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With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.
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Myeloproliferative neoplasms (MPNs) are a group of rare chronic progressive blood cancers that vary widely in clinical presentation, yet all patients have a risk of disease progression and thrombotic complications. Diseases include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. With current treatment approaches, most patients live a prolonged life, but many experience a complex of symptoms that negatively influence their functional status and quality of life. Although significant advances have been made in preventing arterial and venous complications while mitigating inflammatory processes, comprehensive palliative care can help address unmet complex physical and psychosocial needs on a long-term basis. This article, created by a multidisciplinary group of providers, offers an overview of MPNs so palliative care clinicians can better support patients with these hematologic cancers.
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Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.
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Mastocitose Sistêmica , Humanos , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/terapia , Gerenciamento Clínico , Oncologia/normas , Oncologia/métodosRESUMO
Dysregulated JAK/STAT hyperactivity is essential to the pathogenesis of myelofibrosis, and JAK inhibitors are the first-line treatment option for many patients. There are four FDA-approved JAK inhibitors for patients with myelofibrosis. Single-agent JAK inhibition can improve splenomegaly, symptom burden, cytopenias, and possibly survival in patients with myelofibrosis. Despite their efficacy, JAK inhibitors produce variable or short-lived responses, in part due to the large network of cooperating signaling pathways and downstream targets of JAK/STAT, which mediates upfront or acquired resistance to JAK inhibitors. Synergistic inhibition of JAK/STAT accessory pathways can increase the rates and duration of response for patients with myelofibrosis. Two recently reported, placebo-controlled phase III trials of novel agents added to JAK inhibition met their primary endpoint, and additional late-stage studies are ongoing. This paper will review role of dysregulated JAK/STAT signaling, biological plausible additional therapeutic targets and the recent advancements in combination strategies with JAK inhibitors for myelofibrosis.
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Inibidores de Janus Quinases , Janus Quinases , Mielofibrose Primária , Transdução de Sinais , Humanos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Terapia de Alvo Molecular/métodos , Resultado do Tratamento , AnimaisRESUMO
Although polycythemia vera (PV) is a chronic and incurable disease, effective management can allow most patients to maintain functional lives with near-normal life expectancy. However, there remain several inter-related factors that contribute to many ongoing challenges associated with the management of PV, which this review aims to explore. First, as a disease hallmarked by constitutive activation of the JAK/STAT pathway, PV is often accompanied by inflammatory symptoms that negatively impact quality of life. Next, patients often require recurrent therapeutic phlebotomies to maintain their hematocrit below the 45% threshold that has been associated with a decreased risk of thrombotic events. The need to closely monitor hematocrit and perform conditional therapeutic phlebotomies ties patients to the healthcare system, thereby limiting their autonomy. Furthermore, many patients describe therapeutic phlebotomies as burdensome and the procedure is often poorly tolerated, further contributing to quality-of-life decline. Phlebotomy needs can be reduced by utilizing cytoreductive therapy; however, standard first-line cytoreductive options (i.e., hydroxyurea and interferon) have not been shown to significantly improve symptom burden. Collectively, current PV management, while reducing thrombotic risk, often has a negative impact on patient quality of life. As researchers continue to advance towards the goal of developing a disease-modifying therapy for patients with PV, pursuit of nearer-term opportunities to shift the current treatment paradigm towards improving symptoms without compromising quality of life is also warranted, for example, by reducing or eliminating the frequent use of phlebotomy.
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Policitemia Vera , Humanos , Policitemia Vera/terapia , Qualidade de Vida , Gerenciamento Clínico , Flebotomia/métodos , MédicosRESUMO
Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.
