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Higher TBI dose improves NMA conditioning HCT for MDS or MPN
graft rejection (defined as <5% donor T-cell chimerism) or disease progression within 200 days of transplant.
Dose escalation was carried out independently in two groups of patients:
• Arm A: patients with MPN, low-risk MDS (MDS-SLD, MDS-MLD, MDS-U, MDS-RS) or PNH;
• Arm B: patients with high-risk MDS (MDS-EB-1) or CMML.
In each arm, up to 24 patients were accrued to each TBI dose level, in groups of 6 patients, with an escalation rule triggered for excessive HCT failure. If 24 patients were successfully enrolled at a TBI dose level without triggering the escalation rule for HCT failure (or other stopping rules), then that dose level would be considered a success and accrual would be closed for that arm. ARM A was modified after completing accrual of 24 patients at a dose level, to allow accrual of up to 12 additional patients at the same dose level while accrual to Arm B continued. Stopping rules for non-relapse mortality and TBI dose escalation continued to be monitored. Cohorts of 6 patients were only defined for purposes of determining dose escalation and stopping rules; the statistical analysis was based on the operating characteristics of a sequence
of cohorts of 6 patients, not on single cohorts.
All patients received FLU 30 mg/m2/day IV for three
days preceding TBI.
The TBI dose levels were:
1. Dose Level 1: 300 cGy TBI 2. Dose Level 2: 400 cGy TBI 3. Dose Level 3: 450 cGy TBI
Dose escalation rules were imposed for HCT failure >20% at day +200. Stopping rules were imposed for NRM at day 200 of >25% in Arm A and >35% in Arm B. Overall survival (OS) and PFS were estimated by the Kaplan-Meier method. Cumulative incidences of relapse, NRM, and acute and chronic GvHD were estimated as previously described.9 All analyses were performed using SAS (SAS Institute, Cary, NC, USA).
Results
Enrollment
The study was opened on March 2006 and was closed to accrual on March 2017. Overall, 79 patients were screened, and 77 patients were enrolled. Patients’ and
Figure 1. Flow diagram of the progress through the phases of the study. MDS: myelodysplastic syndrome; MPN: myelopro- liferative neoplasm; PNH: paroxysmal noc- turnal hemoglobinuria; CMML: chronic myelomonocytic leukemia; TBI: total body irradiation; cGy: centigray; n: number.
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