Our analysis demonstrates similar OS and PFS after AlloHCT following either MA or NMA conditioning. Older patients, heavily pretreated patients, and patients who relapsed after a prior AuHCT comprised the bulk of the patients in the NMA cohort. The reasons for failure differed with higher TRM after MA conditioning balanced by the greater risk of relapse after NMA conditioning. There was no impact of prior AuHCT on outcomes. Both HLA-identical RD and UCB grafts were suitable for either MA or NMA transplants.
Four retrospective analyses have compared MA to NMA conditioning for lymphoma with varied out-comes [8
]. In a small series (n = 23), Bertz and colleagues [8
] found improved 1-year OS after Flubased NMA conditioning (67%) compared to MA conditioning (23%, P
< .02). Rodriguez et al [9
] reported on 88 patients (matched RD, n = 63; URD, n = 25) transplanted between 1991 and 2003. The MA and NMA cohorts were sequential as the center changed from MA conditioning to NMA conditioning for lymphoma patients in 2000. Similar to our study, they found no difference in OS and PFS at 2 years based on conditioning intensity. An analysis of 168 patients with HL from the European Blood and Marrow Transplantation Group (EBMT) [11
] noted a trend toward improved 5-year OS after NMA conditioning (28% [95% CI: 18-38]) compared to MA conditioning (22% [95% CI: 13-31%]). Multivariate analysis demonstrated a 2-fold relative risk of decreased survival after MA conditioning. Sorror et al.
] reported that improved OS and lower TRM is only realized in those patients with an HCT-specific comorbidity index score of ≥1 receiving an NMA conditioning regimen (score 1-2: n = 46; score 3: n = 62) compared to MA conditioning (score 1-2: n = 18; score 3: n = 22). Similar to our study, all of these analyses are limited by significant differences in patient characteristics because of selection bias for conditioning intensity based on center specific criteria. Despite this limitation, the data from our study and others suggest that NMA conditioning in older or more heavily pretreated patients is a reasonable therapeutic option.
The heterogeneity of histologic subtypes and disease status in lymphoma confounds outcomes assessment after AlloHCT. An analysis from the EBMT evaluated 188 lymphoma patients after NMA conditioning with a short median follow-up (<1 year) [21
]. The estimated 1-year OS and PFS were 62% and 46%, respectively. The EBMT study found that resistant lymphoma or high grade lymphoma yielded inferior PFS. They reported no effect of donor type on transplant outcomes. In our study, only the use of a mismatched RD/URD or a diagnosis of HL led to decreased PFS. Within the exploratory analysis after NMA conditioning, factors associated with improved PFS included an indolent histology, pretransplant CR or PR, and 2 or more years from diagnosis until transplant. Our data, in conjunction with the EBMT report, suggests that the graft-versus lymphoma effect may be most potent in slow growing and responsive disease. Our outcomes after NMA conditioning are similar to other studies reported [22
In multivariate analysis, we demonstrated a 2-fold increased risk of cGVHD after NMA transplantation compared to MA transplantation. This is somewhat unexpected given that UCB transplant was associated with a lower risk of cGVHD and the majority of UCB recipients received NMA conditioning. Possibilities include the differences in graft source, HLA matching, and GVHD prophylaxis that were confounded by the main effect variable of conditioning intensity. However, our incidence of cGVHD after NMA conditioning is similar to other reports of NMA conditioning for lymphoma [22
]. We also noted a trend toward an increased risk of relapse in patients receiving UCB transplant. This may be correlated with the 2-fold reduction in cGVHD for UCB recipients. This suggests that there may be a correlation between cGVHD and the GVL effect.
Retrospective studies comparing MA and NMA conditioning are confounded by differences in patient characteristics for those who receive either conditioning intensity. Our institutional algorithm dictates conditioning intensity based upon age, extent of prior therapy and comorbidity. The heterogeneity of the lymphomas would require that any prospective studies be designed to study the impact of conditioning intensity with attention to specific histologic subtypes and careful identification of patients suitable for each conditioning approach. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN)-Cooperative Intergroup Study is in development to assess the outcomes of NMA AlloHCT in patients with Follicular NHL, a histologic subgroup where AlloHCT has shown promise [24
We observe that similar transplant outcomes are achieved after AlloHCT with MA conditioning in younger patients compared to NMA conditioning in older patients or those with prior AuHCT. Prospective trials studying NMA conditioning in specific histologic subtypes appropriate for patient age and relevant comorbidities are warranted to define the best application of AlloHCT for NHL.