A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-risk myelodysplastic syndromes

Abstract

Patients with relapsed/refractory leukemias or advanced myelodysplastic syndrome (MDS) fare poorly following allogeneic hematopoietic cell transplant (HCT). We report prospective phase II study results of 29 patients given clofarabine 30 mg/m2/day i.v. × 5 days followed immediately by HCT conditioning while at the cytopenic nadir. A total of 15/29 patients (52%) were cytoreduced according to pre-defined criteria (cellularity < 20% and blasts < 10%). Marrow cellularity (P < 0.0001) and blast% (P = 0.03) were reduced. Toxicities were acceptable, with transient hyperbilirubinemia (48%) and gr3–4 infections (10%). In all, 28/29 proceeded to transplant; 27 received ATG or alemtuzumab. Post HCT, 180 day non-relapse mortality (NRM) was 7% (95% confidence interval (CI): 1–21), relapse was 29% (95% CI: 13–46) and OS was 71% (95% CI: 51–85), comparing favorably to published data for high-risk patients. Two-year graft vs host disease incidence was 40% (95% CI: 21–58) and 2 year OS was 31% (95% CI: 14–48). Disease at the nadir correlated with inferior OS after HCT (HR = 1.22 for each 10% marrow blasts, 95% CI: 1.02–1.46). For AML/MDS patients, there was a suggestion that successful cytoreduction increased PFS (330 vs 171 days, P = 0.3) and OS (375 vs 195 days, P = 0.31). Clofarabine used as a bridge to HCT reduces disease burden, is well tolerated, and permits high-risk patients to undergo HCT with acceptable NRM. Late relapses are common; thus, additional strategies should be pursued. NCT-00724009.

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.…”

“…In 2013, Locke et al reported phase II study results in 29 patients with MDS or relapsed/refractory leukemia who received a clofarabine bridge. [5] In this report, 15 of 29 patients (52%) achieved cytoreduction. [5,6] They concluded that disease at the nadir correlated with inferior overall survival and that perhaps successful cytoreduction increased both progression free (330 vs. 171 days) and overall survival (375 vs. 195 days), though neither were statistically significant.…”

“…[5,6] They concluded that disease at the nadir correlated with inferior overall survival and that perhaps successful cytoreduction increased both progression free (330 vs. 171 days) and overall survival (375 vs. 195 days), though neither were statistically significant. [5] Tischer et al also published on the feasibility of such a transplant bridge. [6] This report included 18 patients with either AML or acute lymphoblastic leukemia (ALL).…”

Clofarabine in the treatment of myelodysplastic syndromes

“…Among the 24 patients evaluable for response, 8 patients (33%) achieved a CR, CRp or marrow CR and 4 (17%) HI, for an ORR of 50%. With a median follow-up of 4.9 months (range 1.9 --16.7 months), the median OS was 4.8 months (range 0.5 --13.5 months) and the 4-week mortality was 12% [41]. Common non-hematologic adverse events were nausea (31%), headache (24%), rash (28%), elevated liver enzymes (41%) and febrile neutropenia (28%).…”

“…In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with Ara-C also has demonstrated substantial activity against MDS and AML in the older population. Clofarabine can be used as a bridge to transplantation in patients with MDS [41]. The role of clofarabine in MDS will be to improve outcomes by increasing the response rate and decreasing the treatment-related mortality in these patients.…”