Characteristics of Patients and Grafts
One hundred-and-eight RD-T, 184 URD-T, and 75 CB-T consecutive patients fulfilled eligibility criteria. Patient and graft characteristics are summarized in . All three groups had similar age, gender, weight, recipient cytomegalovirus (CMV) seropositivity, and disease risk. A similar percentage had acute leukemia, with a similar proportion of AML and ALL among the 3 HSC sources. A higher percentage of RD-T and URD-T recipients had MDS, and a higher percentage of CB-T recipients had lymphoma. Consequently, a higher percentage of CB-T recipients had had a prior autologous transplant. The majority of the patients in the 3 groups received myeloablative conditioning. Approximately two-thirds of RD-T and URD-T grafts were T-cell depleted, whereas all CB grafts consisted of double units and were unmodified.
Nearly all (98%) RD-T recipients received grafts that were 10/10 HLA-allele matched, and the majority (60%) of URD grafts were 10/10 HLA-allele matched. CB units were markedly HLA-mismatched at high resolution. While the donor-recipient HLA-match of CB units was 6/6 (n = 5), 5/6 (n = 82), or 4/6 (n = 63) at HLA-A and -B antigens and -DRB1 alleles, units were only a median of 6/10 HLA-allele matched (range 2-9/10) to the patient. CB-T recipients also received more than a log less cells as compared to non-CB-T recipients.
Neutrophil and Platelet Engraftment
The incidences of engraftment after transplantation of the three HSC sources are compared in . Recipients of myeloablative CB-T had a slower neutrophil recovery than myeloablative RD-T or URD-T recipients (p < 0.001). However, there was no difference between the 3 transplant groups in the speed of neutrophil recovery after non-myeloablative conditioning. The 93% (95%CI:87-99) cumulative incidence of sustained neutrophil engraftment after CB-T was accounted for by one unit in nearly all patients, and was lower than the other HSC sources. Five CB-T recipients had graft failure. Four received myeloablative conditioning and had primary (n = 3) or early secondary (n = 1) graft failure. In these patients, early onset multi-organ failure on days 7 and 11 (n = 2), early CMV infection (n = 1), and human herpesvirus 6 viremia18
(n = 1) may have contributed to the failure of engraftment. One additional non-myeloablative CB-T recipient had primary graft failure with autologous recovery.
Comparison of engraftment, GVHD, relapse and survival endpoints after RD-T, URD-T, and CB-T: 2 year OS and PFS after CB-T, RD-T, and URD-T were similar.
By contrast, only one graft failure was seen in a RD-T recipient. This patient had secondary graft failure 4 months after a myeloablative T-cell depleted 10/10 HLA-matched RD graft, but achieved sustained donor engraftment after a stem cell boost. None of the unmodified URD-T recipients had graft failure. However, among recipients of URD myeloablative T-cell depleted grafts, 10 (eight 8-9/10 HLA-matched, and two 10/10 HLA-matched) had secondary graft failure. Six of these patients were successfully treated, and one had spontaneous recovery of donor hematopoiesis. Thus, only 3 URD-T recipients had sustained failure of donor-derived neutrophil engraftment.
The cumulative incidence of day 180 platelet engraftment to > 50 × 109/l was 80% (95%CI:71-89) in CB-T recipients and occurred at a median of 51 days (range 35-182) for recipients of myeloablative conditioning and 38 days (range 21-59) for non-myeloablative recipients. This incidence of recovery was lower than both RD-T recipients [99% (95%CI:96-100)], and URD-T recipients [93% (95%CI:89-97)] (p <0.001). The subset of CB-T recipients alive at day 100, however, had a 97% (95%CI:92-100) incidence of sustained platelet engraftment by day 180. This was lower than the 100% (95%CI:98-100) rate observed in RD-T recipients (p = 0.035), but similar to the 98% (95%CI:95-100) rate seen in URD-T recipients (p = 0.215), alive at day 100
Acute and Late Acute/ Chronic GVHD
The cumulative incidence of grade II-IV acute GVHD at day 100 was 43% (95%CI:31-54) in CB-T recipients. This was not different to that of unmodified RD-T or unmodified URD-T recipients (p = 0.326) ().
The cumulative incidence of late acute/ chronic GVHD at 1 year in CB-T recipients was 28% (95%CI:18-38) () and consisted predominantly of ongoing acute GVHD after day 100 or overlap syndromes. This was similar to the 31% (95%CI:15-47) 1-year incidence of unmodified RD-T recipients, but lower than the 44% (95%CI:31-58) 1-year incidence of unmodified URD-T recipients (p = 0.015). When compared to T-cell depleted grafts, the incidence of late acute/ chronic GVHD at 1 year in CB-T was higher than the 12% (95%CI:4-20) incidence of RD-T recipients, but the difference with the 19% (95%CI:12-27) incidence URD-T recipients did not reach significance (p = 0.072).
Relapse or Disease Progression
The overall cumulative incidence of relapse/ progression was not different between the three groups (p = 0.813) (). Only one of the 27 CB-T recipients with a myeloid malignancy relapsed. The risk for relapse or progression was higher among patients with high-risk disease (data not shown).
The 2 year TRM after CB-T, RD-T, and URD-T were not different: 25% (95%CI:15-35), 15% (95%CI:8-23), and 27% (95%CI:20-34), respectively (p = 0.183, and ). Notably, the early TRM in the first 180 days after CB-T was 21% (95%CI:12-31). This compared to 8% (95%CI:3-14) after RD-T (p = 0.017), and 13% (95%CI:8-18) after URD-T (p = 0.123). However, this was compensated for by a relatively low TRM after day 180 in CB-T recipients.
