This study includes 623 consecutive patients undergoing myeloablative transplantation using TBI at the University of Minnesota between 1980 and 2005. Patient demographics and transplant characteristics for all patients and a secondary cohort of only allogeneic HCT recipients with ALL in CR1 or second complete response (CR2) treated from 1990 to 2005 are presented in . The majority of patients were male (63%). The median age of patients was 13 years, ranging from 6 months to 55 years at transplant. One third were older than the age of 18 and 15% were older than 35 years. Approximately one third of patients (n = 209) received an autologous transplant. Of the whole group, 39% had a matched RD (n = 245), 16% received URD grafts (n = 100; 58 of 100 were HLA mismatched), and 11% received an UCB graft (n = 69; 48 single, 21 double units). Approximately one fourth of patients received transplant in CR1, half in CR2, and the remainder in third or later CR (CR3+) or in relapse. Median follow-up of survivors was 8.3 years (range, 1 to 23 years).
OS at 5 years was poorest for patients receiving either autologous (17%; 95% CI, 12% to 22%) or MM-URD sources (28%; 95% CI, 17% to 39%), while OS was similar for recipients of RD (95% CI, 34% to 49%), WM-URD, PM-URD, and UCB grafts (A). In multivariate analysis, compared to transplantation in first CR, HCT during CR2 or later led to significantly lower OS (). Of note, the survival curves (A) show only few events (53 of 445 deaths; 12%) beyond 2 years after transplantation, even with follow-up to nearly 23 years. Older age, female sex, WBC ≥ 30,000/μL at diagnosis, and CMV seropositivity in either donor or recipient were all associated with significantly poorer OS ().
Fig 1. Transplant outcomes by donor group for 623 acute lymphoblastic leukemia patients who underwent myeloablative hematopoietic cell transplantation. (A) Overall survival; (B) Leukemia-free survival; (C) treatment-related mortality. MM, mismatched; URD, unrelated (more ...)
Outcomes for Patients Undergoing Myeloablative HCT for Acute Lymphoblastic Leukemia: Multivariate Analyses (n = 623)
RD, WM-URD, PM-URD, and UCB HCT led to similar 5-year LFS (95% CI, 31% to 44%; B). As with OS, LFS was lower using autologous or MM-URD, although these differences were at the margin of statistical significance (P = .07; ). In multivariate regression, LFS was superior for younger patients, patients who received transplants in CR1, WBC lower than 30,000/μL at diagnosis, and CMV seronegativity for both donor and recipient ().
Similar results were seen in an analysis of the 203 adult patients undergoing HCT for ALL. At 5 years, OS ranged from 0% (MM-URD and PM-URD) to 51% for UCB. In multivariate analysis of the adult recipients, OS at 5 years was poorest for MM-URD (relative risk [RR], 2.7; 95% CI, 1.5 to 4.6; P < .01) and best for UCB (RR, 0.3; 95% CI, 0.2 to 0.7; P < .01) compared to sibling donor sources. LFS for the 203 adults showed a similar trend as in the entire cohort, ranging from 0% (MM-URD and PM-URD) to 63% for UCB. In multivariate analysis, LFS was inferior for MM-URD (RR, 2.3; 95% CI, 1.3 to 3.9; P < .01) and improved with UCB (RR, 0.5; 95% CI, 0.2 to 0.9; P = .02) compared to related donors.
The cumulative incidence of TRM at 2 years was 66% for MM-URD versus 17% for autologous, 29% for RD, 32% for WM-URD, 35% for PM-URD, and 27% for UCB (P < .01; C). Factors significantly associated with higher TRM include older age, transplant in CR3, CMV seropositivity of either donor or recipient, and grade 3-4 acute GVHD ().
At 5 years, 68% of autologous and 9% to 37% of the allogeneic donor subgroups had relapsed (P < .01). As presented in , the RR of relapse was more than two-fold higher for autologous transplants than for other donor sources (P < .01). In multivariate regression, there was a strong trend (P = .06) for a lower risk of relapse with MM-URD graft recipients while other URD and UCB recipients had relapse risk similar to RD HCT. Other factors significantly associated with relapse included female sex, transplant in CR2 or later, and T-lineage ALL. Augmented conditioning with agents in addition to CyTBI (n = 217) had no significant protective impact on either relapse or TRM. The development of grade 2 to 4 acute GVHD was associated with a significantly lower RR of relapse (RR, 0.6; 95% CI, 0.4 to 0.9; P < .01; ). There was no significant interaction between the protective antileukemic effect of GVHD and either disease status at HCT or donor source.
Allogeneic HCT in CR1 and CR2 (1990 to 2005)
In order to examine a more contemporary population of patients undergoing allogeneic HCT, we restricted the analysis to include only patients in CR1 and CR2 who received transplants between 1990 and 2005. The patient demographics for this cohort were similar to the larger population, except that a larger proportion of patients received transplantation in CR1 and a larger proportion had UCB transplants (). B-lineage ALL was noted in 70%, T-lineage in 10%, 44% had WBC higher than 30,000/μL, and 18% had Philadelphia chromosome–positive ALL. Of the 141 CR2 patients, 31 (22%) had a CR1 duration shorter than 1 year. In this more recent cohort, the median follow-up of survivors was 5.8 years (range, 1 to 14.5 years).
