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ABSTRACT: 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. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 01/2013; · 1.89 Impact Factor
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Michael R Loken,
Todd A Alonzo,
Laura Pardo,
Robert B Gerbing,
Susana C Raimondi,
Betsy A Hirsch,
Phoenix A Ho,
Janet Franklin, Todd M Cooper,
Alan S Gamis,
Soheil Meshinchi
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ABSTRACT: Early response to induction chemotherapy is a predictor of outcome in acute myeloid leukemia (AML). We determined the prevalence and significance of postinduction residual disease (RD) by multidimensional flow cytometry (MDF) in children treated on Children's Oncology Group AML protocol AAML03P1. Postinduction marrow specimens at the end of induction (EOI) 1 or 2 or at the end of therapy from 249 patients were prospectively evaluated by MDF for RD, and presence of RD was correlated with disease characteristics and clinical outcome. Of the 188 patients in morphologic complete remission at EOI1, 46 (24%) had MDF-detectable disease. Those with and without RD at the EOI1 had a 3-year relapse risk of 60% and 29%, respectively (P < .001); the corresponding relapse-free survival was 30% and 65% (P < .001). Presence of RD at the EOI2 and end of therapy was similarly predictive of poor outcome. RD was detected in 28% of standard-risk patients in complete remission and was highly associated with poor relapse-free survival (P = .008). In a multivariate analysis, including cytogenetic and molecular risk factors, RD was an independent predictor of relapse (P < .001). MDF identifies patients at risk of relapse and poor outcome and can be incorporated into clinical trials for risk-based therapy allocation. This study was registered at www.clinicaltrials.gov as NCT00070174.
Blood 05/2012; 120(8):1581-8. · 9.90 Impact Factor
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Todd M Cooper,
Janet Franklin,
Robert B Gerbing,
Todd A Alonzo,
Craig Hurwitz,
Susana C Raimondi,
Betsy Hirsch,
Franklin O Smith,
Prasad Mathew,
Robert J Arceci,
James Feusner,
Robert Iannone,
Robert S Lavey,
Soheil Meshinchi,
Alan Gamis
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ABSTRACT: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML.
AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m(2)/dose was administered on Day 6 of Course 1 and Day 7 of Course 4.
Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 ± 6% and 66 ± 5%, respectively.
This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide.
Cancer 07/2011; 118(3):761-9. · 4.77 Impact Factor
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Todd M Cooper
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ABSTRACT: T-cell malignancies have distinct biochemical, immunologic, and clinical features which set them apart from non-T-cell malignancies. In the past, T-cell leukemia portended a worse prognosis than leukemia of B-cell origin. Cure rates have improved with intensification of therapy and advanced understanding of the molecular genetics of T-cell malignancies. Further advances in the treatment of T-cell leukemia will require the development of novel agents that can target specific malignancies without a significant increase in toxicity. Nelarabine (2-amino-9β-D-arabinosyl-6-methoxy-9H-guanine), a synthesized guanosine nucleoside prodrug of ara-G (9-β-D-arabinofuranosylguanine), recently received accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory T-ALL and T-LBL in adults and children. Nelarabine is water soluble and rapidly converted to ara-G, which is specifically cytotoxic to T-lymphocytes and T-lymphoblastoid cells. Clinical and pharmacokinetic investigations have established that nelarabine is active as a single agent which has led to exploration of an expanded role in the treatment of T-cell hematologic malignances.
Therapeutics and Clinical Risk Management 01/2008; 3(6):1135-41.
