Retransplantation From Haploidentical Donors After Graft Failure in Pediatric Patients Results in Low Transplant Related Mortality and Favourable Long Term Survival
Authors: Teltschik Heiko-Manuel M , Heinzelmann Frank , Feuchtinger Tobias F. , Pfeiffer Matthias , Müller Ingo , Handgretinger Rupert , Lang Peter 
Published: October 2019

Abstract
Abstract 1956
Graft failure is a rare but life-threatening complication after hematopoetic stem cell transplantation. Treatment comprises immunoablative reconditioning regimens and a second stem cell donation as soon as possible to minimize the time of pancytopenia and its sequelae. We report a cohort of 21 pediatric patients with acute leukemias (complete remission (CR)1-2 n= 7, active disease n=4; lymphatic n=7, myeloic n=4), myelodysplastic syndrome (n=2), immunodeficiencies (n=3), aplastic anemias (n=3), and hemoglobinopathies (n=2) who experienced graft failure (nonengraftment n=1; rejection n=20) after busulphan or melphalan based myeloablative transplantation from mismatched related donors (n=14) or matched unrelated or related donors (n=7). All patients were retransplanted with T cell depleted grafts (CD34 positive selection n=3 or CD3/CD19 depleted grafts n=18) from a haploidentical donor. Median time from diagnosis of graft rejection to second transplantation was 19 days. Reconditioning regimens consisted of irradiation (total lymphnode irradiation 7Gray (Gy) or TBI 2 Gy), fludarabine (120mg/m2) in combination with thiotepa (5mg/kg) or cyclophosphamide (60mg/kg body weight (bw)) and ATG/OKT3. A median number of 15×106/kg of body weight stem cells with 54×103/kg residual T cells were infused. Mofetilmycophenolat was given as Graft vs. Host Disease (GvHD) prophylaxis, if residual T cells exceeded 25 000/kg bw. Sustained engraftment was achieved in 20 out of 21 patients. One patient died before engraftment. Median time to absolute neutrophile counts above 500/μl was 9 (9–24) days. Independence from platelet substitution was reached at a median time of 10 (8–22) days. Only 1 patient developed GvHD °III, 10% developed GvHD °II, 33% of all patients developed GvHD °I, and 52% had no signs of GvHD. T cell recovery was delayed, however no lethal viral infection occurred. Severe organ toxicity was observed in 5 patients (bronchiolitis obliterans n=1, hemorrhagic cystitis n=2, leukencephalopathy n=2). Event free survival (EFS) of all patients at 5 years was 71%. 5 year EFS of patients with leukemias in complete remission was 83%. Patients with non-malignant diseases had 5 year EFS of 80%. Transplant related mortality at one year was 10%. Causes of death were: multi organ failure (n=1), fungal infection (n=1) and bronchiolitis obliterans organizing pneumonia, 4 patients with acute leukemias relapsed. None of the patients rejected the second graft. Thus, transplantation of stem cells from haploidentical donors after reconditioning is a realistic option to rescue patients with graft failure within a short time span. Graft rejection itself may have an antileukemic effect since patients with malignant diseases showed a favourable EFS. The use of a different donor in combination with irradiation based conditioning regimens may help to avoid a second rejection and results in a robust engraftment and low TRM.

Disclosures:
No relevant conflicts of interest to declare.