Summary
The efficacy of ciclosporin (CsA) to treat transfusion‐independent non‐severe aplastic anaemia (TI‐NSAA) has not yet been systematically evaluated. We conducted a prospective trial in patients with TI‐NSAA treated with CsA monotherapy. CsA (3.5 mg/kg/day) was administered to patients with TI‐NSAA aged ≥16. The CsA dose was adjusted to maintain a blood CsA level of ≥600 ng/mL at 2 h post‐administration. Blood cell counts were assessed after 8, 16 and 52 weeks of therapy. Thirty‐two evaluable patients from 21 institutions were enrolled. The median age was 63.5 (range: 16–83) years. At 8 weeks, haematological improvement, with increases in haemoglobin (Hb) ≥1.5 g/dL (haematological improvement in erythrocytes [HI‐E]) and platelet count ≥30 × 109/L (haematological improvement in platelets [HI‐P]), was observed in 0/25 (0%) and 6/32 (19%) evaluable cases respectively. HI‐E and HI‐P occurred in 1/25 (4%) and 10/32 (31%) patients at 16 weeks, respectively, and at 52 weeks in 5/25 (20%) and 16/32 (50%) patients respectively. Nine grade 3 adverse events (AEs) occurred in six patients, but there were no grade ≥4 AEs. Ten of the 32 patients experienced grade 2 renal toxicity. Low‐dose CsA is effective in TI‐NSAA patients and demonstrates minimal renal toxicity. However, at least 16 weeks are necessary to adequately evaluate its efficacy.
Keywords: ciclosporin, prospective study, renal toxicity, transfusion‐independent non‐severe aplastic anaemia
INTRODUCTION
Patients with non‐severe aplastic anaemia (NSAA) have traditionally been managed with observation alone if they do not require transfusions, as mild cytopenia typically does not affect their quality of life and spontaneous recovery of blood counts may occur in some cases. However, a significant number of patients experience gradual worsening of cytopenia, which eventually becomes transfusion dependent after a prolonged period. Patients with long‐standing aplastic anaemia (AA) tend to respond poorly to immunosuppressive therapy (IST) once the disease progresses to a severe form. 1 , 2 Consequently, initiation of IST during the mild stage of cytopenia is considered a reasonable approach. However, the efficacy of IST in patients with transfusion‐independent NSAA has not been evaluated in clinical trials, likely because of concerns regarding the potential toxicity of IST.
Ciclosporin (CsA) is a key drug in the treatment of AA and has been used successfully in combination with anti‐thymocyte globulin (ATG) or as monotherapy. Early studies employed relatively high doses of CsA, such as 12 mg/kg/day, as rescue therapy for patients who failed to respond to ATG, which is often associated with renal toxicity. 3 Subsequent studies showed the efficacy of lower CsA doses (up to 4 mg/kg/day) in treating AA 4 ; our retrospective study involving 38 AA patients, including 29 patients with NSAA not requiring transfusion, showed that 53% of the patients (43% of the transfusion‐independent patients) achieved either a partial or complete response to CsA monotherapy. 5 Given the low toxicity observed with the reduced CsA dose in this study and supported by expert consensus, the Japanese guidelines for the treatment of AA patients not requiring transfusion recommend starting CsA at 3.5 mg/kg/day, continued for at least 8 weeks. 6 However, the efficacy of this strategy is yet to be confirmed through prospective clinical trials.
Accordingly, we conducted a multicentre prospective study to evaluate the efficacy of low‐dose CsA therapy in patients with NSAA. In addition, we investigated the correlation between treatment response and immune markers of AA as well as the presence of somatic mutations.
