013Apr 26 doi: 101038/leu2013119. 2013). Molecular prognostication is now well established for acute myeloid leukemia with normal karyotype (NK). There is currently little information on clinical or molecular prognostication in NK-PMF. MethodsDiagnosis of PMF was according to WHO criteria. The study population included all referrals to the Mayo Clinic, Rochester, MN, USA or the University of Florence, Florence, Italy. Information on clinical and laboratory parameters and karyotype was available in all study patients, at time of referral, which coincided with time of sample collection for mutation screening. The current study considered only those patients with NK-PMF. ASXL1, EZH2, SRSF2, IDH1/2 and JAK2 mutations were performed on variable number of patients depending on bone marrow or granulocyte DNA availability. Clinical parameters examined for prognostic relevance included those listed for DIPSS-plus, less unfavorable karyotype. ResultsA total of 690 patients with NK-PMF patients were studied. Median age was 65 years (14-89). The percentage of patients with age >65 years was 48%, red cell transfusion dependent 35%, hemoglobin <10 g/dL 49%, platelets <100 x 10(9)/L 19%, leukocyte count >25 x 10(9)/L 15%, circulating blasts ≥1% 49% and constitutional symptoms 33%. At a median follow-up of 29 months, 351 (51%) deaths and 39 (6%) leukemic transformations were recorded. Mutational frequencies and clinical correlatesThe respective frequencies (mutated/number of patients studied) of JAK2V617F, ASXL1, EZH2, SRSF2 and IDH1/2 mutations were 60% (284/473), 34% (72/214), 8% (14/179), 15% (37/249) and 5% (14/262). There was no significant association between JAK2V617F and any one of the aforementioned mutations. Inter-mutation association was evident only between SRSF2 and IDH1/2 (p=0.0005). Each one of the DIPSS-plus risk parameters was examined for correlation with a specific mutation: ASXL1 was associated with leukocyte count >25 x 10(9)/L (p<0.0001) and circulating blasts ≥1% (p=0.0005); EZH2 with leukocyte count >25 x 10(9)/L (p=0.008); and SRSF2 with age >65 years (p=0.0007), transfusion need (p=0.04) and hemoglobin <10 g/dL (p=0.03). JAK2V617F was associated with age>65 years (p=0.003) and leukocyte count >25 x 10(9)/L (p=0.02). Predictors of overall and leukemia-free survivalIn univariate analysis, all 7 DIPSS-plus parameters, as well as ASXL1, EZH2, SRSF2 and IDH1/2 mutations showed significant association with shortened survival: When each of these analyses was adjusted for age, all except constitutional symptoms and SRSF2 mutations retained their significance. Multivariable analysis of the six age-independent DIPSS-plus variables identified all but transfusion-need as independent predictors of inferior survival. A similar analysis restricted to mutations identified ASXL1 and EZH2 as being independently adverse. When both mutations and DIPSS-plus variables were included in the multivariable model, only four parameters remained significant: age >65 years (HR 4.2; p<0.0001), platelets <100 x 10(9)/L (HR 3.4; p<0.0001), ASXL1 mutations (HR 2.2; p=0.0001) and EZH2 mutations (HR 2.7; p=0.001). A similar analysis identified SRSF2 mutations (HR 5.9; p=0.0003) and platelets <100 x 10(9)/L (HR 4.3; p=0.005) as the only predictors of leukemia-free survival. ConclusionsIn NK-PMF, molecular markers might be prognostically more useful than conventional models that rely on clinical features. In the current study, thrombocytopenia was the only clinical variable, other than age, with additional value to molecular prediction of survival and leukemic transformation. Disclosures:No relevant conflicts of interest to declare.

