RESUMO
BACKGROUND: Primary myelofibrosis (PMF) is the most advanced subtype among the classic Philadelphia chromosomenegative myeloproliferative neoplasms (MPNs). A majority of patients carry one of three mutually-exclusive somatic driver mutations: JAK2 (60-65%), CALR (20-25%), or MPL (5%). Co-occurrence of these mutations is rarely reported. Here we report a case with a triple positive combination of JAK2, CALR and MPL driver mutations. CASE PRESENTATION: A 69-year-old male was admitted to hospital for acute exacerbation of chronic obstructive pulmonary disease (COPD) and was found to have splenomegaly and leukocytosis. Nextgeneration revealed JAK2, CALR, MPL mutations, and additional variants in SF3B1, SRSF2, and STAG2. The patient was diagnosed with PMF and treated with ruxolitinib and COPD therapy. Due to nausea, the ruxolitinib dose was reduced. After therapy, spleen volume decreased and hematologic responses were poor. Another genetic mutation of ASXL1 was later found. After adjusting the medication and adding antiemetics, the patient's condition improved. CONCLUSIONS: The rare coexistence of JAK2, CALR, and MPL mutations challenges the assumption of their mutual exclusivity. Further study of these mutations is essential for developing better treatment strategies.
Assuntos
Calreticulina , Janus Quinase 2 , Mutação , Mielofibrose Primária , Receptores de Trombopoetina , Humanos , Mielofibrose Primária/genética , Mielofibrose Primária/tratamento farmacológico , Masculino , Idoso , Janus Quinase 2/genética , Calreticulina/genética , Receptores de Trombopoetina/genéticaRESUMO
Myelofibrosis should be diagnosed according to the WHO classification (2022, 5th Ed.) and International Consensus Conference 2022 criteria. Testing for driver mutations in the three genes JAK2, CALR, and MPL is recommended to ensure a definitive diagnosis. Ruxolitinib is the only JAK inhibitor currently approved in Japan, but momelotinib is under regulatory review. The MOMENTUM study showed similar spleen volume reduction at 24 weeks and MFSAF-TSS reduction as the COMFORT study of ruxolitinib. Momelotinib acts on ACVR1 and, therefore, improves anemia through suppression of hepcidin. Anemia and/or transfusion dependency are known to be associated with overall survival duration. Consequently, supportive care measures such as ESA and danazol in lieu of transfusion should be considered in addition to JAK inhibitor selection. Mean survival after discontinuation of JAK inhibitors is 11 to 14 months. Pacritinib (not approved in Japan) is suitable for MF patients with thrombocytopenia. JAK inhibitor selection and supportive care by ESA or danazol in lieu of transfusion should be considered. Many classes of drugs other than JAK inhibitors for myelofibrosis are under investigation.
Assuntos
Benzamidas , Inibidores de Janus Quinases , Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/diagnóstico , Humanos , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Hidrocarbonetos Aromáticos com PontesRESUMO
Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.
Assuntos
Interferon alfa-2 , Interferon-alfa , Polietilenoglicóis , Mielofibrose Primária , Proteínas Recombinantes , Humanos , Mielofibrose Primária/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Método Duplo-Cego , Interferon-alfa/uso terapêutico , Interferon-alfa/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon alfa-2/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , IdosoRESUMO
Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF.
Assuntos
Benzamidas , Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Humanos , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Mielofibrose Primária/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Idoso , Feminino , Resultado do Tratamento , Benzamidas/uso terapêutico , Japão , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , População do Leste AsiáticoRESUMO
We report a rare case of a patient with Janus kinase 2-positive myelofibrosis on ruxolitinib, presenting with indolent pneumonia and cavitary lung lesions. Initial transthoracic biopsy was non-specific, but thoracoscopic biopsy revealed necrotising granulomatous disease caused by Pneumocystis jirovecii pneumonia (PJP). The patient, initially treated with trimethoprim-sulfamethoxazole, was switched to atovaquone due to gastrointestinal intolerance. Given the patient's immunosuppression and extensive cavitary lesions, an extended course of atovaquone was administered, guided by serial imaging, resulting in clinical and radiological improvement. Unfortunately, the patient later passed away from a severe SARS-CoV-2 infection before complete radiographic resolution was observed. This case highlights the importance of recognising atypical PJP presentations causing granulomatous disease in immunosuppressed patients. While rare, documenting such cases may improve diagnosis using less invasive methods and help determine optimal treatment durations for resolution of these atypical infections.