METHODS
Study subjects
Patients with NSAA who did not require regular red blood cell transfusions, defined as fewer than 2 units per month, were 16 years of age or older, had no major organ dysfunction and had preserved performance status (PS) assessed by the Eastern Cooperative Oncology Group (ECOG) performance status scale, 7 and who met all of the following criteria: (1) platelet count <100 × 109/L and reticulocyte count <60 × 109/L, with either or both haemoglobin (Hb) concentration <10.0 g/dL and neutrophil count <1.5 × 109/L; (2) bone marrow hypocellularity as demonstrated by a biopsy or normocellularity with a decrease in the number of megakaryocytes; (3) no dysplastic cells representing more than 10% of each lineage.
This study was approved by the Ethics Committee of Kanazawa University (UMIN000030453).
Treatment
CsA 3.5 mg/kg/day was administered orally for 8 weeks, and the dose was adjusted to achieve a blood concentration greater than 600 ng/mL 2 h after CsA administration (C2). No other treatments, such as thrombopoietin (TPO)‐receptor agonists (TPO‐RA) and anabolic steroids, were allowed during the 8‐week period. For patients who achieved the primary end‐point at 8 weeks, treatment was continued for an additional 44 weeks (total, 52 weeks). For patients who did not meet the primary end‐point at week 8, no further treatment was specified beyond week 8.
End‐points of this study
The primary end‐point was the treatment response rate at 8 weeks after CsA initiation, as determined by the improvement in red blood cell count or platelet counts using International Working Group (IWG) criteria 2006. 8 The secondary end‐points were treatment response at 4, 16 and 52 weeks and the incidence of grade ≥3 adverse events (AEs) related to CsA therapy, as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute, USA, ver.4.0. 9
Detection of immune markers of AA
Two immune markers, glycosylphosphatidylinositol‐anchored protein‐deficient cells (paroxysmal nocturnal haemoglobinuria [PNH]‐type cells) and Human Leukocyte Antigen (HLA)‐class I allele lacking leucocytes (HLA‐LLs) in peripheral blood, were detected using high‐sensitivity flow cytometry as previously described. 10 Plasma TPO levels were determined by a chemiluminescent enzyme immunoassay as previously described. 11 TPO ≥320 pg/mL was considered high according to our previous study. 12
Detection of somatic mutations
Peripheral blood obtained before CsA therapy was subjected to targeted sequencing of 79 genes/regions (listed in Table S1) known to be mutated in myeloid cancers as well as PIGA and 1317 single nucleotide polymorphisms, as previously reported. 13 , 14 , 15 , 16 , 17 Details of the analytical methods used for the detection of somatic mutations are provided in Data S1.
Statistical methods
Since there are no reports to estimate the response rate for non‐severe AA, we referred to it for low‐risk myelodysplastic syndrome, and the response rates were 41.2%–63.8%. 18 , 19 , 20 , 21 Considering that the patients had a disease duration of <5 years and thrombocytopenia, and that the study will involve monitoring blood ciclosporin concentrations, a threshold of 40% and an expected rate of 65% were assumed. Thirty patients were required based on a binomial distribution to achieve 80% power with one‐sided alpha of 2.5%. Considering 10% of the ineligible cases, 33 patients were enrolled in the study.
Primary analysis was performed following the intention‐to‐treat principle. Data are expressed as numbers (%) for categorical variables and medians (minimum to maximum) for continuous variables. The Wilson method was used to calculate the 95% confidence intervals for the response rates. The clinical characteristics of patients who responded and those who failed to respond to CsA were compared using Fisher's exact test. p‐Values were two‐sided, and p‐values less than 0.05 were considered statistically significant.
All statistical analyses were performed using the SAS statistical packages version 9.4 (SAS Institute, Cary, NC, USA).
