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Investigation on the effectiveness of rabbit ATG + cyclosporine + eltrombopag therapy for patients with aplastic anemia (W-JHS AA02)

W-JHS AA02 (W-JHS AA02)

60

Sixty subjects with transfusion-dependent more than or equal to stage 2b aplastic anemia were enrolled. 59 subjects were eligible. Protocol treatment was performed in 60 subjects. There were 59 subjects for FAS and 60 subjects for SAS in the analysis. One subject was enrolled with a diagnosis of aplastic anemia, which was later changed to myelodysplastic syndrome (MDS). Therefore, the subject was an ineligible case and was excluded from the FAS. 33 subjects (55.0%) were male and 27 (45.0%) were female. The age (median (min-max), same as below) at the time consent was obtained was 61.5 (18-77) years. The disease duration was 10.5 (1-154) days. PS was 0 in 31 subjects (51.7%), 1 in 28 subjects (46.7%) and 2 in 1 subject (1.7%). Stage 2b, 3, 4, and 5 were reported in 3 (5.0%), 9 (15.0%), 34 (56.7%), and 14 (23.3%) subjects, respectively.

The study began in November 2019 and the last case observation ended on September 30, 2023. The final enrollment was 60 cases.

Eight serious adverse events were reported in seven subjects. One case of death due to septicemia was reported, and the subject died 1.1 weeks after onset. Causality between this case and rATG, CsA and MPST could not be denied, and between and EPAG and PST could be denied. 259 adverse events were reported in 51 subjects (85.0%). Adverse events reported in more than 10% of subjects were nausea in 6 (10.0%), fever in 8 (13.3%), febrile neutropenia in 12 (20.0%), hypertension in 9 (15.0%), proteinuria in 6 (10.0%), GGT increased in 8 (13.3%), aspartate aminotransferase increased in 9 (15.0%), alanine aminotransferase increased in 12 (20.0%), alkaline phosphatase increased in 6 (10.0%), creatinine increased in 22 (36.7%), and blood bilirubin increased in 11 (18.3%). 98 adverse events with undeniable causality to EPAG were reported in 33 subjects (55.0%), among them reported in more than 10% of subjects were hypertension in 7 (11.7%), alkaline phosphatase increased in 6 (10.0%), creatinine increased in 7 (11.7%), and blood bilirubin increased in 9 (15.0%).

[Primary endpoint] - Hematologic response rate at week 12 CR and PR at week 12 were 3 (5.3%) and 27 (47.4%), respectively, and the hematologic response rate (95% CI) was 52.6 (39.0-66.0) %. The one-sided P value of the test for the threshold of 37% was 0.012<0.025, indicating that the hematologic response rate at week 12 was above the threshold of 37%. [Secondary endpoint] - Type and frequency of chromosomal abnormalities detected at protocol treatment initiation Chromosomal abnormalities detected in 5 subjects at protocol treatment initiation. The rate (95% CI) was 8.6 (2.9-19.0) %. The type of chromosomal abnormality was del (13q) in 2 cases, del (20q) in 1 case, and -y in 2 cases, respectively. - Type and frequency of somatic gene mutations detected at protocol treatment initiation Somatic gene mutations detected in 23 subjects at protocol treatment initiation. The rate (95% CI) was 39.0 (26.5-52.6) %. - Hematological response rate at week 26 after protocol treatment Hematological response rate at week 26 after protocol treatment (95%CI) was 76.6 (62.0-87.7) %. - Correlation between hematological response rate at week 2, 4, 8, 12 and 26 after protocol treatment, and rATG blood level and the following markers: PNH-type blood cells, HLA class I allele-lacking cells, plasma thrombopoietin levels The percentages of positive for PNH-type blood cells, thrombopoietin and HLA class I allele-lacking cells were 78.9%, 96.5% and 42.9% at protocol treatment initiation. No items were found to be associated with hematologic response rate. - Hematological response rate at week 52 after protocol treatment and treatment contents at each time point CsA + EPAG was the most common treatment at 52 weeks, with 36 cases (66.7%). Hematological response rates were 86.8% for CsA + EPAG, and 80.0% and 66.7% for CsA monotherapy and CsA + ROMI, respectively. - Response duration and recurrence rate in patients with hematological response There were 6 cases in which the PR was less than PR after response. The proportion of subjects who had a sustained response for one year was 81.7%. There were 4 cases of recurrence, with a 1-year relapse-free interval (95% CI) of 86.5 (66.7, 94.9) %. - Appearance of chromosomal abnormalities at week 12, 26 and 52 after protocol treatment or increase in chromosomal abnormalities detected by then Eight subjects (17.8%) had no abnormalities at baseline and had abnormalities at week 26 or 52. Three subjects (75.0%) had abnormalities at baseline and another or additional chromosomal abnormality at week 26 or 52. - Appearance of somatic mutated clone at week 12, 26 and 52 after protocol treatment or increase in mutated clone detected by then Nineteen cases (33.9%) showed the appearance of somatic gene mutant clones, and increased mutant clones were detected in 12 cases (57.1%). [Safety analysis] Grade 3 or higher adverse events reported in >5% of subjects were sepsis in 3 (5.0%), febrile neutropenia in 12 (20.0%), hypertension in 5 (8.3%), serum sickness in 3 (5.0%), GGT increased in 3 (5.0%), alanine aminotransferase increased in 8 (13.3%), and lymphocyte count decreased. Grade 3 or higher adverse events with undeniable causal relationship to EPAG reported in more than 5% of subjects were hypertension in 5 patients (8.3%), GGT increased in 5 (8.3%), and alanine aminotransferase increased in 3 (5.0%).

