Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Linfocítica Crónica de Células B , Sulfonamidas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Resultado del Tratamiento

RESUMEN

INTRODUCTION: Acute promyelocytic leukemia (APL) is mainly due to the chromosome translocation t(15; 17) (q22; q12), leading to the formation of PML-RARα fusion protein. However, some patients carried rare translocation involving RARα gene, and they were referred to as variant APL caused by the RAR family (RARα, RARB, and RARG) and partner genes. PLZF-RARα was a rare type of molecular genetic abnormality with unfavorable prognosis that has been reported in few cases in variant APL. Knowledge of PLZF-RARα (+) APL treatment remains limited understood. CASE REPORT: We presented a case of variant APL in a 47-year-old female, who was PLZF-RARα positive detected by reverse transcription polymerase chain reaction (RT-PCR). The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. CONCLUSION: Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Decitabina , Leucemia Promielocítica Aguda , Proteínas de Fusión Oncogénica , Sulfonamidas , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Femenino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Decitabina/uso terapéutico , Decitabina/administración & dosificación , Sulfonamidas/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/uso terapéutico

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Sulfonamidas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Infecciones/mortalidad , Infecciones/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/tratamiento farmacológico , Tasa de Supervivencia , Anciano de 80 o más Años

RESUMEN

Lomentospora prolificans is a rare filamentous fungus that causes invasive fungal disease (IFD) in immunocompromised patients with hematological malignancies, as well as hematopoietic cell or solid organ transplant recipients. A 75-year-old woman was diagnosed with acute myeloid leukemia, and started induction therapy with azacitidine and adjusted-dose venetoclax along with antifungal prophylaxis with fluconazole. On day 7, she became febrile and chest CT imaging showed multiple nodules in both lung fields, and the serum galactomannan antigen index became positive, indicating probable IFD. Anti-fungal therapy with liposomal amphotericin B was immediately initiated; however, the patient's condition rapidly deteriorated, and she died on day 15. L. prolificans was later identified in blood culture tests that had been repeatedly performed while she had been febrile. L. prolificans is generally resistant to most antifungal agents, which can make it fatal. As early definitive diagnosis is difficult, it may be appropriate to consider combination therapy when conventional anti-IFD therapy seems inadequate.

Asunto(s)

Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Femenino , Azacitidina/administración & dosificación , Azacitidina/uso terapéutico , Sulfonamidas/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Resultado Fatal , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Quimioterapia de Inducción , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/diagnóstico , Micosis/tratamiento farmacológico , Micosis/diagnóstico

RESUMEN

This study evaluated the therapeutic efficacy and underlying mechanisms of crisaborole combined with vitamin D in the treatment of allergic contact dermatitis. While crisaborole, a phosphodiesterase 4 inhibitor, and vitamin D analogs are commonly used in the treatment of atopic dermatitis, their combined therapeutic potential in allergic contact dermatitis (ACD) remains unexplored. Given their anti-inflammatory properties, we hypothesized that the combination of crisaborole and vitamin D could offer superior efficacy in mitigating the symptoms and underlying mechanisms of allergic contact dermatitis. In vitro, HaCaT cells stimulated with tumor necrosis factor-α and interferon-γ were treated with a combination of crisaborole and vitamin D, followed by cytokine expression analysis. In vivo, male C57BL/6 mice were divided into five groups and treated accordingly: blank control, dinitrochlorobenzene-induced model, crisaborole alone, vitamin D alone, and a combination of crisaborole and vitamin D. On day 14, dorsal skin and ear thickness were measured, followed by comprehensive pathological evaluations. In vivo and in vitro experiments showed that the expression levels of inflammatory factors were significantly lower in the DNCB + VD + Cri group than in the DNCB group. Histological analyses revealed that, compared with the DNCB group, the combined treatment group significantly reduced epidermal hyperkeratosis, improved epidermal transdermal water loss, decreased dermatitis scores, and diminished mast cell infiltration. Moreover, it lowered the expression levels of IL-6, IL-4, TNF-α, iNOS, IL-17, CC chemokine ligand 2 (CCL2), and CC chemokine receptor 2 (CCR2). CCL2 recognizes CCR2 and stimulates inflammatory cells, enhancing the inflammatory response. Increased CCL2 expression correlates with heightened inflammation and dendritic cell infiltration in ACD, while downregulation of CCL2 attenuates inflammation. Thus, the combined use of crisaborole and vitamin D demonstrates superior therapeutic efficacy over monotherapy in a mouse model of ACD. The combination of vitamin D and crisaborole significantly reduces inflammation and epidermal hyperkeratosis in a mouse model of allergic contact dermatitis, demonstrating superior therapeutic efficacy compared to either treatment alone. This suggests that the combined therapy could be a promising approach for the prevention and treatment of allergic contact dermatitis.

