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E. Maffini et al.
longer than 100 days post-transplant, 122 developed chronic GvHD requiring treatment. The cumulative inci- dence of extensive chronic GvHD requiring systemic immunosuppression was 46% [95% Confidence Interval (CI): 39.5-52.4] at one year and 55% (95%CI: 47.7-60.7) at five years. No differences in chronic GvHD incidence were observed between related and unrelated recipients. Of all the surviving patients, 24% required immunosup- pressive therapy for chronic GvHD at five years, 12% at ten years and 4% at 15 years, respectively (Figure 1).
Non-relapse mortality - NRM was 2% at day 100, 14% at five years and 15% at ten years after allogeneic HCT, respectively (Figure 2A). GvHD and treatment-related complications accounted for 30 of the 40 non-relapse- related deaths, while 5 patients died of secondary malig- nancies (Table 3) between 0.3 and 15.2 years after allo- grafting and the remaining 5 died from other causes. Of note, no secondary hematologic cancers were observed. By univariate analysis, only the finding of grade II-IV acute GvHD [Hazard Ratio (HR) 3.12; 95%CI: 1.6-6.2; P=0.001] and ISS stage III at diagnosis (HR: 3.92; 95%CI: 2.0-7.6; P<0.001) significantly impacted NRM. Chronic GvHD, poor performance status, and comorbidities were not associated with higher risk of NRM.
Disease response and relapse - After allogeneic HCT, 111 (46%) patients achieved CR, 42 (17%) achieved VGPR, 49 achieved (20%) PR, and 42 (17%) failed to achieve a response (Table 2). Median time to best response after allografting was 6.68 months (range, 0.7-73.4). Among the 111 patients who achieved a CR as their best response, 46 remained in CR while 65 relapsed. Accordingly, the 10- year relapse incidence was 66% (95%CI: 59-72) (Figure 2A). Nineteen (12%) patients had late relapses beyond five years after allogeneic HCT (range, 5.2-9.8 years). Among patients who did not have extramedullary disease at diagnosis and who relapsed after allogeneic HCT (n=112), 28 (25%) showed extramedullary relapse (23 without evidence of marrow involvement). By multivari- ate analysis, ultra-high-risk patients (HR: 4.99; 95%CI: 2.9-8.7) and those with induction therapy-refractory dis- ease before allografting (HR: 5.35; 95%CI: 3.4-8.6) had significantly higher relapse risks. The development of chronic GvHD did not protect against disease relapse (HR, 0.92; 95%CI: 0.6-1.3; P=0.66) (Table 4). Among patients with available marrow samples who achieved CR after allogeneic HCT (n=28), those with positive MRD (MRD- POS) detected by flow cytometry (n=15) experienced a high- er disease relapse rate than MRNEG patients (n=13) (HR: 10.4; 95%CI: 1.3-82.2; P=0.03).
Overall and progression-free survival - With a median fol- low up of 8.3 years (range, 1-18.1), median OS and PFS were 6.4 (95%CI: 3.9-9.2) years and 1.9 (95%CI: 1.4-2.6) years, respectively. Five-year OS and PFS were 54% (95%CI: 48-60) and 31% (95%CI: 25-36), respectively. Ten-year OS was 41% (95%CI: 34-48) and PFS was 19% (95%CI:13-24) (Figure 2B). By univariate analyses, ISS and R-ISS stage III, LDH >2 upper normal limits, high-risk cytogenetics, grade II-IV acute GvHD, extramedullary dis- ease, induction-refractory disease, and a prior failed autol- ogous HCT were all strongly associated with inferior OS and PFS. By multivariate analysis, only high and ultra-high disease risk and induction-refractory disease remained strongly associated with worsened rates of OS and shorter PFS (Table 4). Among patients with standard-risk disease (n=62), the median OS was not reached, whereas the
median PFS was 6.5 (95%CI: 4.2-9.6) years. High-risk patients (n=73) experienced a median OS of 8.4 (95%CI: 3.9-10.2) years with a PFS of 2.5 (95%CI: 1.4-3.7) years, while ultra-high-risk patients (n=79) had a 2.3 (95%CI: 1.2-3.3) years median OS and 0.7 (95%CI: 0.6-0.9) year PFS (Figure 2C and D). Patients who proceeded to tandem transplantation after a previously failed autologous HCT (n=35) had poor outcomes, with a median OS of 1.2 years (95%CI: 0.6-2.0) years and a median PFS of 0.6 years (95%CI: 0.2-0.7). Similarly, patients who progressed after melphalan and autologous HCT (n=42) did poorly, having a median OS of 1.2 years (95%CI: 0.5-3.0) and median PFS of only 0.4 years (95%CI: 0.2-0.6) (Figure 3A and B); medi- an time to relapse was 4.5 (0.1-61.9) months. Patients with extramedullary disease at diagnosis (n=50) showed medi- an OS and PFS of 2.03 (95%CI: 1.0-3.5) and 0.95 (95%CI: 0.46-1.1) years, respectively. Patients achieving CR after allogeneic HCT displayed superior OS (median 14.9 vs. 3.2 years; HR: 3.2; 95%CI: 2.2-4.6), and PFS (median 6.9 vs. 0.9 years; HR: 4.6; 95%CI: 3.4-6.6) as compared with those who did not enter CR.
Maintenance treatments - Between May 2009 and February 2016, 31 patients received post-transplant main- tenance treatment with bortezomib (n=21) or lenalido- mide (n=10) starting between 61 and 150 days (median
A
B
Figure 3. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) stratified for disease-status after autologous hematopoietic cell transplantation (HCT). Overall survival (OS) (A) and progression-free survival (PFS) (B) among patients with progressive disease (n=42; blue line) and respon- ders (n=202; black line).
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haematologica | 2019; 104(2)