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LONG-TERM REMISSION IN ACUTE MYELOGENOUS LEUKAEMIA
571 LONG-TERM REMISSION IN ACUTE MYELOGENOUS LEUKAEMIA
SIR,-In their partly randomised trial of maintenance therapy in myelogenous leukaemia (AML) (Feb 18, p 379) the Swiss Group for Clinical Cancer Research drew four major conclusions,
acute
which
we
would like
to comment on:
(1) Conventional maintenance treatment after early consolidation does not prolong duration of remission or of survival. (2) Early consolidation increased the median survival time of patients entering remission to 2 - 5 years. (3) Patients up to 65 years of age should be treated as aggressively as younger patients. (4) Patients under 40 should be transplanted if possible. Several trials have indicated long-term remissions in 20-26% of
responders after 4-6 yearsl-5 with a general decrease in relapse rate beyond 3 years. A multicentre evaluation of 100 patients with longterm remissions of 3 to over 8 years suggests that the risk of relapse is 24-8% after 3 years and 14 - 407o after 4 years. The cure rate of AML may not be far away from the long-term remission rate. Remarkably, in the Swiss trial remission rates after 3 or 4 years seem to be below 15%, despite positive selection of patients (by excluding early relapses and including children). We wonder if better results might have been achieved by the more conventional monthly maintenance regimen applied in CALGB trial 7421.5 This wellestablished regimen produced a 5-year-remission rate of 20-25%, whereas the bimonthly version cannot yet be regarded equivalent, the maximum observation time being less than 3 years so far.The question-Does optimal conventional maintenance after early consolidation prolong remission?-may not have been definitely answered by the Swiss study. In the current German AML Cooperative Group trial we are tackling the same question. After intensified induction treatment with one or two courses of a 9-day TAD combinationpatients are randomised to receive one course of induction type consolidation with or without monthly maintenance similar to CALGB protocol 7421.5 In the 95 patients randomised so far, the median remission duration for patients without maintenance is 7’5months and the probability of complete remission after 22 months is 22%; the corresponding figures for the maintenance group are 12’55 months and 40% (p= 0- 15). In the pilot study8 all patients received the 9-day TAD induction regimen but subsequent management at the fifteen centres differed, being either the CALGB type monthly maintenance or one or two courses of induction type consolidation or both or no therapy in remission. Patient characteristics and response data are given in the table. Among all 171 responders the median remission duration is 13 months, median survival is 20 months, and the 4-year complete remission (CR) rate is 23% with 45 patients in continuous CR for 8-51 (median 30) months. The 4-year remission rate of all 133 patients receiving any type of treatment in CR is 30%. The figure compares the Kaplan-Meier plots of the four treatment groups, the "none" group including patients who relapsed before treatment in remission could start and patients with contraindications to further chemotherapy. Including deaths in early CR, median survival of all maintenance patients is 26 months and of all consolidation patients 23 months. Thus, the benefit from conventional monthly maintenance may be about the same as from intensive consolidation.
Kaplan-Meier life table plots of remission duration for the different nonrandomised groups of treatment in remission.
Not only the early consolidation but also the exclusion of deaths in early remission in the Swiss study increased the median survival time to 30 months. In our pilot study median survival was also 30 months for patients receiving monthly maintenance without consolidation, when deaths during the first 8 months (as in the Swiss trial) are excluded. Patients receiving consolidation and completing both consolidation courses (as in the Swiss trial) show a median survival of 38 months. treatment may be helpful in patients over 65 years of age. In our pilot study 26 of the 38 patients (68%) aged 66-78 achieved a complete remission, with a median duration of 10’66 months.