Asunto(s)

Compuestos de Boro , Compuestos Bicíclicos Heterocíclicos con Puentes , Dermatitis Alérgica por Contacto , Ratones Endogámicos C57BL , Vitamina D , Animales , Dermatitis Alérgica por Contacto/tratamiento farmacológico , Dermatitis Alérgica por Contacto/patología , Vitamina D/farmacología , Vitamina D/administración & dosificación , Ratones , Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéutico , Compuestos de Boro/administración & dosificación , Masculino , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Quimioterapia Combinada , Citocinas/metabolismo , Modelos Animales de Enfermedad , Dinitroclorobenceno , Piel/patología , Piel/efectos de los fármacos , Piel/metabolismo

Asunto(s)

Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Linfoma de Células del Manto , Piperidinas , Sulfonamidas , Humanos , Adenina/análogos & derivados , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación

RESUMEN

Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .

Asunto(s)

Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas , Neoplasias de la Mama , Glioblastoma , Inmunoconjugados , Recurrencia Local de Neoplasia , Humanos , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Anciano , Inmunoconjugados/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Estudios Prospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismo

RESUMEN

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory (R/R) FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but the overall survival (OS) is only approximately 20 % and few patients achieve deep and/ or durable response. We retrospectively analyzed 29 R/R FLT3mut AML patients treated on triplet regimens (gilteritinib+ venetoclaxï¼»VEN] +azacitidineï¼»AZA]). Nineteen patients (65.5 %) had received prior FLT3 inhibitor therapy. The modified composite complete remission (mCRc) rate was 62.1 % (n = 18; CR, 4/29,13.8 %; CRi, 6/29, 20.7 %; MLFS, 8/29, 27.6 %). Among 18 patients achieved mCRc, FLT3-PCR negativity was 94.4 % (n=17), and flow-cytometry negativity was 77.7 % (n=14). The mCRc rate was 70 % (n=7) in 10 patients without prior FLT3 TKI exposure and 57.8 % (n=11) in 19 patients with prior FLT3 TKI exposure (P=0.52). At the end of the first cycle, the median time to ANC > 0.5× 109/L was 38 days and platelet > 50× 109/L was 31 days among responders, but 60-day mortality was 0 %. The estimated 2-year OS was 60.9 % for all R/R FLT3mut patients. The 1-year OS was 80 % and 58.8 % in patients without and with prior FLT3 TKI exposure, respectively (P=0.79). The estimated 2-year OS was 62 % in 19 (65.5 %) patients who received allo-HSCT after triplet therapy and 37 % in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.

Asunto(s)

Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Pirazinas , Sulfonamidas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Masculino , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/genética , Femenino , Persona de Mediana Edad , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Estudios Retrospectivos , Compuestos de Anilina/uso terapéutico , Adulto , Pirazinas/uso terapéutico , Pirazinas/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Mutación , Tiofenos/uso terapéutico , Tiofenos/administración & dosificación , Resistencia a Antineoplásicos

RESUMEN

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of malignant myeloid progenitor hematopoietic cells in the bone marrow and peripheral blood. Recent studies have shown promising results with the use of small molecule inhibitors and targeted therapy in the treatment of patients with AML. One such molecule is venetoclax, which has been approved in AML by the FDA in combination with hypomethylating agents or low-dose cytarabine. We thoroughly searched electronic literature related to venetoclax and its role in AML, using databases such as MEDLINE, PubMed, Google Scholar, and PsychInfo, through April 2024. We applied population, intervention, comparison, and outcome criteria, specifically focusing on studies with a population using venetoclax from review articles and clinical trials. All selected studies were required to be in English, and any study that did not involve the use of venetoclax was excluded. A meticulous literature review was conducted to consolidate the current knowledge and new combination therapies on AML. In our review article, we focused on the latest advances in the treatment of patients with AML. Based on the literature, we recommend that physicians prioritize the use of venetoclax in the management of this deadly disease because it has been shown to significantly impact the course of the disease.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/uso terapéutico

RESUMEN

WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the "WIN" site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi have only been shown to be effective against a number of rare cancer types retaining wild-type p53. To explore the full potential of WINi for cancer therapy, we systematically profiled WINi across a panel of cancer cells, alone and in combination with other agents. We report that WINi are unexpectedly active against cells derived from both solid and blood-borne cancers, including those with mutant p53. Among hematologic malignancies, we find that WINi are effective as a single agent against leukemia and diffuse large B cell lymphoma xenograft models, and can be combined with the approved drug venetoclax to suppress disseminated acute myeloid leukemia in vivo. These studies reveal actionable strategies for the application of WINi to treat blood-borne cancers and forecast expanded utility of WINi against other cancer types.

