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Of 91 acute leukaemia patients treated with m-Amsa, 19 received intermittent doses, 23 received daily doses and 49 underwent courses with combined m-Amsa and cytosine arabinoside (Ara-C). Intermittent doses had minimal therapeutic activity and toxicity. Among the 23 patients given daily doses, complete remission was observed in 5/12 relapses of ALL and in 2/11 relapses of AML. When Ara-C (200 mg/m2 x 5 days) was administered concomitantly with m-Amsa (200 mg/m2 x 5 days or 120 mg/m2 x 7 days), 17 out of 37 patients with advanced relapses of ALL (13/25 children and 4/12 adults) went into complete remission. While high doses of m-Amsa alone were well tolerated, the combined treatment with high doses of both drugs resulted in severe gastro-intestinal toxicity. Cardiac disorders were observed in patients who had previously received high doses of anthracyclins; there were 5 cases of dysrhythmia and 1 case each of sudden death, ECG alterations and heart failure. In view of its indisputable activity, m-Amsa should be used at an earlier stage in the treatment of acute leukaemias.

This is a review of the progress achieved in the treatment of acute lymphoblastic leukaemia, based on a series of 1580 children treated in Prof. Jean Bernard's unit, Paris, from 1956 to 1976. The children are retrospectively divided into three prognostic classes and five therapeutic categories. The benefits obtained from successive additions to the therapeutic armentarium during that period are conspicuous in all classes and categories and particularly striking in children with poor initial prognosis. The role of each component of the therapeutic measures applied is discussed.

Burkitt's-type leukemias have specific cytologic, immunologic, and cytogenetic characteristics. Initial symptomatology frequently includes abdominal tumors and initial CNS involvement. Despite intensive treatment including high-dose cyclophosphamide, prognosis remains poor in most patients because of failures to achieve complete remission (CR) or because of early relapses, especially CNS relapses. Class III acute lymphoblastic leukemia in children is defined by the presence of two or more unfavorable parameters and recent progress has been achieved by intensive therapy. Cox's multifactorial analysis allows improved discrimination. A phase I protocol for increased-risk leukemias, including testis preventive irradiation and monthly reinductions without continuous maintenance for the first 6 months of CR, seems promising.

The complete hematological remission (CHR) rate, duration of remission and survival were studied in relation to age, peripheral blast cell (PBC) count, presence or absence of tumor masses, cytological type, and treatment in 650 patients with acute lymphoblastic leukemia. Prognostic factors were considered separately and divided into prognostic classes. Age and PCB count correlated with both the rate and the duration of CHR. This correlation was still observed for more recent treatment schedules though it appears to be becoming progressively less significant. Meningeal relapses were more common in patients less than 1 year old and in those with a high PCB count. It is suggested that stratification of patients according to such factors as age, PCB count, presence or absence of tumor, and cytological type might be necessary for the design of new treatment protocols and for the evaluation of their results.

Amongst 1,200 leukemie children treated between 1958 and 1971, 60 are in complete remission for more than 10 years and 100 for more than 7 years. There were 96 acute lymphoid and 4 acute myeloid leukemias. Ten patients who have relapsed in the past have not done so lately. The F/M sex ratio is 1.5. Poor prognostic features were initially absent in 2/3 of cases. In 1/3 there was associated hyperleucocytosis and/or tumours. 93 children are in remission, their treatment having been stopped for 1 to 12 years. Five children relapsed and 4 are in a second remission for more than 2 years. Two children died in remission: one from a hepatocarcinoma and one from cardiac failure. These patients have been shown to have the following: 1) normal growth; 2) normal puberty: 8 patients have been able to reproduce, giving 10 children, one with multiple malformations; 3) school achievement and later socioprofessional behaviour has been normal. The patients have often sought a medical or paramedical career. Sequelae are minimal, psychological problems being minimal in the child. With the protocols used, mean remission curve shows a plateau after 9 years and complete definitive care is achieved in 92 per cent of patients surviving at 7 years. The very distant future outlook is not known. No other malignant haematological disease has occurred but one child died from a carcinoma.

405 children with acute lymphoblastic leukemia were stratified according to age, initial leucocytes count, lymph nodes, liver and spleen size, into three prognostic classes I, II, III. Protocol 08 LA 74 which they were applied included: 1)initial randomization between Prednisone, Vincristine, Daunorubicin or the same plus Cyclophosphamide for induction and reinductions; 2)doses adjustments to prognostic factors, increased doses being given to increased risk patients; 3)comparison between intrathecal Methotrexate and intrathecal Methotrexate plus Ara-C in addition to skull irradiation for CNS prophylaxis; 4)L-Asparaginase consolidation for all patients; 5)maintenance by 6-Mercaptopurine and Methotrexate in all patients and reinductions. The most striking conclusions to date are the improvement for increased risk patients, the frequency of primary testicular relapses contrasting with the low rate of meningitis, the prognostic implication of sex, the influence on remission duration of the number of courses necessary to achieve complete remission, the importance of using Cox Method to improve the identification of prognostic groups.