The purpose of this study was to evaluate the efficacy and safety of EPAG in combination rATG+CsA therapy in aplastic anemia of stage 2b or higher requiring blood transfusion in a forward-looking manner. The primary endpoint, the hematologic response rate at 12 weeks, was 52.6%, which is above the threshold of 37%, and the safety and incidence of genetic mutations were within acceptable limits. Thus, rATG+CsA+EPAG is an effective and safe treatment for Japanese AA patients who require blood transfusion.

Sept. 03, 2025

No

None

https://jrct.mhlw.go.jp/latest-detail/jRCTs071190032

Ishiyama Ken

Center Hospital of the National Center for Global Health and Medicine

1-21-1 Toyama, Shinjuku-ku, Tokyo

ishiyama-knz@umin.ac.jp

Ishiyama Ken

Center Hospital of the National Center for Global Health and Medicine

1-21-1 Toyama, Shinjuku-ku, Tokyo

+81-3-3202-7181

ishiyama-knz@umin.ac.jp

Complete

Oct. 21, 2019

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Aged >=18 years and <80 years (at time point of the signature of ICF).
2) Patients who understand the informed consent and can sign the informed consent form by his/her free will.
3) Patients who obey the protocol visit and other rules.
4) Good PS (0, 1 and 2)
5) Patients with non-severe or sever aplastic anemia who meet the following both A and B.
A) Meet the following 2 or more and requires or estimated to require periodical transfusion
a) neutrophil count < 1,000/mm3
b) platelet count < 50,000/ mm3
c) reticulocyte count < 60,000/ mm3
B) The percentage of cellular component in a bone marrow biopsy specimen is <25% and no fibrosis and no hematological malignancies.
6) Not pregnant woman
7) Agree to contraception during the study period.

1) Treatment history of rATG, CsA, EPAG, anabolic steroid and allogeneic hematopoietic stem cell transplantation.
2) Fulminant form characterized by the neutrophil count of 0/mm3 at enrollment and that no response to G-CSF treatment for more than or equal to 1 week.
3) Patients with chromosomal abnormalities related to MDS that were defined by WHO 2008 diagnostic. Patients with del (13q) alone and -Y alone positive are eligible.
4) Patients with >= 10% of dysplasia in >= 1 series of category A and B defined in Classification of dysplasia edited by Working Group for preparation of morphologic diagnostic criteria of refractory anemia (myelodysplastic syndromes)
5) Congenital aplastic anemia including Fanconi anemia.
6) Patients who received chemotherapy or radiotherapy or patients who developed a cancer within 5 years of entry.
7) Patients with uncontrollable infections or diabetes mellitus.
8) HBs antigen positive or HBV DNA-positive.
9)Patients with grade 2 or more hepatic disorder, cardiac disorder, or renal dysfunction according to CTCAE v5.0
10)Any other Patients who were judged to have difficulty participating in this study by investigators.

Both

aplastic anemia

1. The administration of rATG; 2.5 mg/kg, iv. daily, day 1 - day 5 + CsA; 5 mg/kg, po. bid (before breakfast and before dinner) +adrenalcorticosteroid (the dose is mentioned after) is started. CsA used is Neoral or generic drug emulsified in the same way with Neoral. A blood level of CsA is measured and the dose which CsA blood level 2 hours after oral administration (C2) reachs 600 - 900 ng/mL is adjusted. The investigator shall reduce the dose of CsA by 25% on this occasion when blood trough level (C0) just before the administration is beyond 250 ng/mL because renal function disorder may occur (2). When serum creatinine level also becomes higher than 150% of baselines, the 25% dose reduction of CsA shall be performed. If C2 did not reach to 600 ng/mL, then dose of CsA is appropriately increased.
2. EPAG; 75 mg, po. daily (before sleep, requires to pass more than at least 2 hours after dinner) is started from day 6.
3. The dose of steroid is as follows:
Day 1 - day 5: methylprednisolone 2 mg/kg/day
Day 6: Methylprednisolone 1 mg/kg/day
Day 8, 10, 12, 14, 16, 18, 20: prednisolone 0.5 mg/kg/day
Discontinuation after day 21
4. The administration of CsA and EPAG is continued for 26 weeks. When it passed 26 weeks, further treatment mentioned above is entrusted to the investigator in each medical institution after 27 weeks if patients reached Camitta criteria CR or PR. However, the administration is continued for 52 weeks even if the dose of CsA is reduced. The treatment after 53 weeks is not specified. If patients did not reach CR or PR at 26 weeks, treatment after 27 weeks is entrusted to the investigator in each medical institution (it is not specified in this study).

CR or PR achievement rate at week 12 after protocol treatment (hematological response rate by Camitta criteria)

1.Type and frequency of chromosomal abnormalities detected at protocol treatment initiation
2.Type and frequency of somatic gene mutations detected at protocol treatment initiation
3.Hematological response rate at week 26 after protocol treatment
4.Correlation between hematological response rate at week 2, 4, 8, 12 and 26 after protocol treatment, and rATG blood level and the following markers: PNH-type blood cells, HLA class I allele-lacking cells, plasma thrombopoietin levels
5.Hematological response rate at week 52 after protocol treatment and treatment contents at each time point
6.Response duration and recurrence rate in patients with hematological response
7.Appearance of chromosomal abnormalities at week 26 and 52 after protocol treatment or increase in chromosomal abnormalities detected by then
8.Appearance of somatic mutated clone at week 12, 26 and 52 after protocol treatment or increase in mutated clone detected by then
9.Frequency of >= grade 3 adverse events, serious adverse events and death associated with the protocol treatment

+81-92-643-7171

Oct. 02, 2019

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