Improved Outcome of Combination Therapy with ATRA, Anthracyclines and Cytarabine, AML99-M3 Protocol, for Childhood Acute Promyelocytic Leukemia.
Authors: Imaizumi Masue , Tawa Akio , Hanada Ryoji , Tsuchida Masahiro , Taguchi Ken , Kobayashi Ryoji , Morimoto Akira , Nakayama Hideki , Hamamoto Kazuko , Kudo Kazuko , Yabe Hiromasa , Kigasawa Hisato , Horibe Keizo , Tsuchiya Shigeru , Tsukimoto Ichiro 
Published: April 2020

Abstract
Therapy with all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is the molecular target therapy, and chemotherapy combined with ATRA of recent studies, in which most patients were adults, have improved the prognosis of patients with APL. However, it is not thoroughly clarified how ATRA should be combined with chemotherapy, or whether such combination therapy is as effective for childhood APL as for adults. The Japanese Childhood AML Cooperative Study Group has conducted AML99-M3 study for childhood APL and we presented here the result of the study.
Patients and Methods: From August 1997 to March 2004, 58 de novo APL children (31 boys and 27 girls) with median age of 11 years (11m to 16y) were enrolled in this study. Median follow-up period was 2.4 years. Diagnosis of APL was made on the hematological features and cytogenetic findings, which revealed 47 patients had t(15;17) translocation, nine had t(15;17) with additional abnormality, and two showed normal karyotype or other abnormality. Mean white blood cell and platelet counts at diagnosis were 20,510/μl and 36,000/μl, respectively. AML99-M3 protocol, which consisted of ATRA (5220 mg/m2 or more), anthracyclines (daunorubicin 135 mg/m2, pirarubicin 90 mg/m2, mitoxantrone 20 mg/m2, and aclarubicin 180 mg/m2) and cytarabine (69400 mg/m2), was characterized by the combination of ATRA, anthracyclines and cytarabine in not only induction but also consolidations, by intermittent administrations of ATRA in maintenance, and by intrathecal treatment at every consolidations.
Results: Overall and event-free survival rates at three years were 92.1% and 90.5%, respectively. Of 58 patients, 56 (96%) achieved complete remission, and two (3.6%) relapsed at bone marrow during consolidation and after completion of protocol, respectively. In induction, exacerbation of coagulopathy in six patients, two of whom died of intracranial or pulmonary hemorrhage, and ATRA syndrome in three patients were principal complications, while ATRA-associated headache/nausea was the most frequent complication all over the protocol. In consolidations, prolonged bone marrow suppression was observed with 10.4 days on the average of neutrophil counts lower than 100/μl, during which one died of sepsis.
Discussion: In recent studies adopting chemotherapy combined with ATRA for APL patients, overall survival rates have increased to 80 to 90% at three to five years, as is the case for this study. Moreover, as compared with recent studies, the lower relapse rate of this study may be attributed to the triple combination therapy (ATRA, anthracyclines and cytarabine) and to the intrathecal treatment. However, exacerbated coagulpathy and sepsis, two major life-threatening complications, remain to be solved. Although further observation is needed, this study suggests that combination therapy of ATRA with anthracyclines and cytarabine for childhood APL may be as effective as for adults, and that this combination therapy, if life-threatening complications were properly managed, would further improve the outcome for patients with APL.