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Haploidentical Stem Cell Transplantation With a Novel Conditioning Regimen in Older Patients: A Prospective Single-Arm Phase 2 Study.

ABSTRACT: Objective: Haploidentical stem cell transplantation (haplo-SCT) has demonstrated encouraging results in younger patients. There is also an increasing need for haplo-SCT in older patients. However, the high risk of treatment-related mortality (TRM) in older patients is still a major concern. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-SCT in older patients. Method: This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia or MDS; (2) without MSD and MUD, and with HID available; and (3) age ?55 years. The Bu/Flu/Cy/ATG regimen consisted of the following agents: Ara-C (2 g/m²/day, injected i.v.) on days-10 and-9; BU (9.6 mg/kg, injected i.v. in 12 doses) on days-8,-7, and-6; Flu (30 mg/m²/day, injected i.v.) from day-6 to day-2; Cy (1 g/m²/day, injected i.v.) on days-5 and-4; semustine (250 mg/m², orally) on day-3 and antithymocyte globulin (ATG) [2.5 mg/kg/day, rabbit, SangStat (Lyon, France)] on days-5,-4,-3, and-2. The primary endpoint was 1-year TRM. Results: From April 1, 2018 to April 10, 2020, a total of 50 patients were enrolled. All patients achieved neutrophil engraftment with complete donor chimerism. The cumulative incidence of grade 2-4 aGVHD at day-100 was 22.0%. The cumulative incidences of CMV viremia and EBV viremia on day 100 were 68.0 and 20.0%, respectively. The cumulative incidence of TRM at 1-year was 23.3%. and the cumulative incidence of relapse (CIR) at 1 year after transplantation was 16.5%. The overall survival (OS) and leukemia-free survival (LFS) at 1 year were 63.5 and 60.2%, respectively. The outcomes were also comparable with patients who received Bu/Cy/ATG regimen using a propensity score matching method. Conclusions: In conclusion, this study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for older patients. The study was registered as a clinical trial. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03412409.

SUBMITTER: Sun YQ

PROVIDER: S-EPMC7952870 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Haploidentical Stem Cell Transplantation With a Novel Conditioning Regimen in Older Patients: A Prospective Single-Arm Phase 2 Study.

Sun Yu-Qian YQ Han Ting-Ting TT Wang Yu Y Yan Chen-Hua CH Wang Feng-Rong FR Wang Zhi-Dong ZD Kong Jun J Chen Yu-Hong YH Chen Huan H Han Wei W Chen Yao Y Zhang Yuan-Yuan YY Zhang Xiao-Hui XH Xu Lan-Ping LP Liu Kai-Yan KY Huang Xiao-Jun XJ

Frontiers in oncology 20210226

<b>Objective:</b> Haploidentical stem cell transplantation (haplo-SCT) has demonstrated encouraging results in younger patients. There is also an increasing need for haplo-SCT in older patients. However, the high risk of treatment-related mortality (TRM) in older patients is still a major concern. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-SCT in older patients. <b>Method:</b> This prospective, single-arm clinical trial was performed at Peking Universi ...[more]

PMID: 33718234

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Project description:IntroductionReducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated.MethodsThe aim of "AlloTreo" prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m2) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who received a first allo-HCT between June 2005 and January 2011, inside the frame of this trial at our center. Median age at allo-HCT was 49 (21-69) years. Disease Risk Index was low in 14 (13%) patients, intermediate in 73 (67.7%), high in 17 (15.7%), and very high in 4 (3.7%). Donors were human leukocyte antigen (HLA)-matched related in 50 cases, 10/10-matched unrelated in 36, and 9/10-mismatched unrelated in 22. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine-A and methotrexate. Anti-T-lymphocyte globulin (ATLG) was administered in patients receiving unrelated allo-HCT. Stem cell source was mainly peripheral blood stem cells (95%).ResultsConditioning regimen was well tolerated. Full donor chimerism was documented for most patients (88%) at day +30. At 12 years, overall survival (OS) was 41.7% (32.2%-50.9%), progression-free survival (PFS) was 31.7% (23%-40.7%), GvHD-free/relapse-free survival was 20.9% (13.7%-29.1%), cumulative incidence (CI) of relapse was 44.5% (34.9%-53.6%), and transplant-related mortality (TRM) was 22.5% (15.1%-30.9%). CI of acute GvHD grades II-IV was 27.8% (19.7%-36.5%) at 100 days; 12-year CI of chronic GvHD was 40.7% (31.3%-49.9%). Relevant long-term adverse effects were 10 secondary malignancy, 3 fatal cardiovascular events, and 1 late-onset transplant-associated thrombotic microangiopathy. Ten successful pregnancies were reported after allo-HCT. In multivariate analysis, older age (≥60 years) at transplant [hazard ratio (HR), 2.157; p = 0.004] and a high/very high disease risk index (HR, 1.913; p = 0.026) were significantly associated with a lower OS.ConclusionsOverall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m2) especially for the younger population.

