Federico Sackmann Muriel

Evaluation of gonadal function following long-term treatment for acute lymphoblastic leukemia in girls

Twenty-four girls were studied following long-term treatment (mean: 50 months) for acute lymphoblastic leukemia; 14 were prepubertal and 10 pubertal. Follow-up during endocrine studies ranged from 2 months to 6.7 years (mean: 2.3 years). Five of 14 prepubertal patients started clinical pubertal development at a normal age and were reevaluated during puberty, increasing the pubertal group to 15 patients. Thirteen of 15 pubertal patients had received cranial radiotherapy. Ten of 15 pubertal patients started menses during the endocrine study. Although age of menarche was normal, in nine patients it was below the normal mean. Except for the remaining patient, all had received cranial cobalt therapy. In 6 of 19 patients bone age was significantly accelerated. Serum gonadotrophin response to LH-RH was normal in 13 prepubertal patients and in 10 pubertal patients. In 3 of 10 pubertal patients follicle-stimulating hormone (FSH) values were temporarily elevated. Only one pubertal patient had oligoamenorrhea. Five patients were studied by measuring serum progesterone on days 19-22 of the cycle to determine corpus luteum function. Three of them showed progesterone levels compatible with adequate corpus luteum function (6, 19, and 12 ng/ml, respectively) and two presented low progesterone levels (2 ng/ml), probably because of their short gynecological age (0.24 and 0.3 years, respectively). This study suggests that neither the disease nor the long-term antileukemia therapy seems to injure gonadal function in girls. A tendency to early sexual development was observed, which may be related to cranial cobalt therapy.

Evaluation of induction of remission, intensification, and central nervous system prophylactic treatment in acute lymphoblastic leukemia†

A total of 146 previously untreated acute lymphoblastic leukemia patients—126 children and 20 adults—has been studied prospectively in order to evaluate the relative efficacy and toxicity of: A) two induction of remission treatments (Group A: Daunorubicin‐vincristine‐prednisone vs. Group B: Adriamycin‐vincristine‐prednisone) and the use of the same drugs as reinforcement courses every 90 days during the 1st year of complete remission and every 180 days thereafter; B) the use of a short course of L‐asparaginase early in remission as intensification treatment (to half of Group A only (Group Aa); Groups Ab and B did not receive this treatment); and C) the use of 2400 rads cobalt‐60 irradiation to cranium coupled with five doses of intrathecal methotrexate as prophylactic CNS treatment. Complete remission was achieved in 85.7% of 112 cases of Group A and in 79.4% of 34 cases of Group B. The median duration of hematologic remission was 23, 21, and 22 months for Groups Aa, Ab, and B respectively. Toxicity was about the same for all regimens. The median duration of complete remission was 24 months, and of hematologic remission 27 months in the CNS prophylactically treated group, against 9 and 18 months, respectively, for the non‐treated group. We have concluded that: A) Adriamycin did not seem to be any better than Daunorubicin in inducing or prolonging complete remission when used in combination with vincristine and prednisone, either as induction treatment or in reinforcement courses; B) we did not demonstrate any significant difference in duration of remission, incidence, or site of relapse between L‐asparaginase‐treated and non‐treated patients; and C) the CNS prophylactic treatment employed in this trial is very effective in preventing CNS relapse, although it does not seem to prevent hematologic relapse.

Induction and maintenance of remission in acute leukemia

A total of 227 patients—124 with acute lymphoblastic leukemia (ALL) and 103 with acute myeloblastic leukemia (AML)—have been studied in order to evaluate the therapeutic effectiveness of vincristine, daunorubicin, and prednisone for induction followed by consolidation courses every 6 months with these drugs and either 6‐mercaptopurine and methotrexate (plan A) or methotrexate alone (plan B) for maintenance of remission. In ALL, complete remission (CR) was achieved in 90.2% of untreated and 71.6% of previously treated patients. In AML, 34.8% untreated and 23.5% previously treated patients obtained CR. There was no statistically significant difference between the two maintenance regimens. Median duration of hematologic remission in ALL was 16 months and that of complete remission terminating in either meningeal, visceral, or bone marrow relapse was 9 months. Median survival was 18.2 months. In AML, the median survival was 11.8% months for those that achieved CR, 4.2 months for the partial remission (PR) group, and 0.9 months for nonresponders.

