TY - JOUR
T1 - Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia
T2 - A phase IB study
AU - Van Eijkelenburg, Natasha K.A.
AU - Rasche, Mareike
AU - Ghazaly, Essam
AU - Dworzak, Michael N.
AU - Klingebiel, Thomas
AU - Rossig, Claudia
AU - Leverger, Guy
AU - Stary, Jan
AU - De Bont, Eveline S.J.M.
AU - Chitu, Dana A.
AU - Bertrand, Yves
AU - Brethon, Benoit
AU - Strahm, Brigitte
AU - Van Der Sluis, Inge M.
AU - Kaspers, Gertjan J.L.
AU - Reinhardt, Dirk
AU - Zwaan, C. Michel
N1 - Publisher Copyright:
©2018 Ferrata Storti Foundation.
PY - 2018/8/31
Y1 - 2018/8/31
N2 - Survival in children with relapsed/refractory a cute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m 2 /day x 5 days) and liposomal daunorubicin (40-80 mg/m 2 /day) were administered with cytarabine (2 g/m 2 /day x 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1 st (n=11), early 1 st (n=15), ≥2 nd relapse (n=8). Dose level 3 (30 mg/m 2 clofarabine; 60 mg/m 2 liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m 2 clofarabine with 60 mg/m 2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine expo-sure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub)clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.
AB - Survival in children with relapsed/refractory a cute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m 2 /day x 5 days) and liposomal daunorubicin (40-80 mg/m 2 /day) were administered with cytarabine (2 g/m 2 /day x 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1 st (n=11), early 1 st (n=15), ≥2 nd relapse (n=8). Dose level 3 (30 mg/m 2 clofarabine; 60 mg/m 2 liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m 2 clofarabine with 60 mg/m 2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine expo-sure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub)clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.
UR - http://www.scopus.com/inward/record.url?scp=85052893582&partnerID=8YFLogxK
U2 - 10.3324/haematol.2017.187153
DO - 10.3324/haematol.2017.187153
M3 - Article
C2 - 29773602
AN - SCOPUS:85052893582
SN - 0390-6078
VL - 103
SP - 1484
EP - 1492
JO - Haematologica
JF - Haematologica
IS - 9
ER -