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The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberrations excluding translocations t(8;21)(q22;q22), t(15;17)(q22;q11–q12) and inv(16)(p13q22). Complex chromosome anomalies were detected in 10% of all cases with a significantly higher incidence in patients 60 years of age (17·8% vs. 7·8%, P < 0·0001). Clinical follow-up data were available for 90 patients. Forty-five patients were < 60 years of age and were randomly assigned to double induction therapy with either TAD-TAD [thioguanine, daunorubicin, cytosine arabinoside (AraC)] or TAD-HAM (high-dose AraC, mitoxantrone). Twenty-one patients achieved complete remission (CR) (47%), 20 patients (44%) were non-responders and 9% of patients died during aplasia (early death). The median overall survival (OS) was 7 months and the OS rate at 3 years was 12%. Patients receiving TAD-HAM showed a significantly higher CR rate than patients receiving TAD-TAD (56% vs. 23%, P = 0·04). Median event-free survival was less than 1 month in the TAD-TAD group and 2 months in the TAD-HAM group, respectively (P = 0·04), with a median OS of 4·5 months vs. 7·6 months (P = 0·13) and an OS after 3 years of 7·6% vs. 19·6%. Forty-five patients were 60 years of age: 28 of these patient were treated for induction using one or two TAD courses and 17 cases received TAD-HAM with an age-adjusted reduction of the AraC dose. The CR rate was 44%, 38% were non-responders and 18% experienced early death. The median OS was 8 months and the OS rate at 3 years was 6%. In conclusion, complex chromosome aberrations in de novo AML predicted a dismal outcome, even when patients were treated with intensive chemotherapy. Patients under the age of 60 years with complex aberrant karyotypes may benefit from HAM treatment during induction. However, long-term survival rates are low and alternative treatment strategies for remission induction and consolidation are urgently needed.
Increasing insights into the biology of acute myeloid leukaemia (AML) disclose a considerable heterogeneity that may also underlie the clinical course and therapeutic perspectives. Recent efforts have concentrated on defining biological and clinical characteristics that may allow the discrimination of specific subtypes of AML, which may ultimately allow a risk-adapted stratification of therapy. Besides patient-associated parameters such as sex and age, leukaemia-associated parameters such as leucocyte count, FAB subtype, lactate dehydrogenase (LDH) and others were found to be related to treatment outcome and prognosis (Bloomfield, 1992; Haferlach, 1996; Wheatley et al, 1996; Büchner et al, 1997a; Cripe, 1997).
Among various pretreatment determinants, cytogenetics are unequivocally considered to be of major importance (Bloomfield et al, 1997; Mrózek et al, 1997) For clinical purposes, karyotype analysis enables discrimination between three major prognostic groups. A favourable outcome under currently used treatment regimens was observed in several studies in patients with t(8;21)(q22;q22), inv(16)(p13q22) or t(15;17)(q22; q11–12) (Berger et al, 1987; Keating et al, 1987; Fenaux et al, 1989; Dastugue et al, 1995; Hiddemann et al, 1995; Haferlach, 1996; Warrell, 1998). Chromosome aberrations with an unfavourable clinical course are −5/del(5q), −7/del(7q), inv(3)/t(3;3) and complex aberrant karyotype (Yunis et al, 1984; Berger et al, 1987; Fenaux et al, 1989; Fonatsch et al, 1994; Hiddemann et al, 1995; Haferlach, 1996; Grimwade et al, 1998). The remainder are assigned to an intermediate prognostic group. This group is very heterogenous because it includes patients with a normal karyotype and rare chromosome aberrations with an as yet unknown prognostic impact.
To date, only few data are available for patients with de novo AML and complex karyotype abnormalities (Yunis et al, 1984; Berger et al, 1987; Arthur et al, 1989; Fenaux et al, 1989; Stasi et al, 1993; Swansbury et al, 1994; Dastugue et al, 1995). Furthermore, the definition of complex aberrant karyotype varies between different study groups. Most commonly, it is defined as at least three cytogenetic abnormalities. The reported complete remission (CR) rates vary between 21% and 46%, with a median overall survival between 1 month and 5 months. The aim of this study was to characterize a large group of patients with de novo AML and complex karyotype aberrations and to analyse their response to intensive treatment.
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- PATIENTS and METHODS
As different therapeutic strategies have become available in the treatment of AML, the definition of distinct subgroups with different prognoses and therapeutic perspectives gains increasing importance for the appropriate selection of therapy. In recent years, the karyotype of leukaemic blasts has become the single most important prognostic determinant for AML, both for initial response to induction therapy, as well as for remission duration and overall survival (Bloomfield et al, 1997; Mrózek et al, 1997) In this study, we characterized a group of patients with de novo AML and complex karyotype abnormalities who showed a poor prognosis despite intensive treatment.
