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3605 A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Non-Biological, Clinical Research, Chemotherapy, Pediatric, Diseases, Therapies, Adverse Events, Myeloid Malignancies, Study Population
Monday, December 13, 2021, 6:00 PM-8:00 PM

Hiroyuki Shimada, MD, PhD1*, Akihiro Watanabe, MD, PhD2*, Masaki Ito, MD, PhD3*, Chikako Tono, MD, PhD4*, Haruko Shima, MD, PhD1, Yuki Yuza, MD, PhD5*, Hideki Muramatsu, MD, PhD6, Masahiko Okada, MD, PhD7* and Akihiko Tanizawa, MD, PhD8*

1Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
2Department of Pediatrics, Niigata Cancer Center Hospital, Niigata, Japan
3Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima, Japan
4Department of Pediatrics, Iwate Prefectural Chubu Hospital, Iwate, IWA, Japan
5Hematological Tumor Internal Medicine, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
6Department of Pediatrics, Nagoya University Graduate School of Medicine, Aichi, Japan
7Misakae no Sono, Nagasaki, Japan
8Department of Pediatrics, Sugita Genpaku Memorial Obama Municipal Hospital, Fukui, Japan

Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP).

Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated.

Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1­­-17). Median observational period for survivors was 82 months (range, 48­­-­118). Median WBC, Hb and platelet counts were 275x109/L (range, 8­­-­765), 9.6g/dL (range, 5.8­­-­14.6) and 560x109/L (range, 110­­­-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades).

Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH