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Analysis on response to darbepoetin alfa in patients with low risk myelodysplastic syndromes. (W-JHS MDS01)

W-JHS MDS01 (W-JHS MDS01)

85

Of 79 subjects included for efficacy analysis, frequency (%) of male and mean (SD) of age were 52(65.8%) and 75.1(9.9), respectively.

85 subjects were enrolled. All subjects treated the protocol treatment at least once were included the full analysis set and the safety analysis set, which were 79 subjects.

Nine SAEs were reported (cellulitis, acute myeloid leukemia, ascites, breast cancer recurrence, pneumonia, heart failure, malignant lymphoma, ileus, subcutaneous tumor). None of them was related to the protocol treatment.

Primary endpoint The frequently mutated genes (10%) included SF3B1 (24 cases, 30.4%), TET2 (20 cases, 25.3%), SRSF2 (10 cases, 12.7%), ASXL1 (9 cases, 11.4%), and DNMT3A (8 cases, 10.1%). Overall response rate (achievement of HI-E according to IWG criteria 2006) was 70.9%. Univariate logistic regression analysis did not show any significant association between these mutations and therapeutic efficacy of DA. To adjust against baseline erythropoietin (EPO) values, multivariate analysis was performed by adding EPO levels (low: <91.8, high: 91.8+ [mIU/mL]) to the explanatory variables, where mutations of ASXL1 gene were associated with significantly worse response (odds ratio 0.180 [0.035-0.928], p = 0.040). Secondary endpoints 1. Minor response to darbepoetin alfa until 16 weeks after the initiation of treatment in blood transfusion dependent patients. Minor response rate (95%CI):9/15=60.0%(35.7-80.2%) 2. Major response to darbepoetin alfa until 16 weeks after the initiation of treatment in blood transfusion dependent patients. Major response rate (95%CI) :7/15=46.7%(24.8-69.9%) 3. Hematological improvement according to IWG criteria 2006 (HI-E) by darbepoetin alfa until 16 weeks after the initiation of treatment in blood transfusion independent patients. Overall response rate (95%CI) :47/64=73.4%(61.5-82.7%) 4. Variety and frequency of gene mutations observed in all subjects. abbreviated 5. Correlation between decreased cell lineages (erythrocytes, leukocytes, platelets) and types of gene mutations. Only mutations of SF3B1 gene were associated with all of these decreased cell lineages. 6. Analysis on mortality and progression to AML from 16 weeks to 1 year after the initiation of treatment. 1-yr OS (95%CI) :83.5% (70.7-91.1%) 1-yr PFS (95%CI) :81.7% (68.6-89.7%) 7. Correlation between highly frequent gene mutations and interval to achievement of the first hematological improvement according to IWG criteria 2006 (HI-E) after the initiation of treatment. None of the frequently mutated genes was associated with the first hematological improvement according to IWG criteria 2006 (HI-E) as the results of both of the univariate and the baseline EPO stratified log-rank tests.

High-frequency (10% or more) gene mutations were found in SF3B1 (24 cases, 30.4%), TET2 (20 cases, 25.3%), SRSF2 (10 cases, 12.7%), ASXL1 (9 cases, 11.4%), and DNMT3A (8 cases, 10.1%). Overall response rate was 70.9%. Univariate logistic regression analysis did not show any significant association between these mutations and therapeutic efficacy of DA. The same results were obtained when the analysis was limited to red blood cell transfusion-dependent patients (n=15). To adjust against baseline erythropoiet

Mar. 10, 2021

No

No planned

https://jrct.mhlw.go.jp/latest-detail/jRCTs071180016

Mitani Kinuko

Dokkyo Medical University Hospital

880 Kita-Kobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, JAPAN

Kinukom-tky@umin.ac.jp

Ichikawa Motoshi

Dokkyo Medical University Hospital

880 Kita-Kobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, JAPAN

+81-282-87-2148

Motoshi-tky@umin.ac.jp

Complete

April. 01, 2016

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1) Patients with definite diagnosis of MDS in diagnostic criteria of refractory anemia (myelodysplastic syndrome) (MHLW, Research and study group on idiopathic hematopoietic disorder, revised in 2010 fiscal year).
2) Patients having anemia associated with MDS, and is aged 16 years or older.
3) Patients categorized in Low or Int-1 risk in IPSS risk categories.
4) Patients who can visit participating institutions in prescribed schedule.
5) Patients providing the written informed consent (in the case of minor subject, taking from both the subject and legal representative).

1) Patients at risk of thromboembolism with present or past medical history of myocardial infarction, pulmonary infarction and cerebral infarction or similar disorders..
2) Patients with uncontrollable hypertension.
3) Patients with medical history of drug hypersensitivity to darbepoetin alfa or other erythropoietin formulation.
4) Patients with severe (need for hospital care, or judgement by investigators) or uncontrollable complication.
5) Patients inappropriate for study participation due to complication of mental disease or psychiatric symptom.
6) Patients with cognitive disorder.
7) Patients judged by investigators to be inappropriate for study participation.

Both

myelodysplastic syndrome

The peripheral blood of patients is collected before administration of darbepoetin alfa, and DNA is extracted. The presence of gene mutations is then analyzed, mainly on highly frequent gene mutations (e.g. SF3B1, TET2, SFRS2, ASXL1, DNMT3A, RUNX1, U2AF1) on the panel of 104 genes in a previous report (Ogawa S, et al. Leukemia 2014) using next-generation sequencing method.
Darbepoetin alfa at a dose of 240 microgram per body is administered every 7 days for 16 times in total.
Effect of darbepoetin alfa is observed up to 16 weeks and it is statistically analyzed whether the presence of specific gene mutation affects the effectiveness or not.

Correlation between highly frequent gene mutations and hematological improvement according to IWG criteria 2006 (HI-E) to darbepoetin alfa until 16 weeks after the initiaion of treatment.

1. Minor response to darbepoetin alfa until 16 weeks after the initiation of treatment in blood transfusion dependent patients.
2. Major response to darbepoetin alfa until 16 weeks after the initiation of treatment in blood transfusion dependent patients.
3. Hematological improvement according to IWG criteria 2003 (HI-E) by darbepoetin alfa until 16 weeks after the initiation of treatment in blood transfusion independent patients.
4. Variety and frequency of gene mutations observed in all subjects.
5. Correlation between decreased cell lineages (erythrocytes, leukocytes, platelets) and types of gene mutations.
6. Analysis on mortality and progression to AML from 16 weeks to 1 year after the initiaion of treatment.
7. Correlation between highly frequent gene mutations and interval to achievement of the first hematological improvement according to IWG criteria 2006 (HI-E) after the initiaion of treatment.

+81-92-643-7171

Jan. 09, 2019

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