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ABSTRACT: The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome-positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10-3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061.
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Enfermedad Veno-Oclusiva Hepática , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Inotuzumab Ozogamicina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Recurrencia , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Neoplasia Residual/tratamiento farmacológicoRESUMEN
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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Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.
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Leucemia Mieloide Aguda , Policitemia Vera , Mielofibrosis Primaria , Trombocitosis , Trombosis , Humanos , Policitemia Vera/complicaciones , Policitemia Vera/genética , Policitemia Vera/terapia , Mielofibrosis Primaria/tratamiento farmacológico , Trombocitosis/terapia , Hidroxiurea/uso terapéutico , Trombosis/terapia , Trombosis/inducido químicamente , Interferón-alfa/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Janus Quinasa 2/genéticaRESUMEN
BACKGROUND: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax. METHODS: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination. RESULTS: Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p < .001). CONCLUSIONS: Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Dasatinib , Sulfonamidas , Humanos , Dasatinib/administración & dosificación , Dasatinib/uso terapéutico , Dasatinib/efectos adversos , Persona de Mediana Edad , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Adulto , Femenino , Anciano , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Adulto Joven , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genéticaRESUMEN
Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR-ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well-tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts.
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Trastornos Mieloproliferativos , Humanos , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/terapia , Trastornos Mieloproliferativos/patología , Trastornos Mieloproliferativos/genética , Adolescente , Adulto , Adulto Joven , Masculino , FemeninoRESUMEN
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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Mastocitosis Sistémica , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/terapia , Manejo de la Enfermedad , Oncología Médica/normas , Oncología Médica/métodosRESUMEN
Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%).
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Patients with chronic myeloid leukemia in chronic phase (CML-CP) can have a normal life expectancy when treated with the BCR::ABL1 tyrosine kinase inhibitors. In recent years, treatment discontinuation and treatment-free remission (TFR) emerged as the new goal of therapy in patients with CML-CP. Deep and sustained molecular remissions for more than 3 to 5 years are associated with higher chances of a successful TFR. However, although uncommon, some patients may still experience molecular or hematological relapse after treatment discontinuation, even after a prolonged duration of remission. In this case series, we report the outcome of four patients with CML-CP who were treated with tyrosine kinase inhibitors and achieved a deep molecular response for ≥8 years, but eventually experienced disease relapse after treatment discontinuation. We discuss the importance of regular monitoring after treatment discontinuation as well as future strategies to increase the chances of TFR in patients with CML-CP.
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Aim: To estimate projected US-based cost and time burden for patients with myelofibrosis and anemia treated with momelotinib compared with danazol. Methods: Cost and time burden were calculated based on the transfusion status of patients in the MOMENTUM trial and estimates extracted from previous studies. Results: Reductions in transfusion associated with momelotinib are projected to result in cost and time savings compared with danazol in transfusion-dependent and transfusion-independent/requiring patients with myelofibrosis, respectively: annual medical costs ($53,143 and $46,455 per person), outpatient transfusion costs ($42,021 and $8,370 per person) and annual time savings (173 and 35 h per person). Conclusion: Fewer transfusions with momelotinib are projected to result in cost and time savings in patients with myelofibrosis and anemia compared with danazol.
Estimated cost & time savings in patients with the blood cancer myelofibrosisMyelofibrosis is a rare blood cancer often associated with bone marrow damage, too few of some types of blood cells and symptoms including tiredness, night sweating, itching and feelings of fullness and pain because of increased spleen size. Patients with anemia (too few red blood cells) may require regular blood transfusions and this is one sign that myelofibrosis is getting worse. MOMENTUM was a Phase III clinical trial showing that the drug momelotinib was safe and effective in patients with myelofibrosis who were previously treated with a type of drug called a JAK inhibitor. In particular, the trial showed that momelotinib reduced the need for transfusions compared with danazol, another drug typically used to treat patients with anemia. Based on this transfusion information from MOMENTUM and other publicly available information about estimated medical costs and patients' time spent in receiving transfusions, the analysis described here shows that a reduction in the number of transfusions with momelotinib compared with danazol is estimated to lead to cost savings as well as reduced patient time spent in transfusion-related travel, preparing and waiting for transfusions and receiving and recovering from transfusions.
