Long-Term Outcome of Six Months Maintenance Chemotherapy for ALL in Children: An Extended Follow up Study of TCCSG L92-13
Authors: Kato Motohiro , Manabe Atsushi , Ishimaru Sae , Tomizawa Daisuke , Hasegawa Daisuke , Inukai Takeshi , Arakawa Yuki , Aoki Takahiro , Okuya Mayuko , Kaizu Kiyohiko , Kato Keisuke , Taneyama Yuichi , Koh Katsuyoshi , Tsuchida Masahiro , Ohara Akira 
Published: October 2019

Abstract

Maintenance therapy is a key component of ALL treatment. Although maintenance with 6-mercaptopurine (6-MP) and methotrexate (MTX) is generally less hemato-toxic, it occasionally causes severe complications such as infections, and too long maintenance is possibly associated with lower adherence. Thus, the duration of maintenance should be as short as possible, but excess shortening of maintenance therapy leads to high relapse incidence, as shown in our previous clinical trial, the Tokyo Children's Cancer Study Group (TCCSG) L92-13 (1992 - 1995, n = 347). In this study, the shortened maintenance therapy to 6 months resulted in EFS of 59.5% at 5.5 years although OS was as good as 81.5%. Especially, higher relapse rate in standard-risk (SR) resulted in EFS of as low as 60.2% (Toyoda Y, et al. J Clin Oncol 2000). However, it should be noted that about 60% of ALL achieved continuous complete remission (CCR) with short maintenance therapy. Thus, to confirm long-term outcome of ALL with this short maintenance therapy, we conducted an extended follow up study of patients enrolled on the TCCSG L92-13.
In the L92-13 trial, previously untreated children (15 years or younger) with ALL were enrolled, and were assigned to three risk groups, standard-risk (SR), high-risk (HR) and extremely high-risk (HEX), according to age at diagnosis, immunephenotype, sentinel cytogenetics and initial leukocyte count. All patients received four-drug induction, followed by consolidation therapy including re-induction. Maintenance therapy with daily 6-MP and weekly MTX was shortened to 6 months, and all treatment was discontinued at 12 months after diagnosis.
The data was analyzed as of 2014 July. A median of follow up period of this extended study was 14.8 years, and the survival curve is shown in Figure 1A. Relapse was reported in 128 patients, with a median time of relapse was 1.8 years from diagnosis. EFS at 12 years for all patients was 58.7 +- 2.7% (59.2% for SR [n = 127], 57.8% for intermediate-risk [IR, n = 122], and 59.2% for high-risk [HR, n = 101]) and OS was 78.7 +- 2.2% (85.4% for SR, 80.0% for IR, and 69.0% for HR). Incidences of relapse and non-relapse mortality were 37.2 +- 2.6% and 3.2 +- 0.9%, respectively. Five patients (0 in SR group, 3 in HR group, and 2 in HEX group) developed secondary malignant neoplasms before relapse, which resulted in cumulative incidence of secondary malignancy of 0.9 +- 0.5% at 12 years.
Patient gender was associated with the outcome, and female had better EFS (65.3 +- 3.7%) compared to male (52.2 +- 3.8%) (p = 0.04, Figure 1B). High-hyperdiploid (HHD) patients had relatively worse prognosis, with EFS of 50.0 +- 11.8%, although it is generally considered as good prognostic factor, and most of the relapsed HHD patients were salvaged and OS was 94.4 +- 5.4%.
It is confirmed that 6 months maintenance therapy is insufficient for male, HHD, and standard risk patients. In contrast, most of patients who had been in first CR at previous analysis maintained CCR status. Our results demonstrate that short maintenance therapy can cure a substantial portion of ALL with extremely low non-relapse mortality, and that it may be possible to shorten the duration of maintenance therapy for female and non-HHD patients. This study provides precise information of leukemia biology and highlights the role of maintenance therapy. Ongoing molecular characterization of the cured patients will clarify the subset of patients who can be cured with short maintenance therapy.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.