Int J Hematol (2008) 87:48–55 DOI 10.1007/s12185-007-0016-9
ORIGINAL ARTICLE
The status of antithymocyte globulin therapy for adult patients in Japan: retrospective analysis of a nationwide survey Mamiko Hattori Æ Teruhiko Terasawa Æ Keitaro Tsushita Æ Makoto Utsumi Æ Fumio Kawano Æ Hidehiko Saito Æ Masanori Shimoyama Æ Haruhiko Ohashi
Received: 20 March 2007 / Revised: 28 September 2007 / Accepted: 18 October 2007 / Published online: 8 December 2007 Ó The Japanese Society of Hematology 2007
Abstract We conducted a nationwide survey on antithymocyte globulin (ATG) therapy for adult patients in Japan. We mailed questionnaires to 454 hospitals with hematology divisions, of which 181 (40%) responded, and the records of 448 patients were collected. Patient characteristics, hematological responses, and adverse effects were evaluated in 421 patients with sufficient data. A total of 366 patients had idiopathic aplastic anemia (AA), 29 had other types of AA, and 25 had other diseases. The response rate (RR) at 6 months was 54% for all patients, and 53% for those with idiopathic AA. Ten patients (2%) died within 30 days, and 11 (3%) died between 31 and 100 days after ATG therapy. In 346 patients with moderate to very severe AA, who received their first ATG therapy, factors that influence the outcomes of ATG therapy were extracted. Among 11 pre-treatment and therapy-related variables, three were found to be correlated with a higher RR: shorter duration of AA, no history of specific therapy for AA, and the use of CsA. Most notably, the RR of patients treated
M. Hattori T. Terasawa K. Tsushita M. Utsumi H. Saito M. Shimoyama H. Ohashi (&) Clinical Research Center for Blood Diseases, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya 460-0001, Japan e-mail:
[email protected] K. Tsushita Chukyo Hospital, Nagoya, Japan M. Utsumi Takayama Kosei Hospital, Takayama, Japan F. Kawano National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
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within 3 months of diagnosis, those between 3 months and 2 years, and those later than 2 years were 68% (130/190), 48% (54/113), and 13% (5/38), respectively. Keywords Aplastic anemia Antithymocyte globulin (ATG) Cyclosporine (CsA) Response rate Overall survival
1 Introduction Antithymocyte globulin (ATG) is an immunosuppressive drug effective for the treatment of patients with aplastic anemia (AA) [1, 2]. Another immunosuppressive drug used for AA therapy is cyclosporine (CsA) [3, 4]. A prospective, randomized trial reported in 1991 established the superiority of ATG/CsA combination therapy over ATG monotherapy [5], and this combination therapy is now considered the standard therapy for patients with severe or very severe AA and transfusion-dependent nonsevere AA, without suitable donors for stem cell transplantation [6]. Although the use of ATG for the treatment of patents with AA was approved in 1995 in Japan, simultaneously with CsA, and it is apparently widely used, the status of ATG therapy in Japan has not been elucidated. Thus, we planned a nationwide, questionnaire-based survey, and mailed a one-page questionnaire to 454 hospitals that have hematology divisions for adult patients. We had three aims regarding this survey. First, we hoped to elucidate to what kind of patients ATG therapy was given in Japan. Second, how effective and safe ATG therapy performed in Japan was. Third, with the accumulated data, we attempted to gain insights into what factors are relevant in the response of AA patients to ATG therapy.
The status of antithymocyte globulin therapy in Japan
2 Materials and methods 2.1 Distribution and recovery of the questionnaire In December 1999, we mailed questionnaires to 454 hospitals all over Japan that have hematology divisions for adult patients. The questionnaire was conducted to obtain information on all patients treated with ATG since 1989 in each hospital, and consisted of 22 questions on patient characteristics, ATG therapy and other contemporaneous treatments, and outcomes of the therapy. The criteria used for the diagnosis and severity of AA and the response to therapy are those proposed by the Study Group of Hematopoietic Disorders supported by the Japanese Ministry of Health and Welfare (JMHW) [7, Appendix 1].