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BACKGROUND: The treatment of patients with myelofibrosis (MF) has evolved in the past decade, as reflected in an increased use of various therapeutic agents that could potentially impact patient outcomes. METHODS: In this retrospective study, the authors evaluated the pattern of therapy and its possible impact on the survival of patients with MF at their institution. Patients (n = 802) with newly diagnosed, chronic, overt MF (MF fibrosis grade ≥2, <10% blasts) seen at their cancer center between 2000 and 2020 were included. RESULTS: Overall, 492 of the included patients (61%) initiated MF-directed therapy during follow-up. The most frequent initial therapy was the JAK inhibitor ruxolitinib (44% of treated patients), investigational agents excluding JAK inhibitors (21%), immunomodulatory agents (18%), other investigational JAK inhibitors (10%), and others (7%). Overall survival was superior for patients who received initial ruxolitinib therapy, with a median survival of 72 months versus approximately 50 months for the remaining approaches, excluding the last group. Thirty-two percent of patients required subsequent therapy (n = 159). The longest survival since the start of second-line therapy was observed in patients who initiated salvage ruxolitinib (median, 35 months; 95% CI, 25-45 months). CONCLUSIONS: This study demonstrated improved outcomes of patients with MF who received treatment with the JAK inhibitor ruxolitinib.
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Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower-intensity chemotherapy regimens. METHODS: The authors reviewed all older/unfit patients with newly diagnosed AML who received lower-intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374). RESULTS: In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated with survival: older age, therapy-related myeloid neoplasm, existence of previous myelodysplastic syndrome or myeloproliferative neoplasms, poor performance status, pulmonary comorbidity, anemia, thrombocytopenia, elevated lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis, and therapy not containing venetoclax. The 3-year survival rates were 52%, 24%, 10%, and 1% in favorable, intermediate, poor, and very poor risk, respectively. This survival model was validated in an independent cohort. In a subset of patients in whom molecular mutation profiles were performed in more recent times, adding the mutation profiles after accounting for the effects of previous factors identified IDH2 (favorable), NPM1 (favorable), and TP53 (unfavorable) mutations as molecular prognostic factors. CONCLUSION: The proposed survival model with lower-intensity chemotherapy in older/unfit patients with newly diagnosed AML may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies. PLAIN LANGUAGE SUMMARY: Lower intensity therapy can be considered for older patients to avoid severe toxicities and adverse events. However, survival prediction in AML was commonly developed in patients who received intensive chemotherapy. In this study, we have proposed a survival model to guide therapeutic approach in older patients who received lower-intensity therapy.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Anciano , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Pronóstico , Aberraciones Cromosómicas , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios RetrospectivosRESUMEN
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR, or MPL in >80% of the cases. PMF that lacks these canonical alterations is termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared with those of conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aimed to identify clinicopathologic and molecular genetic differences between patients with TN-PMF (n = 56) and DM-PMF (n = 89), all of whom fulfilled the 2016 World Health Organization diagnostic criteria for PMF. Compared with the control group, patients in the TN-PMF group were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow in patients with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted next-generation sequencing revealed a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 comutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications.
