Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation

Leukemia relapse and chronic graft-versus-host disease (cGVHD) are still major obstacles of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The numbers and activity of natural killer (NK) and Tregulatory cells can be increased post-transplantation by exposure to interleukin-2 (IL-2). We tested whether administering low-dose IL-2 would decrease leukemia relapse while reducing cGVHD after allotransplantation. This controlled, open-label randomized trial included 90 recipients of allotransplants. Subjects were randomized in a 1:1 ratio to either receive or not receive low-dose IL-2 during the early post-transplantation period. Patients in the IL-2 arm received a subcutaneous injection of low-dose IL-2 (1£10 6 U/d) on day 60 after allo-HSCT. IL-2 was administered daily for 14 d followed by a 14-d hiatus. The primary endpoint was the cumulative incidence of leukemia relapse (CIR). Three-year CIRs for the IL-2 arm and control arm were 23% (range 16-30%) and 11% (range 6-15%; p D 0.20), respectively. Minimal residual disease-positive (MRDC) tests were more common in the IL-2 arm compared to the control arm (36% [range 29-44%] vs. 15% [range 10-20%], p D 0.03). The cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was lower in the IL-2 arm compared to the control arm (33% [range 26-39%] vs. 57% [range 49-64%), p D 0.02). Therefore, the 3-y GVHD-free and GVHD progression-free survival (GPFS) rates were significantly higher in the IL-2 arm compared to the control arm (47% [range 39-55%] vs. 31% [range 25-38%], p D 0.048). Blood Tregs, NK cells, and NK-cell cytotoxicity were increased in subjects in the IL-2 arm between 3 mo and 6 mo post-transplantation. Administration of low-dose IL-2 during the immediate post-transplantation period was associated with a higher GPFS but did not decrease the CIR.

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“…31,36,37 aGVHD was defined and graded from 0 to 4 based on the Seattle criteria. 38 cGVHD was defined and graded according to the NIH criteria.…”

Section: Definitions and Evaluationmentioning

confidence: 99%

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Zhao

Wang

et al. 2016

OncoImmunology

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“…14 The pertinence of this GVHD and relapse-free survival (GRFS) to evaluate the overall outcome after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) integrating a quality of life assessment was recently confirmed. 15 Statistics were computed using R-project 3.1.3 software (www.r-project.org).…”

Section: Statistical Analysesmentioning

confidence: 99%

T-replete haploidentical allogeneic transplantation using post-transplantation cyclophosphamide in advanced AML and myelodysplastic syndromes

Devillier

Bramanti

Fürst

et al. 2015

Bone Marrow Transplant

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Unmanipulated haploidentical transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy) represents an alternative for patients with high-risk diseases lacking HLA-identical donor. Although it provides low incidences of GVHD, the efficacy of Haplo-SCT is still questioned, especially for patients with myeloid malignancies. Thus, we analyzed 60 consecutive patients with refractory (n = 30) or high-risk CR (n = 30) AML or myelodysplastic syndromes (MDSs) who underwent PT-Cy Haplo-SCT. The median age was 57 years (22-73 years), hematopoietic cell transplantation comorbidity index was ⩾ 3 in 38 patients (63%) and Haplo-SCT was the second allogeneic transplantation for 10 patients (17%). Although most of patients received PBSC as graft source (n = 48, 80%), we found low incidences of grade 3-4 acute (2%) and severe chronic GVHD (4%). Among patients with high-risk CR diseases, 1-year non-relapse mortality, cumulative incidence of relapse, progression-free and overall survivals were 20%, 32%, 47% and 62%, respectively. In patients with refractory disease, corresponding results were 34%, 35%, 32% and 37%, respectively. We conclude that PT-Cy Haplo-SCT could provide promising anti-leukemic effect even in the setting of very advanced diseases. Thus, it represents a viable alternative for high-risk AML/MDS patients without HLA-identical donor.

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“…We tested also the recent composite end point GRFS (21), introduced in the 2015, which reflects the survival free of 102 major complications. GRFS events were defined as grade 3-4 acute GVHD or chronic GVHD requiring systemic immunosuppressive treatment at any time, disease relapse or death from any cause during the first 12 and 36 months 104 after alloSCT.…”

mentioning

confidence: 99%

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

Dodero

Milone

Sarina

et al. 2017

Biology of Blood and Marrow Transplantation

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The graft versus host disease free, relapse free survival is 34% after transplantation in 2 lymphomas; 3Reduced extensive chronic GVHD with a combination of ATG and Rituximab in recipients of 4 unrelated graft 5One Rituximab Infusion prevents EBV-related lymphoproliferative disorders 6 Abstract 7The treatment of patients with refractory/relapsed B-Cell non-Hodgkin lymphoma (NHL) is evolving due to the 8 availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and 9 mortality remain a matter of concern. We conducted a multicentre prospective phase II trial to evaluate the benefit of 10 including only one dose of Rituximab (R) in the conditioning regimen before alloSCT. The primary end-point was 11 progression-free survival. The study enrolled 121 patients with relapsed/refractory B-cell lymphomas. The conditioning 12 regimen consisted of thiotepa, cyclophosphamide, fludarabine and R (500 mg/ms). Rabbit anti-thymocyte globulin 13(ATG) was administered only in case of unrelated donors. Sixty-seven (55%) and fifty-four (45%) patients received 14 grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of non-relapse mortality 15(NRM) was 21% at 3-years. The CCI of chronic GVHD at 3-years was 54% and 31% in recipients of matched sibling 16 and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-years progression-free and 17 overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite end-point 18 of graft-versus-host disease-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a 19 prospective trial of lymphomas patients: the 1 and 3-years GRFS were 40% and 34%, respectively. AlloSCT can cure a 20 fraction of patients with rather low NRM and an encouraging PFS and GRFS.

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Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation

Cited by 419 publications

References 21 publications

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

T-replete haploidentical allogeneic transplantation using post-transplantation cyclophosphamide in advanced AML and myelodysplastic syndromes

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

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