Assuntos
Nitrilas , Pneumocystis carinii , Pneumonia por Pneumocystis , Mielofibrose Primária , Pirazóis , Pirimidinas , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/complicações , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/diagnóstico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pneumocystis carinii/isolamento & purificação , Masculino , Evolução Fatal , COVID-19/complicações , Atovaquona/uso terapêutico , Hospedeiro Imunocomprometido , Idoso , SARS-CoV-2RESUMO
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.
Assuntos
Pesquisa Translacional Biomédica , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Benzamidas/farmacologia , Benzamidas/farmacocinética , Benzamidas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Animais , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Hidrocarbonetos Aromáticos com PontesRESUMO
OBJECTIVES: There is limited data on the incidence, prevalence, and treatments for myelofibrosis (MF) in Germany. This retrospective study examined claims data from 3.3 million insured individuals, spanning from 2010 to 2021. METHODS: Four sensitivity scenarios were explored to identify cases of MF. Point prevalence and cumulative incidence of MF were determined as of December 31, 2021, and within 2021, respectively. A cross-sectional analysis used the main scenario definition of MF to identify cases and evaluate the period prevalence of patients receiving treatment for symptoms and/or splenomegaly, including first-line (1L) Janus kinase inhibitor (JAKi), second-line, or further (2L+) MF-related treatment therapies during 2021. The prevalence of anemia treatment was also reported. RESULTS: The estimated standardized point prevalence of MF on December 31, 2021, was 9.9-12.4 cases per 100 000 persons, and cumulative incidence in 2021 was 1.2-1.8 cases per 100 000 persons. Standardized period prevalence in 2021 for MF patients receiving 1L JAKi and/or 2L+ MF-related treatment was 4.0 cases per 100 000. Among these patients, 47.1%-53.7% required treatment for anemia, resulting in a period prevalence of 1.9-2.2 cases per 100 000 individuals. CONCLUSION: The data reveal gaps in MF treatments and the need to improve patient quality of life.
Assuntos
Anemia , Mielofibrose Primária , Humanos , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/diagnóstico , Alemanha/epidemiologia , Anemia/epidemiologia , Anemia/etiologia , Anemia/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Incidência , Prevalência , Adulto , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Estudos Retrospectivos , Estudos Transversais , Revisão da Utilização de Seguros , Análise de Dados , Adulto Jovem , AdolescenteRESUMO
INTRODUCTION: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. METHODS: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. RESULTS: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. CONCLUSION: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02101268.
Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia.
Assuntos
Anemia , Inibidores de Janus Quinases , Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Humanos , Pirimidinas/uso terapêutico , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/complicações , Anemia/tratamento farmacológico , Anemia/etiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Inibidores de Janus Quinases/uso terapêutico , Benzamidas/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Transfusão de Eritrócitos/estatística & dados numéricos , Idoso de 80 Anos ou mais , Resultado do Tratamento , Janus Quinase 2/antagonistas & inibidoresRESUMO
INTRODUCTION: The hallmark discovery of hyperactivation of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was a sentinel moment in the history of myeloproliferative neoplasms (MPNs). This finding paved the way for the development of JAK inhibitors, which now represent the foundation of myelofibrosis therapy. With four JAK inhibitors now approved for myelofibrosis, awareness of their clinical efficacy and safety data and recognition of their unique pharmacologic attributes are of critical importance. Additionally, ruxolitinib represents an integral part of the therapeutic arsenal for polycythemia vera. AREAS COVERED: This review provides a broad overview of the published literature supporting JAK inhibitor therapy for MPNs. Primarily focusing on myelofibrosis, each of the four available JAK inhibitors is reviewed in detail, including pharmacology, efficacy, and safety data. Failure of JAK inhibitors and future directions in JAK inhibitor therapy are also discussed. EXPERT OPINION: JAK inhibitors revolutionized the treatment of MPNs and have dramatically improved patient outcomes. However, data informing selection between currently available JAK inhibitors is limited. These agents are not curative and eventually fail most patients with myelofibrosis. Combining JAK inhibitors with novel targeted agents appears to be the most promising path to further improve outcomes.