RESULTS
Patients
Between January 2018 and June 2021, 34 cases were registered from 21 institutions. Of the 32 cases analysed, 26 and 5 patients had PS‐0 and 1, respectively (Table 1); the median age was 63.5 (range: 16–83) years old; 17 were female; and the median time from the diagnosis to treatment initiation was 20.5 (0–1290) days. The median neutrophil count was 1.20 × 109/L (range: 0.59–2.68 × 109/L), the Hb level was 9.8 g/dL (range: 5.8–13.5 g/dL) and the platelet count was 40.5 × 109/L (range: 9–104 × 109/L). A total of 25 patients completed the study (Figure S1). The reasons for dropout in seven patients were insufficient therapeutic effect in three, decision by the treating physician in two (one due to deterioration in general condition and one due to hospitalization at another institution for a worsening comorbidity), patient wishes to discontinue the study treatment in one and withdrawal of patient consent in one. Chromosomal abnormalities were observed in five cases (Table 2; 46, Y, –X, –1, add(4)(q21), –5, –15, –15, –16, –18, +7, +mar in one, 46, XX, inv(2)(q13q31) in one, 46, XX, del(13)(q12q14)/46, XX, add(13)(q12) in one, 47, XX, +8 in one and 45, X, −Y in one).
TABLE 1.
Patient characteristics.
| Characteristics | Number of cases (%) |
|---|---|
| Age | |
| Median (min–max) | 63.5 (16–83) |
| Sex | |
| Male | 15 (46.9%) |
| Days aft. Dx | |
| Median (min–max) | 20.5 (0–1290) |
| PS | |
| 0 | 26 (81.3%) |
| 1 | 5 (15.6%) |
| 2 | 1 (3.1%) |
| Neutrophils, ×109/L | |
| Median (min–max) | 1.20 (0.59–2.68) |
| Hb, g/dL | |
| Median (min–max) | 9.8 (5.8–13.5) |
| Platelets, ×109/L | |
| Median (min–max) | 40.5 (9–104) |
| Karyotype | |
| Abnormal | 5 (16.7%) |
| Somatic mutation | |
| Positive | 12 (40.0%) |
| PNH‐type cells | |
| Positive | 19 (61.3%) |
| HLA‐LLs | |
| Positive | 4 (14.3%) |
| TPO levels | |
| >320 pg/mL | 26 (81.3%) |
Abbreviations: Dx, diagnosis; Hb, haemoglobin; HLA‐LLs, HLA‐class I allele lacking leucocytes; PNH, paroxysmal nocturnal haemoglobinuria; PS, performance status; TPO, thrombopoietin.
TABLE 2.
Chromosomal abnormalities identified at study entry.
| UPN | Chromosome | n |
|---|---|---|
| A | 40, Y, −X, −1, add(4)(q21), −5, −15, −15, −16, −18, +7, +mar | 1 |
| 46, XY | 19 | |
| B | 46, XX, inv(2)(q13q31) | 20 |
| C | 46, XX, del(13)(q12q14) | 4 |
| 46, XX, add(13)(q12) | 3 | |
| 46, XX | 13 | |
| D | 47, XX, +8 | 1 |
| 46, XX | 19 | |
| E | 45, X, −Y | 20 |
Abbreviation: UPN, unique patients number.
PNH‐type cells and HLA‐LLs were detected at enrolment in 19 (61%) of the 31 patients and 4 (14%) of the 28 evaluable patients respectively. Plasma TPO levels were high in 26 (81%) of 32 patients. In addition, 11 (38%) of the 29 evaluable patients had at least one somatic gene mutation, as shown in Table 1.
Response to the study treatment
The correlation between treatment and response is shown in the swimmer plot in Figure 1. Haematological improvement in erythrocytes (HI‐E) could not be evaluated in seven patients because of the absence of anaemia at baseline. The rates of HI‐E and haematological improvement in platelets (HI‐P) at 4, 8, 16 and 52 weeks were 0 (0/25) and 9% (3/32), 0 (0/25) and 19% (6/32), 4% (1/25) and 31% (10/32) and 20% (5/25) and 50% (16/32) respectively (Figure 2). The response rate at 8 weeks was 19% (95% confidence interval: 9%–35%), and the primary end‐point was not met, as the lower limit of the confidence interval was <40%. Among these cases, for patients with a platelet count <50 × 109/L at the time of study enrolment, the proportions of HI‐E and HI‐P at 8, 16 and 52 weeks after study initiation were 0 (0/21) and 17% (4/24), 0 (0/21) and 29% (7/24) and 19% (4/21) and 46% (11/24) respectively. An increase in reticulocytes of ≥20.0 × 109/L was observed in 6 (19%) of the 32 patients at 8 weeks.
