A therapeutic use of bone marrow in patients with refractory anemia were first at-tempted towards the end of last century and in 1930s bone marrow transplantation were carried out without successful results. Early experimental studies to prevent animals from lethal irradiation formed theoretical basis of bone marrow transplantation. The nuclear accidents in New Mexico and the tragic injuries in Hiroshima and Nagasaki by atomic bombs in 1945 prompted the research of protection from lethal irradiation. After many experimental studies bone marrow transplantation became applicable to the treatment of aplastic anemia and leukemia. By virtue of several factors including conditioning for re-cipients, establishment of histocompatibility between donors and recipients, basic techniques of transplantation, demonstration of engraftment, prevention and treatment of graft-versus-host disease and supportive therapies for the complications, the development of safety and assurance of bone marrow transplantation were made possible. But the present methods are not complete and several secondary problems following bone marrow transplantation are arising. A historical review will be useful for the development of bone marrow trans-plantation.

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Various new antileukemic drugs have been developed in recent years. Because the combination chemotherapies using these antileukemic drugs have been established and the supportive therapy has also made a progress, the remission rate of acute leukemia has remarkably increased and the survival time has been prolonged.
Particularly, introduction of pyrimidine derivatives including cytosine arabinoside and anthracyclines represented by daunorubicin has enabled us to make leukemic cells disappear rapidly.
We are now reaching a new era in which therapeutic goal is not the long-term survival but the cure of acute leukemia. This is quite different from the old days in which we had only 6-MP and adrenal steroid.
In this symposium entitled with “Long-term survivors with acute leukemia” at the X X X VIIth General Meetings for National Hospitals and National Sanatoriums, papers dealing with long-term survival cases of acute leukemia were presented by seven speakers. They demonstrated that the number of long-term surviors with acute leukemia increased at the national hospitals and that excellent therapeutic results were obtained with the newer treatment of acute leukemia.
In view of the present situation in which therapy of acute leukemia is rapidly making a progress, we consider it important to describe detailed results at this point and thus the data of the presentation by the seven speakers at the symposium were compiled into this paper.
What kind of therapeutic modalities should be taken during the remission stage of acute leukemia? What are the subject matters to be concerned with during the period of treatment? At present, the doctors are confronted with these questions and they have yet to be solved in the future.
As the long-term survival cases are accumulated and detailed analysis of the cases are made in the future, a guideline for the treatment after an induction of remission will be set up.
Thus, collection of reports of the long-term survivors with acute leukemia is considered to be of significance.

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Two cases with adult acute myelocytic leukemia who survived more than five years are reported.
Case 1 was a 44 year old housewife. She was diagnosed as acute myelocytic leukemia in Dec. 1973. She was given ACcP therapy with compllete remission. Chemotherapy was discontinued after 5 years and thereafter only immunotherapy was given. Relapse occurred in Oct. 1981, and she died in Mar. 1982. She lived 8 years and 2 months.
Case 2, a 34 year old housewife, recieved DCMP therapy with a diagnosis of acute myelocytic leukemia in Mar. 1978. After 2 months, complete remission was achieved. She has been on maintenance and consolidation therapy without a relapse since then.
These cases and a review of the literatures suggest that long term chemotherapy, at least for 8 years may be necessary to maintain complete remission of acute leukemia.

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A 28-year-old woman was admitted to the Sapporo National Hospital on the 8th of August, 1977, because of high fever and eruption. Physical examination revealed moderate anemia, slight cervical lymphadenopathy, splenomegaly, and generalized drug eruption. Red cell count was 280×10⁴/mm³, hemoglobin 8 g/dl, white cell count 15, 600/mm³, platelet count 8×10⁴/mm³, and nucleated cell count of the bone marrow 275, 000/mm³. Peripheral blood smear revealed 45% of leukemic cell, bone marrow smear 74.2% of leukemic cell, which were well differentiated from myeloblast to myelocyte. Peroxidase stain of these leukemic cells was positive. A diagnosis of acute myeloblastic leukemia was confirmed. According to the FAB classification, this leukemia belonged to M 2 category. She received DCMP therapy immediately after admission, and complete remission was recognized in the middle of January, 1978. She was discharged in July, 1978. Since then, she has been on 40 to 50 mg of citosine arabinoside for 3 to 4 days every 5 to 6 weeks, 50 to 75 mg of 6 MP daily, and 10 mg of prednisolone every two days as intensification therapy. The patient has been under the complete remission since January, 1978, and has been well for 6 years and 8 months since the first medical examination.

