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Cancers Oct 2023Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic...
Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the "RUX-MF" retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after <5 yrs (early death on ruxolitinib, EDR). The cumulative incidence of the blast phase was similar in LTR and STR patients ( = 0.08). Overall survival (OS) was significantly longer in LTR pts ( = 0.002). In multivariate analysis, PLT < 100 × 10/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose <10 mg BID were associated with higher probability of STR. Assigning one point to each significant variable, a prognostic model for STR (STR-PM) was built, and three groups were identified: low (score 0-1), intermediate (score 2), and high risk (score ≥ 3). The STR-PM may identify patients at higher risk of failure with ruxolitinib monotherapy who should be considered for alternative frontline strategies.
PubMed: 37894394
DOI: 10.3390/cancers15205027 -
Blood Cancer Journal Jan 2024We describe 1000 patients with essential thrombocythemia seen at the Mayo Clinic between 1967 and 2023: median age 58 years (18-90), females 63%, JAK2/CALR/MPL-mutated...
We describe 1000 patients with essential thrombocythemia seen at the Mayo Clinic between 1967 and 2023: median age 58 years (18-90), females 63%, JAK2/CALR/MPL-mutated 62%/27%/3%, triple-negative (TN) 8%, extreme thrombocytosis (ExT; platelets ≥1000 × 10/L) 26%, leukocytosis (leukocyte count >11 × 10/L) 20%, and abnormal karyotype 6%. JAK2-mutated patients were older (median 71 years), and CALR mutated (52 years), and TN (50 years) younger (p < 0.01). Female gender clustered with TN (73%) and JAK2 (69%) vs. CALR/MPL (49%/47%) mutations (p < 0.01). ExT clustered with CALR (type-2 more than type-1) and TN and leukocytosis with JAK2 mutation (p < 0.01). In multivariable analysis, risk factors for overall survival were older age (p < 0.01), male gender (HR 1.8), absolute neutrophil count (ANC) ≥ 8 × 10/L (HR 1.6), absolute lymphocyte count (ALC) < 1.7 × 10/L (HR 1.5), hypertension (HR 1.7), and arterial thrombosis history (HR 1.7); for leukemia-free survival, ExT (HR 2.3) and abnormal karyotype (HR 3.1); for myelofibrosis-free survival, ANC ≥ 8 × 10/L (HR 2.3) and MPL mutation (HR 3.9); for arterial thrombosis-free survival, age ≥60 years (HR 1.9), male gender (HR 1.6), arterial thrombosis history (HR 1.7), hypertension (HR 1.7), and JAK2 mutation (HR 1.8); for venous thrombosis-free survival, male gender (HR 1.8) and venous thrombosis history (HR 3.0). Associations between ExT and leukemic transformation and between ANC and fibrotic progression were limited to JAK2-mutated cases. Aspirin therapy appeared to mitigate both arterial (HR 0.4) and venous (HR 0.4) thrombosis risk. HR-based risk models delineated patients with median survivals ranging from 10 years to not reached and 20-year leukemia/myelofibrosis incidences from 3%/21% to 12.8%/49%. The current study provides both novel and confirmatory observations of essential thrombocythemia.
Topics: Humans; Male; Female; Middle Aged; Thrombocythemia, Essential; Leukocytosis; Thrombosis; Mutation; Primary Myelofibrosis; Abnormal Karyotype; Hypertension; Janus Kinase 2; Calreticulin
PubMed: 38238303
DOI: 10.1038/s41408-023-00972-x -
Blood Advances May 2024The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia;...
The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin increase ≥1.5 g/dL from baseline. Among TD patients, ~50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. NCT03194542 clinicaltrials.gov.
PubMed: 38820422
DOI: 10.1182/bloodadvances.2024012939 -
Current Opinion in Hematology Nov 2023Myelofibrosis (MF) is primarily driven by constitutive activation of the Janus kinase/signal transducer of activators of transcription (JAK/STAT) pathway. While JAK... (Review)
Review
PURPOSE OF REVIEW
Myelofibrosis (MF) is primarily driven by constitutive activation of the Janus kinase/signal transducer of activators of transcription (JAK/STAT) pathway. While JAK inhibitors have shown to alleviate disease symptoms, their disease-modifying effects in MF are limited. The only curative treatment remains allogeneic stem cell transplantation, which can be applied to a minority of patients. As a result, there is a need to explore novel targets in MF to facilitate appropriate drug development and therapeutic pathways.
RECENT FINDINGS
Recent research has focused on identifying novel signals that contribute to the abnormal cross-talk between hematopoietic and stromal cells, which promotes MF and disease progression. Inflammation and immune dysregulation have emerged as key drivers of both the initiation and progression of MF. A growing number of actionable targets has been identified, including cytokines, transcription factors, signalling networks and cell surface-associated molecules. These targets exhibit dysfunctions in malignant and nonmalignant hematopoietic cells, but also in nonhematopoietic cells of the bone marrow. The study of these inflammation-related molecules, in preclinical models and MF patient's samples, is providing novel therapeutic targets.
