Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party

We report long-term outcomes of 329 childhood severe aplastic anemia (SAA) patients who underwent hematopoietic SCT (HSCT) from an HLA-matched sibling donor in the Japanese Hematopoietic Cell Transplantation Registry. OS and EFS at 10 years were as high as 89.7 þ / À 1.7% and 85.5 þ / À 2.0%, respectively. Five cases of late malignancies (LM) were identified (malignant peripheral nerve sheath tumor, thyroid carcinoma, colon carcinoma, MDS and hepatoblastoma). Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was lower than that in previous reports. This low incidence is in keeping with the low occurrence of skin cancer in Japanese population and of acute GVHD in our study group. Radiation-containing conditioning was not significantly associated with the incidence of LM after HSCT probably because of absolute low patient number who developed LM in our series. In terms of LM development after HSCT, low-dose TBI in HSCT for SAA to avoid graft rejection, which is commonly used in Japan, might be tolerable in the Japanese population because of its low incidence. Keywords: aplastic anemia; childhood; hematopoietic SCT; long-term outcome; late malignancies INTRODUCTION Aplastic anemia is a hematopoietic disorder characterized by pancytopenia and BM hypoplasia. Therapeutic options for severe aplastic anemia (SAA) are immunosuppressive therapy and hematopoietic SCT (HSCT). In children, if an HLA-matched sibling donor (MSD) is available, HSCT is the first line of therapy for SAA. HSCT from MSD is an established standard therapy for SAA in children and high survival rates have already been reported. However, little is known about long-term outcomes of these children.Late malignancies (LM) are serious complications for patients who undergo HSCT. 3,4 In SAA, LM are also reported in the patients with HSCT and its occurrence is related to radiation-containing conditioning regimen and GVHD grade in adults, 5,6 however, the incidence and prognostic factors of LM in children with SAA who undergo HSCT are totally unknown.In this article, we report long-term outcomes of childhood SAA patients who underwent HSCT from MSD in the centers of the Japanese Hematopoietic Cell Transplantation Registry and describe the occurrence of LM.

Section: Discussionmentioning

confidence: 99%

Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan

Kikuchi

Yabe

Katô³

et al. 2012

“…Cyclosporin A should be gradually reduced until it can be discontinued, in the absence of chronic GvHD, 6-12 months after HSCT. These later recommendations are derived from what has been published in acquired severe aplastic anemia from sibling donors 7 and unrelated transplantation, 8 using bone marrow as a stem cell source. Pre-transplantation serotherapy (either anti-thymoglobuline or alemtuzumab) is recommended for UD-HSCT, but not for matched sibling donor HSCT because of the associated immunosuppression in the early months post HSCT, which has the potential for higher transplantation-related morbidity and mortality owing to opportunistic infections.…”

Section: Gvhd Prophylaxismentioning

confidence: 99%

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes

Latour

Peters

Gibson

et al. 2015

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.

“…These findings suggested that sufficient hematopoietic recovery could be achieved without TBI in RIC allo-HSCT from an HLA-matched-related donor, as previously reported. 12,13 In contrast, Rodrigues et al reported that the addition of low-dose TBI to a RIC regimen improved neutrophil recovery and survival after cord blood transplantation. 7 Low-dose TBI may be important in the setting of unrelated donor transplantation.…”

mentioning

confidence: 99%

Impact of low-dose TBI on outcomes of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation for AML

Aoki

Seo

Kanamori

et al. 2015

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for patients with advanced hematologic malignancy, including those with AML. 1 However, allo-HSCT after conventional myeloablative conditioning (MAC) may be associated with a high rate of transplant-related complications. Reduced intensity conditioning (RIC) was developed with the purpose of reducing regimen-related toxicity. 2,3 RIC is increasingly used for allo-HSCT for AML patients who are otherwise considered unfit for MAC.The primary objective of low-dose TBI in RIC is inhibition of the host immune response to facilitate engraftment. 4,5 Several studies have suggested that the addition of low-dose TBI to the conditioning regimen improved outcomes of transplantation. 6,7 However, favorable outcomes of non-TBI-based RIC transplantation were also reported. 8 Thus, the impact of low-dose TBI on outcomes after allo-HSCT remains controversial, and it is unknown whether the addition of low-dose TBI to RIC is beneficial for AML patients. Therefore, we conducted a retrospective analysis to elucidate the clinical impact of low-dose TBI on outcomes after allo-HSCT from a HLA-matched-related donor in the setting of fludarabine-based RIC.Clinical data were collected from the registry database of the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (excluding acute promyelocytic leukemia) aged 16 years or older who underwent fludarabine-based RIC allo-HSCT from an HLA-matched-related donor between January 2000 and December 2012 were extracted from the database. Patients who underwent two or more HSCT were excluded. We retrospectively analyzed the clinical impact of low-dose TBI on outcomes after RIC allo-HSCT. Overall survival (OS), relapse, nonrelapse mortality (NRM) and hematological recovery of patients who received low-dose TBI as a part of fludarabine-based RIC (TBI group) were compared with those of patients who did not receive TBI (non-TBI group). Low-dose TBI was defined as ⩽ 4 Gy, as previously reported. 9 Fludarabine-based RIC was defined as RIC containing fludarabine 120-180 mg/m 2 . Definitions of RIC other than TBI were as follows: oral busulfan o9 mg/kg (or IV injection in equivalent doses) or melphalan ⩽ 140 mg/m 2 . 10 Cytogenetic subgroups were classified according to the Southwest Oncology Group (SWOG) definition. 11 Neutrophil engraftment was defined as the continuous achievement of neutrophil counts 500 × 10 6 /l or higher. Platelet recovery was also defined as continuous achievement of neutrophil counts 50 × 10 9 /l or higher without transfusion. This study was approved by the Institutional Review Board of the Kanagawa Cancer Center. Table 1 shows patients characteristics. Of the 409 patients, 108 patients were in the TBI group and 301 patients were in the non-TBI group. A higher proportion of patients underwent bone marrow transplantation (BMT) (P o 0.001) and received cyclosporine for GvHD prophylaxis (P = 0.006) in the TBI group. The proportion of male patients (P = 0.07) and patients who un...