FLAG-liposomal Doxorubicin (Myocet) Regimen for Refractory or Relapsed Acute Leukemia Pediatric Patients

Abstract

Despite the success in treating the majority of children with newly diagnosed acute leukemia, children with relapsed or refractory disease are an exceptionally difficult group of patients to cure. We assessed the combination of fludarabine with cytarabine and granulocyte colony-stimulating factor (FLAG) and nonpegylated liposomal doxorubicin (Myocet) in children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) refractory to first-line therapy or who had relapsed after risk-tailored chemotherapy. We treated 35 patients with FLAG-Myocet. The median age at treatment was 9 years and 7 months (range, 1 to 18 y). The 94% of ALL patients (16/17) and the 61% AML patients (11/18) achieved complete remission after FLAG-Myocet. A partial response was observed in the 17% of AML patients (3/18). Twenty-eight of 35 (80%) patients received hematopoetic stem cell transplantation in remission induced by FLAG-Myocet regimen. The ALL and AML overall survival at 3 years after FLAG-Myocet is 33% and 38%, respectively. The probability of ALL and AML event-free survival at 3 years after FLAG-Myocet is 33% and 40%, respectively. The probability of ALL and AML disease-free survival at 3 years after hematopoietic stem cell transplantation is 19% and 58%, respectively. Nonhematological toxicity was remarkably low, while almost all patients showed severe hematological toxicity. FLAG-Myocet is an efficient and a well-tolerated regimen that allows nearly all patients to undergo hematopoetic stem cell transplantation. FLAG-Myocet proved to be safe in terms of acute cardiac toxicity although particular care must be taken to reduce infectious complications due to severe myelosuppression. The promising results shown in our study need to be confirmed by larger and possibly randomized trials.

Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

“…Pharmacokinetics of free DXR after Myocet ® administration has never been published. Table 2 compares the pharmacokinetic parameters of free DXR observed in this study with parameters of total DXR after 60 mg/m 2 observed in adults which were conventionally measured [26]. Pharmacokinetic parameters of free DXR in our paediatric population were very similar to those observed with conventional DXR in adults.…”

“…Considering the advanced disease stage and high level of previous therapy in this population, the efficacy of single-agent Myocet ® should be further explored. To our knowledge, Myocet ® has been used only twice in multi-agent regimen in children [26,27]. In the first study, the combination led to an encouraging remission rate in children with relapsed acute leukaemia.…”

“…Elsewhere, Myocet ® was administered in combination with fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG-Myocet ® regimen) in a very high-risk group of children with relapsed or refractory acute leukaemias at the dose of 50 mg/m 2 [26]. Lastly, a phase I trial of a combination of an mTOR inhibitor and Myocet ® was performed in adults and children with refractory/relapsing sarcoma [27].…”

“…In the first study, the combination led to an encouraging remission rate in children with relapsed acute leukaemia. In the second study, median PFS for the study population of patients with recurrent and refractory bone and soft tissue sarcoma was 118 days [26,27].…”

Prospective, Multicenter, Phase II Study on Reducing the Dosage of Idarubicin and FLAG for Patients Younger than 65 Years with Resistant Acute Myeloid Leukemia: A Comparison with a Higher Dosage Trial

“…Actually, 29.2% of patients were primary refractory and 17.9% of patients relapsed after HCT. Newly tried drugs in relapsed/refractory AML included gemtuzumab ozogamicin [22,23,24], clofarabine [25], 5-azacytidine [26], decitabine [27], liposomal doxorubicin [28], homoharringtonine [29], plerixafor [30], FLT3 inhibitor [31], ruxolitinib [32], vorinostat [33], and tosedostat [34]. The importance of HCT is also stressed [35,36].…”