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The characteristics of the 421 patients, for whom sufficient data for relevant items were available, are shown in Table 1. The median age was 55 years (range: 16–89 years old). Three hundred and sixty-six patients (87%) had idiopathic AA, 29 (7%) had other types of AA, and patients with a diagnosis other than AA were included. Among patients with the diagnosis of AA (395 patients), 378 (96%) had moderate, severe, or very severe disease, while twelve patients with mild AA were also treated with ATG. As to the disease duration before the initiation of ATG therapy, half of the patients were treated with ATG within 3 months after diagnosis, and about 70% of them received ATG within 6 months of diagnosis. Two hundred and forty-six patients (58%) received specific therapy for AA [antilymphocyte globulin/ATG, CsA, steroid pulse therapy, androgens, or granulocyte colony-stimulating factor (GCSF)] before ATG therapy.
2.2 Definition of response Responses to ATG therapy were assessed 6 months after the initiation of ATG administration. The criteria proposed by the JMHW [7, Appendix 2] were used, and the response was divided into four categories: good response (GR), partial response (PR), minimal response (MR), and no response (NR). The response rate (RR) was calculated as the ratio of the patients in GR or PR at 6 months for each group of patients.
2.3 Statistical analysis Statistical analysis was performed with the JMP 4.0 software (SAS Institute, Cary, NC, US). Comparisons of groups were conducted with the v2 test. Survival probabilities were estimated by the Kaplan–Meier method, and differences in survival distributions were evaluated by the log-rank test. For these analyses, P values \0.05 were considered significant.
3.2 How effective and safe was ATG therapy in Japan? The response to ATG therapy was evaluated 6 months after treatment, according to the criteria proposed by the JMHW [7, Appendix 2], and summarized in Table 2. The RR was calculated as the ratio of patients in GR or PR at 6 months for each group of patients. With all 421 patients, the RR was 54%, and that of patients with idiopathic AA was 53%. The RR of patients with diseases other than idiopathic AA was similar to that for idiopathic AA. The overall survival of patients with whom data on survival were available (402 patients, with a median follow-up of 37.1 months) is shown in Fig. 1. We next evaluated the safety of ATG therapy. Among the 421 patients, 63 died during the follow-up period; ten patients died within 30 days, and another 11 patients died between 31 and 100 days after ATG therapy. These 21 patients included 17 with idiopathic AA, one with drug-
1.0 0.9
3 Results 3.1 Subjects of analysis Questionnaires were returned from 181 hospitals (40%), and data on 448 patients treated with ATG were accumulated. The time when the patients were treated with ATG varied from 1987 to 2000; one patient in 1987, one in 1991, six in 1993, five in 1994, seven in 1995, 60 in 1996, 107 in 1997, 134 in 1998, 117 in 1999, and one in 2000, and for nine patients, the information was lacking. Most of the patients received ATG therapy in 1995 or later, when ATG was approved for AA.
Overall survival (%)
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
10
20
30
40 50 60 Time (Months)
70
80
90
Fig. 1 Overall survival of 402 patients, with all diseases being shown
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M. Hattori et al.