FIGURE 1.
Swimmer plot illustrating individual treatment courses and therapeutic responses. The seven patients for whom HI‐E could not be evaluated due to relatively high Hb levels at study enrolment are shown at the bottom. Solid line, period of study treatment; dashed line, period after discontinuation of study treatment; dotted line, period of study treatment in cases where HI‐E could not be evaluated; grey, no response; green, response (HI‐P); blue, response (HI‐E); orange, response (HI‐E and HI‐P); dark red asterisk, discontinuation of study treatment; black diamond, red blood cell transfusion; white diamond, platelet transfusion; red downward triangle, start of eltrombopag; red upward triangle, end of eltrombopag; light blue downward triangle, start of romiplostim; light blue upward triangle, end of romiplostim, purple downward triangle, start of anabolic steroid; purple upward triangle, end of anabolic steroid. Hb, haemoglobin; HI‐E, haematological improvement in erythrocytes; HI‐P, haematological improvement in platelets.
FIGURE 2.
Responses to the study treatment. Light blue bars indicate HI‐E responses, and orange bars indicate HI‐P responses. HI‐E, haematological improvement in erythrocytes; HI‐P, haematological improvement in platelets.
Changes from baseline in reticulocyte, platelet and neutrophil counts in evaluable patients are shown in Figure 3. The reticulocyte, platelet and neutrophil counts increased by 7.4 ± 15.2 × 109/L (mean ± standard deviation), 15.4 ± 22.0 × 109/L, 0.28 ± 0.77 × 109/L, respectively, at week 8; 2.9 ± 12.8 × 109/L, 20.7 ± 22.9 × 109/L, 0.29 ± 0.61 × 109/L, respectively, at week 16 and 5.1 ± 15.2 × 109/L, 37.1 ± 37.4 × 109/L, 0.38 ± 0.51 × 109/L, respectively, at week 52. There was no correlation between the presence of immune markers or somatic mutations and the treatment response (Figure 4).
FIGURE 3.
Changes from baseline in reticulocyte, platelet and neutrophil counts after study treatment. Individual changes in reticulocyte counts (A), platelet counts (B) and neutrophil counts (C) are shown as dotted lines. The vertical lines represent the mean ± SD. Comparison with baseline; *p < 0.01, † p < 0.001. SD, standard deviation.
FIGURE 4.
Relationship between the response rate at 16 weeks and immune markers or somatic gene mutations. (A) Presence of PNH‐type cells. (B) Presence of HLA‐LLs. (C) Presence of any mutation in PIGA, BCOR or BCORL1. (D) Presence of any of the following: PNH‐type cells, HLA‐LLs or mutations in BCOR or BCORL1. HLA‐LLs, Human Leukocyte Antigen‐class I allele lacking leucocytes; PNH, paroxysmal nocturnal haemoglobinuria.
CsA was continued in all patients, except for the seven who discontinued the study treatment after week 8. Additional treatments were administered in eight cases between week 8.1 and 39.1: eltrombopag (EPAG) alone (n = 5), EPAG plus metenolone (n = 2) and EPAG plus romiplostim (ROMI; n = 1). Of the eight patients who received additional treatments, two patients treated with EPAG alone achieved a response at 52 weeks. Among the 24 patients who did not receive additional agents, the proportions achieving HI‐E and HI‐P at 16 and 52 weeks were 5%/42% and 21%/58% respectively.
Transfusions were administered in accordance with the ‘Guidelines for the Use of Blood Products, issued by Ministry of Health, Labour and Welfare of Japan’. Red blood cell transfusions were given when Hb levels fell to 6–7 g/dL, and platelet transfusions were administered when platelet counts were approximately 10 × 109/L. 22 Before CsA treatment, five patients received a total of 10 transfusions, including three red blood cell transfusions in two patients.
