Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning: A Novel Regimen Inducing Immunosuppression Without Myelosuppression

We previously reported the use of BFR, with phase 1 escalating daily doses of 70, 90, 110, or 130 mg/m² of bendamustine daily x 3 days prior to transplantation without dose-limiting toxicity (Khouri et al. ASH 2011, Abstract # 894). In this study, we report results of an expanded phase 2 trial.

Bendamustine 130 mg/m² IV daily on days -5 to - 3 prior to transplantation , together with 30 mg/m² IV of fludarabine given on the same days. Rituximab was given at a dose of 375 mg/m² IV on day –13 and 1000 mg/m² on days -6, +1, and +8, as previously described. Rituximab was omitted in patients with T-cell diseases. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant.

The analysis included all 56 patients who received BFR (48 from the expanded phase 2 trial, and 8 from the phase 1 part). Histologies included: mantle cell (n=16), CLL (n=15) (3 with 17p- and 2 Richter’s), follicular (n=13), Diffuse large cell (n=9), peripheral T-cell lymphoma (n=3). Median age was 56 (range, 59-70) years. Median prior treatments was 3 (range, 1-7); 7 (12%) had failed a prior autotransplant. At study entry,27 (48%) patients were in CR/CRu, 23 (41%) in PR, and 6 (11%) had refractory disease. Thirty (54%) received their transplants from HLA-compatible siblings and 26 (46%) from unrelated donors. Median number of CD34-positive cells infused was 5.58 x 10⁶/kg. Neutrophil counts recovered to > 0.5 x 10⁹/L a median of 6 days after transplantation (range, 0-16 days). The median number of days on G-CSF was 1.5 days (range, 0-8 days). Thirteen patients (23%) did not require G-CSF as they never experienced an ANC < 0.5 x 10⁹/L. Forty-nine patients (87.5%) did not require platelet transfusions. Platelet counts recovered to > 20 x 10⁹/L in the remaining 7 patients after a median of 11 days (range, 10-19 days). All patients engrafted donor cells. By day 30, median donor myeloid and T-cells were 85% and 97%, respectively. Both increased to 100% by day 90. Recovery of donor cells was similar in both sibling and unrelated donor transplantation. Acute grade 2-4 GvHD and chronic extensive GvHD were observed in 7 (12.5%) and 8 (14%) of patients respectively. Treatment-related mortality at 1-year was 9%. Six patients died: 2 of progression, 2 of infection and 2 of GVHD complications. With a median follow-up time of 12 months (range, 2-37 months), the OS and PFS rates were 89% and 80%, respectively.

Our results show that the BFR regimen with bendamustine at a dose level of 130 mg/m² daily x 3 days, constitutes a well-tolerated nonmyeloablative allogeneic conditioning for lymphoid malignancies. It allows engraftment of both sibling and unrelated donor cells with minimal myelosuppression. This regimen can be used as a platform for allogeneic transplantation in the outpatient setting.

Khouri:Cephalon: Research Funding. Off Label Use: Bendamustine in transplantation.