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A. Nagler et al.
advanced ALL (HR=3.35, 95% CI: 2.3-4.88; P<10-5) were associated with an increased risk of therapy failure, whereas a Karnofsky Performance Score ≥90 was associat- ed with better leukemia-free survival (HR=0.68, 95% CI: 0.5-0.93; P=0.01). Figure 1C shows the adjusted leukemia- free survival in the ATG and PTCy groups.
The 2-year overall survival rates were 27.4% (95% CI: 17.4-37.3) in the ATG group and 48.4% (95% CI: 42.3- 54.6) in the PTCy group (P=0.001) (Table 2, Figure 1D). On multivariate analysis (Table 3), PTCy prophylaxis was associated with better survival compared to ATG prophy- laxis (HR=0.6, 95% CI: 0.42-0.82; P=0.003). Independently of the GvHD prevention strategy, disease status of second complete remission or beyond (HR=1.88, 95% CI: 1.33-2.64; P=0.0003) and advanced ALL (HR=3.13, 95% CI: 2.15-4.55; P<10-5) were associated with lower survival, whereas a Karnofsky Performance Score ≥90 was associated with improved overall survival (HR= 0.96, 95% CI: 0.68-1.38; P=0.001). Figure 1D shows adjusted overall survival in the ATG and PTCy groups.
The 2-year GRFS rates in the ATG and PTCy groups were 20% (95% CI: 10.9-29.1) and 31.8% (95% CI: 26.2- 37.5), respectively (P=0.04) (Table 2). On multivariate analysis there was no significant difference in GRFS between the ATG and PTCy groups (P=0.17) (Table 3). However, disease status of second complete remission or beyond (HR=1.42, 95% CI: 1.05-1.92; P=0.02) and advanced ALL (HR=2.45, 95% CI: 1.73-3.47; P<10-5) were associated with a worse GRFS, whereas a Karnofsky Performance Score ≥90 was associated with a better GRFS (HR=0.77, 95% CI: 0.58-1.02; P=0.07).
Causes of death
At last follow-up, a total of 225 patients had died, including 66 patients in the ATG group (67.3%) and 159 patients (47.3%) in the PTCy group (Table 4). The three most common causes of death in the ATG and PTCy groups were ALL relapse (36.5% vs. 38.1%), GvHD (19.1% vs. 14.2%) and infections (31.8% vs. 30.3%). In the PTCy group, veno-occlusive disease and graft failure was the cause of death in six (3.9%) and three (1.9%) patients, respectively, while in the ATG group no death was attributed to these. Secondary malignancy as a cause of death was limited to one patient in the entire cohort (in the PTCy group).
Discussion
GvHD prevention strategies such as ATG, and more recently PTCy, accompanying unmanipulated haploiden- tical allografts have reinvigorated and ushered in a new era of haploidentical HCT for hematologic malignancies. While ATG is directed against a wide range of epitopes, thus allowing extensive T-cell depletion,24,25 PTCy selec- tively targets alloreactive T cells rapidly proliferating early after an HLA-mismatched transplant, without affecting the non-dividing hematopoietic progenitor cells.12,26 In this study we compared post-transplant out- comes in adult patients with ALL undergoing haploiden- tical HCT using ATG or PTCy platforms as GvHD pro- phylaxis and made some important observations. First, no differences in outcome related to acute GvHD, chronic GvHD and non-relapse mortality were seen between the ATG and PTCy groups. Second, relapse risk was signifi-
Table 4. Causes of death in patients with acute lymphoblastic leukemia undergoing haploidentical transplantation with anti-thymocyte globulin or post-transplant cyclophosphamide as graft-versus-host disease pro- phylaxis.
Cause of Death
ALL relapse
Graft-versus-host disease Infection
Veno-occlusive disease Failure/rejection
Cardiac toxicity
Secondary malignancy
Hemorrhage
Interstitial pneumonitis
Multi-organ failure
Missing
ATG N=66 (%)
23 (37.1)
12 (19.4)
21 (33.9)
0
0
1 (1.6)
0
1 (1.6)
2 (3.2)
2 (3.2)
4
PTCy N=159 (%)
59 (38.6)
22 (14.4)
49 (32.0)
6 (3.9)
3 (2.0)
0
2 (1.3)
4 (2.6)
5 (3.3)
3 (2.0)
6
ATG: anti-thymocyte globulin; PTCy: post-transplant cyclophosphamide; ALL: acute lymphoblastic leukemia.
cantly higher among patients who received ATG than in those who received PTCy. Third, leukemia-free survival and overall survival were both significantly better in patients treated with PTCy than int those treated with ATG, but there was no difference in GRFS between the groups.
The cumulative incidences of GvHD, including grade II-IV acute GVHD, grade III-IV (severe) acute GvHD and chronic GvHD were similar in the ATG and PTCy groups. The incidence of severe acute GvHD in the ATG group (11.6%) is comparable to the incidences in previous observational studies.11,25 Interestingly, in the ALL-specific prospective study by Wang et al., the incidence of severe acute GvHD was only 6% in the group that underwent haploidentical HCT with ATG prophylaxis.27 The inci- dence of severe acute GvHD in the PTCy group in this study (14.6%) is higher than the previously reported 4- 5%.12,15 The higher incidence of acute GvHD may be related to the substantial proportions of patients in this study who were given myeloablative conditioning (76%), TBI (41%), and peripheral blood products (52%) and had advanced disease (20%) at the time of HCT, compared to the proportions in other studies. However, the incidences of chronic GvHD in the ATG (28%) and PTCy (32%) groups are comparable to those in prior reports.11,25,27 It is noteworthy that additional immunosuppression in the ATG group consisted predominantly of cyclosporine/ methotrexate/mycophenolate (42.5%) or sirolimus/ mycophenolate (22.3%), whereas in the PTCy group 85% of the patients received a calcineurin inhibitor (cyclosporine or tacrolimus) with mycophenolate (Table 1).
The incidences of non-relapse mortality in the ATG and PTCy groups were similar (33% vs. 27%, respectively), likely reflecting the similarity in GvHD incidences as noted above. The major causes of non-relapse mortality in both groups were GvHD and infection. Interestingly, in the PTCy group, six patients died of veno-occlusive dis- ease presumably related to myeloablative conditioning with TBI, and three patients from graft failure likely due to more bone marrow grafts being used in this group. However, on multivariate analysis, only advanced disease state (relapsed beyond second complete remission and refractory ALL) was an independent predictor of poor
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