As shown in A, at 5 years post-HCT overall survival was 42% for RD (33% to 51%), 42% for WM-URD (95% CI, 14% to 70%), 38% for PM-URD (95% CI, 18% to 58%), 31% for MM-URD (95% CI, 17% to 45%), and 51% for UCB (95% CI, 46% to 66%; P = .12). Compared to transplantation in CR1, patients who received transplantation in CR2 with shorter CR1 (< 1 year) had significantly poorer OS, while longer CR1 followed by HCT in CR2 had a similar OS as in CR1 (). Multivariate regression showed that MM-URD, older age, and WBC ≥ 30,000/μL at diagnosis were associated with significantly poorer OS while HCT during more recent years (2000 to 2005 v earlier) led to significantly better OS.
Fig 2. Transplant outcomes by donor group for 242 acute lymphoblastic leukemia patients who underwent myeloablative hematopoietic cell transplantation from 1990 to 2005. (A) Overall survival; (B) leukemia-free survival; (C) treatment-related mortality. MM, mismatched; (more ...)
Outcomes for Acute Lymphoblastic Leukemia Patients in CR1 or CR2 Undergoing Myeloablative Allogeneic HCT From 1990-2005: Multivariate Analyses (n = 242)
LFS at 5 years yielded similar results, ranging from 27% for MM-URD (95% CI, 14% to 40%) to 49% for UCB recipients (95% CI, 34% to 64%; P = .09; B). As with OS, LFS was inferior using MM-URD, while LFS after allogeneic HCT from all other donor sources was approximately equivalent. LFS was significantly better for younger patients, those with WBC counts lower than 30,000/μL at diagnosis and was improved in more recent years (2000 to 2005 v earlier; ). Patients who received transplantation either in CR1 or in CR2 with long CR1 had significantly better LFS than CR2 after a short CR1.
The cumulative incidence of TRM at 2 years was 62% for patients who received transplantation with MM-URD sources, versus 26% for RD, 33% for WM-URD, 38% for PM-URD, and 24% for UCB (P < .01, C). Predictors of higher TRM include older age, WBC higher than 30,000/μL, grade 3 to 4 acute GVHD, and transplant in CR2 after short CR1 (). TRM was progressively and significantly lower since 1995 for recipients of RD, WM-URD, PM-URD, or UCB donor sources.
Relapse incidence in these CR1 and CR2 HCT recipients were similar across all allogeneic donor sources (P = .33). Multivariate analyses showed a trend to greater relapse in CR2 after brief CR1, but no reduction in relapse rates over the period of the study. Patients with grade 2 to 4 acute GVHD had a significantly lower RR of relapse ().
Analysis of the 91 adult patients undergoing HCT for ALL in CR1 or CR2 between 1990 and 2005 showed no differences between the allogeneic donor sources for OS, LFS, or TRM. There were trends toward improved OS (RR, 0.4; 95% CI, 0.1 to 1.1; P = .08) and LFS (RR, 0.4; 95% CI, 0.2 to 1.1; P = .09) for UCB donor sources compared to matched sibling HCT. There was also a trend toward poorer TRM for MM-URD sources (RR, 2.1; 95% CI, 0.9 to 3.6; P = .07). In these adults, UCB donor grafts were associated with significantly lower risk of relapse (RR, 0.1; 95% CI, 0.02 to 1.0; P = .05).
Acute and Chronic GVHD
Among the CR1 and CR2 allograft recipients, the cumulative incidence of acute GVHD at 100 days was 45% for grade 2 to 4 (95% CI, 39% to 51%) and 16% for grade 3 to 4 (95% CI, 12% to 20%). As presented in , there was no difference in the incidence of grade 2 to 4 acute GVHD between RD and WM-URD sources while PM-URD, MM-URD, and UCB grafts were all associated with a significantly higher, but similar RR. No change in the incidence of acute GVHD was noted by year of transplant. As expected, older patients had a higher RR of grade 2 to 4 acute GVHD (). Grade 3 to 4 acute GVHD occurred most frequently with 29% for MM-URD (95% CI, 16% to 42%) compared to 11% (95% CI, 6% to 16%), 0%, 24% (95% CI, 6% to 42%), and 16% (95% CI, 6% to 26%) after RD, WM-URD, PM-URD, and UCB, respectively (P = .01).
Acute and Chronic GVHD for Acute Lymphoblastic Leukemia Patients in First Complete Response or Second Complete Response Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation From 1990-2005: Multivariate Analyses (n = 242)
Chronic GVHD at 2 years developed in only 18% (95% CI, 13% to 23%) of patients. The risk was significantly (> three-fold) higher in MM-URD compared to all other donor sources. RD and UCB recipients had similar risks of chronic GVHD. WM-URD and PM-URD also had apparently higher RRs (1.9 and 2.1, respectively) of chronic GVHD though the differences were not statistically significant. Older recipients also developed more frequent chronic GVHD. No difference in chronic GVHD was noted by year of transplant. Somewhat surprisingly, patients with WBC of ≥ 30,000/μL at diagnosis had a lower RR of chronic GVHD.