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Dual Growth Factor (rhTPO + G-CSF) and Chemotherapy Combination Regimen for Elderly Patients with Acute Myeloid Leukemia: A Phase II Single-Arm Multicenter Study.

ABSTRACT: Acute myeloid leukemia (AML) is a disease affecting older adults, although optimal strategies for treating such patients remain unclear. This prospective phase II, open-label, multicenter study was designed to assess the efficacy and safety of two hematologic growth factors, recombinant human thrombopoietin (rhTPO) and granulocyte colony-stimulating factor (G-CSF), in combination with decitabine, cytarabine, and aclarubicin (D-CTAG regimen) to treat older adults with newly diagnosed AML (Identifier: NCT04168138). The above agents were administered as follows: decitabine (15 mg/m² daily, days 1-5); low-dose cytarabine (10 mg/m² q12 h, days 3-9); rhTPO (15,000 U daily, days 2, 4, 6, 8, 10-24 or until >50×10⁹/L platelets); aclarubicin (14 mg/m² daily, days 3-6); and G-CSF (300 μg daily, days 2-9). We concurrently monitored historic controls treated with decitabine followed by cytarabine, aclarubicin, and G-CSF (D-CAG) only. After the first D-CTAG cycle, the overall response rate (ORR) was 84.2% (16/19), including 13 (73.7%) complete remissions (CRs) and three (15.8%) partial remissions. This CR rate surpassed that of the D-CAG treatment (p < 0.05). Median overall survival (OS) time in the D-CTAG group was 20.2 months (range, 4-31 months), compared with 14 months in the D-CAG group, and 1-year OS was 78%. The proportion of those experiencing grade III-IV thrombocytopenia was significantly lower for D-CTAG (57.9%) than for D-CAG (88.4%; p < 0.05). Ultimately, the curative effect of adding rhTPO was not inferior to that of D-CAG, and D-CTAG proved safer for elderly patients, especially in terms of hematologic toxicity. A prospective phase III randomized study is warranted to confirm these observations.

SUBMITTER: Liu X

PROVIDER: S-EPMC8485918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn acute myeloid leukaemia (AML), interleukin-6 (IL-6) promotes chemo-resistance and its levels correlate with poor prognosis. IL-6 blockade may represent a promising therapeutic strategy. We aimed to test, tocilizumab, an anti-IL-6 receptor (R) monoclonal antibody in combination with standard intensive AML induction chemotherapy.MethodsThis investigator-initiated single-centre phase 1 trial was conducted at Nantes University Hospital in France. According to a continual reassessment method, three escalating doses were tested of intravenous (IV) tocilizumab (4, 6, and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (IV idarubicine 8 mg/m2 d1 to d5 + IV cytarabine 100 mg/m2 d1 to d7). All adults (aged ≥ 18 years) with an Eastern Cooperative Oncology Group performance status of 0-2 and with a newly diagnosed (excluding patients with a favourable risk according to ELN-2017 classification if <60 year-old) or a relapsed/refractory AML were eligible. The primary objective was to determine the maximum tolerated dose of tocilizumab to administrate with a standard intensive AML induction. Safety outcomes were continuously monitored for at each participant contact. This trial is registered with ClinicalTrials.gov, NCT04547062.FindingsBetween Dec 29, 2020 and Dec 1, 2022, 12 patients were enrolled, of whom 75% had an ELN-2017 high-risk profile, and were treated with tocilizumab- two patients at 4 mg/kg, two at 6 mg/kg and eight at 8 mg/kg of tocilizumab. No dose-limiting toxicity related to tocilizumab was documented. There were nine serious adverse events, none of which were related to tocilizumab, and there was no treatment-related deaths. MTD was thus not reached. Two deaths occurred during induction. In the remaining ten evaluable patients, nine responded to treatment.InterpretationThe combination of tocilizumab with standard AML intensive induction appears to be safe and resulting responses are encouraging. A dose of 8 mg/kg of tocilizumab given at day 8 of induction could be used for further phase 2/3 studies.FundingThe Leucémie Espoir Atlantique Famille (LEAF)-"Tous avec Fabien" association.

Project description:Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients.SignificanceThis phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.

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Dual Growth Factor (rhTPO + G-CSF) and Chemotherapy Combination Regimen for Elderly Patients with Acute Myeloid Leukemia: A Phase II Single-Arm Multicenter Study.

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