Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study

Abstract

Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

“…Apart from the non‐negligible incidence of early toxicity, we found clofarabine‐TBI to be well‐tolerated, as did a recent multicenter phase I trial of clofarabine‐2 Gy TBI as conditioning for pediatric patients (median 9 years old, range 1‐21) with acute lymphoblastic leukemia (n = 11) or AML (n = 7) . Other studies found that clofarabine in cumulative doses ranging from 120 to 300 mg/m 2 could be incorporated into alkylator‐based HCT conditioning regimens.…”

Gamma-Tocotrienol Protects the Intestine from Radiation Potentially by Accelerating Mesenchymal Immune Cell Recovery

“…TBI is used to treat hematopoietic malignancies and solid tumors. Further, TBI and chemotherapeutic drugs are routinely used to prepare patients for hematopoietic stem cell transplants [25,26,27,28,29]. In addition, astronauts are continuously exposed to chronic doses of TBI during their entire period of a space mission.…”

The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia

“…Other studies in relapsed/ refractory leukemia and myelodysplastic syndrome patients have also demonstrated tolerability and low transplantrelated mortality rates with 2 year OS of 31% (CI 95 14-48) utilizing single agent clofarabine with HSCT or clofarabine in combination [23]. The recent CLORIC as well as other trials investigated reduced toxicity conditioning regimen with clofarabine, busulfan, and ATG in high risk leukemia and myelodysplastic syndrome patients [24]. The CLORIC study reported a 1-year OS of 63 ± 9%, with a relapse incidence of 40 ± 9% and low regimen-related toxicity of 3.3 ± 3% [25].…”