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Trastornos Mieloproliferativos , Mielofibrosis Primaria , Humanos , Médula Ósea/patología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Trastornos Mieloproliferativos/genética , Mutación , Pronóstico , Janus Quinasa 2/genética , Factores de Transcripción/genéticaRESUMEN
Patients with chronic myeloid leukemia (CML) and T315I mutation generally have a poor prognosis. Their outcome in the post-ponatinib era remains unclear. We reviewed patients with CML in chronic (CP) or accelerated phase (AP) who developed a T315I mutation between March 15, 2004, and July 26, 2022. Patients were divided into CP, AP, or blastic phase (BP) at the time of mutation detection. Overall survival (OS) was defined from the time of mutation detection to the date of death or last follow-up. We identified a total of 107 patients: 54 (51%) in CP, 14 (13%) in AP, and 39 (36%) in BP. One hundred and two patients received subsequent therapy after the T315I mutation was detected. At a median follow-up of 75 months (95% CI, 41-110), the median OS was 49 months (95% CI, 26-73) and the 5-year OS rate was 44%. Patients who were in CML-CP at the time of mutation detection had better survival compared with those in AP or BP, with a median OS of 132, 31, and 6 months, and 5-year OS rates of 70%, 37%, and 10%, respectively (p < .001). Patients with CML-CP treated with ponatinib and/or asciminib had a 5-year OS of 77% compared with 50% in those who received other treatments (chemotherapy, second-generation tyrosine kinase inhibitors, homoharringtonine, and investigational drugs) (p = .14). In summary, patients with CML-CP at the time of T315I mutation detection may have a relatively indolent disease course with a long-term OS of 70%. Treatment with third-generation tyrosine kinase inhibitors seemed to improve survival in patients with CML-CP.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Piridazinas , Humanos , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéuticoRESUMEN
INTRODUCTION: Median duration of therapy with the first JAK1/2 inhibitor ruxolitinib (RUX) approved for patients with intermediate or high-risk myelofibrosis (MF) is about 3 years. METHODS: In this retrospective study, we aimed to evaluate clinical features, predictive factors, and outcome of patients presenting to our institution who were able to remain on RUX for ≥5 years (RUX ≥5y, n = 73). RESULTS: Comparing baseline demographics of patients who remained on RUX ≥5y (n = 73) with patients who were on RUX for 6 months to 3 years (n = 203), we confirmed that patients on RUX ≥5y lacked advanced clinical features at the start of therapy, such as anemia, neutropenia, thrombocytopenia, higher blasts or monocytes. Predictive independent factors for staying on RUX ≥5y were hemoglobin >10 g/dL, circulating blasts <1%, platelets >150 × 109/L, neutrophils >70%, and having primary MF. Age over 65 years remained significant for outcome in patients on RUX ≥5y. CONCLUSION: In this retrospective study, we report on the relevance of absence of advanced clinical features for long RUX therapy and confirm the role of age on outcome despite therapy.
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Anemia , Mielofibrosis Primaria , Humanos , Anciano , Mielofibrosis Primaria/tratamiento farmacológico , Estudios Retrospectivos , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Resultado del TratamientoRESUMEN
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by an increased platelet count in the peripheral blood and excessive megakaryopoiesis in the bone marrow. In one-third of cases, the disease remains benign and does not lead to complications. In the remaining cases, however, ET may present with thromboembolic and hemorrhagic complications and transform into more aggressive myeloid neoplasms, with a negative effect on morbidity and mortality. Despite extensive research and a better understanding of the pathogenesis and etiology of the complications associated with ET, limited data are available on the management of complications and emergencies. This article highlights the complications and emergencies associated with ET and discusses treatment options and the controversies associated with management.