Table 1 Characteristics of the 421 patients Characteristics
No. of patients
Sex Male
207 (49%)
Female
214 (51%)
Age (years old) 16–19
21 (5%)
20–29
55 (13%)
30–39
53 (13%)
40–49
42 (10%)
50–59
93 (22%)
60–69
101 (24%)
70–79 80–89
52 (12%) 4 (1%)
Disease Idiopathic AA
365 (87%)
Post-hepatitis AA
13 (3%)
Drug-induced AA
11 (3%)
AA-PNH syndrome
5 (1%)
PRCA
11 (3%)
MDS
9 (2%)
Other
5 (1%)
Unknown
2 (1%)
Severity of AA Mild
12 (3%)
Moderate
117 (3%)
Severe
198 (47%)
Very severe
62 (15%)
Unknown 5 (1%) Disease duration prior to ATG therapy Less than 3 months
214 (51%)
3–6 months
78 (19%)
6–12 monnths
44 (11%)
1–2 years
24 (6%)
More than 2 years
56 (13%)
Unknown
5 (1%)
Specific therapies prior to ATG therapy Yes
245 (58%)
No
176 (42%)
Therapies prior to ATG therapy ATG/ALG
6 (1%)
CSP
138 (33%)
Corticosteroid pulse therapy
113 (27%)
Androgens G-CSF
123 (29%) 105 (25%)
induced AA, one with MDS, and two with other diseases. Two patients had moderate disease, 13 had severe disease, and 6 had very severe disease. The age of these 21 patients varied from 21 to 89, and the median age was 60-years old,
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which is slightly older than that of all the patients (55 years). The difference in ratios of patients who died during the observation period for each therapy group (10 of 270 for those with ATG/CsA combination therapy, and 11 of 151 for those with ATG monotherapy) was not significant (P = 0.2137). All 21 patients died of conditions related to pancytopenia, namely infection and/or bleeding. Two patients died of bleeding, ten patients of infection, two patients of both infection and bleeding, and three patients died of infection and multiple organ failure. In the remaining four patients, the causes of death were not specifically described but the deaths were reported to be related to AA. In our questionnaire form, information on adverse events was asked as two separate items: ‘‘severe adverse events’’ and ‘‘other events,’’ the definitions of which were left to the respondents. ‘‘Severe adverse events’’ and ‘‘other events’’ were reported for 73 and 334 patients, respectively, and they are summarized in Table 3. Thus, at least approximately 80% of the patients experienced some adverse events.
3.3 What factors influence the response of AA patients to ATG therapy? We subsequently tried to gain insight into what factors influence the outcomes of AA patients after ATG therapy. From the 421 patients evaluated above, we excluded the following patients from this analysis: patients with diseases other than AA, those with mild AA, and those who had previously received ALG/ATG. As a result, we selected 346 patients with moderate to very severe AA (idiopathic, post-hepatitis, drug-induced, or PNH-AA syndrome), who received their first ATG therapy. The patients were divided into groups according to their pre-treatment characteristics (sex, age, etiology of AA, severity of AA, disease duration before ATG therapy, and specific therapy for AA before ATG therapy) and therapeutic variables (drugs used in combination with ATG), and the response rates at 6 months were compared between groups (Table 4). The RR of all the 346 patients was 56%. Significant differences in RR were confirmed with in following items: disease duration before ATG therapy, history of specific therapy for AA before ATG therapy, and the use of CsA in combination with ATG. For comparison of the pre-ATG disease duration, we included 5 categories in the questionnaire: less than 3 months, 3–6 months, 6 months to 1 year, 1–2 years, and more than 2 years. The RR for patients treated within 3 months of diagnosis (68%) was higher than those in other categories. On the other hand, the RR of patients treated within 3–6 months (49%), 6 months to 1 year (45%), and 1–2 years (47%), respectively, was
The status of antithymocyte globulin therapy in Japan Table 2 Response rates according to diseases
51
GR
PR
MR
NR
Unable to determine
Unknown
Response rates
All patients
190
36
34
113
46
2
226/421 (54%)
Idiopathic AA
168
27
30
100
38
2
195/365 (53%)
5
4
0
3
1
0
9/13 (69%)
Post-hepatitis AA Drug-induced AA
4
2
2
2
1
0
6/11 (55%)
AA-PNH syndrome
3
0
1
1
0
0
3/5 (60%)
PRCA
4
1
0
4
2
0
5/11 (46%)
MDS
5
0
1
1
2
0
5/9 (56%)
Other and unknown
1
2
0
2
2
0
3/7 (43%)
Table 3 Adverse events No. of patients Severe adverse events
73 (17%)
Shock
5 (1%)
Infection Bleeding
44 (11%) 12 (3%)
Others
28 (7%)
Adverse events
monotherapy (P \ 0.01). Sex, age, the etiology of AA, and severity of AA, and the use of corticosteroid, G-CSF, or androgens in combination with ATG were not shown to affect the response rates. The differences in overall survival among patients in different categories were not assessed, because the median follow-up period was short (37.1 months).
