Abstract
ObjectiveTo evaluate the efficacy and safety of standard or low-dose chemotherapy followed by HLA-mismatched allogeneic T-cell infusion (allo-TLI) for the treatment of elderly patients with acute myeloid leukemia (AML) and patients with intermediate-2 to high-risk myelodysplastic syndrome (MDS).MethodsWe carried out a prospective, multicenter, single-arm clinical trial. Totally of 25 patients were enrolled, including 17 AML patients and 8 MDS patients. Each patient received four courses of non-ablative chemotherapy, with HLA-mismatched donor CD3+ allo-TLI 24 h after each course. AML patients received chemotherapy with decitabine, idarubicin, and cytarabine, and MDS patients received decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor.ResultsA total of 79 procedures were performed. The overall response rates of the AML and MDS patients were 94% and 75% and the 1-year overall survival rates were 88% (61–97%) and 60% (13–88%), respectively. The overall 60-day treatment-related mortality was 8%. Compared with a historical control cohort that received idarubicin plus cytarabine (3 + 7), the study group showed significantly better overall response (94% vs. 50%, P=0.002) and overall survival rates (the 1-year OS rate was 88% vs. 27%, P=0.014). Post-TLI cytokine-release syndrome (CRS) occurred after 79% of allo-TLI operations, and 96% of CRS reactions were grade 1.ConclusionElderly AML patients and intermediate-2 to high-risk MDS patients are usually insensitive to or cannot tolerate regular chemotherapies, and may not have the opportunity to undergo allogeneic stem cell transplantation. Our study showed that non-ablative chemotherapy followed by HLA-mismatched allo-TLI is safe and effective, and may thus be used as a first-line treatment for these patients.Clinical Trial Registrationhttps://www.chictr.org.cn/showproj.aspx?proj=20112.
Highlights
Adoptive CD3+ T-cell infusion, such as donor lymphocyte infusion (DLI), is an established treatment strategy for activating donor-derived T-cells to eliminate leukemic cells [1, 2]
DLI has been used as a type of allo-T-cell infusion (TLI) for decades; non-ablative chemotherapy followed by HLA-mismatched stem cell transplantation, referred to as “micro-transplantation”, has been used to treat myeloid malignancies, with a better response, faster blood cell recovery, and lower therapy-related mortality (TRM) rate than conventional regimens, especially in elderly acute myeloid leukemia (AML) patients and patients with Myelodysplastic syndrome (MDS) [13,14,15,16,17, 19, 36,37,38,39]
CD34+ hematopoietic stem cells were mobilized and isolated from HLA-mismatched donors and infused into the recipient, most researchers believed that the main functional anti-leukemia cells were T-cells, and donor CD3+ T-cells were found to interfere with survival after microtransplantation [38, 40]
Summary
Adoptive CD3+ T-cell infusion, such as donor lymphocyte infusion (DLI), is an established treatment strategy for activating donor-derived T-cells to eliminate leukemic cells [1, 2]. Patients with acute myeloid leukemia (AML) respond poorly to current therapies and have low survival rates, with a remission rate of 43%–65% and a therapy-related mortality (TRM) rate of 11%–23% for patients older than 55 years [16,17,18,19], and a 5-year disease-free survival rate for elderly AML patients of only 15% [20]. This poor prognosis for elderly AML patients is primarily related to more cytogenetic abnormalities and elderly individuals do not tolerate chemotherapy well [21]. MDS patients classified at intermediate-2 (int-2) to high risk of AML according to the International Prognostic Score System (IPSS) require chemotherapy [23], these patients are usually insensitive to or unable to tolerate chemotherapy
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