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The History of Japan Adult Leukemia Study Group

It is needless to say the importance of evidence-based medicine for the choice of diagnostic process and treatment modality through an informed consent. To create evidence, a high-quality clinical study based on the guideline for good clinical practice is essential. A high-quality clinical study implies a pursuit of a study scientifically and ethically. Scientific study denotes a study, the results of which are statistically significant and objectively trustworthy. For such study, a large number of patients should prospectively be registered, and participating physicians must follow the designated protocols. Regarding leukemia, the annual incidence of which is around 5 to 6 per 100,000,000 population, a multi-institutional study is crucial for the accrual of a large number of patients.


In the late '70s, high complete remission rates became obtainable and around 20% of adult patients with acute myeloid leukemia were curable with chemotherapy mainly with BHAC-DMP (behenoyl cytarabine + daunorubicin + 6mercaptopurine + prednisolone) therapy at single centers in Japan.


However, it was already a multi-center study era in the world. Several cooperative study groups sponsored by National Cancer Institutes in US, Medical Research Council (MRC) in UK, and European Organization of Research and Treatment of Cancer (EOTRC) in mainly French-speaking Europe conducted large-scale clinical studies, and the results obtained from them were the standard treatment of patients with cancer including leukemia. In addition to the above 3 victorious countries of the 2nd World War, Germany started reporting the results of large-scale multi-center clinical studies in mid-80s, and in 1987 Italy reported their first results of multi-center clinical studies at the 4th International Symposium of Leukemia held in Rome, Italy.


The scale and quality of the study results reported in this symposium were overwhelming to Japanese participants. We were totally thunderstruck, realizing the underdevelopment situation of our clinical study system. In the evening of the last day of symposium, we got together in an Italian restaurant and decided to establish a cooperative leukemia study group in Japan in order to recover the delay of our clinical study. Oldest Japanese participants in this symposium were at their mid-40s, which meant senior clinical researchers in Japan were unaware of the fast development of high-quality clinical studies in the world.


In April, 1987, JALSG was established with 14 institutions, clinical research of which was mainly focusing on the treatment of adult acute leukemia. Ryuzo Ohno, M.D. became the chairperson, and Toshihiro Ohshima, M.D. and Masao Tomonaga, M.D. the co-chairpersons. The members were all at their mid-40s or less, and not sure whether this first cooperative study group would be successful at that time of Japan. All were aware, however, that Japan would become far behind, if we did not take a step forward at this occasion whatever obstacles were.


We did not try to invite other institutions beside the first 14, or rather actually we could not do so at that time of Japan. What we paid thoughtful attention while establishing our group was as follows; 1) democratic management, 2) Thus, the general meeting by all members would be the decision making place, 3) Reporting the results toward the world, 3) Therefore, restriction of the reporting media only in international journals and international meetings, thus using English name only for the group name, 4) Coauthors for papers and abstracts should not be the head of the department but actually working responsible persons for each study, and 5) Operation expenses depending on membership fees and seeking for support from governmental and public grants, and not asking financial supports from pharmaceutical companies to avoid conflict of interest.


Fortunately, in 1988, the chairperson, Dr. Ohno, was appointed as the chairperson of the task force for leukemia study at the Ministry of Health and Welfare. Some members of the task force joined the group and the total number became 23. Tailwinds were also blowing. One was granulocyte-colony stimulating factor (G-CSF). Two Japanese companies were developing G-CSFs at the same times as the world. Our group conducted the first randomized study of G-CSF in patients with acute myeloid leukemia. The result of this study was published in New England Journal of Medicine in 1990. Our paper was the first Japanese clinical study published in this prestigious medical journal. The second was all-trans retinoic acid (ATRA), an active form of vitamin A, for acute promyelocytic leukemia (APL). Prof. Z-Y Wang and his colleagues at Shanghai Second Medical University reported an astonishingly high 96% complete remission (CR) rate by ATRA for 23 patients with APL in 1988. It was hardly believable at first that vitamin A did induce a CR in such a difficult leukemia. In June, 1990, however, at the Japan-China Joint Hematology Conference held in Nagoya, Prof. Wang reported 88% of CR in the extended study including 76 patients. Our group thought this was worthwhile trying, started a phase II study in relapsed/refractory APL using ATRA kindly provided by Prof. Wang, and confirmed its remarkable effectiveness in APL in more than 100 relapsed/refractory cases. From 1992, JALSG started the APL92 Study for newly diagnosed APL with ATRA provided from Hoffman-La Roche Company, Switzerland. Many institutions joined JALSG since they probably thought that they could use this wonderful drug if they became the members. Thus, the number of member institutions jumped up. The activity of JALSG facilitated the governmental approval of ATRA far ahead of other Western countries in early 1995. The interim report of APL92 Study was published in Blood,1995, and attracted the attention of the world. As listed in the publication list elsewhere, other many JALSG papers appeared in international journals from early '90s such as the result of AML87 Study in Cancer, 1993; ATRA therapy on myelodysplatic syndromes in Blood, 1993; a double blind randomized study on priming effect of G-CSF in AML in Blood, 1994; interfereon versus busulfan on chronic myeloid leukemia in Blood, 1995, and so on. We believe these publications in prestigious international journals, their references by other investigators and their inclusion into meta-analysis bestowed confidence and courage to young Japanese hematology/oncologists. Consequently many clinical investigators, especially young ones, willingly joined JALSG in order to participate in the evidence-creating clinical studies, and the number of participating institutions increased steadily. The evidence created by JALSG would be the most trustworthy one for Japanese patients, because it was obtained through the clinical studies performed by Japanese medical staff with the cooperation of Japanese patients within the framework of Japanese medical system. We proudly think that one of the contributions of JALSG is the increase of skill and ability of participating hospitals in the treatment of adult leukemia. We hope we continue to contribute for the increase of cure rates and quality of life of patients with leukemia through the cooperation of the more participating institutions as well as of patients and their family.


In 2001, Dr. Ohshima resigned and Dr. Akihisa Kanamaru succeeded his position as co-chairperson. In 2005, Dr. Ohno, Dr. Tomonaga and Dr. Kanamaru resigned chairpersons, and the new leadership started with Dr. Tomoki Naoe as chairperson, and Dr. Kazunori Ohnishi and Dr. Syuichi Miyawaki as co-chairpersons.

Ryuzo Ohno(Aichi Shukutoku University)

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