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Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
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Antineoplásicos , Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda , Nucleofosmina , Proteínas Proto-Oncogênicas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Neoplasia Residual/tratamento farmacológico , Nucleofosmina/genética , Prognóstico , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Indução de RemissãoRESUMO
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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Hepatopatia Veno-Oclusiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Inotuzumab Ozogamicina/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recidiva , Hepatopatia Veno-Oclusiva/induzido quimicamente , Neoplasia Residual/tratamento farmacológicoRESUMO
ABSTRACT: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061.
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Resistencia a Medicamentos Antineoplásicos , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Feminino , Mutação , Masculino , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , AdolescenteRESUMO
Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted.
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Leucemia Mieloide Aguda , Humanos , Idoso , Fatores de Processamento de RNA/genética , Prognóstico , Fatores de Processamento de Serina-Arginina/genética , Fator de Processamento U2AF/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , MutaçãoRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.
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Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Criança , Humanos , Idoso , Padrão de Cuidado , Subunidade alfa de Receptor de Interleucina-3 , Células Dendríticas/patologia , Recidiva Local de Neoplasia/patologia , Transtornos Mieloproliferativos/patologia , Neoplasias Hematológicas/patologia , Neoplasias Cutâneas/patologia , Doença Aguda , América do NorteRESUMO
"Financial toxicity" has now become a familiar term used in the discussion of cancer drugs, and it is gaining traction in the literature given the high price of newer classes of therapies. However, as a phenomenon in the contemporary treatment and care of people with cancer, financial toxicity is not fully understood, with the discussion on mitigation mainly geared toward interventions at the health system level. Although important, health policy prescriptions take time before their intended results manifest, if they are implemented at all. They require corresponding strategies at the individual patient level. In this review, the authors discuss the nature of financial toxicity, defined as the objective financial burden and subjective financial distress of patients with cancer, as a result of treatments using innovative drugs and concomitant health services. They discuss coping with financial toxicity by patients and how maladaptive coping leads to poor health and nonhealth outcomes. They cover management strategies for oncologists, including having the difficult and urgent conversation about the cost and value of cancer treatment, availability of and access to resources, and assessment of financial toxicity as part of supportive care in the provision of comprehensive cancer care. CA Cancer J Clin 2018;68:153-165. © 2018 American Cancer Society.
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Antineoplásicos/economia , Efeitos Psicossociais da Doença , Financiamento Pessoal/estatística & dados numéricos , Custos de Cuidados de Saúde , Neoplasias/tratamento farmacológico , Neoplasias/economia , Neoplasias/psicologia , Estresse Psicológico/economia , Política de Saúde , HumanosRESUMO
BACKGROUND: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia. METHODS: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3â+â3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513. FINDINGS: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29). INTERPRETATION: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia. FUNDING: ImmunoGen.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neutropenia Febril , Neoplasias Hematológicas , Imunoconjugados , Leucemia Mieloide Aguda , Humanos , Feminino , Masculino , Imunoconjugados/efeitos adversos , Subunidade alfa de Receptor de Interleucina-3 , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.
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BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.
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Glicina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Piridinas , Triazóis , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Triazóis/administração & dosagem , Triazóis/uso terapêutico , Triazóis/farmacocinética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Síndromes Mielodisplásicas/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Piridinas/farmacocinética , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/administração & dosagem , Voriconazol/uso terapêutico , Voriconazol/administração & dosagem , Idoso de 80 Anos ou mais , Interações Medicamentosas , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
BACKGROUND: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. METHODS: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. RESULTS: Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). CONCLUSION: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.
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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 , Compostos Bicíclicos Heterocíclicos com Pontes , Dasatinibe , Sulfonamidas , Humanos , Dasatinibe/administração & dosagem , Dasatinibe/uso terapêutico , Dasatinibe/efeitos adversos , Pessoa de Meia-Idade , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Adulto , Feminino , Idoso , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Adulto Jovem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genéticaRESUMO
BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes. METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation. RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486). CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.
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INTRODUCTION: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. METHODS: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. RESULTS: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs <20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. CONCLUSIONS: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.
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Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, in a single-centre, phase 1/2 study for patients with HR-MDS or CMML after HMA failure. Four doses of CPX-351 (10, 25, 50 and 75 units/m2 ) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR-MDS and 6 (24%) with CMML. Most common grade 3-4 non-haematological treatment-emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2 . Four- and 8-week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse-free and overall survivals of 9.2 (95% CI 3.2-15.1 months) and 8.7 months (95% CI 1.8-15.6 months) respectively. These data suggest that lower doses of CPX-351 are safe. Further studies are needed to evaluate its activity.
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Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Humanos , Prognóstico , Resultado do Tratamento , Recidiva Local de Neoplasia , Citarabina , DaunorrubicinaRESUMO
The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Historically, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with poor outcomes, and allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1). However, in the tyrosine kinase inhibitor (TKI) era, rapid attainment of a complete molecular remission (CMR) is associated with excellent outcomes without allo-HCT, suggesting transplant may not be required for these patients. To test this hypothesis, we retrospectively identified adult patients with Ph+ ALL treated with induction therapy, including TKIs, and attained CMR within 90 days of diagnosis at 5 transplant centers in the United States. We compared outcomes of those who did and did not receive allo-HCT in first remission. We identified 230 patients (allo-HCT: 98; non-HCT: 132). The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (adjusted hazard ratio [aHR]: 1.05; 95% CI, 0.63-1.73) or relapse-free survival (aHR: 0.86; 95% CI, 0.54-1.37) compared with non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR: 0.32; 95% CI, 0.17-0.62) but higher non-relapse mortality (aHR: 2.59; 95% CI, 1.37-4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints. In conclusion, adult patients with Ph+ ALL who achieved CMR within 90 days of starting treatment did not derive a survival benefit from allo-HCT in CR1 in this retrospective study.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Estudos Retrospectivos , Indução de Remissão , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Recidiva , Doença Aguda , Transplante Homólogo , Receptores de Complemento 3bRESUMO
Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.
Assuntos
Leucemia Mieloide Aguda , Proteína Supressora de Tumor p53 , Variações do Número de Cópias de DNA , Epigênese Genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Prognóstico , Proteômica , Proteína Supressora de Tumor p53/genéticaRESUMO
Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as "responders" or "nonresponders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Anticorpos Biespecíficos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , RecidivaRESUMO
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
Assuntos
Segunda Neoplasia Primária , Talidomida , Humanos , Lenalidomida/farmacologia , Talidomida/efeitos adversos , Células-Tronco Hematopoéticas/metabolismo , Genes p53 , Mutação , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.