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

Background

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

Study design

  • 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.

Key findings

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).

Efficacy

  • 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.

Figure 1. Overall survival stratified by number of ACAs

Figure 2. Cumulative incidence of relapse

Table 1. Multivariate analysis of cumulative
incidence of relapse

Key conclusions

  • 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.

References: 1. Schoch C, Haase D, Haferlach T, et al. Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15;17)(q22;q21): a report on 50 patients. Br J Haematol 1996;94(3):493–500. 2. Hiorns LR, Swansbury GJ, Mehta J, et al. Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia. Br J Haematol 1997;96(2):314–21. 3. Slack JL, Arthur DC, Lawrence D, et al. Secondary cytogenetic changes in acute promyelocytic leukemia — prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. J Clin Oncol 1997;15(5):1786–95. 4. De Botton S, Chevret S, Sanz M, et al. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial. Br J Haematol 2000;111(3):801–6. 5. Hernández JM, Martín G, Gutiérrez NC, et al. Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with an ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA. Haematologica 2001;86(8):807–13. 6. Cervera J, Montesinos P, Hernández-Rivas JM, et al. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Haematologica 2010;95(3):424–31. 7. Ono T, Takeshita A, Iwanaga M, et al. Impact of additional chromosomal abnormalities in patients with acute promyelocytic leukemia: 10-year results of the Japan Adult Leukemia Study Group APL97 study. Haematologica 2011;96(1):174–6. 8. Wiernik PH, Sun Z, Gundacker H, et al. Prognostic implications of additional chromosome abnormalities among patients with de novo acute promyelocytic leukaemia with t(15;17). Med Oncol 2012;29(3):2095–101. 9. Lou Y, Suo S, Tong H, et al. Characteristics and prognosis analysis of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide as the front-line therapy. Leuk Res 2013;37(11):1451–6. 10. Poiré X, Moser BK, Gallagher RE, et al. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma 2014;55(7):1523–32. 11. Labrador J, Montesinos P, Bernal T, et al. Clinical significance of complex karyotype at diagnosis in patients with acute promyelocytic leukemia treated with ATRA and chemotherapy based PETHEMA trials. Intl. Symposium on APL Abstracts 2017:CO017. 12. Sanz MA, Martín G, Rayón C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999;94(9):3015–21. 13. Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103(4):1237–43. 14. Sanz MA, Montesinos P, Vellenga E, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA group. Blood 2008;112(8):3130–4. 15. Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115(25):5137–46.