Results of Second or Third Allogeneic Hematopoietic Cell Transplantation As Salvage Therapy for Patients Failing Primary Transplantation

Patients with relapse after allogeneic hematopoietic cell transplantation (HCT) have generally a very poor prognosis. Besides donor lymphocyte infusions, chemotherapy or supportive care, second or even third allogeneic HCT have been performed in selected patients. This is often associated with a high incidence of non-relapse-mortality (NRM) because of heavy pre-treatment or reduced performance status due to comorbidities or pre-treatment related complications.

We report a retrospective analysis of our single center experience with second or third allogeneic HCT between 2000–2011. We searched our database for patients receiving >1 allogeneic HCT in the past 10 years. Details on characteristics and clinical course of the patients were confirmed by retrospective chart review.

47 patients received more than one allogeneic HCT (second HCT, n=44, second and third HCT, n=3). Median age of the patients was 40 (range, 18–65) years. 27 patients were male, 20 female. Diagnoses were acute myeloid leukemia (n=28), acute lymphoblastic leukemia (n=11), multiple myeloma (n=1), chronic myeloid leukemia (n=2), myelodysplastic syndrome (n=2), osteomyelofibrosis (n=2) and non-Hodgkin lymphoma (n=1). Reasons for second or third HCT were relapse (n=49) or primary graft failure (n=1). Median time between first and second HCT was 17 (range, 3–137) months, 12 months between second and third HCT (range, 10–16). For the first HCT 35 patients received myeloablative (MAC) and 12 reduced intensity conditioning (RIC). For the second HCT 16 patients received MAC and 31 RIC, for the third HCT RIC was used in all patients. 6/47 patients (13%) received salvage chemotherapy followed by RIC out of aplasia. Before salvage HCT disease status of the patients was CR=14, PR=33. Time to neutrophil engraftment after second and third HCT was 16 (range, 6–77) and 10 (range, 9–13) days, respectively; to platelet engraftment 16 (range, 9–71) and 23 (range, 14–73) days, respectively. 12 of 47 patients (26%) after second HCT are alive (CR=11, PR=1) and 1 of 3 patients is alive and in remission after receiving a third HCT. Kaplan-Meier estimated 3-year overall and event-free survival is 30% and 25%, respectively, with a median follow-up of 62 (range 6–111) months of patients alive. Outcome was better for patients in CR at HCT (3-year OS with 43% vs. 24%, p=0.13). In the subgroup of patients with acute leukemia 3-year OS and EFS was superior in patients with AML (32% and 31%) while all patients with ALL died. Older age had no negative impact on survival as 3-year OS in patients ≥40 years (n=25) was 43% compared to 15% in patients <40 years (n=22) (p=0.04). Cumulative incidence of NRM at 3 years with death due to relapse as competing risk after second HCT was 43%. 2 of 3 patients after third HCT died due to NRM. The use of RIC was associated with an inferior 3-year OS compared to MAC with 18% vs. 53%, p=0.08. Causes of death were relapse=18, infection=12, multiorgan failure=3, GVHD=1, EBV-LPD=1 and PML=2. Outcome was inferior if the second HCT was performed within 6 months after first HCT with a 3-year OS of 0% vs. 31%, p=0.02. In 8 patients the same donor as for primary HCT was used while in 39 patients an alternative donor (MRD=7, MUD=10, MMUD=7, MMRD=2, haplo=21) was chosen. Using the same donor seems to result in a better outcome with 3-year OS of 63% vs. 23%, p=0.08. Incidence of grade II-IV GVHD was 17%, of chronic GVHD 30%. Presence of cGVHD after second allogeneic HCT was associated with better survival (3-year OS 42% vs. 26%, p=0.31) especially after using RIC (33% vs. 11%, p=0.09)

In view of the otherwise dismal prognosis of patients with relapse after allogeneic HCT, second or third allogeneic HCT is feasible and can achieve long term disease free survival in up to a third of patients, even in patients of more than 40 years of age. Thus, retreatment with allogeneic HCT appears to be the most promising salvage strategy besides DLI for relapse >6 months after allogeneic HCT.

Off Label Use: The use of some agents in the conditioning is off-label.