Late Effects in Survivors of Infant Acute Lymphoblastic Leukemia from the 3 Consecutive Japanese Nationwide Clinical Trials
Authors: Aoki Yuki , Hayakawa Akira , Koike Kazutoshi , Tauchi Hisamichi , Ishii Eiichi , Koh Katsuyoshi , Miyamura Takako , Ishida Yasushi , Kada Akiko , Saito Akiko M , Manabe Atsushi , Horibe Keizo , Mizutani Shuki , Maeda Miho , Tomizawa Daisuke 
Published: November 2019

Background
Very few studies have reported the incidence of and risk factor for late effects of infant leukemia. In addition, the long-term impact of a preparative regimen for very young children undergoing allogeneic stem cell transplantation (SCT) is not evident.
Method
To examine the late effects in survivors of infant acute lymphoblastic leukemia (ALL) treated on the Japanese Infant Leukemia Study Group (JILSG) trials MLL96, MLL98 and the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial MLL03, we performed a cross-sectional survey using questionnaires by the attending pediatricians from 2015 to 2017. In all 3 studies, infants with KMT2A gene rearranged (MLL-R) ALL were allocated to receive SCT in their first remission. Choice of preparative regimen was left to the physician's choice in the MLL96/98 studies, while use of non-total body irradiation (TBI) regimen with busulfan (BU) was mandatory in the MLL03 study.
Results
Seventy out of 102 (69%) eligible subjects were evaluated: 33 were males and 37 were females. 62 patients had an MLL-R ALL. The median age of diagnosis was 5.5 months (range, 0-12m) and 35 (50%) were <6 months of age. At the time of analysis, the median age of the 70 patients was 13.5 years (range, 7-21y) and the median follow-up duration from diagnosis was 12.5 years (range, 7-20y). Fifty-seven (81%) of the 70 patients underwent SCT. Eight patients received the TBI-based regimen, while 35 received BU regimen and one received non-TBI, non-BU regimen. Thirteen patients had SCT twice and twelve patients received both TBI and BU regimen. Relapses occurred in seventeen patients (24%). Only two patients received cranial radiation therapy in 13 patients with central nervous system involved. At least one late effect was observed in 62 of the 68 patients (91%). Identified abnormalities included: underweight (body mass index [BMI]<18.5) (69%), hypogonadism (56%), teeth mal-development (52%), short stature (52%), bone abnormalities (28%), thyroid dysfunctions (27%), skin abnormalities (24%), ophthalmic dysfunctions (24%), pulmonary dysfunctions(22%), neurocognitive dysfunctions (22%), and cardiovascular dysfunctions (14%), gastrointestinal dysfunctions (5%), renal dysfunctions (4%), second malignancy (3%), and overweight (3%). The mean standard deviation (SD) heights at last follow up with TBI regimen were -4.2 and those with multiple SCT (BU+TBI) were -3.8. Both were significantly lower than those with single SCT by BU regimen (-1.4) (TBI vs BU, P=0.014; BU+TBI vs BU, P<0.001). The mean BMI at last follow up was lower in the TBI group (16.8) compared with that in the BU group (17.8) without statistical significance (TBI vs BU, P=0.342), whereas the mean BMI in the BU+TBI group (15.1) was significantly lower than that in the BU group (BU+TBI vs BU, P=0.020). Univariable analysis revealed that the risk of both thyroid dysfunctions (odds ratio [OR]=14.0, P=0.005) and the need of growth hormone (GH) treatment (OR=10.7, P=0.011) were significantly lower in the BU group than those in the TBI group. Hypothyroidism (OR=5.8, P=0.012), teeth mal-development (OR=2.8, P=0.066) and the need of GH treatment (OR=3.5, P=0.084) were more frequently observed in children who were diagnosed at less than 6 months of age. In addition, short stature (OR=23.3, P=0.003), thyroid dysfunctions (OR=4.1, P=0.023), cataract (OR=6.9, P=0.038) and alopecia (OR=6.8, P=0.038) were more frequently observed in relapsed patients. Overall, SCT significantly increased the incidence of short stature (OR=15.5, P=0.012) and underweight (OR=5.3, P=0.018).
Conclusion
In this study, survivors of infant leukemia had prolonged and various types of late effects. We observed serious growth failure in height and weight in patients treated with SCT and it was further pronounced in the TBI group and in the multiple SCT (BU+TBI) group. More than half of the patients had dental late effects and a third of all the patients had thyroid dysfunctions, which were more frequent in children diagnosed earlier. The number of patients over 20 years was limited in our study, more complications may increase in additional follow-up. Continuous long-term follow up and optimal intervention are crucial for survivors of infant leukemia who are transplanted.

Disclosures
Kada: Bayer Yakuhin: Other: personal fees for a member of independent data monitoring committee of clinical trials, outside of the submitted work..