AEs
Twenty‐five of 32 patients (78%) completed the planned 1‐year treatment. Nine grade 3 AEs were reported in six patients; however, no grade ≥4 AEs occurred (Table 3). All AEs resolved promptly after dose reduction or discontinuation of CsA therapy. Creatinine levels increased to 150% of the baseline levels in 10 of 32 patients. Serum creatinine levels significantly increased at all time points after 4 weeks of CsA treatment (Figure S2). The CsA dose was reduced in eight of these 10 patients, while it was maintained in the remaining two patients. None of the 10 patients developed renal impairment of grade ≥3.
TABLE 3.
Adverse events greater than Grade 3.
| Event | Grade | Outcomes |
|---|---|---|
| Hypokalaemia | 3 | Recovered |
| Fever | 3 | Recovered |
| Eczema | 3 | Recovered |
| Menorrhagia | 3 | Recovered |
| Femoral neck fracture | 3 | Recovered |
| Aspiration pneumonia | 3 | Recovered |
| Hypertension | 3 | Recovered |
| Adrenal insufficiency | 3 | Recovered |
| Hyponatraemia | 3 | Recovered |
DISCUSSION
Although the efficacy of CsA in the treatment of SAA and NSAA requiring transfusion has been evaluated in several studies, 23 its efficacy in the treatment of mild AA not requiring transfusion has never been prospectively assessed. This study showed that, although the rate of platelet response to CsA was as low as 19% at 8 weeks, it increased to 31% at 16 weeks and 50% at 52 weeks. This response rate to CsA monotherapy was comparable to that reported in our previous study, which showed a response rate of 34% at 6 months, although lower than the response rate (80%) in transfusion‐free NSAA patients recently reported by Fattizzo et al. 24 The discrepancy in response rates may be attributed to the differences in CsA dosing protocols across institutions and the retrospective design of the previous study. Since thrombocytopenia without significant anaemia is a common initial presentation in patients with mild AA, assessing improvements in Hb levels in this study was challenging. 25
One may be concerned that patients with TI‐NSAA might not truly benefit from CsA therapy, given their only mild cytopenias. However, previous studies have shown that TI‐NSAA can progress to treatment‐resistant SAA if early therapeutic intervention is not initiated. 1 In this study, the response to CsA monotherapy suggests the presence of an ongoing immune‐mediated attack which, if left untreated, could have led to further cytopenia. Conversely, it is likely that these responders would have progressed to refractory SAA without CsA treatment. Therefore, we believe that the increase in platelet counts observed even in patients with relatively high baseline platelet levels may have had meaningful clinical benefit.
We initiated CsA at a relatively low dose of 3.5 mg/kg/day, based on our previous experience, indicating that this dose is rarely associated with renal toxicity. It also achieved a CsA blood concentration exceeding 600 ng/mL 2 h post‐ingestion (C2), the minimum level reported to inhibit calcineurin activity in T lymphocytes in vitro. Monitoring C2, rather than the trough concentration (C0) of CsA, has been successfully used to control nephrotic syndrome in children without worsening renal dysfunction. 26 Using this C2‐monitoring approach, none of the patients in this study cohort experienced grade ≥3 renal impairment, confirming the safety of this dosing strategy.
The prevalence of PNH‐type cells in this cohort (60%) was comparable to that reported in our previous studies involving patients with SAA and NSAA. However, unlike earlier findings, the presence of PNH‐type cells in this study did not correlate with the response to CsA, primarily because of a lower response rate among patients with PNH‐type cells. A possible explanation for this lower response rate is the longer disease duration in PNH+ patients who do not respond to CsA. Prolonged disease duration is a known negative predictor of IST response in patients with AA. 1 , 2 Although this study included only patients with a reported disease duration of less than 4 years, determining the exact onset of cytopenia can be challenging, especially when the condition progresses gradually, as is frequently observed in mild AA cases. It is possible that PNH+ patients who failed to respond to CsA may have had a longer disease duration than those initially reported by their treating physicians.
