Hematopoietic Stem Cell Transplantation For Aplastic Anemia Research Articles

An Antithymocyte Globulin-Free Conditioning Regimen Using Fludarabine and Cyclophosphamide Is Associated with Good Outcomes in Patients Undergoing Matched Related Family Donor Transplantation for Aplastic Anemia

Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic anemia (AA). We describe an antithymocyte globulin (ATG)-free conditioning regimen consisting of Flu and cyclophosphamide (Cy) in patients undergoing matched related donor (MRD) HSCT for AA. Between 2004 and 2019, 212 patients underwent MRD HSCT using Flu (30 mg/m2/day for 6 days) and Cy (60 mg/kg/day for 2 days) for conditioning. The graft source was peripheral blood stem cells in all patients. Graft-versus-host disease (GVHD) prophylaxis consisted mainly of cyclosporine and methotrexate, although 41 patients received post-transplantation Cy as part of a study. Engraftment occurred in 91% of patients at a median of 16 days, whereas 4 patients (1.8%) experienced primary graft failure and 15 (7.1%) died before achieving engraftment. Toxicity was minimal. The incidence of grade II-IV acute GVHD (aGVHD) was 27.9%, and that of grade III-IV aGVHD was 11.3%. Chronic GVHD occurred in 41.6%. 80% were free of immunosuppression at 60 months and long-term complications were seen in 8.4%. At a median of 46 months, 158 patients were alive and well, with a 5-year overall survival (OS) of 75.3 ± 3.0%. The 5-year OS was 80.6 ± 4.1% for patients age <20 years (n=93), 74.5 ± 4.6% for those age 20 to 40 years (n=91), and 59.7 ± 9.5% for those age >40 years (n=28) (P=.11). Patients classified as low risk had better OS compared with those at high risk (93.2 ± 2.9% versus 65.7 ± 4.1%; P=.000). Factors affecting OS on multivariate analysis included aGVHD (P=.02) and graft failure (P=.000). This large series using Flu/Cy for conditioning before MRD HSCT confirms good outcomes in patients with AA, with excellent outcomes in low-risk patients. Suitable modifications are needed to improve outcomes in high-risk patients.

Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia with Pre-Transplant Conditioning Using Fludarabine, Reduced-Dose Cyclophosphamide, and Low-Dose Thymoglobulin:Â Ksgct Prospective Study

Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia with Pre-Transplant Conditioning Using Fludarabine, Reduced-Dose Cyclophosphamide, and Low-Dose Thymoglobulin:Â Ksgct Prospective Study

Treatment and Outcome of the Patients with Donor-Type Aplasia after Bone Marrow Transplantation in Children with Aplastic Anemia

Hematopoietic stem cell transplantation (HSCT) from an HLA-matched donor is the treatment of choice for children with aplastic anemia (AA). However, graft failure (GF), either primary or secondary, remains an important and life-threatening complication. Recently, donor-type aplasia, defined as bone marrow aplasia with full donor chimerism among secondary GF, has been identified after HSCT. Clinical characteristics of donor-type aplasia after HSCT and its treatment and outcome in children with AA were retrospectively reviewed. Forty-two children with AA underwent allogeneic HSCT with 10-year overall survival rate of 85.7%. While primary GF developed in 1 (2.4%), secondary GF was seen in 12 at a median of 8 months (range: 2.0-28.5 months). Among them, 11 developed a donor-type aplasia with the cumulative incidence of 26.2%. Low infused cell number (P =0.002), immunosuppressive therapy (IST) prior to HSCT (P =0.003) and preceding transfusion >40 times (P =0.008) were associated with the development of donor-type aplasia. The survival of patients with donor-type aplasia was 81.8%. Six patients were treated with stem cell rescue as follows: peripheral blood stem cell (PBSC) boost, 3; PBSC boost followed by secondary HSCT, 2; and secondary HSCT, 1. All but 1 who had a longest interval from 1st HSCT to stem cell rescue (54.4 months) showed restoration of graft function. The remaining 5 patients were managed with conservative measures including transfusions. No one showed spontaneous improvement with the median follow-up of 30.1 months (range, 4.2 to 43.0 months). Two patients died of graft failure and infection. Altogether, 4 patients still remain transfusion-dependent. Donor-type aplasia after HSCT for AA is not uncommon. Stem cell rescue, either with PBSC boost or secondary HSCT after conditioning should be attempted to obtain sustained graft function. For those who do not have availability for stem cell rescue, a novel treatment, such as thrombopoietin receptor agonist, should be considered for the future. DisclosuresNo relevant conflicts of interest to declare.

