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Z.R. Rogers et al.
AB
Figure 2. Duration of response. Kaplan-Meier analysis of duration of response for (A) all subjects or (B) subjects treated with horse anti-thymocyte globulin (rATG)/cyclosporine (CyA) who achieved at least a partial response.
cohort. Similar time to treatment was noted for the hATG/CyA group, with a median time from diagnosis of 23 days and an IQ range of 12-40 days.
Response
For the cohort of 314 patients and for the subset treated with hATG/CyA, median time to initial response was six months (range: 3-48 months; IQR: 3-12 months). Best responses for all patients and for the hATG/CyA group are summarized in Tables 4 and 5.
For the 264 subjects treated with hATG/CyA, OR was 71.2% (95%CI: 65.3,76.6), consistent with results from prior adult and pediatric studies.8,9,16-20 The quality of response to hATG/CyA was good, with 59.8% (95%CI: 53.7,65.8) achieving a CR. Further, since the magnitude of a partial platelet response carries clinical implications for quality of life, the group attaining a deep response (Plts ≥50x109/L) was separately analyzed. A deep response was achieved by 68.2% (95%CI: 62.2,73.8). No response (NR) was noted in 66 subjects (25%) and 10 subjects (3.8%) were not evaluable (NE, Tables 4 and 5). Responses at six months post hATG/CyA were as follows: CR 21.6%, VGPR 19.7%, PR 8%, NR 47%, NE 3.7%.
The duration of response among subjects who had any initial response (CR, VGPR, or PR) is shown for all subjects (Figure 2A) and for those treated with hATG/CyA (Figure 2B). The estimated probability of sustained response for all subjects was 94% (95%CI: 89,96) at 24 months and 83% (95%CI: 76,88) at 60 months. For the subset of sub- jects treated with hATG/CyA, the estimated probability of sustained response was 94% (95%CI: 90,97) at 24 months and 84% (95%CI: 76,90) at 60 months. However, there was no plateau for loss of response observed over time even after five years post treatment.
Factors potentially affecting OR or DR for subjects treat- ed with hATG/CyA were evaluated. No correlation with response was detected for telomere lengths <1st or <10th percentiles by flow-FISH, presence of a PNH clone, or red cell macrocytosis (mean corpuscular volume ≥100 fL) (P ≥0.17) (Online Supplementary Table S1). There was also no correlation between OR and median lymphocyte count
(1.1 vs. 1.3;Wilcoxon rank sum test, P=0.51). There was no significant difference in median time from diagnosis to treatment between responders and non-responders (P≥0.29) (Online Supplementary Table S1).
Survival
The estimated overall survival is summarized in Figure 3. Median follow up amongst all 314 subjects was 62 months (59 months for those still alive) and 61 months among the hATG/CyA group (59 months for those still alive). At the time of this analysis, there were 29 (9.3%) deaths amongst all subjects; 21 (8%) amongst hATG/CyA- treated patients. Estimated OS (95%CI) for the entire cohort at 12, 24 and 60 months was 96% (95%CI: 94,98), 95% (92,97), and 92% (88,95), respectively (Figure 3A). Among the subjects who received hATG/CyA, estimated OS (95% CI) at 12, 24 and 60 months was 97% (94,99), 96% ( 93,98), and 93% (89,96), respectively (Figure 3B). Six individuals died after one treatment with hATG/CyA without receiving additional therapy.
Of the 314 subjects, 119 (38%) died or required an addi- tional therapy. The estimated EFS (95%CI) for all subjects at 12, 24, and 60 months was 76% (95%CI: 70,80), 71% (95%CI: 66,76), and 62% (95%CI: 56,68), respectively (Figure 3C). The estimated median EFS for all subjects was 133 months. For patients treated with hATG/CyA, 98 of 264 subjects (37%) had an event. Median estimated EFS was 133 months (Figure 3D). Estimated EFS (95%CI) at 12, 24, and 60 months was 76% (95%CI: 70,81), 72% (95%CI: 66,77), and 64% (95%CI: 57,69), respectively, with events continuing to accrue even after five years post treatment.
No differences were detected in OS (P=0.13), EFS (P=0.26), or response (P>0.25) versus age at diagnosis for all subjects. No differences were detected in OS (P=0.09), EFS (P=0.22), or response (P>0.20) versus age at diagnosis for subjects treated with hATG/CyA.
Cytogenetics and clonal progression
Of the 271 patients in the cohort who had BM metaphase cytogenetics (n=254) and/or FISH (n=133)
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haematologica | 2019; 104(10)