Page 144 - 2019_06-Haematologica-web

F. Monaco et al.
Causes of death
Twenty-four of 36 patients in Arm A died; GvHD and disease progression were the primary causes of death for nine patients each. In Arm B, 31 out of 41 patients died; progression was the primary cause of death for 15 patients (Table 1).
Overall survival and progression-free survival
In Arm A, OS at one year, two years, and five years were 72%, 61%, and 38%, respectively, and PFS were 68%, 58%, and 35%, respectively. Patients who received TBIatdoseLevels1or2(300cGyor400cGy)inArmB had OS at one year, two years, and five years of 24%, 12%, and 12%, respectively, and PFS of 18%, 12%, and 12%, respectively. Patients in Arm B who received TBI at dose Level-3 (450 cGy) had OS at one year, two years, and five years of 60%, 37%, and 22%, respectively, and PFS of 45%, 33%, and 17%, respectively (Table 2 and Figure 3B and C).
Discussion
In the early 2000s, at Fred Hutchinson Cancer Research Center, a regimen for NMA conditioning using the combi- nation of fludarabine and 200 cGy TBI was developed. This regimen allowed for donor cell engraftment but was characterized by a high incidence of early disease progres- sion or graft rejection,2-5 especially for high-risk patients. In 2006, Scott et al.10 published results on 38 patients affected by MDS or acute myeloid leukemia (AML) who received
an NMA regimen with 3-year rates of OS, PFS, and NRM of 27%, 28%, and 41%, respectively. These results were retrospectively compared with patients who underwent myeloablative conditioning, and no statistically significant differences were seen. Disease progression was the main issue with a cumulative incidence of 31% at three years. Laport et al.11 reported data from our retrospective study on 148 patients diagnosed with MDS or MPN who under- went allogeneic HCT after NMA conditioning. PFS and OS at three years were both 27% for all patients, with a progression incidence of 41%. When stratifying data, PFS rates at three years for patients with de novo MDS (n=40), treatment-related MDS (n=25), MPN (n=27), and CMML (n=7) were 22%, 29%, 37%, and 43%, respectively, and OS rates were 20%, 27%, 43% and 43%, respectively. For all patients, NRM at three years was 32%. In both analy- ses, disease progression was the major cause of treatment failure and the leading cause of death; it appears that this regimen may not have conferred enough cytoreduction for adequate disease control. The data from these retro- spective reviews formed the basis for the current study.
Cliff et al.12 had previously shown that an escalation in TBI dose to 15.75 Gy from 12 Gy reduced relapse/progres- sion (13% vs. 35%). This result demonstrated that a decrease in tumor burden before transplantation led to a decreased risk of disease progression; however, most patients with MDS or MPN are not candidates for mye- loablative TBI conditioning regimens either due to advanced age or comorbidities.
Taking into consideration these data, along with results from pre-clinical studies,13,14 we hypothesized that raising
Table 2. Results.
Overall survival
Arm A TBI dose Level-1(300 cGy) 72 Arm B TBI dose Level-1 or 2 (300–400 cGy) 24 Arm B TBI dose Level-3 (450 cGy) 60
Progression-free survival
Arm A TBI dose Level-1(300 cGy) 68 Arm B TBI dose Level-1 or 2 (300–400 cGy) 18 Arm B TBI dose Level-3 (450 cGy) 45
Relapse incidence
Arm A TBI dose Level-1(300 cGy) 17 Arm B TBI dose Level-1 or 2 (300–400 cGy) 53 Arm B TBI dose Level-3 (450cGy) 24
Non-relapse mortality
Arm A TBI dose Level-1(300 cGy) 17 Arm B TBI dose Level-1 or 2 (300–400 cGy) 29 Arm B TBI dose Level-3 (450 cGy) 31
61 38 12 12 37 22
58 35 12 12 33 17
19 22 53 53 24 32
22 43 35 35 43 51
%at100days %at1year %at2years %at5years
Chronic GvHD 38 45
Arm A TBI dose Level-1(300 cGy)
Arm B TBI dose Level-1 or 2 (300–400 cGy) Arm B TBI dose Level-3 (450 cGy)
Acute GvHD (grades 2-4) 58 Arm A TBI dose Level-1(300 cGy) 56 Arm B TBI dose Level-1 or 2 (300–400 cGy) 65 Arm B TBI dose Level-3 (450 cGy) 57
Acute GvHD (grades 3-4) 13 Arm A TBI dose Level-1(300 cGy) 17 Arm B TBI dose Level-1 or 2 (300–400 cGy) 12 Arm B TBI dose Level-3 (450 cGy) 9
TBI: total body irradiation; GvHD: graft-versus-host disease.
53 35 40
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haematologica | 2019; 104(6)