Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan

Taga, Takashi; Watanabe, Tetsu; Tomizawa, Daisuke; Kudo, Kazuko; Terui, Kiminori; Moritake, Hiroshi; Kinoshita, Akitoshi; Iwamoto, Shotaro; Nakayama, Hideki; Takahashi, Hiroyuki; Shimada, Akira; Taki, Tomohiko; Toki, Tsutomu; Ito, Etsuro; Goto, Hiroaki; Koh, Katsuyoshi; Saito, Akiko; Horibe, Keizo; Nakahata, Tatsutoshi; Tawa, Akio; Adachi, Souichi

doi:10.1002/pbc.25789

Cited by 39 publications

(49 citation statements)

References 16 publications

(18 reference statements)

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“…Whereas in most European and North American trials for ML-DS courses with highdose cytarabine (3 g/m 2 per day) are applied, [9][10][11][12] Japanese studies (Japan Pediatric Leukemia/Lymphoma Study Group [JPLSG] AML D05) obtained excellent results (3-year OS: 88% 6 4% 3-year EFS: 83% 6 4%) and low TRM (1.4%) using standard-dose cytarabine (100 mg/m 2 per day) only. 15 Together with the results of the Toronto group that used a low-dose cytarabine-based regimen, 13,32 which contained no anthracyclines and no etoposide, these data indicate that subgroups of patients with ML-DS can be cured even with much lower doses than in the current ML-DS 2006 trial. But the identification of clear prognostic factors that would predict which patients are at risk of relapse and need intense therapy remained elusive.…”

Section: Discussionmentioning

confidence: 97%

“…[9][10][11][12][13][14][15] The role of high-dose cytarabine and the dosing of anthracyclines especially have yet to be defined. Whereas in most European and North American trials for ML-DS courses with highdose cytarabine (3 g/m 2 per day) are applied, [9][10][11][12] Japanese studies (Japan Pediatric Leukemia/Lymphoma Study Group [JPLSG] AML D05) obtained excellent results (3-year OS: 88% 6 4% 3-year EFS: 83% 6 4%) and low TRM (1.4%) using standard-dose cytarabine (100 mg/m 2 per day) only.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12][13][14][15] Whereas recent North American and European studies use high doses of anthracyclines and cytarabine, [9][10][11][12][13] Japanese studies achieved comparable survival rates using less intense treatment regimens. 14,15 In contrast, the prognosis of relapsed ML-DS patients is extremely poor. 12,19,20 This means that ML-DS treatment schemata have to particularly strive for the balance between appropriate chemotherapy dosage to avoid relapses and treatment-related toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12][13][14][15] Different international study protocols for ML-DS vary in their treatment intensity and drug scheduling. [9][10][11][12][13][14][15] Whereas recent North American and European studies use high doses of anthracyclines and cytarabine, [9][10][11][12][13] Japanese studies achieved comparable survival rates using less intense treatment regimens. 14,15 In contrast, the prognosis of relapsed ML-DS patients is extremely poor.…”

Section: Introductionmentioning

confidence: 99%

“…8 To date, excellent cure rates have been achieved for ML-DS using dose-reduced treatment protocols without hematopoietic stem cell transplantation. [9][10][11][12][13][14][15] The reduced-intensity arm for ML-DS of the Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) 98 trial consisted of 4 courses of chemotherapy, containing cytarabine, idarubicin, etoposide, or mitoxantrone, and resulted in event-free survival (EFS) after 5 years of 89%. 9 This is in contrast to a 5-year EFS of 54% in non-DS children with AML FAB M7 (non-DS-AMKL).…”

Section: Introductionmentioning

confidence: 99%

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Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Rasche

