High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

Abstract

Background and aims. Aplastic anemia (AA) is a rare but life-threatening disease. The introduction of immunosuppressive treatment (IST) and hematopoietic stem cell transplantation (HSCT) has considerably improved the outcome of patients with AA. However, modern-day population-based data are limited. This thesis aimed to retrospectively analyze the incidence, treatment modalities, survival, and immune markers in the bone marrow of patients diagnosed with AA in Sweden from 2000-2011. Patients and methods. Patients were included via the National Patient Registry and diagnosed according to the Camitta criteria. All data were collected from medical charts. In paper IV, immunohistochemistry was used to obtain data on regulatory T cells and macrophages in the bone marrow. Results and conclusions. We identified 257 confirmed cases, with an overall incidence of 2.35 cases per million inhabitants per year. The 5-year overall survival (OS) was >90% in patients aged up to 39 years but 38.1% in patients aged ≥60 years. Multivariate analysis showed that age ≥40 years, very severe AA, and no specific therapy were independent risk factors for inferior survival. First-line IST treated patients (n=158) showed a 47% response rate with no difference regarding the age groups or anti-thymocyte globulin (ATG) formulation. The response was significantly associated with the severity grade at the time of treatment initiation, and very severe AA patients exhibited a response rate of 22%. Sixty-eight patients underwent HSCT with a 5-year OS of 86.8%. The graft-versus-host-disease-free, relapse/rejection-free survival at 5 years was 69.1%. Patients aged ³40 years had higher transplant-related mortality that translated into a lower 5-year OS. In paper IV, we found lower numbers of FOXP3-positive regulatory T cells in AA patients without predictive value for IST response and that patients with a higher number of CD163-positive macrophages had a better 5-year OS, but this benefit was only observed in the non-severe AA group. In conclusion, younger patients have very good long-term survival regardless of the choice of therapy, whereas the outcome for patients ≥60 years remains poor. Very severe AA patients respond poorly to ATG, which indicates the need for a different treatment approach.

Análise dos fatores associados ao retransplante de células-tronco hematopoiéticas: estudo caso-controle

“…Graft failure and disease relapse are the main reasons that lead to retransplantation mentioned in a study 16 . Factors associated with graft failure include HLA incompatibility, underlying disease, type of conditioning regimen, source of CPH employed, low HPC dose, ex vivo T cell depletion, major ABO incompatibility, grafts from female donors to male recipients and disease status at the transplantation time, infection or sepsis and non-adherence to drug therapy with ursodeoxycholic acid and immunosuppressants in the post-HSCT period 17 .…”

“…HSCR seems a little promising approach, but there are few treatment options for relapse after the first transplant such as chemotherapy with new drugs, infusion of donor lymphocytes for allogeneic transplantation, retransplantation or a combination of them. In this context, HSCR is the treatment which favors greater OS 7 , 16 .…”

Cyclosporine/methotrexate versus tacrolimus/methotrexate with or without anti-thymocyte globulin as GVHD prophylaxis in adult patients with aplastic anemia

“…GRFS is a composite endpoint that is mainly used for transplants against hematological malignancies [25]. Recent studies on the outcomes of transplants for aplastic anemia also reported GRFS or GFFS, both of which were defined as the same criterion with relapse-free indicating GF-free [30][31][32][33]. A recent Korean retrospective study suggested a favorable effect of the use of ATG for GRFS only in PBSCT or mismatched donor transplant cohorts [30].…”

High Overall and GVHD-Free Survival in Patients with Aplastic Anemia Receiving in vivo T-cell Depletion Transplants and Long-Term Complications

“…The term＂GRFS＂is used as a composite endpoint, focused on survival without relapse and the absence of clinically relevant GVHD, and is primarily used for malignant disorders where there is a benefit from the Blood Cell Therapy-The official journal of APBMT-AlloHCT for SAA using T-cell depletion graft-versus leukemia(GVL)effect 24 . A novel definition for GRFS, for aplastic anemia, was recently suggested to use rejection-free survival instead of relapse-free survival, maintaining the standard inclusions of grade Ⅲ-Ⅳ cGVHD and clinically significant cGVHD 25 . We proposed a modification of the original definition of GRFS to include grade Ⅱ aGVHD and mild cGVHD in nonmalignant hematological disorders, as there is no benefit from the GVL effect 26 .…”

“…Disease monitoring GVHD-Free⊘Rejection-free survival(GRFS)was calculated in months from the date of alloHSCT to the date of the event or last follow-up whichever came first. Grades Ⅱ-Ⅳ acute GVHD, any grade of chronic GVHD, graft failure, and death were recorded as events, as SAA is a non-malignant disorder 25,26 . Long-term complications were studied through retrospective chart review.…”