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Prognostic factors of 27 patients with nonlymphocytic acute leukemia (AML: 18, AMOL: 5, AMMOL: 2, APL: 2) between Nov. 1975 and Aug. 1980 were analyzed. Median age was 54 years (range 18-72 years). Complete remission (CR) rate and median period required to achieve CR were 77.8% and 45 days, respectively. Median duration of CR and survival time were 10.1 months and 17.3 months, respectively.
Survival time were shorter in the patients over the age of 60 years. An elevated hemoglobin level and increased platelet count before treatment were associated with prolongation of survival time. However, the number of bone marrow nucleated cell count and the percentage of leukemic cell also increased in these long-term survivors. Survival time was longer among AML compared to non-AML. Shorter period to achieve CR and longer duration of CR were strongly related to prolongation of survival time. Complications including meningeal leukemia were the causes of death in three cases out of five cases which had a short survival in spite of a short period to achieve CR.
Three cases (11%) survived more than five years. In all three cases, the ages were under 46 and morphologic diagnosis was AML. In two cases, Auer body was positive and M₂ according to FAB classification was noticed. The interval to achieve CR were shorter than 46 days and duration of CR were over 24 months in two cases.
As the prognostic factors of long-term survivors, host, tumor and antileukemic agents were closely correlated. From our results, it is suggested that the short period to achieve CR and supportive therapy for the complications including central nervous system prophy-laxis were significantly important factors to prolong the length of survival time.

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Long-term survivors were studied in 150 patients with acute leukemia (11-83 years of age) who recieved initial treatment at the 2nd Tokyo National Hospital from January, 1964 to May, 1981.
Seventeen of 150 patients were cases of survival for over 2 years. Out of 17 patients, 6 were cases of survival for over 5 years and 2 patients of them for over 10 years. There were 15 non-lymphocytic leukemia (14 adult cases) and 2 lymphocytic leukemia (11 and 13 years of age at the time of diagnosis).
According to the initial hematological findings, there were no significant differences in the median erythrocyte and platelet counts between the long-term survival group and the control group, but the long-term survival group showed lower median leucocyte and absolute leukemic cell counts.
Maintenance chemotherapy consisting of cytosine arabinoside and 6-MP (or cytosine arabinoside alone) was performed in 8 adult patients with acute non-lymphocytic leukemia who achieved a complete remission. Three of 8 patients have been remaining in the first complete remission for over 3 years.

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Pathophysiologic characteristics and methods of consolidation and maintainance therapy were compared between long-term (more than 3 years) suvivors and control patients who survived less than 3 years. The median age of the long-term survivors was 32 years, which was significantly younger than the control. The hematologic parameter at the time of diagnosis did not determine the outcome of the patients. Most of the long-term survivors of ANLL received the induction therapy of DCMP or BH-AC·DMP. The long-term survi-vors were found retrospectively to have a less frequent relapse as compared with the control, and also to survive the relapse with the chemotherapy including Vindesine and Aclacinomycin. However, the relapsed patients died including those who survived more than 3 years. More intensive chemotherapy would be necessary especially for the relapsed cases.

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A case of acute promyelocytic leukemia (APL) of complete remission (CR) for 11 years without a relapse is reported.
A forty-six-year-old female patient was admitted to Shikoku National Cancer Center Hospital in November 1971 because of bleeding tendency, cough and fever. On admission, WBC was 58, 000, /mm³ with 6% of myeloblasts and 82% of promyelocytes, and bone marrow showed 4.4% of myeloblasts and 83.2% of promyelocytes.
Chemotherapy with daunomycin, ara-c, 6MP and prednisolone induced the patient into complete remission. Patient has been remaining in complete remission for 11 years and is considered to be “cured” from APL.

