Outcome of Children Who Experience Disease Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies,

According to the Center for International Blood and Marrow Transplantation and Research (CIBMTR) data, relapse accounts for 41% of deaths after matched sibling donor hematopoietic stem cell transplantation (HSCT) and 34% of deaths after unrelated donor HSCT. Overall long term survival of 25–30% has been reported in patients who relapse after HSCT. Most of these data are from adult studies. In a recent study, survival following a second allogeneic HSCT ranged from 25–50%. There are limited data on the treatment outcome of children who relapse after an allogeneic HSCT for hematological malignancies.

This multicenter retrospective study was done with the primary objective to examine the incidence and outcome of children who experience relapse after allogeneic HSCT. Patients with a primary diagnosis of acute lymphatic leukemia (ALL), acute or chronic myeloid leukemia (AML or CML), juvenile myelomonocytic leukemia (JMML), biphenotypic leukemia (BL), acute undifferentiated leukemia (AUL), and myelodysplastic syndrome (MDS) were included. After IRB approval, data was collected from review of the medical charts of patients who underwent HSCT at 5 institutions across North America.

Data on 532 patients was analyzed; these included 328 males and 204 females. These included ALL (n=254), AML (n=187), MDS (n=35), CML (n=26), JMML (n=3), sAML (n=12), Biphenotypic leukemia (n=10), AUL (n=3) and 1 each with APL and secondary ALL. The median age at HSCT was 9.7 years (range 0.44 to 24.98). Four hundred and fifty (85%) of the 532 patients were in complete remission (CR) at the time of HSCT. Five hundred and fifteen (97%) underwent a myeloablative (MA) HSCT and 16 (3%) had a non-myeloablative (NMA) HSCT. Total body irradiation (TBI) was part of the conditioning therapy in 334 (63%) while 198 (37%) had chemotherapy based regimens. Standard graft versus host disease (GvHD) prophylaxis with calcineurin inhibitors and methotrexate was used in 76% of patients. Grade 1–2 acute GvHD developed in 180 (34%) of patients and 82 (15%) had grade 3–4 acute GvHD. Chronic GvHD was seen in 118 (22%) cases with half having extensive chronic GvHD. After HSCT, 85 (16%) patients died of transplant related complications at 1 year, with infection as the leading (26%) cause of death. The 2, 5 and 10 year overall survival for the entire group was 58.5%, 46% and 44% respectively. Following HSCT, 131 (25%) patients relapsed at a median duration of 7.7 months (range 0.6 to 66.4 months).

Of the 131 patients who relapsed 80 (61%) received salvage therapy, 39(30%) did not get any therapy and data were not available for another 12 (9%) patients. Salvage therapy included a combination of withdrawal of immunosuppression, ALL or AML re-induction therapy, or other remission inducing agents, clofarabine, and/or donor lymphocyte infusions (n=22). After salvage therapy 46 (57.5%) patients achieved CR, 26 (32.5%) had no response, 3 (4%) partial response, 2 unknown and 4 (5%) had marrow aplasia and no recovery of counts.

Sixty-three (48%) of the relapsed patients underwent a second HSCT: 26 (41%) received a MA, 21 (33%) NMA, 3 (5%) with no conditioning and in 13 (21%) conditioning therapy was unknown. Nearly 22 different conditioning regimens were used for the second HSCT. After the second HSCT 19 (41%) patients died because of transplant related mortality (TRM) and 24 patients died because of relapse. Seventeen (27%) patients are alive and disease free.

Relapse remains a major complication following allogeneic HSCT for hematologic malignancies. Our data shows that patients who relapse after HSCT have poor prognosis. In our study 30 different salvage therapies were used for these patients. Currently there is no standard acceptable salvage therapy and most cooperative group or industry sponsored clinical trials exclude patients who underwent HSCT. In addition there are no standard conditioning regimens designed specifically for the second HSCT, which could contribute to the high TRM seen during second HSCT. There is urgent need to develop prospective clinical trials to better understand the optimal therapy for this group of patients.

No relevant conflicts of interest to declare.