Asunto(s)

Neoplasias Hematológicas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Ratones , Línea Celular Tumoral , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Puntaje de Propensión , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/diagnóstico , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Masculino , Anciano , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más Años

RESUMEN

The aim of this study was to observe the effects of different conditioning regimens on fine immune indices after microtransplantation (MST) in patients with acute myeloid leukaemia (AML). This article discusses the possible immune mechanism of microtransplantation and describes a more optimized conditioning regimen. A total of 55 AML patients who received MST treatment at the Second Hospital of Lanzhou University from August 2015 to October 2023 were included in this study, and 13 AML patients who did not receive MST but directly received the maintenance therapy were included as the control group (C). The MST patients were divided into a conditioning regimen with venetoclax group (A) and a conditioning regimen without venetoclax group (B). The fine immune indices were detected by flow cytometry and cytometric bead array analysis. Changes in the immune indices before and after treatment were observed, and the progression-free survival (PFS) and overall survival (OS) of patients in the MST group were analysed. Compared with those in Group B, patients in Group A had better PFS and OS. The proportion of Treg cells and the expression level of IL-2 were increased, while TNF-α and IFN-α were decreased after MST (P < 0.05). In Group B, total T cells, CD4+T cells and CD4+/CD8+T cells decreased; NK cells and total B cells increased; and IL-17A first increased and then decreased during the MST (P < 0.05). There were significant differences in total B cells, IL-4 and IFN-γ between Group A and Group B during MST. Moreover, there were significant differences in total T cells, CD4+T cells, Treg cells, IL-17A, IFN-γ and IL-2 between the patients in the MST group and those in the control group (P < 0.05). The MST conditioning regimen containing venetoclax significantly changed the fine immune indices and showed improved efficacy, which is worthy of further study and clinical application.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Acondicionamiento Pretrasplante , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Acondicionamiento Pretrasplante/métodos , Adulto , Trasplante de Células Madre Hematopoyéticas/métodos , Antígenos HLA/inmunología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Adulto Joven , Linfocitos T Reguladores/inmunología , Anciano , Adolescente

RESUMEN

Background: Chronic myelomonocytic leukemia is a clonal hematological disorder with an inherent risk of transformation to acute myeloid leukemia. Recently, there has been exponential discovery of molecular abnormalities in patients with chronic myelomonocytic leukemia. Some of these mutations independently contribute to a higher risk of transformation and result in inferior overall survival. Treatment strategies for patients undergoing blastic transformation in chronic myelomonocytic leukemia, especially after progressing on hypomethylating agents, are currently limited.Case presentation: We present a case of a 70-year-old male patient with chronic myelomonocytic leukemia blastic transformation with RUNX1 mutation following azacitidine monotherapy. Notably, he achieved hematological complete remission after the first course of venetoclax plus azacitidine, leading to the disappearance of RUNX1 mutation. We performed serial assessments of molecular analysis by next generation sequencing throughout his clinical course.Conclusion: The presence of RUNX1 mutation is associated with higher response rates to venetoclax-based combination therapies in chronic myelomonocytic leukemia with blastic transformation. Our findings suggest that even after azacitidine monotherapy, venetoclax plus azacitidine is effective in targeting leukemic clones harboring RUNX1 mutations. Furthermore, we emphasize the significance of molecular analysis, including next-generation sequencing, in providing insights into the detailed dynamics of clonal evolution and guiding treatment decisions.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mielomonocítica Crónica , Mutación , Sulfonamidas , Humanos , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Masculino , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Antineoplásicos/uso terapéutico

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Inotuzumab Ozogamicina , Sulfonamidas , Humanos , Masculino , Persona de Mediana Edad , Aminoglicósidos/administración & dosificación , Aminoglicósidos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/uso terapéutico , Azacitidina/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Inotuzumab Ozogamicina/uso terapéutico , Leucemia Bifenotípica Aguda/tratamiento farmacológico , Lectina 2 Similar a Ig de Unión al Ácido Siálico/antagonistas & inhibidores , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico

