AUTHORS
Fumi Nakamura, Yoshikazu Ito, MD, PhD2, Takahiro Yamauchi, MD, PhD3, Akiko Saito4, Kazutaka Ozeki, MD, PhD5, Koichi Watamoto6, Toshiro Kurokawa7, Naoko Hosono, MD8, Shingo Kurahashi9, Daiki Hirano10, Rikio Suzuki11, Shinya Sato12, Katsuhiro Shono13, Miki Kobayashi14, Shinichiro Yoshida15, Masanori Makita, MD, PhD16, Tomohiro Kajiguchi17, Satsuki Murakami18, Keijiro Sato19, Kohtaro Toyama20, Hiroto Ishii, MD, PhD21, Ken Ishiyama22, Tomoya Maeda, MD, PhD23, Koichi Onodera24, Naoto Imoto25, Yosuke Minami, MD, PhD26, Toru Kiguchi, MD, PhD27, Akira Katsumi, MD28, Emiko Sakaida, MD, PhD29, Yoshinobu Maeda, MD., PhD30, Itaru Matsumura, MD, PhD31, Yasushi Miyazaki, MD32, Hitoshi Kiyoi, MD, PhD33
AFFILIATIONS
1 Dokkyo Medical University Hospital, Tochigi, Japan
2 Tokyo Medical University Hospital, Tokyo, Japan
3 University of Fukui, Fukui, Japan
4 NHO Nagoya Medical Center, Nagoya, Japan
5 JA Aichi Konan Kosei Hospital, Konan, Japan
6 Komaki City Hospital, Komaki, Japan
7 Toyama Red Cross Hospital, Toyama, Japan
8 University of Fukui, Fukui, Japan
9 Toyohashi Municipal Hospital, Toyohashi, Japan
10 NHO Nagoya Medical Center, Nagoya, Japan
11 Tokai University Hospital, Isehara, Japan
12 Nagasaki University Hospital, Nagasaki, Japan
13 Chiba Aoba Municipal Hospital, Chiba, Japan
14 Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
15 NHO Nagasaki Medical Center, Nagasaki, Japan
16 Chugoku Central Hospital, Fukuyama, Japan
17 Tosei General Hospital, Seto, Japan
18 Aichi Medical University, Nagakute, Japan
19 Japanese Red Cross Nagano hospital, Nagano, Japan
20 Fujioka General Hospital, Fujioka, Japan
21 The Jikei University School of Medicine, Tokyo, Japan
22 National Center for Global Health and Medicine, Tokyo, Japan
23 Saitama Medical University International Medical Center, Hidaka, Japan
24 Tohoku University Hospital, Sendai, Japan
25 Toyohashi Municipal Hospital, Toyohashi, Japan
26 National Cancer Center Hospital East, Kashiwa, Japan
27 Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
28 National Center for Geriatrics and Gerontology, Obu, Japan
29 Chiba University Hospital, Chiba, Japan
30 Okayama University Hospital, Okayama, Japan
31 Kindai University Hospital, Sakai, Japan
32 Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
33 Nagoya University Graduate School of Medicine, Nagoya, Japan
ABSTRACT
Background: Intensive chemotherapy remains a key treatment option for medically fit elderly patients with acute myeloid leukemia (elderly AML). However, their outcomes remain unsatisfactory, partly because of age-related vulnerabilities and heterogeneity in host fitness. Nonetheless, the usefulness of geriatric assessment (GA) for treatment decision-making in AML remains unclear. In current practice, standardized criteria for selecting candidates for intensive chemotherapy or determining optimal dose intensity have not been established.
Aims: This prospective phase II study aimed to evaluate the efficacy and safety of protocol-defined intensive chemotherapy in fit patients aged 65–74 years with newly diagnosed AML in Japan. A secondary objective was to investigate whether baseline host-related factors assessed by the Charlson Comorbidity Index (CCI) and GA were associated with their outcomes.
Methods: Patients aged 65–74 years with newly diagnosed AML who fulfilled predefined fitness criteria were enrolled. Induction chemotherapy consisted of daunorubicin (45 mg/m2/day for patients aged 65-69 years and 35 mg/m2/day for those aged 70-74 years, days 1-3) plus cytarabine (100 mg/m2/day, days 1-7). Upon achieving complete remission (CR), only patients meeting the criteria for post-remission therapy received three courses of consolidation chemotherapy to optimize treatment delivery. The consolidation regimen was designed to approximate the dose intensity used in younger adults in Japan, to maximize the therapeutic benefit in patients who can tolerate intensive treatment. Before initiation of chemotherapy, host-related factors were prospectively evaluated using the CCI and a multidomain GA assessing motivation, cognitive function, activities of daily living, and mood. Patients were categorized as Robust, Vulnerable, or Frail according to GA findings. Associations between baseline host factors and clinical outcomes, including treatment response, treatment discontinuation, and grade ≥3 adverse events (AE), were analyzed. Approved by the NHO Review Board for Clinical Trials, Nagoya (CRB4180009); registered as jRCTs041190088.
Results: Between December 2019 and July 2023, 128 patients were enrolled, and 121 patients who fulfilled the predefined criteria for the Full Analysis Set were analyzed. The CR rate was 57.0%. The primary endpoint, 2-year event-free survival (EFS), was 22.5% (95% confidence interval [CI], 15–30%). The primary endpoint was not met because the lower limit of the 95% CI did not exceed the prespecified threshold of 19%. The median follow-up was 3.64 years (range, 0.02-5.49 years). The 2-year overall survival (OS) and relapse-free survival (RFS) analyzed for 69 patients in CR were 54.6% and 36.3%, respectively. These outcomes compared favorably with the previous Japanese prospective JALSG GML200 study. Two patients (1.7%) died during induction therapy before response assessment. Grade ≥3 AE occurred in 107/121 (88.4%) patients during the first induction course, in 33/51 (64.7%), 27/44 (61.4%), and 28/40 (70.0%) of the patients who received the first, second, and third consolidation course, respectively. Forty patients completed all three courses of consolidation therapy, and 23 patients underwent allogeneic hematopoietic stem cell transplantation. No significant differences were observed in CR rate, treatment discontinuation, or grade ≥3 AE according to age group (65–69 years vs. 70–74 years). Similarly, CCI did not adequately discriminate treatment outcomes. Patients with CCI ≥3 had a treatment discontinuation rate of 82.6%, whereas others had a rate of 63.3%. In contrast, GA demonstrated significant association with treatment response. Among 121 patients, 78, 25, and 18 patients were classified as Robust, Vulnerable, and Frail, respectively. The CR rates were 64.1%, 52.0%, and 33.3%, respectively, showing a significant decline in CR rate according to frailty status (P=0.018).
Conclusions: This study provides contemporary evidence supporting intensive chemotherapy with predefined treatment continuation criteria in selected elderly AML in Japan. Although the primary endpoint was not met, multidimensional GA identified patients with a lower probability of achieving CR. Frailty assessment may therefore provide clinically relevant information for treatment selection. These findings support the incorporation of GA into future clinical trials and the development of frailty-guided therapeutic strategies for elderly AML.
DISCLOSURES
Fumi Nakamura: Symbio, Nippon Shinyaku Co., Ltd., Genmab, Chugai, Novartis, Abbvie - Honoraria; Kyowa Kirin - Consultancy (Includes expert testimony)