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With respect to acute leukemia in childhood, we have encountered up to the present time 7 cases of long-term survivors and 7 cases of poor prognosis. Therefore, we were able to make some clinical observations as well as a comparative study for prognostic fac-tors between the two groups.
All of the 7 long survival cases were ALL and the initial examination of peripheral blood revealed a decrease in leukocyte count in four cases and in the remaining 3 cases a remarkable increase in leukocyte. On the other hand, in the group of poor prognosis, there was no case which indicated a decrease in leukocyte count, but a prominent increase was noted especially in the incomplete remission cases. Although such a prominent increase in leukocyte count was changed to a decrease within a short period of treatment, blast cells continued to exist in the group of poor prognosis while they disappeared in the group of long survivors. It was found that the tendency of anemia was stronger among the long survival cases based on the red blood cell count and there was no clear-cut difference of the platelet count between the two groups.
Hepatosplenomegaly and lymphadenopathy was hardly observed in the group of long survivors and even in those who indicated a remarkable increase in leukocyte, it was only of slight degree. As compared to the above, in the group of poor prognosis, hepatosplenomegaly and lymphadenopathy were observed, especially in those cases in which the remission was incomplete. The only case which was diagnosed as having no possibility of remission was the 12 year old patient who was found to be B cell type ALL. The investigation of HLA typing of the long-term survival group indicated a higher rate of AW 31 as compared with the control group.

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Since the first case of Philadelphia chromosome-positive acute lymphocytic leukemia (Ph¹+ALL) in 1970, about forty cases were reported, but in Japan only several cases were reported. We reported a case of Ph¹+ALL and reviewed the literature.
The case was a 64-year-old female. In September 1982 she was admitted to a hospital and was diagnosed as acute leukemia. After DCVMP she was inducted into complete remission and was discharged in November 1982. In February 1983 she was admitted to our hospital. On admission neither splenomegaly nor lymphadenopathy was found, no abnormal laboratory findings except leukocytosis were found. About one month after admission she was relapsed and showed leukocytosis (21900) with numerous blast cells. Hematological examinations showed the findings compatible with acute lymphocytic leu-kemia and chromosomal analysis showed Phl-positive. Various combination therapies were tried but not so effective and she died in September 1983. Chromosomal analysis of her bone marrow cells showed that numbers of Phl-positive cells varied in parallel with numbers of blast cells. These clinical, hematological and chromosomal findings were compatible with Ph¹+ALL.

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The risk of secondary malignancies by anticancer therapy including chemotherapy and/or radiation therapy against primary malignancies is increasing and it is becoming an important problem. It is well-known that the risk of acute leukemia is relatively high in malignant lymphomas. But reports of acute promyelocytic leukemia as secondary malignancies are rare.
A 38-year-old male was admitted to our hospital suffering from anorexia, weight loss and right chest pain. On admission swelling of the lymph nodes on his right side of the neck and right armpit was found, but no hepatosplenomegaly was seen. CT-scan showed a tumor originating from his right lateral pleura and other laboratory examination also con-firmed this finding. Biopsy of the lymph node on his right side of the neck revealed findings compatible with malignant lymphoma (diffuse, large cell type). After VEPA therapy and irradiation to his right side of the chest, the tumor and the swelling of the lymph nodes disappeared and he was discharged. About one year after the remission leukopenia developed and he was hospitalized again. Bone marrow examination showed increased numbers of promyelocytes with Auer bodies and the diagnosis of acute promyelocytic leukemia was made. After 3 courses of BHAC-AMP therapy a remission was induced and he is now doing well.

