RESUMO
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
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
Introduction: The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works. Materials and methods: We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the JAK2 V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their JAK2 V617F variant allele frequency (n = 24 in total). Results: The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively). Discussion: Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.
Assuntos
Janus Quinase 2 , Transtornos Mieloproliferativos , Nitrilas , Pirazóis , Pirimidinas , Humanos , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Janus Quinase 2/genética , Janus Quinase 2/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Modelos Teóricos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Myeloproliferative neoplasms (MPN) are blood cancers that appear after acquiring a driver mutation in a hematopoietic stem cell. These hematological malignancies result in the overproduction of mature blood cells and, if not treated, induce a risk of cardiovascular events and thrombosis. Pegylated IFN$\alpha $ is commonly used to treat MPN, but no clear guidelines exist concerning the dose prescribed to patients. We applied a model selection procedure and ran a hierarchical Bayesian inference method to decipher how dose variations impact the response to the therapy. We inferred that IFN$\alpha $ acts on mutated stem cells by inducing their differentiation into progenitor cells; the higher the dose, the higher the effect. We found that the treatment can induce long-term remission when a sufficient (patient-dependent) dose is reached. We determined this minimal dose for individuals in a cohort of patients and estimated the most suitable starting dose to give to a new patient to increase the chances of being cured.
Assuntos
Teorema de Bayes , Interferon-alfa , Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Interferon-alfa/administração & dosagem , Conceitos Matemáticos , Relação Dose-Resposta a DrogaRESUMO
Here, we present a rare case of myeloproliferative neoplasms (MPN) with eosinophilia harboring both BCR::ABL1 and PDGFRB rearrangements, posing a classification dilemma. The patient exhibited clinical and laboratory features suggestive of chronic myeloid leukemia (CML) and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), highlighting the diagnostic challenges associated with overlapping phenotypes. Despite the complexity, imatinib treatment swiftly achieved deep molecular remission, underscoring the therapeutic efficacy of tyrosine kinase inhibitors in such scenarios. Furthermore, the rapid attainment of deep remission by this patient in response to imatinib closely resembles that observed in MLN-TK patients with PDGFRB rearrangements. Further research is warranted to elucidate the underlying mechanisms driving the coexistence of multiple oncogenic rearrangements in MPNs and to optimize therapeutic strategies for these complex cases.
Assuntos
Eosinofilia , Proteínas de Fusão bcr-abl , Mesilato de Imatinib , Transtornos Mieloproliferativos , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Humanos , Mesilato de Imatinib/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/complicações , Eosinofilia/genética , Eosinofilia/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética , Rearranjo Gênico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , FemininoRESUMO
Many novel agents have been developed for BCR::ABL1-negaive myeloproliferative neoplasms (MPN), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Some of these agents not only achieve hematologic complete response, reduce spleen size, and alleviate constitutional symptoms, but also induce molecular response, which means that they reduce the allele burden of driver gene mutations. These agents also prevent and alleviate fibrosis in bone marrow, which reduces the incidence of thrombotic events and disease progression and might improve prognosis. This article discusses the latest findings and promising treatments, including ongoing clinical trials, in PV, ET, and PMF.
Assuntos
Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/diagnóstico , Mutação , Terapia de Alvo MolecularRESUMO
SUMMARY: Dunbar, Bowman, and colleagues present here a novel genetic mouse model with inducible and reversible expression of the JAK2V617F mutation in the endogenous locus. Results from this study clearly demonstrate an absolute requirement for myeloproliferative neoplasm-initiating cells for this mutation in their survival and imply that more efficacious inhibitors could be curative for these patients even in the setting of additional cooperating mutations. See related article by Dunbar et al., p. 737 (8).
Assuntos
Janus Quinase 2 , Transtornos Mieloproliferativos , Janus Quinase 2/genética , Janus Quinase 2/antagonistas & inibidores , Animais , Camundongos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Humanos , Mutação , Modelos Animais de Doenças , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaAssuntos
Variante 6 da Proteína do Fator de Translocação ETS , Proteínas Proto-Oncogênicas c-ets , Proteínas Repressoras , Quinase Syk , Humanos , Quinase Syk/antagonistas & inibidores , Quinase Syk/genética , Proteínas Repressoras/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Rearranjo Gênico , Masculino , Feminino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológicoAssuntos
Janus Quinase 2 , Transtornos Mieloproliferativos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/tratamento farmacológico , Mutação , Terapia de Alvo Molecular , AnimaisRESUMO
We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30â¯mg, 40â¯mg or 60â¯mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58â¯%) patients had FLT3 mutations and 5 (42â¯%) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42â¯%), anemia (n=4, 33â¯%), lung infection (n=2, 17â¯%), skin infection (n=2, 17â¯%), hyponatremia (n=2, 17â¯%) and sepsis (n=2, 17â¯%). The overall response rate was 83â¯% with median relapse-free and overall survivals of 15.1 months (95â¯% CI 0.0-38.4 months) and 17.5 months (95â¯% CI NC-NC), respectively. FLT3 mutation clearance was observed in 57â¯% (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.
