Fludarabine phosphate and melphalan: a reduced intensity conditioning regimen suitable for allogeneic transplantation that maintains the graft versus malignancy effect

Abstract

Reduced intensity conditioning (RIC) for allogeneic stem cell transplantation allows stable donor cell engraftment with the maintenance of a graft versus malignancy effect. Many different regimens exist employing various combinations of chemotherapy, radiotherapy and T-cell depletion. We examined the role of non-T-cell depleted RIC regimens in 56 patients with haematological malignancies. Patients received fludarabine phosphate for 5 days (30 mg/m 2 in 35 patients, 25 mg/m 2 in 21 patients) and melphalan for 1 day (140 mg/m 2 in 36 patients, 100 mg/m 2 in 20 patients). Immunosuppression was with CyA alone in 33 patients and CyA/MTX in 23 patients. Twenty-four of the 26 patients with chimerism data showed 495% donor chimerism at 3 months post transplant. aGVHD occurred in 18% of patients receiving CyA/MTX compared to 53% of patients receiving CyA. The 100-day mortality rate was 0.16 (95%CI 0.08-0.28) and 1-year nonrelapse mortality was 0.24 (95%CI 0.13-0.38). Thirty-three patients remained alive and in CR at a median of 19 months post transplant (range 3-38 months). We have shown that patients transplanted with fludarabine phosphate, melphalan 100 mg/m 2 and with CyA/MTX as post transplant immunosuppression can achieve good disease control with an acceptable level of toxicity. Further studies are required to confirm these findings.

Phase II prospective study of treosulfan-based reduced-intensity conditioning in allogeneic HSCT for hematological malignancies from 10/10 HLA-identical unrelated donor

“…We did not observe any increase in hepatic, cardiac, CNS, or pulmonary toxicities as reported in studies that used either MAC or RIC based on busulfan, melphalan, or total body irradiation [11,[29][30][31][32]. Nevertheless, we observed three cases of EBV infections that lead to later lymphoma development.…”

“…Acute and chronic GVHD Seventeen patients developed acute GVHD ≥grade II (eight grade II, two grade III, and seven grade IV) with a cumulative incidence at 3 months of 31% (95% CI, [25][26][27][28][29][30][31][32][33][34][35][36][37][38]. The cumulative incidence of chronic GVHD at 12 months was: 32% (95% CI, 25-39) limited and 6% (95% CI, 2-10) extensive and at 18 months was 34% (95% CI, 27-47) limited and 8% (95% CI, 5-12) extensive.…”

Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan

“…17 On the other hand, the NRM rate associated with the FM regimen in the current study was 40%, very similar to the original report by Giralt et al, 8 reaching 45%, 2 years after SCT, and was 20-40% in most other series. [23][24][25][26][27][28][29][30] These rates are more similar to those associated with myeloablative conditioning in patients eligible for such therapy. The high NRM was related to increase in the rate of organ toxicity, but to a larger extent due to increase in the incidence of acute GVHD.…”

CD34+ cell dose and establishment of full donor chimerism at day +100 are important factors for survival with reduced-intensity conditioning with fludarabine and melphalan before allogeneic hematopoietic SCT for hematologic malignancies

“…5 Its use results in the rapid establishment of donor chimerism, excellent rates of engraftment and a reduction in relapse risk compared with other RIC regimens. [6][7][8] Fludarabine/melphalan RIC also has proven tolerable in patients who have failed a previous autologous or allogeneic HSCT, although a high rate of relapse as well as late complications of HSCT may adversely affect outcome in this high-risk group of patients. 9 Because those who undergo RIC allogeneic HSCT have either a guarded prognosis from a disease or comorbidity standpoint or both, we sought to determine modifiable factors associated with survival to identify potential therapeutic targets to improve outcome in this group of patients.…”