Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial

Abstract

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.

Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) as a Novel Therapeutic Target in Multiple Myeloma

“…To assess the potential clinical relevance of RRM1 inhibition in MM, we next examined the effect of the purine nucleoside antimetabolite CLO, an RRM1 inhibitor that is approved for the treatment of acute lymphocytic leukemia [26–30], on MM cell lines (NCI-H929, MM.1S, MOLP-8, RPMI8226, OPM2, U266, and KMS-11). TP53-wild type cells (NCI-H929, MM.1S, and MOLP-8) were more sensitive to CLO treatment compared to TP53-mutant (RPMI8226, OPM2, and U266) or TP53-null (KMS-11) cells (Figure 5A).…”

Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

“…Clofarabine is a nextgeneration purine analog with significant antileukemic activity, particulary in relapsed AML and acute lymphoblastic leukemia. [14][15][16][17][18] We found that a RIC regimen combining clofarabine, bulsulfan and anti-thymocyte globulin was safe, with a 1-year NRM rate of 6%, and allowed efficient disease control in AML patients in CR. 19 Thus, the use of clofarabine as an alternative to fludarabine in the setting of RIC allogeneic SCT appears to be very attractive.…”

Clofarabine as a bridge to hematopoietic stem cell transplant

“…[1][2][3] Previous retrospective and small phase-II studies suggested utility of clofarabine as 'bridge' to transplant in patients with active disease when followed by a reduced intensity conditioning regimen. [4][5][6][7] We sought to confirm these findings by examining survival following a clofarabine bridge to HSCT. Clofarabine is currently approved in the United States for the treatment of acute lymphoblastic leukemia (ALL) in children and has been used off label for the treatment of ALL and AML in adults.…”