I read with interest the Diffusion article by Dr. Kristen O'Dwyer (Back to HiDAC: Administering the Optimal Treatment for Children With Down Syndrome and Acute Myeloid Leukemia. The Hematologist. 2022;19[2]:11) on the recent article by Dr. Johann Hitzler and colleagues for the Children's Oncology Group (COG) on the treatment of myeloid leukemia (ML) in Down syndrome (ML-DS; AAML1531).1 Yes, the omission of courses of high-dose cytarabine (HiDAC) played a role in the inferior outcomes of patients treated on the COG1531 trial compared to prior trials, but equally important are the changes in pharmacodynamics of exposure to daunorubicin (DNR) in this trial compared to prior COG trials and those conducted by other groups.
The use of dexrazoxane (DXZ) as a cardioprotectant necessitated administration of DNR as a short bolus infusion (15 minutes) compared to the infusion time of DNR over 90 minutes are greater in other pediatric acute ML trials (infusion times of up to 6 hours are used in trials from United Kingdom Medical Research Council trials). The known pharmacokinetic properties of daunorubicin and the time to intercalation of daunorubicin with DNA suggest that a minimal infusion time of 90 minutes is required for the optima binding of daunorubicin to DNA.2 Thus, while ML-DS cells are exquisitely sensitive to DNR an optimal time of exposure is still required.3 This is illustrated two early publications on the high curability of ML-DS not cited by Dr O'Dwyer nor Dr. Hitzler and colleagues. The Pediatric Oncology Group study 8498 was the first to identify the curability of ML-DS and included courses of HiDAC after a 3+7 induction in which DNR was given as a 15-minute bolus.4 Soon thereafter, studies from Japan indicated that standard dose regimens also resulted in high cure rates in ML-DS; in these studies, anthracyclines were administered in longer infusion times (> 1 hour).5
It is to be noted that in the early studies of DXZ as a cardioprotectant in patients with breast cancer, even with near doubling of the dose of doxorubicin when administered with DXZ, there was minimal or no increase in disease-free survival rates, suggesting a blunting of the cytotoxic effect of anthracyclines.6 This fact is often overlooked in the design of clinical trials using DXZ as a cardioprotectant in many cancers. Fortunately for patients with ML, the evolving replacement of 3+7 DNR/cytarabine regimens with liposomal encapsulated formulations (e.g., CPX-351) optimizes the pharmacokinetic-based dosing of anthracyclines and cytarabine.
— Yaddanapudi Ravindranath, MBBS, from Wayne State University School of Medicine, Detroit, MI
Reply: Professor Ravindranath raises the issue of the pharmacodynamics of anthracycline therapy in his response to my article on the treatment of ML-DS. He points out that, in addition to the omission of HiDAC consolidation therapy for standard-risk patients, the change of the anthracycline infusion duration, from a continuous infusion schedule to bolus administration, potentially contributed to the inferior outcomes for patients treated on protocol AAML1531.
This observation is interesting. Altered pharmacokinetics of DNR in patients with DS could be one of the variables that contributes to treatment outcome, given the in vitro data that Dr. Ravindranath cites in his letter.1,3 The COG trial AAML1531 used a bolus infusion of daunorubicin (1-15 minutes) along with dexrazoxane as a cardioprotectant, cytarabine continuous infusion, and oral thioguanine as the induction regimen. The HiDAC (induction 2) course was eliminated in standard-risk patients, based on minimal residual disease risk stratification and to reduce treatment-associated morbidity and mortality. In contrast, the previous trial designed for children with DS, AAML0431, used continuous-infusion daunorubicin and cytarabine over 96 hours and oral thioguanine as the induction therapy, and also introduced HiDAC earlier in the treatment protocol. Given that there were multiple changes in the treatment protocol of AAML1531 as compared to AAML0431, it is difficult to isolate the effect of the daunorubicin infusion duration on the treatment outcome. Nevertheless, the elimination of the HiDAC consolidation therapy was viewed as the most substantial change to the treatment regimen and the most likely explanation for the inferior outcome of the AAML1531.
I thank Dr. Ravindranath for noting this possible additional factor in the results.
— Kristen M. O'Dwyer, MD, from Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