Out of 90 patients with de novo AML and complex aberrant karyotypes, only 46% achieved a complete remission, which was of short duration (median CR duration: 7·0 months), in spite of intensive double induction therapy and subsequent consolidation and maintenance in remission. These data are in accordance with other reports of low CR rates and short survival times for patients with complex karyotype aberrations and/or abnormalities of chromosomes 5 and/or 7 (Yunis et al, 1984; Berger et al, 1987; Fenaux et al, 1989; Haferlach, 1996). These aberrations are frequently associated and complex karyotypes often include −5/del(5q) and −7/del(7q) abnormalities. Recently, Ravandi et al (1997) reported that patients suffering from AML, myelodysplastic syndrome (MDS) refractory anaemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-T) with simple −5/−7 abnormalities experienced a significantly better outcome than patients with −5/−7 and complex aberrant karyotype abnormalities. In two earlier studies, a rather good prognosis for patients with isolated 7q– or −7 was also observed (Fenaux et al, 1989; Swansbury et al, 1994). We also found evidence that the clinical outcome of patients with unfavourable but not complex aberrant karyotype (5/5q–, −7/7q–, 3q abnormalities, 11q23 abnormalities, 12p abnormalities or 17p abnormalities) differed from those patients with complex aberrant karyotype: patients with complex karyotype showed a significantly shorter relapse-free survival (4 months vs. 8 months, P = 0·004) and overall survival (8 months vs. 12 months, P = 0·042) (unpublished data). In our study, 19 out of 90 patients showed neither an involvement of chromosome 5 nor of chromosome 7, but clinical outcome did not differ from patients with abnormalities of chromosomes 5 and/or 7. Therefore, the complexity of the karyotype itself seems to be relevant for prognosis, independent of the involvement of chromosomes 5 and/or 7. Data from Pedersen-Bjergaard et al (1990) support this finding by demonstrating that the number of chromosome aberrations was an independent prognostic factor for patients with secondary myelodysplastic syndrome.
Complex karyotype aberrations are also frequently found in secondary AML occurring after treatment with radiotherapy and/or alkylating agents. The Groupe Francais de Cytogenetique Hematologique (1994) reported on 21 patients with treatment-related AML and complex aberrant karyotype who received intensive induction therapy. CR was achieved in 24% of cases and median CR duration was only 4 months. Although the CR rate was higher in our patients with de novo AML and complex karyotype abnormalities, the dismal outcome is similar to patients with de novo and secondary AML showing both complex karyotype aberrations.
In our study, the prognosis of younger patients with complex aberrant karyotype was as poor as in elderly cases. In contrast, Dastugue et al (1995) observed that complex aberrant karyotypes were predictive of short survival in older patients only. This discrepancy might be as a result of the fact that the younger patient group with complex aberrant karyotypes in the French study consisted of only 10 cases, three of whom had favourable chromosome abnormalities [t(8;21)(q22;q22) and inv(16)(p13q22)].
Bloomfield et al (1998) analysed the effect of dose intensification of AraC in post-remission therapy according to karyotype. Remission duration was prolonged in patients with t(8;21)(q22;q22), inv(16)(p13q22)/t(16;16)(p13;q22), del(16) or normal karyotype, but not in those with other karyotypic abnormalities. The poor overall outlook for patients with complex karyotype abnormalities is only marginally improved by including high-dose AraC into the induction treatment. Thus, a beneficial effect may only be expected from allogeneic bone marrow or peripheral stem cell transplantation. In our study, all three long-term survivors had received an allogeneic BMT. However, Gale et al (1995) pointed out that the impact of cytogenetic abnormalities may not be overcome by this procedure. Hence, leukaemia-free survival was lower in recipients of HLA-compatible sibling transplants with poor prognosis cytogenetics (24%) than in all other subgroups (54%) owing to a significantly higher rate of leukaemic recurrences (58% vs. 21%). In two further studies, Ferrant et al (1995, 1997) also observed that myeloablative therapy may not correct for the poor prognosis of an unfavourable karyotype. The main cause of failure was relapse, illustrating the inefficiency of current therapeutic approaches to eradicate the malignant clone in most patients, even if allogeneic BMT is performed. In the MRC AML 10 trial, patients with adverse cytogenetics did equally poorly after chemotherapy alone, autologous or allogeneic bone marrow transplantation (Grimwade et al, 1998).
The resulting genetic heterogeneity may also explain the high degree of treatment resistance. Hence, expression of the multidrug resistance protein mdr1 is associated with unfavourable cytogenetics (Willman, 1996; Leith et al, 1997), especially with abnormalities of chromosome 7 (Guerci et al, 1995). Data from Wattel et al (1994) also demonstrate an association of p53 mutations with unfavourable karyotypes and, in particular, with complex cytogenetic abnormalities. We detected a deletion of one p53 allele in 14 out of 30 patients with AML and complex karyotype abnormalities analysed using fluorescence in situ hybridization.
Recent studies from our own group also indicated that leukaemic blasts with complex aberrant karyotypes have a low proliferative activity that is, by itself, also associated with a poor response to induction therapy (Jahns-Streubel et al, 1997). These data may lead to new therapeutic perspectives that take the biology of AML with complex aberrant karyotypes into account. Chemotherapy priming with granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) was tested in several clinical trials. To date, however, priming in vivo with G-CSF or GM-CSF has not been shown to augment the efficacy of chemotherapy (Büchner et al, 1997b; Löwenberg et al, 1997; Terpstra & Löwenberg, 1997). This might be owing to the fact that only a small subgroup might benefit from priming strategies. Recent in vitro data from Jahns-Streubel et al (1996) demonstrated that proliferative activity of blasts with unfavourable karyotypes was as a result of low production of growth stimulatory cytokines. Adding GM-CSF to the culture medium resulted in a significant increase in proliferation and growth rate. Priming with G-CSF or GM-CSF might, therefore, be a promising concept for improving treatment results in the subgroup of patients with complex karyotype abnormalities.
In conclusion, our data show that patients with complex aberrant karyotypes account for 10% of patients with de novo AML. The outcome of these patients treated with standard intensive therapy is poor at both younger and higher ages. Prognosis is similar to patients with complex karyotype aberrations suffering from secondary AML. Therefore, new therapeutic options have to be tested in this group. Younger patients might benefit from an intensification of induction therapy, including high-dose AraC, to increase the CR rate, immediately followed by an allogeneic bone marrow transplantation. For elderly patients not suitable for intensification, it has to be discussed whether a palliative treatment may be the better approach (Hiddemann et al, 1999). Most importantly, however, new insights into the biology of these leukaemias need to be gained that may not only enable a better understanding but also a more effective treatment of this AML subtype.