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The results of treatment for childhood malignant lymphoma, which were treated at Sapporo National Hospital from January, 1972 to September, 1984, were analyzed.
Ages of 5 patients with Hodgkin's disease (4 males and 1 female) ranged from 4 to 14 years old (average 10.4 years old). Clinical stages in 3 cases belonged to stage I: each of the other 2 cases to III sB, and to IV B respectively. Two cases were histopathologically classified as lymphocytic predominance, and 3 cases as mixed cellularity. The patient in stage I was treated with only irradiation, a case in stage III only with chemotherapy, and one in stage IV with combination of irradiation and chemotherapy. All of them have been surviving without relapse and any complications.
Ages of 3 cases of Burkitt's lymphoma were 3 years, 5 years and 10 years. All of them were female. Two of them were treated with COM, COMP regimen, and the other with VAC regimen, of which only 1 patient survived.
Fifteen patients had non-Hodgkin lymphoma other than Burkitt's one (11 males and 4 females), and their ages ranged from 1 to 16 years old. Most cases were histopathologically classified as diffuse type. In clinical stages, 2 cases were in stage I, 3 cases in stage II, 5 cases in stage III and 5 cases in stage IV. The patients with stage I and 11 were treated with CHOP plus irradiation, those in stages III and IV were treated with modified LSA₂-L₂ regimen. All patients in stage I and II are alive without relapse and any complications. Out of 5 cases in stages III, , only 1 patient died and survival rate has been remained 0.8, whereas almost all patients in stage IV died.
Therefore, more effective regimen must be developed to cope against non-Hodgkin lymphoma in stage IV.

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Patients with acute lymphocytic leukemia and non-Hodgkin lymphoma were shown to have high activity of erythrocyte uroporphyrinogen synthetase (URO-S), the enzyme which converts porphobilinogen to uroporphyrinogen. Patients with chronic granulocytic leukemia also demonstrated the high erythrocyte uroporphyrinogen synthetase activity. Erythrocyte URO-S activities in patients with acute lymphocytic leukemia were not affected by the chemotherapy of the leukemia.

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There are some factors, which involve Ørskov's hemolysis test i. e. NH₄ C1-, NH₄ HCO₃-mediated, and acetazolamide modulated, hemolysis test. Those are 1) carbonic anhydrase in erythrocytes 2) strength of erythrocytes membrane, 3) permeability of acetazolamide through erythrocyte membrane and 4) the shape of erythrocytes. Reaching time to 50%, 95% hemolysis (H₅₀, H₉₅) and those under suppression by acetazolamide (DH₅₀, DH₉₅) were evaluated on erythrocytes from 9 cases of iron deficiency anemia. No differences were noticed between the patients and normal controls in H₅₀ and DH₅₀, but the prolongation of hemolysis time in H₉₅ and DH₉₅ was statistically significant (p<0.01, p<0.02 respectively). The level of carbonic anhydrase C, activity of the enzyme including both isozymes showed a slightly high value, which however was not related to the abnormal values in this hemolysis test. We speculated that the prolongation of hemolysis time in this test resulted mainly from the morphological changes of erythrocytes in iron deficiency anemia.

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The author experienced a typical case of policythemia vera accompanied by various complications, and reported the case with some previous literatures and clinical considera-tions.
In this case the numbers of erythrocyte, granulocyte and platelet were remarkably increased, and the bone marrow puncture revealed an increase in the numbers of three haematopoietic cellular classes and argentaffin fibers, dilatation of sinuses and innumerable formations of erythroblastic island, and Philadelphia chromosome and trisomy of C group were not present through chromosomal analysis. Clinically, this case developed cerebral infarction, myocardial infarction, atrial fibrillation, left homonymous hemianopsia, impaired hearing, renal dysfunction and hypertension which were primarily ascribed to hyperviscosity syndrome of polycythemia vera.
Furthermore, this case was accompanied by hypoglycemia and positive RA test, and the former was conceivably due to an increase in blood cells but the latter supported the ECG findings of myocardial infarction. The fact that the serum level of erythropoietin did not decrease in this case was likewise explained by renal hypoxia due to hyperviscosity syndrome seen in polycythemia vera.

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According to the treatment protocol of the research group of the Ministry of Health and Welfare, we treated 3 cases of chronic ITP of the children with danazol, who did not undergo splenectomy. All were given 200 mg of danazol daily, whereas the other factors such as age, duration of the disease, efficiency of previous treatment, and the duration of danazol administration, were different among the 3 cases. The treatment with danazol turned out to be ineffective in all three cases, which showed no or transient increase in platelet count, and no improvement of clinical symptoms including purpura. Although on subjective side effects were observed, elevation of alkaline-phosphatase was seen in 2 cases. The guide does not include examination of γ-GTP, LAP, Na, K, which should be examined from now on. Since the mechanisms of the action of danazol are not known, we think it is necessary to experience many cases in order to discuss the feasibility and efficacy of danazol in the treatment of ITP of the children.

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