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Background: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine., Patients and Methods: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2)/d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse., Results: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2)), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2)), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2). There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation., Conclusion: Clofarabine MTD was 32 mg/m(2)/d in this combination which appeared feasible and effective in this population., (© 2015 Wiley Periodicals, Inc.)

Background: Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients)., Methods: Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity., Results: Patients were treated with a median of three chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2) /day for 5 days. Cycles were administered every 28 days for a median of six cycles (range: 2-8 cycles). Seventeen of 18 patients are alive. All surviving patients showed demonstrable improvement after two to four cycles of therapy, with 11 (61%) complete responses, 4 (22%) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections., Conclusion: Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population., (© 2013 Wiley Periodicals, Inc.)

Background: Outcomes for children with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are dismal. In an effort to improve outcomes, we performed a phase I/II study of a novel clofarabine based combination regimen called TVTC. Herein, we report the response rates of patients in the phase II portion of the study., Procedure: Seventeen patients with R/R ALL, AML, or biphenotypic leukemia were enrolled. Sixteen patients were evaluable for response. Patients were treated at the maximum tolerated dose (MTD) from the phase I portion of the study (clofarabine 40 mg/m(2) /day IV × 5 days, topotecan 1 mg/m(2) /day IV continuous infusion × 5 days, vinorelbine 20 mg/m(2) /week IV × 3 weeks, thiotepa 15 mg/m(2)/day IV × 1 day). The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp)., Results: The ORR was 69% (10 CR, 1 CRp). Among the 11 responders, 9 (82%) proceeded to hematopoietic stem cell transplantation. The most common grade 3+ non-hematologic toxicities were febrile neutropenia (82%) and transient transaminase elevation (47%)., Conclusions: TVTC demonstrates significant activity in patients with R/R acute leukemia. The activity in R/R AML patients was very encouraging, with 8 of 12 (67%) patients achieving a CR/CRp. Patients with high risk de novo AML may benefit from incorporation of TVTC therapy into frontline treatment regimens. This regimen warrants further exploration in a larger cohort of patients with R/R leukemia., (© 2013 Wiley Periodicals, Inc.)

Background: The discovery of effective re-induction regimens for children with more than one relapse of acute lymphoblastic leukemia (ALL) remains elusive. The novel nucleoside analog clofarabine exhibits modest single agent efficacy in relapsed ALL, though optimal combinations of this agent with other active chemotherapy drugs have not yet been defined. Herein we report the response rates of relapsed ALL patients treated on Children's Oncology Group study AAML0523, a Phase I/II study of the combination of clofarabine and cytarabine., Procedure: AAML0523 enrolled 21 children with ALL in second or third relapse, or those refractory to re-induction therapy. The study consisted of two phases: a dose finding phase and an efficacy phase. The dose finding portion consisted of a single dose escalation/de-escalation of clofarabine for 5 days in combination with a fixed dose of cytarabine (1 g/m(2)/day for 5 days). Eight patients received clofarabine at 40 mg/m(2)/day and 13 patients at 52 mg/m(2)/day., Results: Toxicities observed at all doses of clofarabine were typical of intensive chemotherapy regimens for leukemia, with infection being the most common. We did not observe significant hepatotoxicity as reported in other clofarabine combination regimens. The recommended pediatric Phase II dose of clofarabine in combination with cytarabine for the efficacy portion of AAML0523 was 52 mg/m(2). Of 21 patients with ALL, 3 (14%) achieved a complete response (CR). Based on the two-stage design definition of first-stage inactivity, the therapy was deemed ineffective., Conclusion: The combination of clofarabine and cytarabine in relapsed/refractory childhood ALL does not warrant further clinical investigation., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: By inhibiting DNA repair, clofarabine (CLO) may augment cyclophosphamide (CY)-induced DNA damage and apoptosis. We performed a Phase I study for refractory and/or relapsed (R/R) leukemia in children to determine maximum-tolerated dose (MTD) of time-sequential CLO followed by CY., Procedure: Thirteen patients with (R/R) ALL (n = 8) and AML (N = 5), median age 9 years (range: 2-12 years), were treated with escalating doses of CLO on days 1, 2, 3 and 8, 9, 10 and CY 200 mg/m(2) /day on days 0 and 1 then 400 mg/m(2) /day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20 mg/m(2) /day) and three patients at DL2 (CLO 30 mg/m(2) /day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2 hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2 hours after CLO followed by CY on day 1., Results: Two patients at DL2 had dose-limiting toxicities (DLTs) that included hypotension with cardio-respiratory failure (1) and hepato-renal failure (1). Complete remission (CR) was achieved in 2/11 (18.2%) and partial remission (PR) in 2/11 (18.2%) for an overall response (OR) of 36.4%. The use of CLO before CY augmented CY-induced DNA damage in leukemic blasts compared to CY alone., Conclusion: In pediatric patients with R/R leukemia, 20 mg/m(2) /day is the MTD for CLO in timed sequential combination with CY. Increased DNA damage with the use of this combination suggests a mechanism for the sequential timing of these two chemotherapeutic agents., (Copyright © 2012 Wiley Periodicals, Inc.)

Clofarabine is a second-generation purine nucleoside analog and has significant anti-leukemic activity as a single agent. It is approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children. Combinations of clofarabine with purine nucleoside analogs or DNA-damaging agents have been investigated utilizing synergistic effects and now tested in a number of studies including a frontline study. In this article, we review the development of clofarabine, rationale and history of combination regimens, and their potential roles and toxicities in the treatment of pediatric ALL that are important to treating clinicians., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: We determined the maximum tolerated dose (MTD) of clofarabine when administered with topotecan, vinorelbine, thiotepa, and dexamethasone (TVTC) for children with relapsed or refractory acute leukemia, and observed the efficacy and toxicities of this therapy., Procedure: Twelve patients with acute lymphoblastic or myeloblastic leukemia were given a 14-day remission induction therapy. Clofarabine was administered at a dose of 30 or 40 mg/m(2)/day over 2 hr for five consecutive days in six patients each. Patients who achieved a remission proceeded to a stem cell transplant (HSCT). A second cycle could be administered prior to HSCT., Results: Of the six patients at the 30 mg/m(2) clofarabine dose, two achieved a complete response (CR) and one a PR and proceeded to BMT. Three patients had progressive disease. Five of the six patients at the 40 mg/m(2) achieved a CR. Four proceeded to HSCT, and one relapsed prior to HSCT. One patient died on day 45 with marrow hypoplasia without evidence of leukemia. Hematologic and infectious adverse events were universal. The one dose limiting non-infectious toxicity observed was prolonged marrow hypoplasia., Conclusion: TVTC has significant anti-leukemic activity in both acute lymphoblastic and myeloblastic leukemia. The MTD of clofarabine is 40 mg/m(2)/day in this combination. This is the recommended dose for the phase II study in patients with refractory or relapsed leukemia, a population which has limited therapeutic options.