Allogeneic hematopoietic cell transplantation in morphologic leukemia-free aplastic state
Authors: Armin Rashidi, Alaa M. Ali, Kiran R. Vij, Ryan Shanley, Rizwan Romee, Sarah A Cooley, Peter Westervelt, John F. DiPersio, Jeffrey S. Miller, Daniel J. Weisdorf, Celalettin Ustun
Journal: American Journal of Hematology (2017)

The presence of residual disease before allogeneic hematopoietic cell transplantation (allo-HCT) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is best assessed in a cellular bone marrow. As a result, HCT is usually postponed until hematopoietic recovery and resolution of aplasia. The available evidence for safety and efficacy of HCT in morphologic leukemia-free aplastic state is limited to sporadic case reports.1-3 The generalizability of the available results is limited by potential publication bias because of successful cases having a higher chance of being reported and published. We adopted an unbiased approach and retrospectively reviewed the transplant databases of two large transplant centers. We limited our search to the period between January 2003 and December 2016, and the transplant databases of both centers (University of Minnesota [Minneapolis, MN], Washington University [St. Louis, MO]) were reviewed. The inclusion criteria were: (i) Age at the time of HCT ≥ 18 years, (ii) Diagnosis of AML or MDS, (iii) Bone marrow biopsy within 30 days prior to allo-HCT demonstrating aplasia in a morphologic leukemia–free state. Aplasia was defined as bone marrow cellularity <5% and red cell and platelet transfusion dependence. We did not consider a minimum required aplasia duration or last treatment-to-HCT interval. Patients with hematopoietic recovery after the last treatment but aplastic (for any reason) on pre-HCT assessment were not included. The cumulative incidence method was used to estimate relapse while treating non-relapse mortality (NRM) as a competing risk, and to estimate NRM while treating relapse as a competing risk. Kaplan-Meier curves were used to estimate overall survival (OS) and relapse-free survival (RFS). R 3.0.2 was used for analysis. A total of 18 patients were included, representing 0.8% of all 1,666 patients in the two centers who underwent allo-HCT for AML or MDS within the same time period. Table 1 shows patient and transplant characteristics as well as outcomes. The median (range) age of patients was 57 (24–73) years and 56% were males. Secondary AML was the most common diagnosis (n = 9, 50%, including 6 patients transformed from MDS, 1 from aplastic anemia, 1 from myelofibrosis, and 1 from chronic myelomonocytic leukemia), followed by de novo AML (n = 6, 33%). The remaining patients had de novo MDS (n = 3, 17%). Adverse-risk cytogenetic/molecular abnormalities were present in 8 (44%) patients. The median (range) number of cycles of treatment (including prior transplantation in four cases) before the development of aplasia was 4 (1–24). The treatment immediately preceding aplasia was intensive chemotherapy in 9 (50%; high-dose cytarabine: 2, 7 + 3: 3, 5 + 2: 1, Cladrabine + Cytarabine + Filgrastim + Mitoxantrone [CLAG-M]: 1, Mitoxantrone + Etoposide + Cytarabine [MEC]: 1, ME: 1), hypomethylating agents in 5 (28%), and haploidentical natural killer (NK) cell adoptive transfer following lymphodepleting chemotherapy in four (22%) patients. At the time of HCT, 13 (72%) and 5 (28%) patients were in first and second morphologic leukemia-free aplastic state, respectively. Flu/Thiotepa/ ATG/TBI-MUD, MAC Transplant conditioning was reduced-intensity in 10 (56%) and myeloablative in 8 (high-dose total body irradiation [TBI]-based: 4) patients. The donor was matched unrelated (MUD) in 10 (56%), matched sibling in 5 (28%), and umbilical cord blood (UCB) in 3 (17%) patients. Three (17%) transplants were cytomegalovirus (CMV) seronegative donor to seronegative recipient. Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor-based in 15 (83%) patients, anti-thymocyte globulin (ATG) was used in 4 (22%) patients, and post-transplant cyclophosphamide was used in 1 (6%) patient. Two (11%) patients received sirolimus-based prophylaxis. The median (range) interval between the last treatment and HCT was 53 (23–88) days and the median (range) diagnosis-to-HCT interval was 3.8 (1.8–35.0) months. There are six survivors (3+ months: 2 patients; 6+ months: 2 patients; 5+ years: 2 patients; all measured from allo-HCT). Primary graft failure did not occur in any patient. The cumulative incidence of grade II-IV acute GVHD by day 180 was 50 (25–75)% and chronic GVHD did not occur in any patient. The cumulative incidence of relapse at 6 months and 1 year was 18 (5–36)% and 25 (7–46)%, respectively. Relapse-free survival at 6 and 12 months was 47 (22–68)% and 40 (17–62)%, respectively. The corresponding estimates for OS were 65 (38–83)% and 38 (21–67)%. The cumulative incidence of NRM at 6 and 12 months was 35 (13–58)%. Most deaths were attributed to relapse (6 of 11; 55%) and infection (3 of 11; 27%). Death due to aGVHD occurred in 1 patient. A German study of aplasia-inducing chemotherapy using the FLAMSA regimen (fludarabine, cytarabine, and amsacrine) followed by reduced-intensity allo-HCT in 62 consecutive AML patients with refractory or relapsed disease achieved 2-year event-free survival and OS of 26% and 39%, respectively.4 HCT in this study was performed on day 12 of chemotherapy, whereas in our series it was performed at a median of 53 days after the last treatment. Several observations from our study are worth emphasis. First, our two long-term survivors were among those with the shortest intervals between the last treatment and HCT (43 and 23 days), suggesting prolonged pre-HCT aplasia as a negative prognostic factor. Second, lack of engraftment failure in patients with prolonged pre-HCT aplasia argues against intrinsic bone marrow microenvironment defects. Third, 3 of the 4 patients with aplasia after haploidentical NK cell transfer but only 3 of the 14 patients with aplasia after chemotherapy have survived to date. This finding suggests that the etiology of aplasia (immunotherapy vs. chemotherapy) may be relevant to HCT outcomes. Finally, a concern that post-HCT relapse may be unacceptably high due to the uncertainty of residual disease measures in an aplastic marrow was not apparent. These results warrant validation in larger cohorts. The authors have no conflicts of interest. Designed the study: A.R. and C.U. Collected the data: A.R., A.M.A., and R.S. Reviewed the pathology slides: K.R.V. Analyzed the data: R.S. Wrote the manuscript: A.R. Critically evaluated the results and the manuscript: A.R., A.M.A., K.R.V., R.R., S.A.C., P.W., J.F.D., J.S.M., D.J.W., and C.U.