In contrast, the prevalence of HLA‐LLs in this study cohort (14%) was lower than the 40% reported in our recent study using high‐sensitivity flow cytometry with a combination of different anti‐HLA allelic antibodies (Zaimoku et al. unpublished observation), which primarily included transfusion‐dependent patients with SAA or NSAA. This suggests that CD8+ T‐cell‐mediated attack on haematopoietic stem cells (HSCs), as indicated by the presence of HLA‐LLs, may play a less prominent role in the development of mild cytopenia than in severe cytopenia.
In this cohort, the proportion of cases with somatic mutations (40%) and the proportion of multiple mutations (6.7%) were comparable to those previously reported in SAA patients 27 , 28 and higher than the prevalence reported in NSAA patients (17% and 18%) by Fattizzo et al. 24 and Patel et al. 29 The difference may be attributed to the older median age of our study cohort (63.5 years old) than in earlier studies. Consistent with previous findings, somatic mutations did not negatively affect the response to CsA. Therefore, unlike screening for germline mutations, testing for acquired somatic mutations is unnecessary when developing treatment plans for patients with mild AA.
Several limitations associated with the present study warrant mention. Due to the limited study duration, it was not possible to assess whether or not CsA treatment leads to a prolonged survival in patients with mild AA. Long‐term follow‐up of the treated patients is necessary to address this clinical question. In addition, the introduction of eltrombopag at 16 weeks in patients refractory to CsA contributed to some study discontinuations, potentially affecting the overall evaluation of treatment outcomes.
Our study demonstrated the efficacy of low‐dose CsA monotherapy in transfusion‐naïve patients with NSAA without serious adverse events. Since most cases required more than 8 weeks of therapy to achieve a response, extending the treatment beyond 16 weeks appears necessary for maximum benefit. In contrast, 6 of 10 (60%) patients who responded to CsA at 16 weeks had already shown a platelet or reticulocyte count increase of at least 10 × 109/L by 8 weeks. In contrast, none of the patients who failed to show an increase of ≥5.0 × 109/L in either reticulocytes or platelets at week 8 achieved a response by week 16. This finding suggests that evaluating early haematological responses at 8 weeks may help guide decisions on whether or not to continue CsA therapy. Given that CsA is often combined with TPO‐RAs, such as EPAG and ROMI for the treatment of NSAA, the results of this study provide a basis for considering TPO‐RA addition either concomitantly or sequentially with CsA in clinical practice.
AUTHOR CONTRIBUTIONS
KI, YK and SN designed the study scheme; KI, SO and SN performed the study; KI and SN analysed the data; and KI, HY, MY, HM, NH, KU, KT, HS, NA, KY, SO, YK, IM, KA and SN wrote the paper.
FUNDING INFORMATION
This study was supported by the Clinical Research Support Center Kyushu.