SUMMARY
The identification of immunotherapeutic targets is expanding the therapeutic landscape of MF. This review provides a summary of the most recent advancements in the study of immunotherapeutic targets in MF.
Topics: Humans; Primary Myelofibrosis; Janus Kinases; Hematopoietic Stem Cell Transplantation; Immunotherapy; Janus Kinase 2
PubMed: 37548363
DOI: 10.1097/MOH.0000000000000778 -
Future Oncology (London, England) Nov 2023Fedratinib is an oral selective JAK2 inhibitor approved in the USA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary...
Fedratinib is an oral selective JAK2 inhibitor approved in the USA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF). This observational study assessed adult US patients who received ruxolitinib for primary MF (Flatiron Health database: 1 January 2011-31 October 2020). Patients were stratified by post-ruxolitinib treatment (fedratinib vs non-fedratinib). Characteristics were comparable between fedratinib (n=70) and non-fedratinib (n=159) groups (median age: 71.0 vs 70.0 years; females: 55.7 vs 50.3%; median follow-up: 7.0 vs 6.0 months). Median overall survival (not reached vs 17 months) and 12 month survival (71.6 vs 53.5%) were improved with fedratinib versus the non-fedratinib therapies. In MF patients who received frontline ruxolitinib, survival was improved with subsequent fedratinib versus non-fedratinib care.
PubMed: 37991002
DOI: 10.2217/fon-2022-1256 -
World Journal of Hepatology Nov 2023Classical Philadelphia-negative myeloproliferative neoplasms (MPNs), , polycythemia vera, essential thrombocythemia, and primary/secondary myelofibrosis, are clonal... (Review)
Review
Classical Philadelphia-negative myeloproliferative neoplasms (MPNs), , polycythemia vera, essential thrombocythemia, and primary/secondary myelofibrosis, are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs. MPNs are characterized by mutations in driver genes, the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies. Thus, JAK inhibition has emerged as a potential therapeutic strategy in MPNs, with ruxolitinib being the first JAK inhibitor developed, approved, and prescribed in the management of these blood cancers. However, the use of ruxolitinib has been associated with a potential risk of infection, including opportunistic infections and reactivation of hepatitis B. Here, we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.
PubMed: 38075009
DOI: 10.4254/wjh.v15.i11.1188 -
American Journal of Hematology Apr 2024Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.
Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.
Topics: Humans; Prognosis; Primary Myelofibrosis; Mutation; Janus Kinase 2; Gene Frequency
PubMed: 38291566
DOI: 10.1002/ajh.27203 -
Journal of Nephrology Nov 2023
Topics: Humans; Hematopoiesis, Extramedullary; Primary Myelofibrosis; Kidney; Kidney Diseases; Urinary Tract
PubMed: 37067698
DOI: 10.1007/s40620-023-01621-z -
BMJ Case Reports Nov 2023Paediatric primary myelofibrosis (PMF) is exceedingly rare and distinct compared with adult PMF. It is characterised by peripheral blood cytopenias,...
Paediatric primary myelofibrosis (PMF) is exceedingly rare and distinct compared with adult PMF. It is characterised by peripheral blood cytopenias, leucoerythroblastosis, reticulin fibrosis, extramedullary haematopoiesis and hepatosplenomegaly. In the absence of laid down diagnostic criteria, the diagnosis is largely of exclusion. Though early haematological stem cell transplant (HSCT) remains the treatment of choice, spontaneous remission or remission with steroids and/or cytoreductive agents is described in around 20% of cases of paediatric PMF. Moreover, HSCT in paediatric PMF is associated with high mortality (30%-45%). Therefore, it may be prudent to consider a trial of steroids and/or cytoreductive agents in all transfusion-dependent paediatric PMF while considering HSCT and ongoing bone marrow donor search. We describe one such infant with PMF who had complete remission of clinical and haematological parameters with a combination therapy of steroids and hydroxyurea.
Topics: Humans; Infant; Hydroxyurea; Primary Myelofibrosis; Remission, Spontaneous; Steroids; Thrombocytopenia
PubMed: 37993140
DOI: 10.1136/bcr-2023-256210 -
Leukemia & Lymphoma Jul 2024A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK)... (Randomized Controlled Trial)
Randomized Controlled Trial
A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.
Topics: Humans; Pyrimidines; Pyrazoles; Primary Myelofibrosis; Nitriles; Male; Female; Middle Aged; Hemoglobins; Aged; Treatment Outcome; Benzamides; Double-Blind Method; Anemia; Adult; Protein Kinase Inhibitors; Aged, 80 and over; Janus Kinase 1; Janus Kinase 2
PubMed: 38501751
DOI: 10.1080/10428194.2024.2328800