Low Incidence of Osteonecrosis in Childhood Acute Lymphoblastic Leukemia Treated With ALL-97 and ALL-02 Study of Japan Association of Childhood Leukemia Study Group

Abstract

Purpose Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL); however, data relating to ON in Asian pediatric patients with ALL are scarce. Therefore, we performed a retrospective analysis of cohorts of Japanese patients with ALL to clarify the incidence, clinical characteristics, and risk factors of ON. Patients and Methods The incidence and characteristics of ON were determined in patients with ALL (n = 1,662) enrolled in two studies from the Japan Association of Childhood Leukemia Study (JACLS) group (n = 635 and n = 1,027 patients treated with the ALL-97 and ALL-02 protocols, respectively). Results In total, 24 of 1,662 patients suffered from ON, of which 12 of 635 and 12 of 1,027 patients were treated with the ALL-97 and the ALL-02 protocol, respectively. Of the 24 patients, 23 were older than 10 years. In multivariate analysis, age (≥ 10 years) was the sole significant risk factor for ON ( P < .001). Separate evaluation of patients ≥ 10 years of age indicated a 5-year cumulative incidence of ON of 7.2% (95% CI, 4.0% to 12.6%) and 5.9% (95% CI, 3.3% to 10.4%) in the ALL-97 and the ALL-02 protocol, respectively, which was lower than reported previously, despite an administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and l-asparaginase was reduced in the JACLS protocols. Conclusion We identified a low frequency of ON in the JACLS ALL-97 and ALL-02 studies. Although the sole risk factor for ON was age (≥ 10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and l-asparaginase are administered, which affects the clearance of DEX, may be associated with ON incidence in patients with ALL.

DNA methylation-based classification reveals difference between pediatric T-cell acute lymphoblastic leukemia and normal thymocytes

“…We enrolled 79 pediatric T-ALL patients (Supplemental Table 1), mainly from two large cohorts from the Tokyo Children's Cancer Study Group (TCCSG) 15 and the Japan Association of Childhood Leukemia Study (JACLS). 16 All cases were previously analyzed by WTS (Supplemental Table 2) and TCS for 158 ALL-related genes and regions (Supplemental Tables 3 and 4). 4 Samples for DNA methylation analysis were collected from the study participants after receiving written, informed consent according to the protocols approved by the Human Genome, Gene Analysis Research Ethics Committee of the University of Tokyo and other participating institutes.…”

Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L‐asparaginase induction therapy in pediatric acute lymphoblastic leukemia

“…The study population included consecutive newly diagnosed patients with ALL enrolled from August 2014 to March 2018 at four core hospitals for pediatric hematology and oncology in Japan. All patients received induction chemotherapy following the guidelines of either the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol, consisting of a total of six doses of Escherichia coli L-Asp (Leunase R , Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan) 6000 U/m 2 (JACLS group, Day 15,17,19,22,24,and 26) or the Berlin-Frankfurt-Münster (BFM) 95 oriented protocol consisting of a total of eight doses of E. coli L-Asp (Leunase R ) 5000 U/m 2 (BFM group, Days 12,15,18,21,24,27,30, and 33) ( Figure 1). 14,15 Thromboprophylaxis including FFP transfusion, usually without cryoprecipitate because of it being an uncommon product in Japan, for low fibrinogen (Fbg) levels (≤50 mg/dL), AT supplementation for low AT levels (≤70% of control), and administration of Dana for anticoagulation was included in these protocols, if required, ultimately based on the decision of each clinician.…”

The incidence of symptomatic osteonecrosis is similar between Japanese children and children in Western countries with acute lymphoblastic leukaemia treated with a Berlin‐Frankfurt‐Münster (BFM)95‐based protocol

“…[3][4][5][6] Previously, we reported a low frequency of symptomatic ON in the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-97 and ALL-02 studies of Japanese cohorts. 7 We postulated that the low incidence of symptomatic ON may be due to the lower cumulative dose of combination dexamethasone (DEX) and L-asparaginase (L-asp) than that used in Western countries. We screened patients with B-cell precursor (BCP)-ALL, all of whom were treated with the ALL-08 Study [ALL-Berlin-Frankfurt-M€ unster (BFM)95-based protocol], to examine the incidence, risk factors, treatment and clinical outcomes of symptomatic ON in a Japanese paediatric cohort.…”

“…Previously, we reported a low frequency of symptomatic ON in the Japan Association of Childhood Leukemia Study Group (JACLS) ALL‐97 and ALL‐02 studies of Japanese cohorts 7 . We postulated that the low incidence of symptomatic ON may be due to the lower cumulative dose of combination dexamethasone (DEX) and L‐asparaginase (L‐asp) than that used in Western countries.…”