RESUMEN

PURPOSE: To explore cancer-related cognitive impairment (CRCI) in older adults with acute myeloid leukemia (AML) receiving venetoclax in combination with hypomethylating agents or low-dose cytarabine chemotherapy. METHODS: This study is a longitudinal, qualitative descriptive study. Participants were recruited using purposive sampling. Semi-structured interviews were conducted among 11 older adults with AML at cycle 2, cycle 4, and cycle 7 of chemotherapy. An early end-of-study interview was conducted for those who changed treatment plans during the study follow-up. RESULTS: A total of 22 transcripts were included for thematic analysis. Four themes emerged: (1) CRCI experiences, (2) impact of CRCI, (3) CRCI coping strategies, and (4) perceived CRCI-related factors. Older adults with AML experienced challenges in memory, language, and attention both intermittently and daily. These cognitive changes impacted their emotion, daily activities, social connection, and their caregivers' responsibilities. Hence, these older adults with AML developed problem-solving and emotional coping strategies to cope with CRCI. Older adults with AML also identified demographic, physiology/clinical, psychological, and other factors that might contribute to CRCI. CONCLUSION: This study offers important insight for clinicians to understand how older adults with AML experience CRCI and how it impacts their daily routines. It indicates that clinicians should ask patients about their experience with cognitive changes at each encounter to provide support or coping strategies as needed to prevent CRCI from further hindering their quality of life.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/psicología , Leucemia Mieloide Aguda/complicaciones , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Masculino , Femenino , Estudios Longitudinales , Sulfonamidas/administración & dosificación , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Disfunción Cognitiva/etiología , Investigación Cualitativa , Adaptación Psicológica , Citarabina/administración & dosificación

RESUMEN

Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07-0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Femenino , Masculino , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Adulto , Tasa de Supervivencia , Metilación de ADN/efectos de los fármacos

RESUMEN

PURPOSE: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. METHODS: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. RESULTS: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. CONCLUSION: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compuestos Bicíclicos Heterocíclicos con Puentes , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Homoharringtonina , Leucemia Mieloide Aguda , Proteína 1 Compañera de Translocación de RUNX1 , Sulfonamidas , Humanos , Homoharringtonina/administración & dosificación , Homoharringtonina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Femenino , Estudios Retrospectivos , Azacitidina/administración & dosificación , Sulfonamidas/administración & dosificación , Anciano , Adulto , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Adulto Joven

RESUMEN

BACKGROUND: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options. OBJECTIVE: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara. METHODS: Thirty-one patients with AL were included in this bi-institutional retrospective analysis. RESULTS: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections. CONCLUSION: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.

Asunto(s)

Anticuerpos Monoclonales , Compuestos Bicíclicos Heterocíclicos con Puentes , Cromosomas Humanos Par 14 , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Sulfonamidas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Estudios Retrospectivos , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 11/genética , Adulto , Anciano de 80 o más Años , Translocación Genética , Resultado del Tratamiento , Antineoplásicos/uso terapéutico

RESUMEN

OBJECTIVE: The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. METHODS: The analysis required the extraction of a 50 µl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH 2 PO 4 (pH 3.5) (60/40, v/v) on a Diamond C 18 (4.6 mm × 250 mm, 5 µm) column at a flow rate of 1.0 ml/min. The quantitative method was validated based on standards described in 'Bioanalytical Method Validation: Guidance for Industry' published by the US Food and Drug Administration (FDA). RESULTS: The calibration curve was linear ( R2  = 0.9998) over the range of 75-4800 ng/ml, with limits of quantification of 25 ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration ( Cmax ) was 1881.19 ±â€…756.61 ng/ml, while the trough concentration ( Cmin ) was 1212.69 ±â€…767.92 ng/ml in acute myeloid leukemia patients. CONCLUSION: Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Monitoreo de Drogas , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/sangre , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Sulfonamidas/administración & dosificación , Monitoreo de Drogas/métodos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Anciano , Medicina de Precisión/métodos , Adulto Joven , China , Pueblos del Este de Asia

Asunto(s)

Compuestos Bicíclicos Heterocíclicos con Puentes , Miositis , Sulfonamidas , Humanos , Sulfonamidas/uso terapéutico , Miositis/tratamiento farmacológico , Miositis/inmunología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antineoplásicos/uso terapéutico , Masculino , Persona de Mediana Edad , Femenino