334 (79%)
Fever
263 (62%)
Erruption
175 (42%)
Arthritis
76 (18%)
Liver dysfunction
62 (15%)
Stomatitis
35 (8%)
Edema
14 (3%)
Vasculitis
4 (1%)
Hypertension
4 (1%)
Chest pain
4 (1%)
Infectious mononucleosis
4 (1%)
similar, while that of patients who received ATG after more than 2 years was very low (13%). We confirmed significant differences in RR in all combinations between the five groups (P between\0.0001 and 0.0080), except for the following combinations: (less than 3 months) and (1– 2 years) (P = 0.0734), (3–6 months) and (6 months to 1 year) (P = 0.7090), (3–6 months) and (1–2 years) (P = 0.8733), and (6 months to 1 year) and (1–2 years) (P = 0.8996). When the patients whose pre-ATG disease duration was between 6 months and 2 years were combined (113 patients), we could note significant differences between the RR for the following three groups; those treated within 3 months, those treated between 3 months and 2 years, and those treated later than 2 years after diagnosis (P between \0.0001 and 0.0004). The RR of the patients who received any specific therapy for AA before the initiation of ATG therapy was lower than that of patients who received ATG as the initial therapy. The patients treated with ATG/CsP combination therapy exhibitied a higher response rate than those treated with ATG
4 Discussion We conducted a nationwide survey on ATG therapy, and data on 448 adult patients were accumulated from 181 hospitals. We first examined the characteristics of the patients treated with ATG. The age of patients varied from 16 to 89 years, and ATG therapy was given not only to young and middle-aged, but also to elderly patients in Japan. As expected, most of the patients were diagnosed with AA; however, 25 patients (6%) had pure red cell aplasia, myelodysplastic syndromes, or other diseases. Among patients with a diagnosis of AA, 66% had severe or very severe disease, while 30% of the patients had moderate disease and 3% mild disease. Whether those patients with nonsevere AA were transfusion-dependent could not be determined, because relevant data were lacking. In any case, ATG therapy is given to many patients with nonsevere AA in Japan. As for the timing of ATG therapy, only half the patients’ ATG therapy was initiated within 3 months after diagnosis, and only for about 40%, was ATG given as first-line therapy. This implies that many patients received ATG therapy after trials of other therapies. The reason(s) that many patients is not given ATG therapy immediately after diagnosis are not known. One possible situation is that a patient first diagnosed to have mild AA was observed without specific therapy for some time; then, the disease progressed and ATG therapy was initiated. As shown in Table 1, however, many patients had received specific therapies for AA before ATG therapy, which suggests that the decision to initiate ATG therapy might have been unduly delayed in some cases. This is particularly
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Table 4 Response rates of AA patients
No. of patients
Patients in GR/PR
346
193 (56%)
Male
165
89 (54%)
Female
181
104 (58%)
All patients Sex
NS
Age (years old)
NS for all combinations
15–29
60
35 (58%)
30–49
75
37 (49%)
50–69
161
96 60%)
70–89
50
25 (50%)
Etiology Idiopathic
NS for all combinations 322
179 (56%)
Post-hepatitis
11
7 (64%)
Drug-induced
8
4 (50%)
AA-PNH syndrome
5
3 (60%)
Severity of AA Moderate Severe Very severe
NS for all combinations 110
60 (55%)
180
105 (58%)
56
28 (50%) –a
Disease duration before ATG therapy Less than 3 months 3–6 months
190
130 (68%)
65
32 (49%)
6 months to 1 year
31
14 (45%)
1–2 years
17
8 (47%)
More than 2 years
38
5 (13%)
Unknown
5 \0.0001
Specific therapies before ATG therapy Yes
192
77 (40%)
No
154
116 (75%)
Use of any drugs in combination with ATG Yes No Use of corticostroids
341 5
NS 191 (56%) 2 (40%) NS
Yes
324
179 (55%)
No
22
14 (64%)
Use of CSA (ATG/CSP vs monotherapy)
0.0021
Yes
228
141 (62%)
No
118
52 (44%)
Yes
221
128 (58%)
No