Agressive
PILOT STUDY
Age under 40 as the only criterion for bone marrow transplantation may not be satisfactory for other protocols. In our pilot study 7 of the 13 patients who have been in continuous remission for 3-4 years so far are 40 years old or younger. Early indices of response may permit the identification of patients with a low risk of relapse. Thus, among patients responding to the first induction course and completing two consolidations, those with a serum lactate dehydrogenase (LDH) on day 15 of treatment below the median value for all patients showed a 68% 4-year remission rate vs 0% in patients with a day 15 LDH above the median (p<0 005). Department of Internal Medicine,
University of Münster, D-4400 Münster, West Germany; Departments of Internal Medicine, Universities of Munich, Düsseldorf, and Cologne and Evangelisches Krankenhaus
Essen-Werden,
Champlin R, Jacobs A, Gale RP, et al. Prolonged survival in acute myelogenous leukemia without maintenance chemotherapy. Unpublished. 2. Clarkson BD. The elusive goal: Presidential address. Cancer Res 1981; 41: 4865-84. 3. Gale RP, Foon KA, Cline MJ, Zighelboim J. The UCLA acute leukemia study group: intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med 1981; 94: 1.
(1978)
Department of Biostatistics, University of Münster; and Department of Haematology, University of West Berlin
T. BÜCHNER B. EMMERICH D. URBANITZ A. HEINECKE J. FISCHER W. HIDDEMANN M. PFREUNDSCHUH H. RÜHL F. WENDT for the AML Cooperative Group
753-57. 4.
5. 6. 7
8.
Keating MJ, Smith TL, McCredie KB, et al. A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia. Cancer 1981; 47: 2779-88. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood 1981; 58: 1203-12. Whittaker JA, Reizenstein P, Callender ST, et al. Long survival in acute myelogenous leukaemia: an international collaborative study. Br Med J 1981; 282: 692-95. Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia. a CALGB study. Blood 1982; 60: 454-62. Büchner T, Urbanitz D, Emmerich B, et al. Multicentre study on intensified remission induction therapy for acute myeloid leukemia. Leukemia Res 1982, 6: 827-31.
INFLAMMATION OF THE ILEUM IN PATIENTS WITH B27-POSITIVE ARTHRITIS
SiR,-Dr Mielants and Professor Veys (Feb 4, p 288) report that individuals with B27-associated perhipheral arthropathy revealed some evidence of inflammatory change in the terminal ileum. They then suggest that these findings imply the presence of idiopathic 9. Foon
KA, Zighelboim J, Yale C, Gale RP. Intensive chemotherapy is the treatment of 1981; 58: 467-69.
choice for elderly patients with acute myelogenous leukemia. Blood
SIR,-In their partly randomised trial of maintenance therapy in myelogenous leukaemia (AML) (Feb 18, p 379) the Swiss Group for Clinical Cancer Research drew four major conclusions,
acute
which
we
would like
to comment on:
(1) Conventional maintenance treatment after early consolidation does not prolong duration of remission or of survival. (2) Early consolidation increased the median survival time of patients entering remission to 2 - 5 years. (3) Patients up to 65 years of age should be treated as aggressively as younger patients. (4) Patients under 40 should be transplanted if possible. Several trials have indicated long-term remissions in 20-26% of
responders after 4-6 yearsl-5 with a general decrease in relapse rate beyond 3 years. A multicentre evaluation of 100 patients with longterm remissions of 3 to over 8 years suggests that the risk of relapse is 24-8% after 3 years and 14 - 407o after 4 years. The cure rate of AML may not be far away from the long-term remission rate. Remarkably, in the Swiss trial remission rates after 3 or 4 years seem to be below 15%, despite positive selection of patients (by excluding early relapses and including children). We wonder if better results might have been achieved by the more conventional monthly maintenance regimen applied in CALGB trial 7421.5 This wellestablished regimen produced a 5-year-remission rate of 20-25%, whereas the bimonthly version cannot yet be regarded equivalent, the maximum observation time being less than 3 years so far.The question-Does optimal conventional maintenance after early consolidation prolong remission?-may not have been definitely answered by the Swiss study. In the current German AML Cooperative Group trial we are tackling the same question. After intensified induction treatment with one or two courses of a 9-day TAD combinationpatients are randomised to receive one course of induction type consolidation with or without monthly maintenance similar to CALGB protocol 7421.5 In the 95 patients randomised so far, the median remission duration for patients without maintenance is 7’5months and the probability of complete remission after 22 months is 22%; the corresponding figures for the maintenance group are 12’55 months and 40% (p= 0- 15). In the pilot study8 all patients received the 9-day TAD induction regimen but subsequent management at the fifteen centres differed, being either the CALGB type monthly maintenance or one or two courses of induction type consolidation or both or no therapy in remission. Patient characteristics and response data are given in the table. Among all 171 responders the median remission duration is 13 months, median survival is 20 months, and the 4-year complete remission (CR) rate is 23% with 45 patients in continuous CR for 8-51 (median 30) months. The 4-year remission rate of all 133 patients receiving any type of treatment in CR is 30%. The figure compares the Kaplan-Meier plots of the four treatment groups, the "none" group including patients who relapsed before treatment in remission could start and patients with contraindications to further chemotherapy. Including deaths in early CR, median survival of all maintenance patients is 26 months and of all consolidation patients 23 months. Thus, the benefit from conventional monthly maintenance may be about the same as from intensive consolidation.