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Trastornos Mieloproliferativos , Policitemia Vera , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/terapia , Urgencias Médicas , Médula Ósea/patologíaRESUMEN
BACKGROUND: The management of myelofibrosis (MF) has changed over the last several years and could have an impact on patient outcome. This study evaluates the survival of patients with MF at the authors' institution to determine whether it changed in the last decade. METHODS: This retrospective study consists of 844 patients (64% male; median age, 66 years; range, 20-90 years) who were examined between 2000 and 2020 with a new diagnosis of MF. Only patients with available marrow biopsy who had reticulin fibrosis of grade 2 or higher were included. Patients were compared by year of presentation: 2000-2010 (n = 373) and 2011-2020 (n = 471). RESULTS: A statistically significant improvement in median survival in the last decade was noted: from 48 months (95% CI, 42-54 months) to 63 months (95% CI, 55-71 months) (P < .001; HR, 0.78 [95% CI, 0.64-0.95]). Improved survival was observed also in patients 65 years old or older and those having intermediate 2 or high-risk Dynamic International Prognostic Scoring System (DIPSS) or DIPSS-Plus risk scores. Among 532 patients treated with MF-directed therapy, patients exposed to JAK inhibitor ruxolitinib had superior outcomes with median overall survival of 84 months (95% CI, 70-94 months). CONCLUSIONS: The results demonstrate that survival of patients with MF has improved in the last decade. This improvement is likely due to increased disease awareness, advances in supportive care, and the development of effective treatments.
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Mielofibrosis Primaria , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
The promising activity of BET protein inhibitors (BETi's) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear ß-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the ß-catenin-TCF7L2-JMJD6-c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear ß-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the ß-catenin-TCF7L2-JMJD6-c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.
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Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Factores de Transcripción/metabolismo , beta Catenina/metabolismoRESUMEN
The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios RetrospectivosRESUMEN
Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, worse performance status, cardiac comorbidity, leukocytosis, anemia, thrombocytopenia, elevated creatinine and lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis except fever of unknown origin. We categorized patients into four prognostic groups, favorable (7%), intermediate (43%), poor (39%), and very poor (11%) with estimated 5-year survival rates of 69%, 36%, 13%, and 3% respectively (p < .001). The predictive model was validated in an independent cohort. In a subset of patients with molecular mutation profiles, adding the mutation profiles after accounting for the effects of previous factors identified NPM1 (favorable), PTPN11, and TP53 (both unfavorable) mutations as molecular prognostic factors. The new proposed predictive model for survival with intensive chemotherapy in patients with AML is robust and can be used to advise patients regarding their prognosis, to modify therapy in remission (e.g., proposing allogeneic stem cell transplantation in first remission), and to compare outcome and benefits on future investigational therapies.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Aberraciones Cromosómicas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Pronóstico , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Multi-agent induction chemotherapy (IC) improves response rates in younger patients with acute myeloid leukemia (AML); however, relapse remains the principal cause of treatment failure. Improved induction regimens are needed. A prospective single-center phase Ib/II study evaluating fludarabine, cytarabine, G-CSF, and idarubicin combined with venetoclax (FLAG-IDA + VEN) in patients with newly diagnosed (ND) or relapsed/refractory AML. The primary efficacy endpoint was assessment of overall activity (overall response rate [ORR]: complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi] + morphologic leukemia free state + partial response). Secondary objectives included additional assessments of efficacy, overall survival (OS), and event-free survival (EFS). Results of the expanded ND cohort with additional follow-up are reported. Forty-five patients (median age: 44 years [range 20-65]) enrolled. ORR was 98% (N = 44/45; 95% credible interval 89.9%-99.7%). Eighty-nine percent (N = 40/45) of patients attained a composite CR (CRc + CRh + CRi) including 93% (N = 37/40) who were measurable residual disease (MRD) negative. Twenty-seven (60%) patients transitioned to allogeneic stem cell transplant (alloHSCT). Common non-hematologic adverse events included febrile neutropenia (44%; N = 20), pneumonia (22%, N = 10), bacteremia (18%, N = 8), and skin/soft tissue infections (44%, N = 20). After a median follow-up of 20 months, median EFS and OS were not reached. Estimated 24-month EFS and OS were 64% and 76%, respectively. FLAG-IDA + VEN is an active regimen in ND-AML capable of producing high MRD-negative remission rates and enabling transition to alloHSCT when appropriate in most patients. Toxicities were as expected with IC and were manageable. Estimated 24-month survival appears favorable compared to historical IC benchmarks.