Rare and Complex (≥ 5) Chromosomal Abnormalities Predict A Worse Outcome in Older AML Patients

Abstract & Commentary

By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.

Synopsis: Outcomes for older adults with AML are generally poor. Cytogenetics and outcomes of 635 adults 60 years and older from CALGB cooperative group treatment trials were evaluated. Five-year survival overall was 6.6% and most cytogenetic abnormalities offered little independent predictive value. Rare chromosomal abnormalities and ≥ 5 abnormalities in a single clone, however, were strongly and independently associated with worse outcomes.

Source: Farag SS, et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood. 2006:108:63-73.

The prognosis for older adults diagnosed with acute myeloid leukemia (AML) remains poor. Pre-treatment cytogenetics has become an essential tool to risk-stratify younger AML patients.1 In older adults, AML has a high prevalence of adverse cytogenetics, as well as multi-drug resistance, though to contribute to the poor outcome.2,3 Further, older adults may have a greater prevalence of performance status limitations, diminishing tolerability of intensive chemotherapy.3 Selecting older adults who may benefit from intensive chemotherapy and/or consolidation is a critical but answered question.

Farag and colleagues analyzed newly diagnosed AML patients 60 years of age or older who were enrolled on Cancer and Leukemia Group B (CALGB) treatment protocols between July 1984 and June 1999 and had evaluable karyotype analysis. Cases of APL were excluded. Among 837 older adults, 635 (76%) had evaluable cytogenetics and comprised the study group. In general, induction chemotherapy employed cytarabine and daunorubicin. In some protocols, etoposide and/or PSC-833 (a multi-drug resistance protein modulator) was added. Post-remission therapy included multiple cycles of cytarabine. In many protocols, further consolidation with cytarabine and an anthracycline was used.

The median age was 68 years (range, 60-86 years) and 29 patients were 80 years or older. Only 5% harbored core-binding factor mutations (eg, inversion 16 and translocation 8;21). Normal karyotype occurred in 45%. Complex karyotype with 3 or more abnormalities was found in 19% and complex karyotype with 5 or more was found in 15%. Deletions were relatively common in chromosome 5 (14%) and 7 (15%). Thirty three (5%) were allocated to a group of rare chromosomal abnormalities.

Outcomes were analyzed using a tree-structure analysis which obviates the need to select a reference group. Induction therapy achieved a CR in 48.5% and lead to death in 20%. Overall survival was 6.6% (95% CI, 4.9%-8.7%) at 5 years. Diminished CR and survival was independently associated with male sex, older age, and increasing WBC count. Rare aberrations and 1 or more non-rare aberrations (not including CBF mutations) independently predicted for lower rates of CR. Complex cytogenetics (HR = 4.5; 95% CI, 2.85, 7.06) and rare abnormalities (HR = 2.2; 95% CI, 1.3-3.8) portended for worse overall survival.

Commentary

In this study, the authors report outcomes in a large series of adults 60 years and older with AML. The 5-year survival of 6.6% is disappointing, since these were select patients considered eligible for intensive therapy, and most were younger than 80 years of age. One can argue based upon these data that the best supportive care may be a more viable strategy for older adults with AML then chemotherapy, absent a clinical trial. However, there may be a benefit of prolonged survival and quality of life from treatment.

Two cytogenetic groups were identified with particularly dismal outcomes, ≥ 5 abnormalities in one clone and 1-2 rare abnormalities. No patients were disease free at 19 months and none survived for 5 years.

These important findings challenge traditional cytogenetic classifications schemes. Complex karyotype has usually been categorized as ≥ 3 abnormalities. In this study, clones harboring ≥ 5 abnormalities had inferior DFS (P = .02) and OS (P = .01) compared with having 3 or 4 abnormalities in a single clone. None of those with ≥ 5 were alive at 5 years. However, similar to the group as a whole, 7.1% of those with 3 or 4 abnormalities were alive. Interestingly, deletions of chromosome 5 by itself did not result in a worse prognosis but most such cases also had a complex karyotype, limiting any independent prognostic value. Rare abnormalities have often been classified as intermediate risk. The data here are consistent with select series of specific rare abnormalities that typically have indicated very poor outcomes.

Interestingly, another recent study by Appelbaum and colleagues evaluated the influence of age and outcome in AML.3 Older adults did much poorer than younger adults with similar cytogenetic risk groups. Although not directly compared, it appeared that there were not major differences in outcome in older adults stratified by standard cytogenetic risk groups (ie, favorable, intermediate, and poor). These data challenge our notion of the value of cytogenetics in older AML patients and reaffirm the need to specifically analyze older cohorts rather than making inferences from younger subjects.

It is important to recognize these results apply to older adults with AML, rather than younger adults and specifically to those considered fit enough to be enrolled on clinical trials. The results span 15 years, so advances in supportive care may have improved outcome.

Identifying patients unlikely to achieve at least a CR may be one strategy to select those who should either be offered best supportive care or a clinical trial. Alternatively, whether more intensive consolidation for relatively healthy older AML adults, such as allogeneic hematopoietic transplant, can overcome the overall poor outcome remains unknown.

References

1. Slovak ML, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075-4083.

2. Moorman AV, et al. Karyotype and age in acute myeloid leukemia. Are they linked? Cancer Genet Cytogenet. 2001;126:155-161.

3. Appelbaum FR, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481-3485.