Serum Ferritin Level At Referral Provides Independent Prognostic Information For Overall Survival In Primary Myelofibrosis

BackgroundRecent studies have suggested that increased circulating free light chains, inflammatory cytokines, hepcidin, ferritin, and ASXL1 mutated status have independent prognostic value for survival in primary myelofibrosis (PMF). In the current retrospective study, we studied all the aforementioned variables in the context of DIPSS-plus to examine their relative prognostic contributions for overall and leukemia-free survival. MethodsThe diagnosis of PMF was according to WHO criteria. The study population included all consecutive referrals to the Mayo Clinic, Rochester, MN where complete information on clinical and laboratory parameters and bone marrow karyotype was available. Inclusion to the study required availability of a research blood sample collected at referral. Levels of circulating free light chains (FLC) (J Clin Oncol. 2012 Apr 1;30(10):1087), inflammatory cytokines (J Clin Oncol. 2011 Apr 1;29(10):1356), hepcidin and ferritin (Am J Hematol. 2013 Apr;88(4):312) were determined as previously described. Disease-relevant mutations (ASXL1, SRSF2, EZH2, IDH-1/2, SF3B1, JAK2V617F and MPLW515) were identified as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). ResultsA total of 224 PMF patients were studied (66% male; median age 63 years, range 18-83 years). The DIPSS-plus distribution was: Low 23 (10%), Int-1 26 (12%), Int-2 98 (44%), and High 77 (34%). Clinical characteristics were: unfavorable karyotype 13%, hemoglobin <10 g/dL 58%, leukocyte count >25 x 109/L 13%, platelet count <100 x 109/L 20%, peripheral blasts ≥1% 62%, red blood cell transfusion-dependent 38%, and constitutional symptoms 36%. Mutation frequencies were: JAK2V617F 61% (n=220), MPLW515 6% (n=204), ASXL1 34% (n=154), SRSF2 16% (n=189), IDH-1/2 3% (n=209), EZH2 1.5% (n=134), SF3B1 5% (n=91) and SETBP1 4% (n=114). Distribution of circulating biomarkers was: FLC >receiver operating characteristic (ROC) cutoff of 3.78 mg/dL 37% (n=222), interleukin (IL)-2R and/or IL-8 >3 standard deviations above normal mean (SD) 75% (n=197), ferritin ≥1000 mcg/L 18% (n=146), ferritin ≥500 30% (n=146), and hepcidin >3SD 72% (n=203).Median follow up from the time of referral was 45 months (range 1-317 months); during this period, 139 deaths (62%) and 27 (12%) leukemic transformations have been documented.The median overall survival of the entire cohort was 61 months. The following variables had DIPSS-plus independent predictive value for inferior survival: ferritin ≥1000 mcg/L (HR 1.9), ASXL1 mutated status (HR 1.7) and FLC >ROC cutoff (HR 2.0) and IL-2R and/or IL-8 >3SD (HR 1.6) (all p<0.05). When the aforementioned variables were added to the multivariate model (sequentially or altogether), only serum ferritin >1000 mcg/L retained its significance for overall survival independent of DIPSS-plus (HR 2.1; p=0.03). The predictive significance for increased ferritin level was maintained in RBC transfusion-dependent (ferritin ≥1000 mcg/L; n=26/54; median survival 21 versus 59 months; p=0.03) and -independent (ferritin >500 mcg/L; n=5/92; median survival 20 versus 80 months; p=0.0002) patients.Multivariable analysis identified the following predictors for inferior leukemia-free survival: SRSF2 mutated status (HR 4.8), unfavorable karyotype (HR 4.0), and circulating blasts ≥1% (HR 3.0) (p<0.05). ConclusionsWhen considering composite risk-assessment in PMF where input variables were disease-relevant mutations and circulating biomarkers in addition to traditional clinical parameters, only increased serum ferritin levels at time-of-referral retained adverse predictive value for overall survival independent of DIPSS-plus. The prognostic value of serum ferritin was independent of anemia and RBC transfusion need. It appears to more fully capture the severity of the underlying erythropoietic defect in PMF by also likely reflecting (as an acute-phase reactant) the marrow-suppressive effect of disease-related inflammation. The shortened survival in patients with increased ferritin levels was unrelated to iron overload since none of the deaths, where information was available, were caused by cardiac siderosis. Serum ferritin levels were not associated with leukemic transformation risk. In the latter analysis, only SRSF2 mutations, unfavorable karyotype and presence of circulating blasts were independently associated with inferior leukemia-free survival. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Mutations and Survival in Primary Myelofibrosis

The variable prognosis in patients with primary myelofibrosis (PM) has prompted investigators to search for survival factors in this disorder. Interest