Allogeneic Hematopoietic Cell Transplantation for the Treatment of Hematologic Malignancies Not in Remission: The Anti-Tumor Effect of Reduced-Intensity Conditioning Is Comparable to That of Conventional Myeloablative Conditioning.
Authors: Maruyama Dai , Fukuda Takahiro , Kato Ruri , Yamasaki Satoshi , Usui Eiji , Morita Yuriko , Kim Sung-Won , Mori Shin-ichiro , Tanosaki Ryuji , Tajima Kinuko , Heike Yuji , Makimoto Atsushi , Tobinai Kensei , Takaue Yoichi 
Published: October 2019

Myeloablative conditioning has been used to maximally reduce the tumor burden before hematopoietic cell transplantation (HCT) in patients not in remission. However, the potential of reduced-intensity conditioning has not been fully questioned. To address this point, we retrospectively reviewed the medical records of 132 patients with hematologic malignancies not in remission who underwent allogeneic HCT at our center between 2000 and 2004. Eighty-two patients had myeloid malignancies, and 50 had lymphoid malignancies. Disease status was primary refractory (n=42), refractory relapse (n=65), blastic crisis or accelerated phase of chronic myelogeneous leukemia (CML, n=8), or untreated disease (n=17). Patients with CML in chronic phase, myelodysplastic anemia-refractory anemia, and those in partial remission were not included. Donors included HLA-matched (n=54) or mismatched (m=16) relatives and unrelated volunteers (n=62). Stem cell source was G-CSF-mobilized peripheral blood stem cell (n=70), bone marrow (n=47), or cord blood (n=15). We compared the non-relapse mortality (NRM), relapse or progressive disease (PD), overall survival (OS), and progression-free survival (PFS) of patients who received fludarabine-based reduced-intensity (RIST group, n=80) or conventional myeloablative conditioning (CST group, n=52). The median age of the RIST group was significantly older than that of the CST group (53 years vs 40 years, p<0.0001). The RIST group included higher proportions of patients with lymphoid disease, those with more comorbidity, and those who received grafts from HLA-matched relatives. Disease status was similar between the two groups. The probabilities of achieving complete remission and the incidences of grades II-IV and III-IV acute graft-versus-host disease in the RIST vs CST groups were 70% vs 83%, 50% vs 50%, and 28% vs 23%, respectively. Figure 1 shows the Kaplan-Meier estimate of overall survival stratified according to conditioning regimen. The 2-year probabilities of NRM (38% vs 37%), PD (49% vs 52%), OS (38% vs 29%), and PFS (29% vs 27%) in the RIST vs CST groups were not significantly different. Multivariate analyses revealed that a higher HCT-specific comorbidity index and transplant from donors other than HLA-matched relatives were associated with increased risks of high NRM and poor OS, and patients who did not receive aggressive chemotherapy within 2 months before HCT were associated with a lower risk of PD and better PFS. After adjusting for these variables, the risks of NRM, PD, OS, and PFS in the RIST group were not significantly different from those in the CST group.

In conclusion, our study suggests that the anti-tumor effect of RIST is comparable to that of conventional myeloablative HCT, and hence RIST is feasible for the treatment of hematologic malignancies not in remission. A prospective study is warranted to confirm this conclusion.

Overall Survival of patients not in remission according to conditioning regimen Overall Survival of patients not in remission according to conditioning regimen