The Pattern Of Cytogenetic Aberrations In CML BC Stratified For Treatment

The impact of the type of therapy on cytogenetic evolution in chronic myeloid leukemia (CML) regarding the occurrence of additional cytogenetic aberrations (ACA) at the time point of blast crisis (BC) may be critical. The aim of this analysis was to elucidate whether patients (pts) treated with imatinib (IM) had ACA less frequently than pts treated with BU and other therapies used prior to IM as hydroxyurea (HU) and interferon alpha (IFN). We comparatively analyze the BC karyotype of CML pts treated in consecutive trials of the German CML Study Group (Studies I, II and IV) to answer the following question: Does CML therapy influence the occurrence or even induce ACA or do these alterations rather reflect the natural history and the biology of the disease and are independent of therapy?

Cytogenetic data of 157 pts with Philadelphia chromosome and BCR-ABL positive CML in BC were analyzed from a total of 2,380 pts randomized to CML study I (BU vs. HU vs. IFN, recruitment 1983 – 1991), CML study II (IFN + HU vs. HU, recruitment 1991 – 1994), and CML study IV (IM 400 mg vs. IM 800 mg vs. IM 400 mg +IFN vs. IM 400 mg + AraC vs. IM 400 mg after IFN failure recruitment 2002 – 2012). Cytogenetic analysis was reported according to ISCN 2005. ACA were divided into major route (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and minor route alterations (reciprocal translocations other than the t(9;22)(q34;q11), e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20) (Fabarius et al., Blood 2011).

Confirmatory testing of pairwise comparisons of therapies with regard to their frequency of major ACAs was performed using two-sided chi-square test. To keep the level of significance at 0.05 despite multiple testing, a priori hypotheses were hierarchically ordered: First, frequency of major route ACA of pts on IM was compared with that on BU, then, with HU and with IFN. Next, the comparisons of IFN vs. BU and IFN vs. HU were planned. Cumulative incidences were estimated under consideration of death before BC as a competing risk.

115 of 188 pts randomized to BU (CML study I), 117 of 194 pts randomized to HU (CML study I only) and 159 of 360 randomized to IFN-based therapy (CML studies I+II) progressed to BC. Eight-year cumulative incidence probability of BC was 0.63 [95%-confidence interval (CI): 0.56; 0.69], 0.60 [95%-CI: 0.53; 0.66], and 0.49 [95%-CI: 0.43; 0.54] in pts randomized to BU, HU, and IFN-based therapy, respectively and 0.06 [95%-CI: 0.04; 0.07] in pts on IM (CML-study IV). Three-year survival probabilities after BC were 0.009 [95%-CI: 0.001; 0.043] with BU, 0.017 [95%-CI: 0.003; 0.055] with HU, 0.013 [95%-CI: 0.003; 0.042] with IFN, and 0.252 [95%-CI: 0.157; 0.368] with IM.

Cytogenetic data at BC with banding analysis were available from 21 pts on BU, 31 on HU, 56 on IFN and 49 on IM. 81% of pts treated with BU, 52% with HU, 38% with IFN and 55% with IM showed major route ACA. All other pts had minor route ACA or translocation t(9;22)(q34;q11) and variant translocation (t(v;22)) without ACA (Table 1). The difference in major route ACA between BU and IM was significant (p = 0.04, two-sided chi-square test). There was no statistically significant difference in ACA between pts on HU and IFN in comparison to IM. According to the testing order, further comparative testing was not possible. However, the differences of induction of major route ACA between HU and BU and IFN and BU were even more pronounced than the difference between IM and BU. The most frequently observed major route ACA was trisomy 8 in all studies and therapy arms.

The type of cytogenetic aberrations in CML BC after different therapies is comparable. The characteristic major route ACA after various therapies points to a CML BC-related chromosomal pattern rather than a therapy-induced effect. Pts treated with IM showed a significantly lower rate of major route ACA than BU. IM not only reduces the frequency of BC and increases survival probabilities but appears to moderately change the biology of BC as compared to BU

Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Kolb:Pierre Fabre, Therakos: Honoraria; Kolb Consulting UG: Consultancy, Equity Ownership. Saussele:BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Travel Other.