Aclarubicin plus cytosine arabinoside versus daunorubicin plus cytosine arabinoside in previously untreated patients with acute myeloid leukemia: a Danish national phase III trial. The Danish Society of Hematology Study Group on AML, Denmark.
A regimen of aclarubicin (ACR) of 75 mg/m2 daily for 3 days plus a continuous intravenous infusion of cytosine arabinoside (ara-C) of 100 mg/m2 per day for 7 days was compared with daunorubicin (DNR) 45 mg/m2/day for 3 days plus ara-C for 7 days as first-line chemotherapy of de novo acute myeloid leukemia (AML) in a randomized, nationwide Danish study. A total of 180 patients aged between 17 and 65 years were entered onto the protocol. Patients who achieved complete remission (CR) were given five courses of intensive consolidation therapy consisting of two courses of high dose ara-C, two courses of amsacrine plus etoposide, and one course of DNR plus ara-C. Of 174 evaluable patients, 99 achieved CR. The rate of CR was significantly higher on ACR plus ara-C than on DNR plus ara-C [66% versus 50% (p = 0.043)] and decreased significantly with increasing age. The hematological toxicity was identical for the two regimens. A total of 83 patients entered consolidation therapy. At 4 years, 37% of patients with CR following ACR were still in remission compared with 33% following DNR (p = 0.48), and the total survival at 4 years was 29% versus 20% (p = 0.26). The duration of remission and total survival both decreased with increasing age. ACR plus ara-C seem at least as good or better than DNR plus ara-C as first-line chemotherapy of AML.
During the period from 1995 to 1997, we studied 19 new cases of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), extending our series to 180 consecutive cases: 123 patients with t-MDS and 57 patients with t-AML. Cytogenetically unrelated clones were observed in 13 patients: 11 patients with two unrelated clones, one patient with three unrelated clones, and one patient with four unrelated clones. Twelve cases of unrelated clones presented as t-MDS, whereas only one case presented as overt t-AML. Partial or complete deletions of the long arms or monosomy for chromosome 5 or chromosome 7, which are characteristic of t-MDS and t-AML, were observed in both unrelated clones in four patients and in one unrelated clone only in six patients, whereas three patients showed aberrations in both clones that were uncharacteristic of t-MDS or t-AML. Three different interpretations of the origin and significance of cytogenetically unrelated clones in t-MDS and t-AML are presented, although the disease is still considered to be monoclonal. First, patients with different defects of the long arm of chromosome 5 or chromosome 7 in two unrelated clones often seem to have acquired these aberrations as independent events. For this reason, it is possible that they may play an important role in leukemic transformation, for instance, by activating or potentiating the effect of a genetic change that is present in all cells but not disclosed as a visible chromosome abnormality. In cases with involvement of other chromosomes, unrelated clones sometimes develop by cytogenetic change in only a subclone of cells, indicating that they play a role only in tumor progression. Finally, unrelated clones in t-MDS and t-AML may represent two different monoclonal diseases: the primary tumor and t-MDS. This view is supported by the significant excess of unrelated clones observed in t-MDS following multiple myeloma (4 in 13 cases) compared with other diseases (9 in 167 cases; P = 0.02), and by results from a case with a balanced translocation that is highly characteristic of non-Hodgkin's lymphoma in one clone and a t-MDS-associated deletion of the long arm of chromosome 5 in another.
During the period from 1970 to 1981, 391 nonselected patients with Hodgkin's disease were staged and treated with chemotherapy or radiotherapy or both at the Finsen Institute, Copenhagen. Secondary acute nonlymphocytic leukemia or its earlier stages--preleukemia or an acute myeloproliferative syndrome with cytopenia and specific cytogenetic abnormalities of the bone marrow--were observed in 17 patients. A Kaplan-Meier estimate of the cumulative probability of leukemic complications was 3.9 +/- 1.3 per cent (mean +/- S.E.M.) five years after the start of treatment, and 9.9 +/- 2.9 per cent at nine years. All 17 cases of leukemic complications occurred among the 312 patients treated with chemotherapy or combined-modality therapy, whereas no case was observed among 79 patients treated exclusively with radiotherapy (P = 0.003). A significantly increased risk of leukemic complications was observed in chemotherapy-treated patients 40 years old or older (P = 0.001). Despite the observed relatively high risk of secondary leukemia, the rate of death from progressive Hodgkin's disease, nonleukemic complications, and unrelated causes still far exceeds the rate of leukemia-related deaths in these patients.
Therapy-related myelodysplasia and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series.
Therapy-related acute myeloid leukemia (t-AML), often presenting as myelodysplasia (t-MDS), has become the most serious long-term complication of cancer therapy and offers a unique opportunity to study chemical leukemogenesis. Seven cohorts of patients treated for six different types of primary tumor have been followed closely for leukemic complications, and 115 consecutive patients with t-MDS or t-AML, including 45 cases from the cohorts, have been investigated cytogenetically at our institutions during the past 16 years. In patients primarily treated with alkylating agents, the risk of t-MDS and t-AML increased by approximately 1% per year from 2 to at least 8 years after start of treatment. In most cases, the disease presented as t-MDS with loss of a whole chromosome 5 or 7, or various parts of their long arms, and the leukemias were of FAB-subtypes M1, M2, or M4. In patients treated with drugs targeting at DNA-topoisomerase II, such as etoposide, doxorubicin, 4-epidoxorubicin, or mitoxantrone combined with drugs reacting directly with DNA, such as cisplatin or alkylating agents, the risk of leukemia increased much more steeply from only one year after start of therapy. These early onset cases often presented as overt leukemia of FAB-subtypes M4 or M5 with balanced translocations to chromosome bands 11q23 and 21q22, whereas later onset cases often shared characteristics with cases observed after therapy with alkylating agents alone. Both alkylation of DNA and poisoning of DNA-topoisomerase II may result in development of t-AML with different clinical and cytogenetic characteristics. There may be a synergistic leukemogenic effect between the two types of drug, and in patients with germ cell tumors treated with etoposide, cisplatin and bleomycin, reassessment suggested the risk of leukemia to increase exponentially with increasing doses of cisplatin and etoposide.