Clinical Significance of Additional Chromosomal Abnormalities In Ph-Positive and Ph-Negative Cells In Patients with Chronic Myeloid Leukemia Treated by Tyrosine Kinase Inhibitors

Abstract 1683 Introduction. Additional chromosomal abnormalities (ACA) in Ph9-positive (Ph9+) cells firstly described more than 30 years ago were associated with progression of chronic myeloid leukemia (CML) and often were founded in advanced stages of the disease. Prognostic significance of ACA in Ph9+ cells in the era of tyrosine kinase inhibitors (TKI) are not yet fully clarified. The ACA in Ph9-negative (Ph9-) cells seem to have no adverse prognostic impact, but it is not possible to exclude the development of myelodisplasia within the long lasting persistence of such clones. Long-term cytogenetic monitoring can better understand the biological aspects of CML. Aim. To estimate the clinical significance of ACA in Ph9+ and Ph9- cells in CML patients (pts) treated by TKI 1st and 2nd generation (TKI-1 or 2). Materials and methods. The complete peripheral blood count, morphological and cytogenetic examination of bone marrow (BM) cells have been done for 435 CML pts in different disease stages: chronic phase (CP)/accelerated phase (AP)/blast crisis (BC) pts were 336/78/21 respectively. The median (Me) age was 50 years (y) (16–61), Me follow-up- 97 months (mo) (5−265). Results and discussion. The ACA in Ph9+ cells were revealed by conventional cytogenetic study generally in 50 (11,5%) of 435 CML pts. ACA in Ph9+ cells were a rare event for CP and AP: 9% and 14% of pts respectively and more frequent for BC: 43% of pts. The most frequent ACA was the additional Ph9-chromosome (addPh9+) found in 50% of cases. 17pts had addPh9+ alone, while 13pts had also other ACA: trisomy 8 (8 cases), deletion or monosomy 7 (3 cases) and complex abnormalities (2 cases in CP & AP); dominated by male (M: F=23: 7). The duration of IM treatment in 16pts with addPh9+ was from 6mo to 5,5y. The follow-up duration of pts with addPh9+ was from 26 to 176 mo (Me 107 mo). All 16 pts have achieved complete hematological response (CHR) after 3 to 6mo of Imatinib (IM) treatment, but all pts with standard IM doses had primary cytogenetic resistance. Complete cytogenetic response (CCyR) was achieved in 56%pts without ACA, in 24% with ACA, and only in 7% with addPh9+. Due to IM resistance, 14 pts were switched to TKI-2 (Dasatinib – 10pts, Nilotinib – 3pts, Bosutinib – 1pt); 3 of these pts later progressed to AP; for 2 of them T315I mutation was found. All of the 11 pts still in CP have achieved CHR; partial cytogenetic response was founded in 45% and CCyR in 36% cases. At present, 43% pts with ACA died: 11% in CP, 82% in AP and all in BC. The 8-year overall survival (OS) for CML CP pts with ACA was 83%, no statistically significant (p>0,5) difference with the general CML CP pts group, treated by TKI. The assessment by multifactorial Cox model with variable risk factors revealed the increased probability of fatal outcome in CML CP more than 16 times higher in pts with ACA vs. patients without ACA. The variant chromosome abnormalities were rare: 13pts (3 %), but in 77% of them there was cytogenetic resistance pts and high risk of progression. ACA in Ph9- cells were founded in 13 (3%) pts only after the achievement of major cytogenetic response. 10 of them received IM 600–800mg daily; 3pts received 2nd generation of TKI. All those patients got the MCR only after 18–36 mo of treatment and 11 (85%) of 13pts achieved the CCyR. Ph9- clone was constantly founded only in 1 patient, in all other cases it was not constant but persisted from one analyses to other. No myelodisplastic changes were founded in the BM of 5 examined pts after IM treatment within 3–7y. All pts with ACA in Ph9- cells are alive. Conclusion. The durable persistence of Ph9+ cells in CML CP pts is a marker of therapy resistance but not all cases are associated with disease progression. The addPh9+ during IM treatment was associated with cytogenetic resistance. The dose escalation of IM was ineffective in the majority of cases, only TKI-2 therapy could restore Ph9- neg. hematopoiesis and suppressed addPh9+ clone more effectively. This finding should be tested in large-scale studies. The male predominance in pts with addPh9+ also needs further investigation. In contrast to other reported data, we founded that the prognosis for 77% of pts with the variant chromosome abnormalities was poor and associated with cytogenetic resistance and high risk of progression on TKI-1 and 2 therapy. In most pts with ACA in Ph9- cells a dose escalation of IM and switching to TKI-2 was needed but generally the disease prognosis was favorable. Disclosures: Turkina:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Vinogradova:Novartis: Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Chelysheva:Novartis: CML registry, Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Lazareva:Novartis: CML registry, Research Funding, Speakers Bureau. Gusarova:Novartis: Honoraria, Speakers Bureau. Khoroshko:Novartis: Speakers Bureau; Bristol: Speakers Bureau.