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Calgranulina B , Cromossomos Humanos Par 8 , Transtornos Mieloproliferativos , Proteínas Proto-Oncogênicas c-myc , Trissomia , Cromossomos Humanos Par 8/genética , Humanos , Trissomia/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Animais , Camundongos , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Mielofibrose Primária/metabolismo , Transdução de Sinais/genéticaRESUMO
Hypereosinophilia (HE) presents with an elevated peripheral eosinophilic count of >1.5 × 109/L and is composed of a broad spectrum of secondary non-hematologic disorders and a minority of primary hematologic processes with heterogenous clinical presentations, ranging from mild symptoms to potentially lethal outcome secondary to end-organ damage. Following the introduction of advanced molecular diagnostics (genomic studies, RNA sequencing, and targeted gene mutation profile, etc.) in the last 1-2 decades, there have been deep insights into the etiology and molecular mechanisms involved in the development of HE. The classification of HE has been updated and refined following to the discovery of clinically novel markers and targets in the 2022 WHO classification and ICOG-EO 2021 Working Conference on Eosinophil Disorder and Syndromes. However, the diagnosis and management of HE is challenging given its heterogeneity and variable clinical outcome. It is critical to have a diagnostic algorithm for accurate subclassification of HE and hypereosinophilic syndrome (HES) (e.g., reactive, familial, idiopathic, myeloid/lymphoid neoplasm, organ restricted, or with unknown significance) and to follow established treatment guidelines for patients based on its clinical findings and risk stratification.
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Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.
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Dasatinibe , Derrame Pleural , Inibidores de Proteínas Quinases , Humanos , Dasatinibe/efeitos adversos , Dasatinibe/administração & dosagem , Dasatinibe/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Derrame Pleural/induzido quimicamente , Derrame Pleural/epidemiologia , Adulto , Incidência , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Idoso de 80 Anos ou mais , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Substituição de Medicamentos , Compostos de Anilina/efeitos adversos , Compostos de Anilina/uso terapêutico , Compostos de Anilina/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/uso terapêutico , Adulto Jovem , Estudos Retrospectivos , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêuticoRESUMO
PURPOSE: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes. METHODS: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin. RESULTS: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients. CONCLUSION: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib.
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Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Esplenomegalia , Humanos , Esplenomegalia/complicações , Esplenomegalia/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/complicações , Mielofibrose Primária/diagnóstico , Resultado do Tratamento , Albumina Sérica/uso terapêuticoRESUMO
BACKGROUND: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation. PATIENTS AND METHODS: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations. RESULTS: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib. CONCLUSION: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.
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Mutação , Mielofibrose Primária , Humanos , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Mielofibrose Primária/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do Tratamento , Idoso de 80 Anos ou mais , Prognóstico , Janus Quinase 2/genética , Janus Quinase 2/metabolismoRESUMO
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.
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Janus Quinase 2 , Transtornos Mieloproliferativos , Nitrilas , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Pirazóis , Pirimidinas , Janus Quinase 2/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Animais , Transtornos Mieloproliferativos/tratamento farmacológico , Humanos , Camundongos , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. PATIENTS AND METHODS: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. RESULTS: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. CONCLUSION: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.
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Compostos Bicíclicos Heterocíclicos com Pontes , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Nucleofosmina , Sulfonamidas , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidade , Masculino , Feminino , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Pessoa de Meia-Idade , Adulto , Idoso , Estudos Retrospectivos , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , RecidivaRESUMO
Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.
A review of what interferons are and how they are used in the treatment of the myeloproliferative neoplasms polycythemia vera, essential thrombocythemia, and primary myelofibrosis Why was this paper written? This paper was written to summarize the current clinical landscape of the use of interferons for the treatment of myeloproliferative neoplasms (MPN). What are interferons and how are they used in MPNs? Interferons are small proteins involved in cellular signaling that have been used to treat MPNs, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), for more than 35 years. They can have modulatory effects on the immune system and on the fundamental causes of disease. The use of interferons as treatment was initially limited due to difficulties with their administration and the potential for significant adverse effects. Many of these shortcomings were addressed by chemically binding a biocompatible polymer, polyethylene glycol (PEG), to the structure of the interferon, which increases the stability of the protein, prolongs the time during which it is active, and reduces negative effects to the immune system. The combined chemical structure of PEG and interferon (pegylated interferon or peginterferon) is recommended for use in the treatment of PV, ET, and PMF. What topics are discussed in this paper? In this review paper we evaluate the clinical effectiveness and safety of two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi) and discuss the practical clinical management of interferon-based therapies, along with the authors' opinions on whether to and how to switch therapy from hydroxyurea. Key topics and questions related to the use of interferons, such as their safety and tolerability, the significance of their effects on mutated cells, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. What do the findings mean? Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy.
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BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).