125
65 (52%)
Yes
54
32 (59%)
No
292
161 (55%)
Use of G-CSF
NS
Use of androgens NS not significant a
Described in detail in the text
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P value
NS
The status of antithymocyte globulin therapy in Japan
important, because our survey suggests that the timing of ATG therapy has a strong effect on the RR to the therapy. The RR, defined as the proportion of patients in GR or PR after 6 months of ATG therapy, was 54% (226/421) for the patients with all diseases and 53% (195/365) for patients with idiopathic AA. These rates shown above are slightly lower than those for ATG/CsA combination therapy in randomized and nonrandomized studies (61–77%) [5, 8– 11]. The difference may be explained by the fact that the present survey is retrospective, the patients were unselected, and also because one third of our patients received ATG monotherapy. As for the etiology of bone marrow failure, patients with non-idiopathic AA and disorders other than AA responded to ATG. This result is in accordance with previous reports [12–14], although the number of such patients was too small to draw any conclusions. There are always concerns regarding the safety of ATG therapy, since the reagent is the purified serum of nonhuman animals and an allergic reaction is expected. As a result, at least about 80% of the patients experienced some adverse effects, in spite of the fact that most of them received corticosteroid as prophylaxis. Ten patients (2%) died within 30 days, and 21 (5%) within 100 days after ATG therapy. For most of these patients, it is difficult to determine whether the deaths were due to ATG therapy or to the underlying diseases. ATG itself is known to worsen pancytopenia, and all cases died of conditions related to neutropenia and thrombocytopenia (infection and/or bleeding). The deaths of three patients due to multiple organ failure and infection (4, 9, and 27 days after ATG therapy), and those of two patients with moderate AA due to infection (24 and 54 days after ATG therapy) might have mainly been therapy-related. In summary, although adverse reactions related to allergy are quite common, therapy-related deaths are relatively rare with ATG therapy. To gain insights into what factors influence the outcomes of AA patients after ATG therapy, we analyzed data on 346 patients with moderate to very severe AA. Among the eleven factors (pre-treatment characteristics and therapy conditions), three were found to be correlated with the response rate at 6 months: duration of disease before ATG therapy, history of specific therapy for AA before ATG therapy, and administration of CsA in combination with ATG. The use of G-CSF, which was found to be associated with a higher response rate and a lower relapse rate by a randomized clinical trial in Japan [15], was not extracted as a significant factor (Table 4). It has been suggested that shorter intervals between the diagnosis and initiation of ATG therapy were associated with a better RR and survival [9]. Our results show that patients treated within 3 months had a high RR (68%), and patients who were treated 3 months to 2 years after diagnosis exhibited a RR of around 48%. On the other hand, patients who received
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ATG therapy more than 2 years after diagnosis responded very poorly to ATG (response rate: 13%). The patients who received ATG therapy as first-line therapy for AA appeared to respond better than those who had undergone other therapy for AA before ATG. The patients who received ATG after trials of other therapy probably had a longer disease duration than those who received ATG as first-line therapy. Also, it is possible that some of the previously treated patients might have been poor responders to IST other than ATG (CsA monotherapy or corticosteroid pulse therapy). The patients treated with ATG/CsA combination therapy had a higher RR than those treated without CsA, which corroborates the results