Appropriate Dose Modification in Induction Therapy Is Essential for the Treatment of Infants with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).
Authors: Tomizawa Daisuke , Tawa Akio , Watanabe Tomoyuki , Saito Akiko Moriya , Kudo Kazuko , Taga Takashi , Iwamoto Shotaro , Shimada Akira , Terui Kiminori , Moritake Hiroshi , Kinoshita Akitoshi , Takahashi Hiroyuki , Nakayama Hideki , Koh Katsuyoshi , Kigasawa Hisato , Kosaka Yoshiyuki , Miyachi Hayato , Horibe Keizo , Nakahata Tatsutoshi , Adachi Souichi 
Published: October 2019

Abstract
Abstract 2615

Background:
Infants (age <1 year) with AML are naturally vulnerable to intensive cytotoxic therapy, and we have previously reported unacceptably high early death rate mainly due to pulmonary complications among the first 32 infants (28 eligible) enrolled in the JPLSG AML-05 study, which prompted us to suspension of patient accrual and protocol amendment (Tomizawa D. 52ndASH abstract #2146). Seventeen additional infants were enrolled after the amendment, and here we report the final outcome of total 45 infants with AML treated on AML-05 study.

Patients & Methods:
JPLSG AML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and Down syndrome patients excluded). Three patients who discontinued from the study during induction therapy are excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient's request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. For patients <2 years old, drug dosages were reduced by calculating on body weight basis, and after the study amendment, additional dose reduction by 33% in initial induction course was made for infants <1 year old.

Results:
The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years). Although, there was no difference in 3-year probability of event-free survival (pEFS) between infants and patients ≥1 year old [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (49.8 – 60.2%) (p = 0.63)], 3-year probability of overall survival (pOS) in infants was inferior; 56.0% (95%CI, 37.9 – 70.7%) vs. 75.0% (70.0 – 79.4%) (p = 0.011). When the outcome of infants were compared with patients 1 - <2 years old (N=58) and ≥2 year old (N=341), again, there was no difference in 3y-pEFS [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (40.6 – 67.6%) vs. 55.3% (49.5 – 60.7%) (p = 0.83)], but worse 3y-pOS was observed in infants [56.0% (95%CI, 37.9 – 70.7%) vs. 77.0% (62.8 – 86.4%) vs. 74.8% (69.2 – 79.5%) (p= 0.037)].
The inferiority of pOS in infants compared to the patients 1 - <2 years old and ≥2 year old was because of higher early death and non-relapse death observed in infants: 11.1% (5/45) vs. 1.7% (1/58) vs. 0.3% (1/341) (p < 0.001) and 22.2% (10/45) vs. 6.9% (4/58) vs. 9.4% (32/341) (p = 0.033), respectively. However, reduction of both early death and non-relapse death was observed after the study amendment, although not statistically significant because of small numbers; 17.9% (5/28) to 0.0% (0/17) (p = 0.14) and 32.1% (9/28) to 5.9% (1/17) (p = 0.064). Notably, in spite of dose reduction in the first induction course, CR rate [pre-amendment vs. post-amendment; 67.9% (19/28) vs. 82.4% (14/17) (p = 0.28)], 2y-pEFS [58.6% (35.1 – 76.1%) vs. 49.0% (22.0 – 71.4%) (p = 0.56)], and 2y-pOS [67.8% (47.3 – 81.8%) vs. 74.1% (44.0 – 89.6%) (p= 0.41)] did not deteriorate.

Conclusions:
Our experience suggests that appropriate chemotherapeutic dose modification in induction therapy to avoid early deaths is essential in treating infants with de novo AML. As dose intensification approach is difficult to apply for this age subgroup, incorporation of less toxic targeted agents based on biological features is needed to attain better outcome for infants with AML.

Disclosures:
No relevant conflicts of interest to declare.