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Hepcidinas , Peptídeos , Policitemia Vera , Humanos , Hematócrito , Hepcidinas/administração & dosagem , Hepcidinas/uso terapêutico , Ferro , Policitemia/diagnóstico , Policitemia/tratamento farmacológico , Policitemia/etiologia , Policitemia Vera/tratamento farmacológico , Policitemia Vera/complicações , Policitemia Vera/diagnóstico , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Injeções , Método Duplo-Cego , Fármacos Hematológicos/administração & dosagem , Fármacos Hematológicos/uso terapêuticoRESUMO
The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.
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Progressão da Doença , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Nucleofosmina , Humanos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Masculino , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Fatores de Risco , Mutação , Prognóstico , Adulto Jovem , AdolescenteRESUMO
ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in â¼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.
Assuntos
Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Humanos , Leucemia Mieloide Aguda/patologia , Mutação , Proteínas Nucleares/genética , Nucleofosmina , PrognósticoRESUMO
Myelofibrosis (MF) is commonly diagnosed in older individuals and has not been extensively studied in young patients. Given the infrequent diagnosis in young patients, analyzing this cohort may identify factors that predict for disease development/progression. We retrospectively analyzed clinical/genomic characteristics, treatments, and outcomes of patients with MF aged 18-50 years (YOUNG) at diagnosis. Sixty-three YOUNG patients were compared to 663 patients diagnosed at 51 or older (OLDER). YOUNG patients were more likely to be female, harbor driving CALR mutations, lack splicing gene mutations, and have low-risk disease by dynamic international prognostic scoring system (DIPSS) at presentation. Thirty-six patients (60%) presented with incidental lab findings and 19 (32%) with symptomatic disease. Median time to first treatment was 9.4 months (mo). Fourteen (22%) YOUNG patients underwent allogeneic hematopoietic stem cell transplant (median 57.4 mo post-diagnosis). Five (8%) developed blast-phase disease (median 99 mo post-diagnosis). Median overall survival (OS) for YOUNG patients was not reached compared to 62.8 mo in OLDER cohort (p < 0.001). The survival advantage for YOUNG patients lost significance when compared to OLDER patients lacking splicing mutations (p = 0.11). Thirty-one (49%) had comorbidities predating MF diagnosis. Presence of a comorbidity correlated with increased disease risk as measured by serial DIPSS (p=0.02). Increased disease risk correlated with decreased OS (p = 0.05). MF is rare in young adults, has distinct clinical/molecular correlates, and a favorable prognosis. The high frequency of inflammatory comorbidities and their correlation with progression of disease risk clinically highlights the role of inflammation in MF pathogenesis.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Adulto Jovem , Humanos , Feminino , Idoso , Masculino , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/terapia , Mielofibrose Primária/genética , Estudos Retrospectivos , Prognóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Comorbidade , MutaçãoRESUMO
A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/etiologia , Transplante de Células-Tronco , Fatores de Ligação ao Core/genética , Estudos RetrospectivosRESUMO
Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.
RESUMO
BACKGROUND: The phase III trial that led to the approval of CPX-351 for treating secondary acute myeloid leukemia (sAML) in 2017 did not study the effect of specific mutations on outcomes. METHODS: This retrospective study was done to evaluate the effect of next-generation sequencing (NGS) results at the time of best response and before allogeneic stem cell transplant (alloSCT) in patients treated with CPX-351 as frontline therapy for sAML between 2017 and 2021. RESULTS: The most common mutations seen were DNMT3A (n = 17, 29.8%), SRSF2 (n = 13, 22.8%), RUNX1 (n = 13, 22.8%), TET2 (n = 9, 15.8%), ASXL1 (n = 9, 15.8%), and BCOR (n = 9, 15.8%). Median OS (mOS) for the entire cohort was 47 months. Though 64.7% patients cleared the DNMT3A mutation, only 44.4% and 22.2% of patients cleared the TET2 and ASXL1 mutations, respectively. The mOS for patients who cleared their mutations vs. for those who did not was not significantly longer (46 vs. 30 months; P = .991). The relapse-free survival (RFS) for patients who cleared mutations was numerically longer compared to those who had persistent mutations; however, this did not reach statistical significance (44 months vs. 26 months; P = .786). CONCLUSION: This is the first study reporting NGS at best response and before alloSCT and its effect on OS and RFS. We found that OS and RFS were numerically longer among patients who cleared mutations; however, this did not reach statistical significance. In addition, alloSCT led to improved RFS irrespective of mutational clearance.