Reduced Intensity Conditioning (RIC) Prior to Allogeneic Stem Cell Transplantation in AML Patients with An Intermediate Risk Karyotype: No Difference in Outcome as Compared to Standard Myeloablative Conditioning (MAC).
Authors: Hemmati Philipp , Massenkeil Gero , Terwey Theis , Neuburger Stefan , le Coutre Philipp D. , Vuong Lam G , Dörken Bernd , Arnold Renate 
Published: October 2019

Purpose: Allogeneic stem cell transplantation (alloSCT) following standard MAC is associated with a considerable treatment-related mortality (TRM) and, therefore, is usually limited to medically fit patients younger than 55 years. In contrast, RIC allows to offer alloSCT to patients ineligible to transplantation following standard MAC due to substantial comorbidities or advanced age. However, depending on the presence of additional factors, i.e. favorable, intermediate, or poor risk cytogenetics, it is not clear whether the reduced TRM in patients undergoing alloSCT following RIC is outweighed by an increased relapse rate.

Patients and Methods: Here, we present a retrospective single-institution analysis of 53 AML patients (median age 38 (17 – 68) years) who underwent alloHSCT in CR1 between 1999 and 2007 (median follow-up of the surviving patients 60 (8 – 114) months). All patients had an intermediate risk karyotype as defined by the SWOG/ECOG (Slovak et al., Blood 2000): normal, +8, +6, -Y, del(12p). As stem cell source 48/53 patients (91%) received peripheral blood stem cells (PBSC), whereas bone marrow (BM) was given in 5/53 patients (9%). In 32/53 patients (60%) standard MAC (12 Gy total body irradiation + 120 mg/kg cyclophosphamide) (MAC group) was given. 21/53 (40%) patients received RIC (fludarabine 180 mg/m2 + oral busulfane 8 mg/kg + anti-thymocyte globulin 30 mg/kg) (RIC group). A matched-related donor was available for 35/53 patients (66%), whereas alloHSCT was performed from a matched unrelated donor or a mismatched unrelated donor in 16/53 (30%) or in 2/53 (4%) patients. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporin (CSA) + metothrexate (MTX) in the MAC group or CSA + mycophenolate mofetil (MMF) in the RIC group. Notably, 35/53 patients (66%) had an intermediate (1–2 points) hematopoietic cell transplantation-specific comorbidity index (HCT-CI), whereas or 18/53 patients (34%) had an unfavorable (33 points) HCT-CI. As expected, patients in the RIC group were significantly older (RIC: 48 (21 – 48) years versus MAC: 33 (17 – 66) years; p = 0.003) or had a significantly higher HCT-CI (p = 0.003).

Results: Projected overall survival (OS) or disease-free survival (DFS) of the whole cohort at 1, 3, and 5 years was 83%, 69%, and 66% or 72%, 65%, 65%. Causes of death were relapse (10/53 patients, 19%) or TRM (7/53 patients, 13%). The OS in the MAC group versus the RIC group at 1, 3, and 5 years was 76% versus 86%, 64% versus 66%, and 64% versus 66% and did not differ significantly (p = 0.79). Furthermore, there was no significant difference in the 1, 3, and 5-year DFS (75%, 64%, and 64% versus 75%, 68%, and 68%) between the MAC group and the RIC group (p = 0.78). Notably, OS and DFS reached a plateau at 39 months (MAC group) or 23 months (RIC group). There were no significant differences in the cumulative incidences of relapse in the MAC group versus the RIC group at 1 year (11% versus 5%), 3 years (23% versus 21%), or 5 years (27% versus 21%) (p = 0.63). The cumulative incidences of TRM were 13% versus 10%, 13% versus 17%, and 13% versus 17% at 1, 3, and 5 years and did not differ significantly between both groups (p = 0.88). Also, there was no significant difference in the incidence of chronic GvHD between the MAC group and the RIC group.

Conclusions: AML patients with an intermediate risk karyotype may achieve durable long-term remissions after alloSCT following RIC. Furthermore, relapse rates were not increased as compared to alloSCT upon standard myeloablative conditioning, which supports the high efficacy of the graft-versus-leukemia (GvL) effect. Consequently, alloHSCT following RIC may represent a therapeutic option for all AML patients with an intermediate risk karyotype.