CONFLICT OF INTEREST STATEMENT
MY, HM, KT, HS, KY and YK have nothing to disclose. KI has conducted consulting work for Alexion Pharmaceuticals, Inc., and has received honorarium from Bristol‐Myers Squibb Co., NH has received honorarium from AbbVie GK, Astellas Pharma Inc. and Nippon Shinyaku Co., Ltd. HY has received honorarium from AbbVie GK, Astellas Pharma Inc., Novartis Pharma K.K. and Daiichi Sankyo Co., Ltd., and the speakers bureau of Novartis Pharma K.K. NA has received research funding from Novartis Pharma K.K. and the speakers bureau of AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Kyowa Kirin Co., Ltd., Meiji Seika Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd. KU has conducted consulting work for Alnylam Japan K.K., Chugai Pharmaceutical Co., Ltd., Ohara Pharmaceutical Co., Ltd. and Sobi Japan, and the medical institution to which KU belongs has received research funding from Astellas Pharma Inc., AbbVie GK, Alexion Pharmaceuticals, Inc., Apellis Pharmaceutical, Inc., Bristol‐Myers Squibb Co., Celgene Corporation, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Incyte Japan, Kyowa Kirin Co., Ltd., MSD K.K., Nippon Shinyaku Co., Ltd., Novartis Pharma K.K., Ohara Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Takeda Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd., and has received honorarium from Novartis Pharma K.K., AbbVie GK, Alexion Pharmaceuticals, Inc., Amgen Inc., Asahi Kasei Pharma Corporation, AstraZeneca K.K., Bristol‐Myers Squibb Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Incyte Japan, Kyowa Kirin Co., Ltd., Meiji Seika Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan K.K., Sanofi K.K., Takeda Pharmaceutical Co., Ltd. and Janssen Pharmaceutical K.K. SO has conducted consulting work for Eisai Co., Ltd. and Chordia Therapeutics Inc., and has ownership interest in Asahi Genomics Co, Ltd., and has received research funding from Eisai Co., Ltd., Chordia Therapeutics Inc. and Otsuka Pharmaceutical Co., Ltd. IM has conducted consulting work for Otsuka Pharmaceutical Co., Ltd.; received research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Pharma Co., Ltd., Asahi Kasei Pharma Corporation, Eisai Co., Ltd., Taiho Pharmaceutical Co., Ltd., AbbVie GK, and Otsuka Pharmaceutical Co., Ltd.; and has received honoraria from Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Bristol‐Myers Squibb Co., Pfizer Japan Inc., Otsuka Pharmaceutical Co., Ltd., AbbVie GK, Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Sanofi K.K., Astellas Pharma Inc., AstraZeneca K.K., and Janssen Pharmaceutical K.K. KA has received research funding from Asahi Kasei Pharma Corporation, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., AbbVie GK, Bristol‐Myers Squibb Co., Janssen Pharmaceutical K.K. and has received honorarium from Kyowa Kirin Co., Ltd., AbbVie GK. SN has received honorarium from Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Sanofi K.K., Pfizer Japan Inc., Asahi Kasei Pharma Corporation, Sobi Japan, SymBio Pharmaceuticals Ltd., Alexion Pharmaceuticals, Inc.
Supporting information
Data S1.
ACKNOWLEDGEMENTS
We thank all patients and medical staff of the participating institutions who contributed to this study. We are indebted to the following doctors for providing us with clinical information: Dr. H. Iwasaki of NHO Kyushu Medical Center, Dr. H. Hanamoto of Kindai University Nara Hospital, Dr. K. Ishitsuka of Kagoshima University, Dr. K. Sato of Nagano Red Cross Hospital, Dr. T. Kajiguchi of Tosei General Hospital, Dr. M. Hagiwara of Eiju General Hospital, Dr. K. Mitani of Dokkyo Medical University, Dr. T. Murayama of Hyogo Cancer Center, Dr. N. Kadowaki of Kagawa University, Dr. Y. Miyazaki of Nagasaki University, Dr. A. Sawasaki of Fukuiken Saiseikai Hospital, Dr. T. Ichinohe of Hiroshima University and Dr. A. Goto of Tokyo Medical University. We also thank Ms. Kawashiri for her data centre work; Dr. Kiyomi, Ms. Aritake, and Mr. Takeyasu for their data management and analysis; and Mr. Aratani and Mr. Miyashita for their administrative management at Clinical Research Support Center Kyushu.
Ishiyama K, Yamazaki M, Maruyama H, Hosono N, Yamaguchi H, Asada N, et al. Efficacy of ciclosporin monotherapy in non‐severe aplastic anaemia not requiring transfusions: Results from a multicentre phase II study. Br J Haematol. 2026;208(1):295–303. 10.1111/bjh.70144
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Supplementary Materials
Data S1.