Assuntos
Azacitidina , Benzotiazóis , Mutação , Síndromes Mielodisplásicas , Compostos de Fenilureia , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Benzotiazóis/administração & dosagem , Benzotiazóis/uso terapêutico , Benzotiazóis/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas c-cbl/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , AdultoRESUMO
ABSTRACT: Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later. In total, 202 patients were identified; median overall survival (OS) was 0.86 years. We also analyzed patients based on first-line treatment; the 3 most common approaches were intensive chemotherapy (n = 65), DNA methyltransferase inhibitor (DNMTi)-based regimens (n = 65), and DNMTi + venetoclax-based regimens (n = 54). Median OS was not significantly different by treatment type. In addition, we evaluated response by 2017 European LeukemiaNet AML criteria and 2012 MPN-BP criteria in an effort to understand the association of response with survival outcomes. We also analyzed outcomes in 65 patients that received allogeneic hematopoietic stem cell transplant (allo-HSCT); median OS was 2.30 years from time of allo-HSCT. Our study demonstrates that survival among patients with MPN-AP/BP is limited in the absence of allo-HSCT even in the current era of therapeutics and underscores the urgent need for new agents and approaches.
Assuntos
Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/mortalidade , Transtornos Mieloproliferativos/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Adulto , Resultado do Tratamento , Transplante de Células-Tronco Hematopoéticas , Idoso de 80 Anos ou mais , Crise Blástica/terapia , Crise Blástica/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. METHODS: To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. RESULTS: ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. CONCLUSIONS: Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.
Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Resultado do Tratamento , Haplótipos , Células Germinativas , Interferon lambda , Interleucinas/genéticaRESUMO
OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma , Mieloma Múltiplo , Transtornos Mieloproliferativos , Policitemia Vera , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/epidemiologia , Estudos Retrospectivos , Japão/epidemiologia , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/diagnóstico , Linfoma/epidemiologia , Linfoma/etiologia , Linfoma/terapiaRESUMO
NRAS and KRAS activating point mutations are present in 10-30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.
Assuntos
Mutação , Humanos , Prognóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas p21(ras)/genéticaAssuntos
Transtornos Mieloproliferativos , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Masculino , Transtornos Mieloproliferativos/tratamento farmacológico , Feminino , Idoso , Pessoa de Meia-IdadeRESUMO
The treatment landscape for BCR/ABL-negative myeloproliferative neoplasms (MPNs), driven by JAK2, CALR, and MPL mutations, has evolved significantly over the last decade. Recent regulatory approvals in polycythemia vera (PV) include the JAK inhibitor ruxolitinib, and more recently, a novel recombinant interferon alfa-2 (IFN-α) therapeutic agent. Many clinical trials have documented the safety and efficacy of IFN-α therapy in PV and essential thrombocythemia, the classical BCR/ABL-negative MPNs. Used off-label for more than 30 years as a cytoreductive agent, IFN-α therapy promotes significant clinical, hematologic, and molecular responses. In some IFN-α-treated patients, partial or complete reduction of the mutant JAK2 allele burden may lead to a durable measurable residual disease state, owing to the ability of long-term IFN-α therapy to selectively deplete mutant JAK2-harboring hematopoietic stem cells. Pegylated IFN-α forms were developed to improve the drug stability and tolerability of first-generation IFN-α therapeutics. More recently, a novel pegylated IFN-α, ropeginterferon alfa-2b, received approval for PV by the European Medicines Agency and the US Food and Drug Administration in 2019 and 2021, respectively. This article reviews the clinical research and recent advances that led to the first regulatory approval of IFN-α in a BCR/ABL-negative MPN and its future promise as a disease-modifying therapeutic agent.
Assuntos
Transtornos Mieloproliferativos , Estados Unidos , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Interferon-alfa/uso terapêutico , Imunoterapia , Neoplasia Residual , Polietilenoglicóis/uso terapêuticoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Antígeno CD47 , Sulfonamidas , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Antígeno CD47/antagonistas & inibidores , Masculino , Resistencia a Medicamentos Antineoplásicos , Idoso , Pessoa de Meia-Idade , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/diagnósticoRESUMO
ABSTRACT: Pegylated interferon alfa (pegIFN-α) can induce molecular remissions in patients with JAK2-V617F-positive myeloproliferative neoplasms (MPNs) by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFN-α. We investigated whether DNMT3A loss leads to alterations in JAK2-V617F LT-HSC functions conferring resistance to pegIFN-α treatment in a mouse model of MPN and in hematopoietic progenitors from patients with MPN. Long-term treatment with pegIFN-α normalized blood parameters and reduced splenomegaly and JAK2-V617F chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFN-α in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared with VF were less prone to accumulate DNA damage and exit dormancy upon pegIFN-α treatment. RNA sequencing showed that IFN-α induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ than from VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFN-α signaling. Transplantations of bone marrow from pegIFN-α-treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from patients with MPN with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFN-α exposure, whereas in patients with JAK2-V617F alone, the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFN-α combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.
Assuntos
DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Hematopoéticas , Interferon-alfa , Janus Quinase 2 , Transtornos Mieloproliferativos , Animais , DNA Metiltransferase 3A/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Interferon-alfa/farmacologia , Camundongos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/metabolismo , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Autorrenovação Celular , Camundongos Endogâmicos C57BL , Polietilenoglicóis/farmacologia , Proteínas RecombinantesAssuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Transtornos Mieloproliferativos , Neoplasias , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/diagnóstico , MutaçãoRESUMO
Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.