Labrador J, et al. APL 2017:CO017
Clinical significance of complex karyotype at diagnosis in patients with APL treated with ATRA and chemotherapy-based PETHEMA trials
In acute promyelocytic leukemia (APL), the presence of the promyelocytic leukemia-retinoic acid receptor alpha translocation between chromosomes 15 and 17 (t[15;17]/PML-RARα) predicts sensitivity to treatment with all-trans retinoic acid (ATRA) and arsenic trioxide. Up to 30% of patients with APL will have chromosomal abnormalities in addition to conventional t(15;17).1–10 The majority of studies have not shown a prognostic impact of additional chromosomal abnormalities (ACAs) in patients with APL treated with ATRA and chemotherapy-based front-line therapies.3–7,9 Results from a study that further explored this relationship were presented at the International Symposium on APL 2017.11
- Between 1996 and 2012, 1,559 consecutive adult and pediatric patients were enrolled in the PETHEMA LPA 96, 99, and 2005 trials.12–15
- All patients had de novo genetic diagnosis of PML-RARα APL.
- Treatment consisted of ATRA and idarubicin induction followed by risk-adapted consolidation.12–15
- Cytogenetic analyses in bone marrow samples at diagnosis were performed in local laboratories.
- ACAs were classified as follows:
- Normal karyotype or t(15;17) alone was considered as no ACA.
- Multiple rearrangements (i.e., triple rearrangements involving chromosomes 15, 17, and other) were considered as one ACA.
- Abnormalities detected in fluorescence in situ hybridization were considered as ACA.
- A complex karyotype was defined as ≥2 ACAs.
- A very complex karyotype was defined as ≥3 ACAs.
Baseline characteristics and disposition
- Cytogenetic reports were available for 1,128 patients (72%).
- From this group, 842 patients (75%) had no ACA, 197 (17%) had 1 ACA, 48 (4%) had 2 ACAs, and 41 (4%) had ≥3 ACAs.
- Baseline characteristics were similar in the group of patients with <2 ACAs (n = 1,039) compared to the group of patients with ≥2 ACAs (n = 89).
- Median age was 42 years in the <2 ACA group and 40 years in the ≥2 ACA group (p = 0.18).
- The majority of patients were male (51% in the <2 ACA group and 52% in the ≥2 ACA group; p = 0.98) with a platelet count ≤40 x 109/L (75% vs. 79%; p = 0.55) and intermediate relapse risk (52% vs. 64%; p = 0.10).
- White blood cell counts were ≥10 x 109/L in 28% of patients in the <2 ACA group and in 21% of patients in the ≥2 ACA group (p = 0.31).
- The only clinical or biological characteristic associated with a complex karyotype was cluster of differentiation-34 antigen negativity in leukemic blasts (p = 0.04).
- Induction death rates were similar between groups (8% in the <2 ACA group vs. 7% in the ≥2 ACA group; p = 0.74).
- Number of ACAs did not significantly affect overall survival. (Figure 1)
- Cumulative incidence of relapse was lower in the <2 ACA group versus the ≥2 ACA group (12% vs. 18%; p = 0.09) and in the <3 ACA group versus the ≥3 ACA group (12% vs. 27%; p = 0.003). (Figure 2)
- Multivariate analysis confirmed that a very complex karyotype was significantly associated with incidence of relapse. (Table 1)
- Female gender, higher relapse-risk group, and enrolment in the PETHEMA LPA 96 or 99 trials were also predictors of relapse.
- This study shows an increased risk of relapse for patients with very complex karyotype (≥3 ACAs) among patients with APL treated with ATRA plus chemotherapy front-line regimens.
- This increased risk did not influence overall survival.
- It should be noted that only 4% of patients with an evaluable cytogenetic profile had a very complex karyotype.
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