Assuntos
Inibidores de Janus Quinases , Transtornos Mieloproliferativos , Mielofibrose Primária , Humanos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Transtornos Mieloproliferativos/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Nitrilas/uso terapêutico , Animais , Desenvolvimento de Medicamentos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Pirimidinas/uso terapêutico , Pirimidinas/farmacologiaRESUMO
Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.
Assuntos
Fator Plaquetário 4 , Mielofibrose Primária , Proteômica , Fator Plaquetário 4/metabolismo , Fator Plaquetário 4/genética , Animais , Camundongos , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Humanos , Proteômica/métodos , Megacariócitos/metabolismo , Megacariócitos/patologia , Camundongos Endogâmicos C57BL , Diferenciação CelularRESUMO
Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-ß (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-ß) signaling and TGF-ß trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-ß content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-ß or CXCL1).
Assuntos
Janus Quinase 1 , Selectina-P , Mielofibrose Primária , Pirimidinas , Receptores de Interleucina-8B , Fator de Crescimento Transformador beta , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Selectina-P/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8A/metabolismo , Camundongos , Janus Quinase 2/metabolismo , Janus Quinase 2/antagonistas & inibidores , Nitrilas/uso terapêutico , Nitrilas/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA1/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , HumanosAssuntos
Bexaroteno , Proteínas Proto-Oncogênicas c-ret , Humanos , Bexaroteno/uso terapêutico , Bexaroteno/farmacologia , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Antineoplásicos/uso terapêutico , Tetra-Hidronaftalenos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Mutação , Piridinas/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Aprovação de Drogas , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Pirimidinas/uso terapêutico , Morfolinas/uso terapêutico , Tiazóis/uso terapêutico , Tiazóis/farmacologia , Éxons , BenzamidasRESUMO
ABSTRACT: In September 2023, the US Food and Drug Administration approved momelotinib for the treatment of myelofibrosis (MF) with anemia, marking the fourth US regulatory approval of a Janus kinase inhibitor for MF. A positive opinion from the European Medicines Agency followed in November 2023. Momelotinib's ability to address splenomegaly, symptoms, and anemia, including in patients with thrombocytopenia (with platelet counts of ≥25 × 109/L), the ease of switching from ruxolitinib, and good tolerability uniquely position it to substantially impact the MF treatment landscape.
Assuntos
Benzamidas , Mielofibrose Primária , Pirimidinas , Mielofibrose Primária/tratamento farmacológico , Humanos , Pirimidinas/uso terapêutico , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.
Assuntos
Inibidores de Janus Quinases , Nivolumabe , Mielofibrose Primária , Pirrolidinas , Humanos , Mielofibrose Primária/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Pirrolidinas/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Alemanha , Transtornos Mieloproliferativos/tratamento farmacológico , Nitrilas/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , BenzenossulfonamidasRESUMO
Myelofibrosis is a rare and often fatal hematological neoplasm, and the treatment of myelofibrosis-associated anemia remains suboptimal, with no improved therapies. Luspatercept was shown to display some efficacy in a phase 2 clinical trial for Myelofibrosis with anemia, yet relevant research are limited. Threrfore, data from patients diagnosed with refractory anemic primary or post-essential thrombocythemia/polycythemia vera myelofibrosis, who were treated with luspatercept for at least 9 weeks, were retrospectively collected. Eighteen patients with myelofibrosis treated with luspatercept were enrolled. Median age was 68 years (range, 44-80 years), and 27.8% were males. Ten (55.6%) were transfusion-dependent. Ten (55.6%) were Dynamic International Prognostic Scoring System intermediate-1, and eight (44.4%) were intermediate-2. The median follow-up was 7 (4-16) months. Erythroid response occurred in eight patients (44.4%) at week 12, four patients (30.8%) at week 24, and nine (50%) at the end of follow-up. Patients who were transfusion-dependent and not transfusion-dependent had similar HI-E responses, at different time points (P > 0.05). Patients had a significantly higher hemoglobin level at 12 weeks, 24 weeks, and at the end of follow-up, than at baseline (P = 0.001, P = 0.021, and P = 0.005, respectively). Treatment-related adverse events occurred in five (16.7%) patients, with no serious adverse events. Two (11.1%) patients relapsed at weeks 15 and 31. One patient progressed to acute myeloid leukemia. No patients had died by the end of follow-up. Luspatercept induced a good response in patients with anemic myelofibrosis, with a low relapse rate and good tolerance.