Zimmermann

et al. 2017

Blood

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Key Points• Reducing therapy intensity in the ML-DS 2006 trial did not impair the excellent prognosis in ML-DS compared with the historical control.• Early treatment response and gain of chromosome 8 are independent prognostic factors.Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% 6 3% vs 90% 6 4%; P log-rank 5 .64), event-free survival (EFS; 87% 6 3% vs 89% 6 4%; P log-rank 5 .71), and cumulative incidence of relapse/ nonresponse (CIR/NR; 6% 6 3% vs 6% 6 2%; P Gray 5 .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% 6 16% vs 88% 6 3%; P log rank 5 .0008) and gain of chromosome 8 (CIR/NR, 16% 6 7% vs 3% 6 2%, P Gray 5 .02; 5-year EFS, 73% 6 8% vs 91% 6 4%, P log rank 5 .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2. (Blood. 2017;129(25):3314-3321)

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Rasche

Zimmermann

et al. 2017

Blood

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Management of Down Syndrome–Associated Leukemias

et al. 2023

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ImportanceDown syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS.ObservationsA recent National Institutes of Health-sponsored conference, ImpacT21, reviewed research and clinical trials in children, adolescents, and young adults (AYAs) with DS-AL and are presented herein, including presentation and treatment, clinical trial design, and ethical considerations for this unique population. Between 10% to 30% of infants with DS are diagnosed with transient abnormal myelopoiesis (TAM), which spontaneously regresses. After a latency period of up to 4 years, 20% to 30% develop myeloid leukemia associated with DS (ML-DS). Recent studies have characterized somatic mutations associated with progression from TAM to ML-DS, but predicting which patients will progress to ML-DS remains elusive. Clinical trials for DS-AL have aimed to reduce treatment-related mortality (TRM) and improve survival. Children with ML-DS have better outcomes compared with non-DS AML, but outcomes remain dismal in relapse. In contrast, patients with DS-ALL have inferior outcomes compared with those without DS, due to both higher TRM and relapse. Management of relapsed leukemia poses unique challenges owing to disease biology and increased vulnerability to toxic effects. Late effects in survivors of DS-AL are an important area in need of further study because they may demonstrate unique patterns in the setting of chronic medical conditions associated with DS.Conclusions and RelevanceOptimal management of DS-AL requires specific molecular testing, meticulous supportive care, and tailored therapy to reduce TRM while optimizing survival. There is no standard approach to treatment of relapsed disease. Future work should include identification of biomarkers predictive of toxic effects; enhanced clinical and scientific collaborations; promotion of access to novel agents through innovative clinical trial design; and dedicated studies of late effects of treatment.

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Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing

Terui

Toki

Taga

et al. 2019

Genes Chromosomes & Cancer

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Myeloid leukemia associated with Down syndrome (ML‐DS) is characterized by a predominance of acute megakaryoblastic leukemia, the presence of GATA1 mutations and a favorable outcome. Because DS children can also develop conventional acute myeloid leukemia with unfavorable outcome, detection of GATA1 mutations is important for diagnosis of ML‐DS. However, myelofibrosis and the significant frequency of dry taps have hampered practical screening of GATA1 mutations using bone marrow (BM) samples. In response to those problems, 82 patients were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML‐D11 study. GATA1 mutations were analyzed by Sanger sequencing (SS) using genomic DNA (gDNA) from BM and cDNA from peripheral blood (PB) followed by targeted next‐generation sequencing (NGS) using pooled diagnostic samples. BM and PB samples were obtained from 71 (87%) and 82 (100%) patients, respectively. GATA1 mutations were detected in 46 (56%) and 58 (71%) patients by SS using BM gDNA and PB cDNA, respectively. Collectively, GATA1 mutations were identified in 73/82 (89%) patients by SS. Targeted NGS detected GATA1 mutations in 74/82 (90%) patients. Finally, combining the results of SS with those of targeted NGS, GATA1 mutations were identified in 80/82 (98%) patients. These results indicate that SS using BM gDNA and PB cDNA is a rapid and useful method for screening for GATA1 mutations in ML‐DS patients. Thus, a combination of SS and targeted NGS is a sensitive and useful method to evaluate the actual incidence and clinical significance of GATA1 mutations in ML‐DS patients.

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Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan

Abstract: The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.

Cited by 39 publications

References 16 publications

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

Management of Down Syndrome–Associated Leukemias

Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing

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