TY - JOUR
T1 - Equipotent doses of daunorubicin and idarubicin for AML
T2 - a meta-analysis of clinical trials versus in vitro estimation
AU - Adige, Sunil
AU - Lapidus, Rena G.
AU - Carter-Cooper, Brandon A.
AU - Duffy, Alison
AU - Patzke, Ciera
AU - Law, Jennie Y.
AU - Baer, Maria R.
AU - Ambulos, Nicholas P.
AU - Zou, Ying
AU - Bentzen, Søren M.
AU - Emadi, Ashkan
N1 - Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - In the treatment of acute myeloid leukemia (AML), the “7 + 3”-based strategy, combining cytarabine 100–200 mg/m2 for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7–20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64–4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9–4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.
AB - In the treatment of acute myeloid leukemia (AML), the “7 + 3”-based strategy, combining cytarabine 100–200 mg/m2 for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7–20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64–4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9–4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.
KW - Acute myeloid leukemia (AML)
KW - Anthracycline
KW - Chemotherapy equipotency
KW - Daunorubicin
KW - Idarubicin
KW - Meta-analysis
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U2 - 10.1007/s00280-019-03825-2
DO - 10.1007/s00280-019-03825-2
M3 - Article
C2 - 30968179
AN - SCOPUS:85065188866
SN - 0344-5704
VL - 83
SP - 1105
EP - 1112
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -