Nivolumab maintenance in high-risk acute myeloid leukemia patients: a single-arm, open-label, phase II study.
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ABSTRACT:
SUBMITTER: Reville PK
PROVIDER: S-EPMC7969746 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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Nivolumab maintenance in high-risk acute myeloid leukemia patients: a single-arm, open-label, phase II study.
Reville Patrick K PK Kantarjian Hagop M HM Ravandi Farhad F Jabbour Elias E DiNardo Courtney D CD Daver Naval N Pemmaraju Naveen N Ohanian Maro M Alvarado Yesid Y Xiao Lianchun L Alatrash Gheath G Loghavi Sanam S Rausch Caitlin R CR Borthakur Gautam G Konopleva Marina M Cortes Jorge J Kadia Tapan M TM
Blood cancer journal 20210317 3
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Project description:Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305.
| S-EPMC6397669 | biostudies-literature
Project description: Not available
| S-EPMC9616883 | biostudies-literature
Project description:PurposeStandard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.Patients and methodsOne hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.ResultsMean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.ConclusionSubjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.
| S-EPMC8500663 | biostudies-literature
Project description:BackgroundPatients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC).Patients and methodsThis single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR).ResultsBetween 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months).ConclusionsThe primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious.
| S-EPMC9808483 | biostudies-literature
Project description:BackgroundNivolumab monotherapy has demonstrated superior efficacy in advanced unresectable gastric cancer (GC), but its impact on resectable GC remains unknown. This phase I study aimed to evaluate safety, feasibility, and potential biomarkers of neoadjuvant nivolumab monotherapy in resectable GC.MethodsUntreated, resectable, cT2 or more advanced gastric adenocarcinomas with clinical stage I, II, or III were treated with two doses of nivolumab before gastrectomy. Patients were excluded if their tumors may be applicable to neoadjuvant chemotherapy. The primary endpoint was the incidence of adverse event (AE) categories of special interest.ResultsAll of the 31 enrolled patients completed 2 doses of nivolumab monotherapy. While 30 (97%) patients underwent surgery with curative intent, 1 patient discontinued before the planned surgical intervention because of a newly emerging liver metastasis. Seven patients (23%) had nivolumab treatment-related AEs, and one patient had a treatment-related AE of grade 3-4. The incidences of treatment-related AE categories of special interest ranged from 0 to 6%. Notable surgical complications included two cases of grade 3 anastomotic leakage and two cases of pancreatic fistula. The major pathologic response (MPR) assessed by the independent pathology review committee was achieved in five (16%) patients, of which one patient had a pathologic complete response. The MPR was mostly observed in patients with positive PD-L1 expression, high microsatellite instability, and/or high tumor mutation burden.ConclusionsNeoadjuvant nivolumab monotherapy is feasible with an acceptable safety profile and induces a MPR in certain patients with resectable GC. (Registration: clinicaltrials.jp, JapicCTI-183895).
| S-EPMC9013329 | biostudies-literature
Project description:Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.
| S-EPMC6172068 | biostudies-literature
Project description:BackgroundAs the outcome of immunotherapy can be improved when concurrently or sequentially combined with cytotoxic chemotherapy or radiotherapy, we investigated the efficacy of immunotherapy maintenance following platinum-based chemotherapy in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (EGFR-TKI) failure.MethodsIn this prospective, open-label, single arm phase 2 trial, we enrolled patients aged 18 years or older with EGFR-mutant NSCLC, which progressed after first- or second-line EGFR-TKI. Patients received platinum-based chemotherapy followed by nivolumab maintenance therapy. They were intravenously administered 240 mg of nivolumab every 2 weeks for 3 months followed by 480 mg every 4 weeks until disease progression or unacceptable toxic effects occurred. The primary endpoint was progression-free survival (PFS). Secondary outcomes were overall survival (OS) and incidence of grade 3-4 treatment-related adverse events (AEs).ResultsWe enrolled 26 patients between May 2020 and July 2021. The median PFS was 1.7 months (95% CI: 0.401-2.999 months). The median OS was 21.4 months (95% CI: 18.790-24.010 months) with 6- and 12-month OS rates of 96.2% and 76.9%, respectively. The objective response rate was 7.7% (2/26) and disease control rate, 11.5% (3/26). The tumor mutational burden by next-generation sequencing in blood was not related to the treatment outcomes. Grade 3-4 treatment-related AEs occurred in four (15.4%) patients; the most frequent AE was increased alanine aminotransferase (7.7%).ConclusionNivolumab maintenance following platinum-based chemotherapy did not show clinical benefits after EGFR-TKI failure in patients with EGFR-mutant NSCLC.
| S-EPMC10626224 | biostudies-literature
Project description:Tumor-associated macrophages correlate with poor prognosis and resistance to immune checkpoint inhibitor therapy in cancer patients. Disulfiram, a drug for alcoholism treatment, has been identified as an inhibitor for FROUNT, which facilitates chemokine-mediated macrophage accumulation to tumor sites. A combination of disulfiram with a PD-1 antibody synergistically inhibits tumor progression in the mouse model. Here, we performed the single-cell transcriptome analysis of gastric cancer specimens before and after treatment with disulfiram plus nivolumab. We explored the immunophenotypical features associated with the response to the treatment.
2022-11-27 | GSE189926 | GEO
Project description:BackgroundMold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug-drug interactions compared with other triazoles.MethodsIn our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose.ResultsSixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations.ConclusionsISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies.Clinical trials registrationNCT03019939.
| S-EPMC8130026 | biostudies-literature
Project description:In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.
| S-EPMC9728404 | biostudies-literature