The Impact Of Balanced and Unbalanced Karyotypes On Prognosis Of CML: From Chronic Phase To Blast Crisis

Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the balanced reciprocal translocation t(9;22)(q34;q11) or the variant translocation t(v;22) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show ACA already at diagnosis and more than 80% of patients acquire ACA during the transformation process into BC. Therefore, alterations at diagnosis as well as acquisition of chromosomal changes during treatment are considered as a poor prognostic factor.

Differences in progression-free survival (PFS) and overall survival (OS) have been detected depending on the type of ACA. Patients with major route ACA (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and with other alterations like -X, del(1)(q21), del(5)(q11q14), +10, -21 at diagnosis resulting in an unbalanced karyotype have a worse outcome. Patients with minor route ACA (for example 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)) resulting in a balanced karyotype show no differences in OS and PFS compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). Here we compare the type of chromosomal changes (i.e. balanced vs. unbalanced karyotypes) during the course of the disease from CP to BC aiming to provide a valid parameter for future risk stratification.

Clinical and cytogenetic data available from 1,346 out of 1,524 patients at diagnosis (40% females vs. 60% males; median age 53 years (range, 16-88)) with Philadelphia and BCR-ABL positive CP CML included until March 2012 in the German CML-Study IV (a randomized 5-arm trial to optimize imatinib therapy) were investigated. ACA were comparatively analyzed in CP and in BC.

At diagnosis 1,174/1,346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). Ninety-seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had ACA. Regarding the patients with ACA thirty-six of the 53 patients (68%) had an unbalanced karyotype and 17/53 patients (32%) a balanced karyotype.

During the course of the disease 73 patients (out of 1,524 patients) developed a BC during the observation time (5%). Cytogenetic data were available in 52 patients with BC (21 patients with BC had no cytogenetic analysis). Three patients had a normal male or female karyotype after stem cell transplantation. Nine patients showed the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) (six and three patients, respectively) only and in 40 patients ACA could be observed in BC (40/49 (82%)). Out of these 40 patients with ACA, 90% showed an unbalanced karyotype whereas only 10% of patients had a balanced karyotype. No male patient in BC showed the loss of the Y chromosome pointing to a minor effect of this numerical alteration on disease progression.

We conclude that patients with CML and unbalanced karyotype at diagnosis are under higher risk to develop CML BC compared to patients with balanced karyotypes or compared to patients without ACA. In BC, 90% of CML patients showed unbalanced karyotypes (only 68% of CML patients at diagnosis have unbalanced karyotypes) supporting the hypothesis that the imbalance of chromosomal material is a hallmark of disease progression, representing the natural history of the disease from CP to BC and indicating therefore a strong prognostic impact. Consequently, different therapeutic options (such as intensive therapy or stem cell transplantation) should be considered for patients with unbalanced karyotypes in CP CML at diagnosis.

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