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1.
Blood Adv ; 8(9): 2074-2084, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38471063

RESUMO

ABSTRACT: Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose. The primary end point of the study was feasibility, which would be achieved if ≥80% of participants able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment-naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary end point, with 9 of 10 participants completing all eligible doses. Organ-specific LGI complete response rate at day 28 was 70%. Initial clinical response was observed within 1 week for all responders, and clinical responses were durable without recurrent LGI GVHD in complete responders. Exploratory analyses suggest that alpha diversity increased after FMT. Although recipient microbiome composition never achieved a high degree of donor similarity, expansion of donor-derived species and increases in tryptophan metabolites and short-chain fatty acids were observed within the first 7 days after FMT. Investigation into the use of microbiome-targeted interventions earlier in the treatment paradigm for acute LGI GVHD is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT04139577.


Assuntos
Transplante de Microbiota Fecal , Doença Enxerto-Hospedeiro , Humanos , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Microbiota Fecal/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Microbioma Gastrointestinal , Idoso , Projetos Piloto , Doença Aguda , Resultado do Tratamento
2.
Clin Cancer Res ; 29(11): 2034-2042, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37014667

RESUMO

PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. PATIENTS AND METHODS: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. RESULTS: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%. CONCLUSIONS: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndrome do QT Longo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Recidiva , Isocitrato Desidrogenase/genética
3.
Blood Adv ; 6(22): 5857-5865, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36150050

RESUMO

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).


Assuntos
COVID-19 , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva
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