In acute lymphoblastic leukaemia the combination prednisone-vincristine induces more than 85% complete remissions. L-asparaginase which was used in complete remissions, seemed to increase their duration. Actually the best maintenance treatment consists in the combination of 6-mercaptopurine and methotrexate interrupted by reinductions. In other respects C.N.S. prophylaxis with intrathecal methotrexate and craniospinal irradiation is necessary. The well-known prognostic factors are: age, leucocytosis, tumoral syndrome, and cytological type: 216 cases of long remission have been observed. One group of these patients was treated by old methods: this represents 0.8 to 1% of the material, while 20% were treated by recent protocols with reinductions (20%).

Amongst 1500 cases of acute lymphoblastic leukaemia, affecting both sexes, the authors noted 111 testicular recurrences and 2 ovarian recurrences, i.e. an incidence of 16 percent. Clinical diagnosis is easy and testicular needle biopsy was reserved for doubtful cases only. Amongst 12 lymphographies, only one showed lumbar node involvement. Testicular involvement may exist before, after or in association with a bone marrow or a meningeal relapse. In 47 cases the first signal recurrence was a testicular tumour. The majority of these recurrences occured during the first two years of the disease, but late recurrences affecting the gonads are possible. Mean survival after an isolated testicular recurrence was 14 months, identical with meningeal recurrences. General chemotherapy and local radiotherapy were in general followed by an in situ or contralateral recurrence. Bilateral irradiation at a dose of 2400 rads is the best local treatment. However, in the light of the frequency of bone marrow recurrences a short time after, intensification of general treatment is necessary.

We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other "sanctuary" areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P = 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P = 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.

The cases of one hundred and forty-one patients (85 males, 56 females) treated for hyperleucocytic acute lymphocytic leukemia (H-ALL) were reviewed. In all cases the initial white blood cell count was over 100,000/cu mm. One hundred patients (71%) attained complete remission (CR). The median duration of CR was six months and the median survival was nine months for all patients and 11 months for those who attained CR. Age, initial hemoglobin, and the height of initial white blood cell count over 100,000 had no significant prognostic value. Relapses occurred earlier in patients with a mediastinal mass. The results depended on the treatment used. With modern treatment, including more intensive chemotherapy and central nervous system prophylaxis, CR rate increased from 65% to 81% and median duration of CR improved from four months to ten months. The most important prognostic difference was related to the sex: CR rate was higher (78.5% vs. 66%) and median duration of CR and hematological remission was longer for females (nine months vs. six months and ten months vs. 6.5 months, respectively). This difference only appeared with modern treatments, however: before 1972 the median duration of CR was four months for both sexes, and after 1972, it was eight months for males and 17 months for females. This difference could be explained by the site of the first relapse, which was testicular in only 2% of cases before 1972 and 27% (47% of the males who relapsed) after 1972.

During acute lymphoblastic leukemia in children, bacterial infections occur during initial treatment, whereas virus infections are observed during remission. Mycoses and pneumocystis carinii infections are the commonest late complications. During agranulocytosis, any prolonged fever should be considered as due to infection and probably septicemia. The bacteria are usually of digestive origin. Antibiotic therapy is only very inconstantly efficacious, and the course follows closely the number of granular cells, thus justifying the use of white cell transfusions.

Case report of a 4-year-old girl in whom a unilateral ocular localization appeared after 1 1/2 year of maintained remission of acute lymphoblastic leukaemia. The evolution of this localization can be divided in three phases: 1. During the first 17 months, an apparent simple relapsing conjunctivitis of the left eye. 2. During the following 5 months, repeated episodes of the left iritis with mydriasis and discolouration of the iris. 3. Finally, left uveitis involving the anterior chamber, with hypopion, hyphaema and glaucoma; the clinical presentation at this stage was suggestive of ocular lymphoblastosis. Radiotherapy to the lesion (total dose, 1 200 rads) was quickly followed by resolution without sequelae. No relapse was observed during the following 30 months, till death. The ocular disease remained the only manifestation of leukaemia during its evolution. A haematological relapse occurred 11 months after cure of the iritis, followed 1 year later by a second, treatment-sensitive relapse, and finally by a third, fatal relapse. The patient survived 5 years 9 months.