Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy

Abstract

Reduced conditioning intensity has extended the option of allogeneic hematopoietic stem cell transplantation to patients who cannot tolerate fully myeloablative regimens. However, relapse and graft-versus-host disease (GVHD) continue to be major causes of morbidity and mortality. We prospectively tested whether a moderate reduction of the intensity of the preparative regimen would lead to significant reduction in regimen-related toxicity without compromising tumor control in a cohort of 44 patients ineligible for conventional hematopoietic stem cell transplantation. Patients were conditioned with fludarabine, busulfan, mycophenolate, and total lymphoid irradiation. Tacrolimus and methotrexate were given as prophylaxis for GVHD. Donors were 5 of 6 or 6 of 6 matched family members. The median age was 61 years. Eleven patients had comorbid conditions that precluded conventional myeloablative transplantation. Fatal regimen-related organ toxicity occurred in 3 patients. The cumulative incidence of grade 2 to 4 or grade 3 to 4 acute GVHD by day 100 was 38% (95% confidence interval [CI] = 25%, 55%) and 20% (95% CI = 10%, 39%), respectively, with a median time to onset of 66 days. For the entire cohort, 1-year overall survival, disease-free survival, and relapse rates were 54% (95% CI = 41%, 71%), 47% (95% CI = 35%, 65%), and 37% (95% CI = 19%, 51%), respectively. Outcomes differed based on stage of disease at time of transplantation, advanced (n = 19) versus nonadvanced (n = 25). Median survival times were 138 days and 685 days for subjects with advanced and nonadvanced disease, respectively (P =.005). After adjusting for age and comorbidity, disease stage continued to be significantly associated with overall survival (P =.005). In conclusion, a moderate reduction in conditioning dose intensity resulted in delayed onset of acute GVHD (compared with historical controls). A reduction in conditioning intensity is associated with poor survival for patients with advanced-stage disease, highlighting the importance of the conditioning regimen for tumor control.

Impact of human leucocyte antigen mismatch on graft‐versus‐host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors

“…Our finding, that HLA disparity impacts on grade II-IV aGVHD in patients receiving RICT, was quite consistent with earlier findings in conventional myeloablative SCT (Beatty et al, 1985;Ringden & Nilsson, 1985;Anasetti et al, 1990;Anasetti & Hansen, 1994;Sasazuki et al, 1998;Morishima et al, 2002;Kanda et al, 2003), but has not been well described in the setting of RICT. The cumulative incidence of grade II-IV aGVHD after HLAmatched RICT was 39% in this study population, which is similar to that in recent reports from other groups following RICT (Levine et al, 2003;Martino et al, 2003;Wong et al, 2003;Bacigalupo, 2004;Diaconescu et al, 2004;Goggins & Rizzieri, 2004), although a recent retrospective comparison of myeloablative SCT with RICT conditioned with 2 Gy TBI and fludarabine showed less aGVHD after RICT in matched unrelated donor transplants .…”

Functional Evaluation of GJB2 Variants in Nonsyndromic Hearing Loss

“…This trial is based on the institutional experience of GVHD with RIC regimens. Prior experience with this approach showed a 42% incidence of grades II-IV GVHD, with a 50% two-year survival rate (204). The trial is now built on this experience to evaluate whether adding HDACi, SAHA (vorinostat) will reduce the incidence of grade II-IV GVHD to 25%.…”

Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantation

“…Today, some transplants are performed using reduced-intensity non-myeloablative treatments which decrease the toxicity and neutropenia associated with the more aggressive treatments. However, this is not always advantageous since, in the case of HSCT for cancer, there is a higher chance of relapse [56].…”