Kaplan-Meier life table plots of remission duration for the different nonrandomised groups of treatment in remission.
Not only the early consolidation but also the exclusion of deaths in early remission in the Swiss study increased the median survival time to 30 months. In our pilot study median survival was also 30 months for patients receiving monthly maintenance without consolidation, when deaths during the first 8 months (as in the Swiss trial) are excluded. Patients receiving consolidation and completing both consolidation courses (as in the Swiss trial) show a median survival of 38 months. treatment may be helpful in patients over 65 years of age. In our pilot study 26 of the 38 patients (68%) aged 66-78 achieved a complete remission, with a median duration of 10’66 months.
Agressive
PILOT STUDY
Age under 40 as the only criterion for bone marrow transplantation may not be satisfactory for other protocols. In our pilot study 7 of the 13 patients who have been in continuous remission for 3-4 years so far are 40 years old or younger. Early indices of response may permit the identification of patients with a low risk of relapse. Thus, among patients responding to the first induction course and completing two consolidations, those with a serum lactate dehydrogenase (LDH) on day 15 of treatment below the median value for all patients showed a 68% 4-year remission rate vs 0% in patients with a day 15 LDH above the median (p<0 005). Department of Internal Medicine,
University of Münster, D-4400 Münster, West Germany; Departments of Internal Medicine, Universities of Munich, Düsseldorf, and Cologne and Evangelisches Krankenhaus
Essen-Werden,
Champlin R, Jacobs A, Gale RP, et al. Prolonged survival in acute myelogenous leukemia without maintenance chemotherapy. Unpublished. 2. Clarkson BD. The elusive goal: Presidential address. Cancer Res 1981; 41: 4865-84. 3. Gale RP, Foon KA, Cline MJ, Zighelboim J. The UCLA acute leukemia study group: intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med 1981; 94: 1.
(1978)
Department of Biostatistics, University of Münster; and Department of Haematology, University of West Berlin
T. BÜCHNER B. EMMERICH D. URBANITZ A. HEINECKE J. FISCHER W. HIDDEMANN M. PFREUNDSCHUH H. RÜHL F. WENDT for the AML Cooperative Group
753-57. 4.
5. 6. 7
8.
Keating MJ, Smith TL, McCredie KB, et al. A four-year experience with anthracycline, cytosine arabinoside, vincristine and prednisone combination chemotherapy in 325 adults with acute leukemia. Cancer 1981; 47: 2779-88. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood 1981; 58: 1203-12. Whittaker JA, Reizenstein P, Callender ST, et al. Long survival in acute myelogenous leukaemia: an international collaborative study. Br Med J 1981; 282: 692-95. Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia. a CALGB study. Blood 1982; 60: 454-62. Büchner T, Urbanitz D, Emmerich B, et al. Multicentre study on intensified remission induction therapy for acute myeloid leukemia. Leukemia Res 1982, 6: 827-31.
INFLAMMATION OF THE ILEUM IN PATIENTS WITH B27-POSITIVE ARTHRITIS
SiR,-Dr Mielants and Professor Veys (Feb 4, p 288) report that individuals with B27-associated perhipheral arthropathy revealed some evidence of inflammatory change in the terminal ileum. They then suggest that these findings imply the presence of idiopathic 9. Foon
KA, Zighelboim J, Yale C, Gale RP. Intensive chemotherapy is the treatment of 1981; 58: 467-69.
choice for elderly patients with acute myelogenous leukemia. Blood