of randomized trials [5, 8]. Acknowledgments The authors are most grateful to the hematologists throughout Japan who generously cooperated in our questionnaire-based survey. The following hospitals provided data on their patients: Aiiku Hospital, Asahikawa Medical College Hospital, Asahikawa General Hospital, Obihiro-Kosei General Hospital, National Hospital Organization Hokkaido Cancer Center, Tonan Hospital, Sapporo Medical University Hospital, Asahikawa City Hospital, Kushiro City General Hospital, Tenshi Hospital, SapporoKosei-Kitano General Hospital, Shibecha Hospital, Shichinohe Hospital, Iwate Prefectural Otuchi Hospital, Kamaishi City Hospital, Miyagi Cancer Center, Japanese Red Cross Akita Hospital, Akita University Hospital, Yamamoto Kumiai General Hospital, Shonai Hospital, Yamagata Prefectural Central Hospital, Yamagata University Hospital, Hobara Central Hospital, Fukushima Medical University Hospital, Ibaraki Seinan Medical Center, Moriya Daiichi Hospital, Tsukuba Memorial Hospital, Ashikaga Red Cross Hospital, Jichi Medical School Hospital, Isesakisawa Medical Hospital, Gunma University Hospital, Fujioka Hospital, Saitama City Hospital, Saitama Red Cross Hospital, Koshigaya Hospital, Dokkyo University Hospital, National Defense Medical College Hospital, Chiba Aoba Municipal Hospital, Chiba University Hospital, Kanamecho Hospital, National Tokyo Medical Center, Mitsui Memorial Hospital, Juntendo University Hospital, St. Luke’s International Hospital, Nishi Tokyo Central General Hospital, Teikyo University Hospital, Tokyo Medical and Dental University Hospital, Tokyo Medical University Hospital, Tokyo Metropolitan Police Hospital, Tokyo Kousei-Nenkin Hospital, The Jikei University School of Medicine Hospital, The Jikei University School of Medicine Aoto Hospital, The Jikei University School of Medicine Daisan Hospital, Metropolitan Komagome Hospital, Metropolitan Bokutoh Hospital, Nihon University Hospital, Kanagawa Cancer Center Hospital, Shonan Kamakura General Hospital, St. Marianna University Hospital, Yokohama City Seibu Hospital, Tokai University Hospital, Yokohama City University Hospital, Sado General Hospital, Nagaoka Red Cross Hospital, Niigata Kobari Hospital, Niigata City General Hospital, Kenwakai Hospital, Matsumoto National Hospital, Toyoshina Red Cross Hospital, Nagano Matsushiro General Hospital, Prefectural Tajimi Hospital, Gifu University Hospital, Kumiai Hospital, Gifu Prefectural Gifu Hospital, Shizuoka General Hospital, Juntendo University Izunagaoka Hospital, Numazu City Hospital, Hamamatsu University Hospital, Yaizu City Hospital, Okanami General Hospital, Saiseikai Matsuzaka Hospital, Yokkaichi City Hospital, Suzuka Kaisei Hospital, Takeuchi Hospital, Matsuzaka City Hospital, Nagoya City University Hospital, Aichi Prefectural Cancer Center Hospital, Okazaki City Hospital, Kyoritsu General Hospital, National Hospital Organization Nagoya Medical Center, Showa Hospital, Social Insurance Chukyo Hospital, Higashi Municipal Hospital of Nagoya, Nishio Municipal Hospital, Hekinan Municipal Hospital, Toyama
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54 Medical and Pharmaceutical University Hospital, University of Fukui Hospital, Fukui Prefectural Hospital, Fukui Red Cross Hospital, NTT West Kanazawa Hospital, Ishikawa Prefectural General Hospital, Omihachiman City Hospital, Otsu Municipal Hospital, Otsu RedCross Hospital, Shiga University of Medical Science Hospital, Shiga Medical Center for Adults, Social Insurance Shiga Hospital, Takeda Hospital, Kyoto-katsura Hospital, Kyoto Second Red Cross Hospital, Kyoto Prefectural University of Medicine Hospital, National Hospital Organization Kyoto Medical Center, Maizuru Municipal Hospital, PL Hospital, Izumi City Hospital, Osaka Medical College Hospital, Osaka City General Hospital, Osaka City University Medical Hospital, Osaka Red Cross Hospital, Osaka University Hospital, Noe Saiseikai Hospital, Osaka Medical Center for Cancer and Cardiovascular