Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias

Abeer Abd Elmoneim, Lia Gore, Rebecca M. Ricklis, Jessica Boklan, Todd Cooper, Aru Narendran, Katherine Rolla, Tammy Scott, Robert J. Arceci

Research output: Contribution to journalArticle

Abstract

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 200mg/m2/day on days 0 and 1 then 400mg/m2/day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20mg/m2/day) and three patients at DL2 (CLO 30mg/m2/day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2hours 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, 20mg/m2/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.

Original languageEnglish (US)
Pages (from-to)1252-1258
Number of pages7
JournalPediatric Blood and Cancer
Volume59
Issue number7
DOIs
StatePublished - Dec 15 2012

Fingerprint

Cyclophosphamide
Leukemia
DNA Damage
Maximum Tolerated Dose
clofarabine
DNA Repair
Respiratory Insufficiency
Hypotension
Renal Insufficiency
Pediatrics
Apoptosis
Drug Therapy
Therapeutics

Keywords

  • Clofarabine
  • Cyclophosphamide
  • Pediatric leukemias
  • Phase I
  • Relapsed/refractory

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias. / Abd Elmoneim, Abeer; Gore, Lia; Ricklis, Rebecca M.; Boklan, Jessica; Cooper, Todd; Narendran, Aru; Rolla, Katherine; Scott, Tammy; Arceci, Robert J.

In: Pediatric Blood and Cancer, Vol. 59, No. 7, 15.12.2012, p. 1252-1258.

Research output: Contribution to journalArticle

Abd Elmoneim, A, Gore, L, Ricklis, RM, Boklan, J, Cooper, T, Narendran, A, Rolla, K, Scott, T & Arceci, RJ 2012, 'Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias', Pediatric Blood and Cancer, vol. 59, no. 7, pp. 1252-1258. https://doi.org/10.1002/pbc.24264
Abd Elmoneim, Abeer ; Gore, Lia ; Ricklis, Rebecca M. ; Boklan, Jessica ; Cooper, Todd ; Narendran, Aru ; Rolla, Katherine ; Scott, Tammy ; Arceci, Robert J. / Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias. In: Pediatric Blood and Cancer. 2012 ; Vol. 59, No. 7. pp. 1252-1258.
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abstract = "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 200mg/m2/day on days 0 and 1 then 400mg/m2/day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20mg/m2/day) and three patients at DL2 (CLO 30mg/m2/day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2hours 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, 20mg/m2/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.",
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T1 - Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias

AU - Abd Elmoneim, Abeer

AU - Gore, Lia

AU - Ricklis, Rebecca M.

AU - Boklan, Jessica

AU - Cooper, Todd

AU - Narendran, Aru

AU - Rolla, Katherine

AU - Scott, Tammy

AU - Arceci, Robert J.

PY - 2012/12/15

Y1 - 2012/12/15

N2 - 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 200mg/m2/day on days 0 and 1 then 400mg/m2/day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20mg/m2/day) and three patients at DL2 (CLO 30mg/m2/day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2hours 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, 20mg/m2/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.

AB - 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 200mg/m2/day on days 0 and 1 then 400mg/m2/day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20mg/m2/day) and three patients at DL2 (CLO 30mg/m2/day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2hours 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, 20mg/m2/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.

KW - Clofarabine

KW - Cyclophosphamide

KW - Pediatric leukemias

KW - Phase I

KW - Relapsed/refractory

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