Changing to a New Donor for Second Hematopoietic Stem Cell Transplantation in Fanconi Anemia Seems to Improve Survival.

Abstract 2294Poster Board II-271This retrospective analysis of the EBMT ProMISe database was designed to investigate the role of donor choice for second hematopoietic stem cell transplantation (HSCT) in Fanconi Anemia (FA). Our hypothesis was that using a different donor for the second HSCT would increase the probability of survival, the patient not being sensitized to donor antigens as a result of the first HSCT. We conducted a survey of the EBMT ProMISe database in order to identify FA patients transplanted more than once for bone marrow failure and retrospectively analyzed their data to determine overall survival and presence of acute GvHD. A donor for the second HSCT was defined as the “same” as for the first if both donors had identical: birth date, relation to patient (identical sibling or not), gender and family relation or donor number. A donor was “different” when this information indicated that a different person donated for second HSCT. One hundred and three patients were eligible for the study by the following criteria: diagnosis of Fanconi Anemia (confirmed by chromosome breakage test), presentation with aplastic anemia (AA) and having undergone two HSCTs between August, 1980 and December, 2007. FA patients with myelodysplasia or acute leukemia were excluded. After retracing data in the database, additional questionnaires were sent out to 44 EBMT centers that had performed second HSCTs for FA-AA, asking for supplementary data. In 80 cases (study population), enough information was collected to identify first and second donors. Forty four subjects (25 males and 19 females) received a second HSCT from the “same donor” (SD) and 36 patients (15 males and 21 females) from a “different donor” (DD). The mean age of the study population at second HSCT was 10.7 years (range, 1.8-34.5). Median interval between first and second HSCT was 63 days.At first HSCT patient gender, age at HSCT, use of cyclophosphamide and irradiation in the conditioning regimen and type of rejection were not differently distributed in the SD and DD group whereas significantly more HLA identical sibling donors were used in the SD (31%) vs. DD (11%) group (p=0.027). In 68.2% of the SD group bone marrow was used vs. in 52.7% of the DD group (p=0.002). Median cell dose in SD group was 9×106 CD34+/kg and in DD group 1.8×106 CD 34+/kg (p=0.002). At second HSCT age at HSCT, use of cyclophosphamide and irradiation in the conditioning regimen, dose of CD34+ cells and cell source were not differently distributed between SD and DD groups whereas significantly more HLA identical sibling donors were used in SD (31%) vs. DD (11%) group (p=0.027).Overall survival of all 80 patients at one year from second transplant is 36%. Probability of overall survival after 7 years is 35%. An interval between first and second HSCT of >80 days resulted in better survival (p=0.007). Overall survival at 7 years is 41% in DD and 26% in SD patients (Cox regression, HR 0.483, p=0.017). This difference remained significant after correction for the confounding effects of irradiation in first HSCT and relation donor/patient (identical sibling or not). Rejection rate after second HSCT was similar in SD and DD group (54.5%). Death occurred in 73% of SD vs. 56% of DD. Causes of death included infections (70% in SD vs. 48% in DD) and rejection (39% in SD and 38% in DD). Noteworthy more than one major cause of death was often found in the same patient. Only 2 secondary tumors were reported in the whole group. Acute GvHD gr II-IV was not significantly different in SD vs DD groups (multivariate logistic regression models, OR 1.642, p=0.47).Our data suggest that after having failed a first transplant, using the same or a different donor does not affect the occurrence of aGVHD, whereas change of donor would improve the survival of FA patients in need of a second HSCT for AA. Mechanisms underlying rejection of a first HSCT should be studied more in depth. International centers should collaborate in finding the most appropriate regimen for first and second transplants in FA. Disclosures:No relevant conflicts of interest to declare.