Diseases, Yao City Hospital, Kansai Medical University Hospital, Kansai Denryoku Hospital, Kitano Hospital, Koudokai Hospital, Kishiwada City Hospital, Sakai Municipal Hospital, Suita Municipal Hospital, Toyonaka Municipal Hospital, Matsubara Municipal Hospital, Hokusetsu General Hospital, Akashi Municipal Hospital, Kinki Central Hospital, Kobe University Hospital, Kakogawa Hospital, National Hospital Organization Himeji Medical Center, Nishi-Kobe Medical Center, St. Mary’s Hospital, The Hospital of Hyogo College of Medicine, Hyogo Prefectural Amagasaki Hospital, Hyogo Medical Center for Adults, Nara Prefectural Nara Hospital, Tenri Hospital, Wakayama Medical University Hospital, Kitaoka Hospital, Masuda Red Cross Hospital, Okayama Saiseikai General Hospital, Okayama Rosai Hospital, Hiroshima City Hospital, Chugoku Central Hospital, Iwakuni Medical Center, Yamaguchi University Hospital, Naruto Hospital, Ehime Prefectural Central Hospital, Uwajima City Hospital, Matsuyama Red Cross Hospital, Kochi Medical School Hospital, Kochi Municipal Central Hospital, Kochi Red Cross Hospital, Kyushu University Faculty of Medicine, Kurume University Hospital, Kokura Memorial Hospital, Hamanomachi Hospital, Sin-Koga-Hospital, Saga Medical School Hospital, Nagasaki University Hospital, The Japanese Red Cross Nagasaki Atomic Bomb Hospital, NTT West Kyushu General Hospital, Japanese Kumamoto Red Cross Hospital, National Hospital Organization Kumamoto Medical Center, Oita Memorial Hospital, Oita Prefectural Hospital, Oita City Medical Association Almeida Hospital, Nankai Hospital, Koga General Hospital, Miyazaki Medical College Hospital, Miyazaki Prefectural Miyazaki Hospital, Imamura Bunin Hospital, Kagoshima City Hospital, Okinawa Chubu Hospital, Okinawa Prefecture Naha Hospital. We also thank Ms. Iwasaki for her excellent clerical assistance. This work was supported in part by a grant for the Department of Clinical Research, Nagoya National Hospital, the Ministry of Health and Welfare, Japan, and by a grant from the Research Committee for Idiopathic Hematopoietic Disorders, the Ministry of Health, Labour, and Welfare, Japan.
Appendix 1 Definition of the severity of aplastic anemia, proposed by The Research Committee for Idiopathic Hematopoietic Disorders supported by the Ministry of Health, Labour and Welfare of Japan. Severe AA Bone marrow hypoplasia Two out of the following: 1. Neutrophils \ 500 mm-3
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M. Hattori et al. Continued 2. Platelets \ 20,000 mm-3 3. Reticulocytes \ 20,000 mm-3 Moderate AA Bone marrow hypoplasia Two out of the following: 1. Neutrophils \ 1,000 mm-3 2. Platelets \ 50,000 mm-3 3. Reticulocytes \ 60,000 mm-3 Not fulfilling the definition of severe AA Mild AA Bone marrow hypoplasia Not fulfilling the definition of severe or moderate AA
Appendix 2 Response criteria of aplastic anemia, proposed by The Research Committee for Idiopathic Hematopoietic Disorders supported by the Ministry of Health, Labour and Welfare of Japan 1. Good Response (GR) Transition from Grade I to III Transition from Grade I to II or Grade II to III, with an increase in the hemoglobin concentration of 2 g/dl without transfusion 2. Partial Response (RR) Transition from Grade I to Grade I or Grade II to Grade II, with an increase in the hemoglobin concentration of 2 g/ dl without transfusion 3. Minimal Response (MR) Transition from Grade I to II or Grade II to III, without an increase in the hemoglobin concentration of 2 g/dl without transfusion 4. No Response (NR) Not fulfilling any of the above.
Definition of grades Grade I
Grade II
Grade III
At least 2 of the following:
At least 2 of the following:
At least 2 of the following:
Granulo \ 500
Granulo \ 1,000
1,000 B Granulo
Plt \ 20,000 Reticulo \ 20,000
Plt \ 50,000 Reticulo \ 60,000
50,000 B Plt 60,000 B Reticulo
(excluding grade I)
The status of antithymocyte globulin therapy in Japan
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