Guy Garay

Evaluation of intensification and maintenance programs in the treatment of acute lymphoblastic leukemia.

This cooperative prospective study was designed to answer the following questions in cases with acute lymphoblastic leukemia induced to achieve complete remission with the combination of vincristine and prednisone (if by day 29 the bone marrow was not M1, daunorubicin was added to the former regimen) and who received preventive CNS therapy with 2400 rad of cobalt‐60 to cranio‐cervical region and simultaneously intrathecal methotrexate and dexamethasone: 1) Is a short intensification with cytosine‐arabinoside and cyclophosphamide immediately after complete remission useful? 2) Does the use of weekly doses of 6‐mercaptopurine and methotrexate have the same maintenance effect as daily 6‐mercaptopurine and twice weekly methotrexate? and 3) Do further 3 month‐doses of intrathecal methotrexate and dexamethasone help to decrease still more the incidence of meningeal leukemia? From October 1972 to December 1975, 473 previously untreated patients entered this study and 465 (390 children and 75 adults) are evaluated in this paper. Of them, 373 (80%) achieved complete remission (children 84% and adults 61%). Out of 109 “high risk”children (one or more of the following characteristics at diagnosis: marked organomegaly, mediastinal widening, leukocytosis above 50000/ mm3 and CNS involvement) 83 (76%) and out of 281 “standard risk”children (all the others) 244 (87%) achieved complete remission. The median duration of complete remission according to different prognostic factors was as follows: “high risk”children 10 months, adults 24 months and “standard risk”children 25 months. Duration of complete remission of the “standard risk”children in relation to with or without intensification, daily or weekly maintenance and additional intrathecal therapy or none, showed no significant difference; however, those who received intensification, daily maintenance and further intrathecal therapy behaved slightly better. Median survival for all the cases of this study was as follows: adults 10 months, “high risk”children 12 months and “standard risk”children 26. months. At 36 months, 13% of “high risk”children, 25% of adults and 39% of “standard risk”children are still alive. We conclude that the variables studied in this protocol did not show significant extension of complete remission, however the sum of them seems to offer some advantage. Moreover, what appears clear is the importance of prognostic factors which must be taken into account in future studies. Cancer 42:1730–1740, 1978.

Combined chemotherapy cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) V.S. CVPP PLUS CCNU (CCVPP) in Hodgkin's disease

With the purpose of exploring new combinations less toxic and easier to manage, the Argentine Group for the Treatment of Acute Leukemia (GATLA) started a randomized controlled study to compare differences in efficacy of treatment in Hodgkins disease using six courses of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) versus the same drugs plus CCNU (CCVPP). A total of 298 patients entered this study; 157 with CVPP and 141 with CCVPP. No statistically significant difference was observed between both groups in each of the following features: prior therapy, sex, age, class, stage and histology. The doses in every monthly cycle are: cyclophosphamide 600 mg/m2 iv on day 1, vinblastine 6 mg/m2 iv on day 1, procarbazine 100 mg/m2/day 1 orally on day 1 to 14 and prednisone 40 mg/m2/day orally on day 1 to 14 in all the courses. The CCVPP group received also CCNU 75 mg/m2 day 1 orally on alternate cycles. Patients with stage I or II A received radiotherapy (4,000 rads) to involved areas as induction and were subsequently randomized to receive maintenance therapy. Patients in all other stages received only combination chemotherapy at random. Maintenance therapy consisted of one cycle every 2 months during the first year, every 4 months the second year and every 6 months the third year. Complete remission was obtained in 111 out of 157 patients (71%) of those receiving CVPP and in 110 out of 141 patients (78%) receiving CCVPP. There was no statistically significant difference between both regimens. The percentages of complete remission according to clinical stage and symptoms were: I‐IIA 88%. III‐IVA 84%, I‐IIB 76%, IIIB 76% and IVB 58%. After 42 months of remaining in complete remission 53% and 64% of those patients were treated with CVPP or CCVPP, respectively. The survival percent as a function of therapeutic response at 48 months for patients who achieved complete remission was 80%, 63% for partial remission, and 14% for those who failed to respond or died within the first six courses, with a median duration of survival of 6 months.

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.

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.