Assuntos
Mielofibrose Primária , Proteínas Recombinantes de Fusão , Humanos , Masculino , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/complicações , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , China , Anemia Refratária/tratamento farmacológico , Receptores de Activinas Tipo II/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Resultado do Tratamento , Seguimentos , Anemia/tratamento farmacológico , Anemia/etiologiaRESUMO
BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.
Assuntos
Decitabina , Janus Quinase 2 , Mielofibrose Primária , Humanos , Idoso , Masculino , Feminino , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/mortalidade , Decitabina/uso terapêutico , Decitabina/farmacologia , Decitabina/administração & dosagem , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Estudos Retrospectivos , Uridina/análogos & derivados , Uridina/uso terapêutico , Uridina/farmacologia , Uridina/administração & dosagem , Administração Oral , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.
Assuntos
Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Pirrolidinas , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/diagnóstico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Pirrolidinas/uso terapêutico , Resultado do Tratamento , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , COVID-19/epidemiologia , Idoso de 80 Anos ou mais , SARS-CoV-2 , Baço/patologia , Baço/efeitos dos fármacos , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , BenzenossulfonamidasRESUMO
INTRODUCTION: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, cytopenias, a potential for leukemic transformation, and increased mortality. Patients who are ineligible for stem cell transplant rely on pharmacologic therapies of noncurative intent, whose cornerstone consists of JAK inhibitors (JAKi). While current JAKi are efficacious in controlling symptoms and splenic volume, none meaningfully reduce clonal burden nor halt disease progression, and patients oftentimes develop JAKi intolerant, relapsed, or refractory MF. As such, there remains an urgent necessity for second-line options and novel therapies with disease-modifying properties. AREAS COVERED: In this review, we delineate the mechanistic rationale, along with the latest safety and efficacy data, of investigational JAKi-based MF treatment strategies, with a focus on JAKi monotherapies and combinations of novel agents with approved JAKi. Our literature search consisted of extensive review of PubMed and clinicaltrials.gov. EXPERT OPINION: A myriad of promising MF-directed therapies are in late-phase studies. Following their approval, treatment selection should be tailored to patient-specific treatment goals and disease characteristics, with an emphasis on combination therapies of JAKi with novel agents of differing mechanistic targets that possess anti-clonal properties, in attempt to alter disease course and concurrently limit dose-dependent JAKi toxicities.
Assuntos
Janus Quinase 2 , Inibidores de Janus Quinases , Mielofibrose Primária , Humanos , Mielofibrose Primária/tratamento farmacológico , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Animais , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Progressão da DoençaRESUMO
We evaluated RDW in a single-center series of 61 consecutive patients with primary and secondary MF at diagnosis and during treatment with ruxolitinib (RUX) and examined any possible prognostic impact. Elevated RDW values were present in all but 4 patients at diagnosis with a median RDW of 18.9%. RDW was higher in subjects with palpable splenomegaly (p = 0.02), higher ferritin, as well as among those cases who did not receive any cytoreduction before RUX (p = 0.04). Interestingly, higher RDW at diagnosis also correlated with a shorter time from MF diagnosis to RUX start (-4.1 months per one RDW unit; p = 0.03). We observed a modest increase (< 1%) in RDW during the first 6 months of RUX treatment. In a multivariable random-intercept model that considered all time points and contained the covariates time and RUX dose, we also observed a clear decrease in RDW with increasing hemoglobin (Hb) during RUX (slope: -0.4% per g/dL of Hb; p < 0.001). The median RDW at diagnosis of 18.9% was used as a cut-off to identify two subgroups of patients [Group 1: RDW 19.0-25.7%; Group 2: RDW 13.1-18.7%], showing a difference in mortality [Group 1 vs. 2: crude HR 2.88; p = 0.01]. Using continuous RDW at diagnosis, the crude HR was 1.21 per RDW unit (p = 0.002). In a Cox model adjusted for gender, age and Hb at diagnosis, the HR was 1.13 per RDW unit (p = 0.07). RDW may have prognostic significance at MF diagnosis and during RUX, helping in the rapid detection of patients with poor prognosis.