Delayed Infusion of Allogeneic Stem Cells (72 Hours) Does Not Reduce the Severity of Acute Graft Versus Host Disease in Patients with Chronic Myeloid Leukemia after Myeloablative Conditioning Regimen.

Background: Some animal studies suggested that severity of aGVHD after allogeneic myeloablative hematopoietic cell transplantation (HCT) was affected not only by the histoincompatibility between donor and recipient cells but also by the inflammatory cytokines released during the conditioning regimen. Furthermore it was also shown that delayed transplantation reduced acute GVHD mortality and increased overall survival in normal mice. Our own human studies indicated that delay in stem cells infusion to 72 hours increased the recovery of absolute neutrophil (ANC) and platelet (PLT) counts. Based on these data we hypothesized that delay infusion of stem cells might reduce the incidence and severity of aGVHD without extending the duration of pancytopenia, thus improving OS. Here we retrospectively compared the incidence of grade II-IV aGVHD, time to ANC>500/uL and PLT>50,000/uL recovery and 100-day survival in 65 chronic myeloid leukemia patients from our center¹ who received infusion of stem cells 72 hours (Group-72) to 57 similar patients from the comparable center² but receiving stem cells 24 hours after the end of conditioning regimen (Group-24). Both groups did not differ in the EBMT pre-transplant (Gratwohl) risk score, however more patients (77%) were transplanted with peripheral blood in Group-24 compared to Group-72 (15%). All patients were conditioned with standard dose of busulfan (16mg/kg) and cyclophosphamide 120mg/kg, and received for aGVHD prophylaxis a short course of methotrexate and cyclosporine.

Results: The increase of ANC>500/uL occurred after a median 19 (10–92) days in Group-72 and 20 (13–80) days in Group-24, whereas PLT count> 50,000/uL was achieved at a median of 27 (10–129) days in Group-72 and 22 (12–284) days in Group-24. The probability of reaching ANC>500/ul was not statistically different between two groups (p=0.15) whereas the probability of reaching PLT>50,000/ul was suggestively greater in Group-24 compared to Group-72 (RR=1.44, 95%CI [0.98–2.13], p=0.06). Data of acute GVHD grade were missing in 9 patients from Group-72. Grade II-IV aGVHD was scored in 29 (51%) patients in Group-24 and in 24 (43%) patients in Group-72. The probability of developing grade II-IV aGVHD was similar in both groups (p=0.15). Before day 100, six patients (11%) died in Group-24 and 15 (23%) in Group-72. The probability of 100-day survival was statistically significantly higher in Group-24 (0,89± 0.12) compared to Group-72 (0.76± 0.12), p=0.02. The increased mortality in Group-72 mainly resulted from infectious complications.

Conclusion: Delay in allogeneic transplantation did not decrease the incidence of grade II-IV aGVHD and did not improve overall survival, therefore should not be recommended for further clinical studies.