Multicenter study of subcutaneous alemtuzumab administered at reduced dose in patients with fludarabine-relapsed/refractory chronic lymphocytic leukemia: final analysis

Abstract Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) has been the motive behind a large number of studies in recent years, and previous response, its duration, and development of clonal evolution appear to be the best indicators for the choice of a new regimen. Although alemtuzumab in relapsed/refractory CLL may be beneficial, the optimal dosage and risk of infection related to its use remain thus far deeply controversial issues. In this pilot phase II study we investigated the feasibility of, toxicity of, and response to alemtuzumab at a reduced dose (30 mg s.c. for 2 weeks and then once a week at extended intervals: every 2, 4, 6 weeks up to 1 year). The overall response rate was 95%, with 51% complete response. The complete response range was 55% in fludarabine-relapsed patients and 28% in patients with fludarabine-refractory disease, without significant difference between the two groups. The regimen was well tolerated with mild toxicity and few cytomegalovirus (CMV) infections. With a median follow-up of 27 months, the overall survival (46% at 3 years) appears to be similar to that with other regimens although with fewer adverse events. In conclusion, treatment with alemtuzumab at a reduced dose seems to be safe and increases the event-free survival of patients with relapsed/refractory CLL, compared with the standard dose. A randomized study comparing both regimens including a larger number of patients is warranted.

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.

Randomized study of chemotherapy alone vs. chemotherapy plus radiotherapy in Clinical Stages IA-IIA Hodgkin’s disease

Major radiotherapy centers or collaborative groups report 5-year survival rates of 80–90% or higher in patients with Stages I-IIA Hodgkin’s disease [1–4]. These results have been achieved with megavoltage equipment, variable irradiated fields (involved field to total lymphoid) and doses between 3,500 and 4,400 rad. Adjuvant chemotherapy has significantly increased relapse-free survival compared with irradiation alone (87–92% vs 66–79% at 5 years). However, 5-year survival rates are identical. Comparisons at 10 or more years remain to be determined [1, 2, 4].

59 CONTINUATION THEFAPY IN ACUTE LYMPHOBLASTIC LEUKEMIA: EVALUATION OF DIFFERENT REGIMENS

This investigation has the following scheme: Induction: vincristine (VCR)+daunorubicin+prednisone (PRED); CNS prevention: intrathecal methotrexate (MTX)+dexamethasone × 6 early doses followed by one trimesterly; and Continuation: 6-mercaptopurine daily and MTX twice weekly with reinforcement of pulse doses of VCR 1.5 mg/m2 × 1 + PRED 40 mg/m2/day × 7 (arm A) or VCR+PRED alternating with arab. cit. (Ara.C) 50 mg/m2/sc q. 12 h × 10 + cyclophosphamide (CTX) 600 mg/m2 × 1 (arm B). Pulses are performed in both arms at 1,2,3,4,6 mo, and trimesterly thereafter: In addition, half of the cases received levamisole (LEV) 120mg/m2/oral/daily and the other half, none.From Jan. 1976 to Dec. 1978, 378 patients entered this study. 282/322 (88%) children and 44/56 (78%) adults achieved complete remission (CR) (P<0.05). The % of CR at 30 mo. are, arm A > 20.000 leukocytes 46%, > 20.000 37% and arm B > 20.000 78%, > 20.000 33% (P < 0.01 between and > 20.000 leukocytes in both arms and P < 0.05 between arms A and B in patients with > 20.000 leukocytes). In addition, 59% of the LEV-treated patients and 50% of the control group are still in the first CR at 30 mo. (P < 0.05).We conclude that: 1) usefulness of alternating reinforcement pulses of VCR+PRED with Ara.C-CTX in relation to VCR+PRED alone, and 2) immunotherapy with LEV is effective in prolonging CR.

6 EFFECTIVENESS OF PREVENTION OF CNS LEUKEMIA WITH INTRATHECAL (IT) METHOTREXATE (MTX) AND DEXAMETHASONE (DMT) IN ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

A protocol was started in 1976 for the treatment of ALL. It included 3 injections of IT MTX-DMT during the induction, another 3 early in remission followed by one injection every 3 months as prevention of CNS disease.Thus far 24 (8,9%) CNS relapses were observed in 270 patients who achieved complete remission(median: 18 months, range: 1 to 33). Data from earlier protocols of our group, which included radiotherapy (RT) to cranium plus 5 doses of IT MTX showed 49 patients (11,6%) of a total of 443 who experienced CNS relapse. The comparison of the incidence of CNS leukemia of both preventive methods according to life table analysis is the following:We conclude that in comparison with earlier protocols which included RT the present regimen compares favourably in standard and high risk patients.