Chemoimmunotherapy with levamisole in acute lymphoblastic leukemia

Patients with acute lymphoblastic leukemia (ALL) who were in two consecutive protocols and in complete remission (CR) with maintenance therapy, were randomized to receive or not receive levamisole. A total of 15 of 55 low‐risk patients of protocol 10‐LLA‐72 with levamisole had relapses, compared with 25 of 54 not receiving levamisole; 67 and 49%, respectively, remain in CR at 48 months (P < 0.025). In protocol 1‐LLA‐76, 14 of 91 low‐risk patients on levamisole and 25 of 93 patients not receiving levamisole had relapses; 78 and 61%, respectively, remain in CR at 36 months (P < 0.05). Seventeen of 39 high‐risk patients (children with a leukocyte count higher than 50,000 and adults) receiving levamisole had relapses compared with 37 of 61 not on levamisole. The DNCB skin test shows at 18 and 24 months a 74 and 85% positivity in the levamisole group vs. a 38 and 35% positivity in the control group (P< 0.025). We conclude that levamisole prolongs the duration of CR and survival in low‐risk patients with ALL.

Sequential therapy for induction and maintenance of remission in acute myeloblastic leukemia

A total of 114 previously untreated patients with myeloblastic leukemia was included in a sequential therapy protocol. Daunorubicin, vincristine, and prednisone were employed for the first 3 weeks, followed by two or more 5‐day courses of cytosine arabinoside and 6‐mercaptopurine; there was a 5‐day rest between courses. Maintenance therapy was as follows: the continuing 6‐mercaptopurine and methotrexate treatment was interrupted every 30 days for sequential reinforcement courses consisting of one dose of daunorubicin and vincristine and 7 days of prednisone, or by a 5‐day course of cytosine arabinoside plus 6‐mercaptopurine. Of the 114 patients, 48 obtained complete remission, 14 had partial remission, 16 failed to respond, and 36 died during the course of treatment. The remission rate in children (under 16) was 57%; in adults (16–45) 54%; and in those over 45, 19%. The difference in the incidence of complete remission in patients under 45 and those over 45 was statistically significant (p < 0.01). The median duration of complete remission was 8 months: 12 months in children and 5 months in adults. The over‐all survival rate was 4 months: 13 months for patients with complete remission, 4 months for those with partial remission, and 1 month for patients who did not respond to therapy. The difference in survival of those with complete remission and all the others was significant (p < 0.01).

Long‐term survival in acute leukemia in Argentina. A study of 78 cases

A total of 78 patients with acute leukemia [69 acute lymphoblastic leukemia (ALL) and 9 acute myeloblastic leukemia (AML)] survived more than 4 years. In the years between 1958 and 1967 the number of patients with ALL in Argentina who survived 4 years was 1%. This increased to 21% in the years between 1967 and 1972. The major cause of this increase was the initiation in 1967 of protocols of therapy on a national scale through a cooperative group known as GATLA. In AML patients the number of long‐term survivals remained unchanged during both periods. A large percent of the long‐term survivors had lower WBC, a higher platelet count, and no hepato‐ or splenomegaly, lymphadenopathy, or hemorrhagic manifestations at diagnosis. However, only for those patients with a WBC under 100,000/mm3 at diagnosis was there a significant prognostic implication (p < 0.01). Patients with acute lymphoblastic leukemia who survive more than 4 years without relapse have about an 80% chance of long survival. For those who have lived 4 years with one or more relapses, there is only a 17% chance of long survival, and of these only those who develop extramedullary relapse (CNS or testicular) without bone marrow involvement have a chance of long survival. Patients who live 4 years in continuous complete remission have the same chance of very long survival regardless of previous therapy.