Project description:ObjectiveTo investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft.MethodsKidney recipients with biopsy-proven cABMR were treated with allogeneic third-party BM-MSCs in this open-label, single-arm, single-center, two-dosing-regimen phase I/II clinical trial. In Regimen 1 (n=8), BM-MSCs were administered intravenously at a dose of 1.0×106 cells/kg monthly for four consecutive months, while in Regimen 2 (n=15), the BM-MSCs dose was 1.0×106 cells/kg weekly during four consecutive weeks. The primary endpoints were the absolute change of estimated glomerular filtration rate (eGFR) from baseline (delta eGFR) and the incidence of adverse events associated with BM-MSCs administration 24 months after the treatment. Contemporaneous cABMR patients who did not receive BM-MSCs were retrospectively analyzed as the control group (n =30).ResultsTwenty-three recipients with cABMR received BM-MSCs. The median delta eGFR of the total BM-MSCs treated patients was -4.3 ml/min per 1.73m2 (interquartile range, IQR -11.2 to 1.2) 2 years after BM-MSCs treatment (P=0.0233). The median delta maximum donor-specific antibody (maxDSA) was -4310 (IQR -9187 to 1129) at 2 years (P=0.0040). The median delta eGFR of the control group was -12.7 ml/min per 1.73 m2 (IQR -22.2 to -3.5) 2 years after the diagnosis, which was greater than that of the BM-MSCs treated group (P=0.0342). The incidence of hepatic enzyme elevation, BK polyomaviruses (BKV) infection, cytomegalovirus (CMV) infection was 17.4%, 17.4%, 8.7%, respectively. There was no fever, anaphylaxis, phlebitis or venous thrombosis, cardiovascular complications, or malignancy after BM-MSCs administration. Flow cytometry analysis showed a significant decreasing trend of CD27-IgD- double negative B cells subsets and trend towards the increase of CD3+CD4+PD-1+/lymphocyte population after MSCs therapy. Multiplex analysis found TNF-α, CXCL10, CCL4, CCL11 and RANTES decreased after MSCs treatment.ConclusionKidney allograft recipients with cABMR are tolerable to BM-MSCs. Immunosuppressive drugs combined with intravenous BM-MSCs can delay the deterioration of allograft function, probably by decreasing DSA level and reducing DSA-induced injury. The underlying mechanism may involve immunomodulatory effect of MSCs on peripheral B and T cells subsets.

Project description:To improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval. Adult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate. A total of 16 patients were enrolled with median age of 36 (16-60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3-10) with a median of 55% (1%-90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5-40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol is accepted as being warranted for further study. Based on the above data, our phase II study demonstrated that the sequential FLAG-IDA cytoreduction chemotherapy followed by Flu-BU conditioning regimen given at the hematological nadir was feasible and has sufficient activity to warrant further investigation prospectively with a larger patient sample (clinicaltrials.gov identifier: NCT01496547).

Dataset Information

Haploidentical Stem Cell Transplantation With a Novel Conditioning Regimen in Older Patients: A Prospective Single-Arm Phase 2 Study.

Publications

Haploidentical Stem Cell Transplantation With a Novel Conditioning Regimen in Older Patients: A Prospective Single-Arm Phase 2 Study.

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