The cumulative incidence of TRM after CB-T, RD-T, and URD-T: increased early mortality after CB-T was compensated for by reduced late mortality such that the 2 year TRM after CB-T was not different to that of RD-T and URD-T recipients.
With a median follow-up of 22 months (range 6-52), 65% (95%CI:55-77) of CB-T recipients were alive at 2 years. This OS was similar to that seen in RD-T recipients [70% (95%CI:61-80)], and URD-T recipients [62% (95%CI:54-70)] (, ). There was also no difference in the PFS (p = 0.573), with the 2 year PFS of 55% (95%CI:45-68) in CB-T, 66% (95%CI:57-76) in RD-T, and 55% (95%CI:48-64) in URD-T recipients as shown in and .
The Kaplan-Meier incidence of OS after CB-T, RD-T, and URD-T: OS after CB-T was similar when compared with RD-T and URD-T.
The Kaplan-Meier incidence of PFS after CB-T, RD-T, and URD-T: 2 year PFS after CB-T was not different to that of RD-T and URD-T recipients.
Multivariate Cox regression analysis showed that the HSC source was not associated with PFS [RD-T versus CB-T hazard ratio 0.68 (95%CI:0.39-1.20), p = 0.185; URD-T versus CB-T hazard ratio 0.78 (95%CI:0.47-1.29), p = 0.329]. The method of GVHD prophylaxis was also not significant [unmodified versus TCD hazard ratio 0.83 (95%CI:0.55-1.25), p = 0.362]. The only significant factors were age at transplantation [increasing age per 5 years hazard ratio 1.07 (95%CI:1.02-1.11), p = 0.005], and high-risk disease [high-risk versus standard-risk disease hazard ratio 2.48 (95%CI:1.33-4.60), p = 0.004].
Causes of Death
In order to better understand the causes of early versus late mortality after CB-T, a detailed cause of death analysis was performed in these patients (). Overall, the percentage of CB-T recipients who died before day 180 post-transplantation was 25% (19/75) , as compared to 14% (15/108) of RD-T, and 16% (29/184) of URD-T recipients. Organ failure was the leading cause of early mortality in CB-T recipients (n = 7/19, 37%). Organs involved included lung (n = 4), liver (n = 2), and central nervous system (n = 1). This was followed by early deaths due to graft failure, relapse, and GVHD, with the least common primary cause of early mortality being infection. The leading cause of early mortality in RD-T recipients was relapse and in URD-T recipients was GVHD.
Primary cause of death after CB-T: a relatively low incidence of late mortality compensated for a higher early post-transplant mortality.
Notably, however, the increased early mortality after CB-T was compensated for by a decreased late mortality after day 180, which was observed in only 7/56 (13%) of CB-T recipients alive at day 180. This compared with 17/93 (18%) of RD-T, and 38/155 (25%) of URD-T recipients alive at day 180. The leading cause of late mortality in CB-T recipients was relapse (n = 5, 71%), with no late deaths from graft failure, organ failure, or infection. The leading cause of late mortality in both RD-T and URD-T recipients was also relapse, followed by GVHD.
A comparison of the causes of death in the first 2 years after transplantation of the 3 HSC sources is shown in . Overall, relapse was the leading primary cause of death in each group. Further, GVHD was as common as graft failure as a primary cause of death after CB-T.
Figure 4 Comparison of causes of death in the 2 years post-transplant according to HSC source: relapse followed by organ failure were the most frequent primary cause of death in RD-T and CB-T recipients, whereas relapse and GVHD were the most frequent primary (more ...)
Comparison of Transplant Outcomes after RD-T, URD-T and CB-T in Patients with Acute Leukemia
The subset of 202 patients (64 RD-T, 99 URD-T, and 39 CB-T) with acute leukemia was analyzed in order to compare outcomes of a more uniform patient group. A similar percentage of the 3 sub-groups were adults and they had similar genders, weights and rates of CMV seropositivity (). Nearly all patients received myeloablative conditioning. However, CB-T recipients had more advanced disease with only 19 (49%) in first CR as compared to 47 (73%) of RD-T and 59 (60%) URD-T recipients (p = 0.048). Outcomes are compared in . Rates of neutrophil and platelet engraftment, and acute GVHD were similar to those observed in the overall analysis. There was no difference in the incidence of late acute/ chronic GVHD among unmodified RD-T, unmodified URD-T, and CB-T recipients (p = 0.915).
Demographics and graft characteristics in patients with acute leukemia: while CB-T recipients were younger, a similar percentage were adults, and CB-T recipients had more advanced disease.
Comparison of transplant outcomes after RD-T, URD-T, and CB-T in patients with acute leukemia: 2 year disease-free survival after CB-T, RD-T and URD-T were similar.
As in the entire dataset, a relatively high mortality in the first 180 days post-transplant in CB-T recipients with acute leukemia was compensated by a reduced late mortality. Most notably, the incidence of relapse over the first 2 years post-transplant was low in CB-T recipients at only 5% (95%CI: 0-12) (, p = 0.072 by log rank analysis). Statistical comparison of the 2 year relapse incidence using the Wald test showed this 5% incidence after CB-T was significantly lower than that of all RD-T recipients (p = 0.007), and URD-T recipients transplanted with T-cell depletion (p = 0.008), and similar to that seen after unmodified URD-T (p = 0.686). Over the entire follow-up period, the OS (p = 0.491), and disease-free survival (p = 0.482) in patients with acute leukemia were similar among the three transplant groups by log rank analysis.
Comparison of relapse after CB-T, RD-T, and URD-T in patients with acute leukemia transplanted in remission: CB-T recipients had a low risk of relapse.