Chemoimmunotherapy with corynebacterium parvum in acute myelocytic leukemia

The purpose of this study is to see if immunotherapy with C. parvum and prevention of central nervous system relapse with intrathecal methotrexate can prolong duration of complete remission and survival as well as avoid central nervous system relapse. For induction, three weekly I.V. injections of vincristine and Daunorubicin were given with daily prednisone orally, followed by 5‐day courses of Cytosine Arabinoside and 6‐mercaptopurine. The patients were randomized to chemotherapy or chemoimmunotherapy. Maintenance consisted of vincristine, Daunorubicin, and prednisone one week every odd month, and a 5‐day course of Cytosine Arabinoside and 6‐mercaptopurine every even month. Every week, the chemoimmunotherapy group also received, without chemotherapy, one injection of C. parvum 4 mg, subcutaneously. All patients received five weekly injections of intrathecal methotrexate 13 mg/m2 right after complete remission was achieved. Out of 181 evaluable cases, 80 (44%) achieved complete remission, 45 were randomized to chemotherapy, and 35 to chemoimmunotherapy. In the chemoimmunotherapy group 32/35 relapsed, and in the chemotherapy group 36/45. Median duration of complete remission and survival were: for group chemotherapy, 8 and 15 months; for group chemoimmunotherapy, 5 and 10 months. This difference is not significant. Intrathecal methotrexate was given to all patients. Six patients (7%) had central nervous system leukemia at the time of the first injection. None had central nervous system relapse after prevention with intrathecal methotrexate. This method seems useful in preventing central nervous system relapse in patients with acute myeloblastic leukemia, but does not seem to prolong complete remission.

Vindesine, prednisone, and daunomycin in acute lymphoblastic leukemia in relapse

SummaryPatients with resistant or recurrent acute lymphoblastic leukemia were treated with vindesine 3 mg/m2/IV weekly x 4, daunomycin 25 mg/m2/IV weekly x 4, and prednisone 40 mg/m2/PO daily x 28.Seventeen (44%) of 38 evaluable patients achieved complete remission. Fifty-one percent of 31 patients in first relapse achieved complete remission, while only one of five in second or third relapse and neither of two resistant to first induction achieved complete remission. The major toxicity was hematologic. The median duration of complete remission was only 6 weeks and median survival from start of the study, 3 months, with 22% patients remaining alive at 10 months.We conclude that the vindesine, prednisone, and daunomycin combination is no more effective than vincristine, prednisone, and daunomycin in achieving remission of relapsed acute lymphoblastic leukemia patients, and is more toxic than the latter regimen.

Results of therapy in osteosarcoma: Experience in Childrens hospitals in Buenos Aires

This is a summary report about the results of the application of therapy in osteosarcoma by the authors’ experience during our previous work at the Children’s Hospital, the Department of Pediatrics of the Italian Hospital, and the Pediatric Hospital in Buenos Aires, Argentina.

Epidemiology of hemopoietic system neoplasms in Argentina

The mortality caused by blood neoplasms in Argentina shows great irregularity. This was found to be caused in certain ways by (a) differences in the sexes and ages of the populations studied; (b) differences in available health services; and (c) environmental factors. Thus high rates and clusters of lymphomas and multiple mylomas were observed in zones with arsenical water, for example.In rural districts, the rates are lower, especially among old-aged people.Lower rates of leukemias were also observed among Spaniards compared to Italians (p=0.001) residing in Argentina. Turkish, Syrian, and Lebanese showed higher rates than Argentinians, Spaniards, or Italians.The results of a case-control study are given in which the following were observed:(a)Among the ancestors of cases HSN there are fewer Spaniards (not significant) and Latin-Americans (p=0.03) and more people who were born in Central or Eastern Europe (p=0.01).(b)In case group, there was more frequent contact with animals, especially dogs; and a greater exposure to petroleum and its products, and to insecticides.