Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment

Ghayas C. Issa, Hagop M. Kantarjian, Graciela Nogueras Gonzalez, Gautam Borthakur, Guilin Tang, William Wierda, Koji Sasaki, Nicholas J. Short, Farhad Ravandi, Tapan Kadia, Keyur Patel, Raja Luthra, Alessandra Ferrajoli, Guillermo Garcia-Manero, Mary Beth Rios, Sara Dellasala, Elias Jabbour, Jorge E. Cortes

Research output: Contribution to journalArticle

Abstract

Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%); the most common were 2Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which –Y was the only clonal abnormality, and all others. We found that patients with non –Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P 5 .02), EFS (68% vs 86%, P 5 .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P 5 .03). In a multivariate analysis, non –Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P 5 .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10% at 3 months was included in the analysis. In conclusion, non –Y CCA/Ph- are associated with decreased survival when emerging in patients with chronic-phase CML across various TKIs. This trial was registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, and #NCT00050531 (imatinib); #NCT00254423 (dasatinib); #NCT00129740 (nilotinib); and NCT01570868 (ponatinib).

Original languageEnglish (US)
Pages (from-to)2084-2091
Number of pages8
JournalBlood
Volume130
Issue number19
DOIs
StatePublished - Nov 9 2017
Externally publishedYes

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Emitter coupled logic circuits
Metaphase
Chromosomes
Philadelphia Chromosome
Chromosome Aberrations
Protein-Tyrosine Kinases
Survival
Leukemia, Myeloid, Chronic Phase
Therapeutics
Disease-Free Survival
Hazards
Multivariate Analysis
Clinical Trials
Confidence Intervals

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. / Issa, Ghayas C.; Kantarjian, Hagop M.; Gonzalez, Graciela Nogueras; Borthakur, Gautam; Tang, Guilin; Wierda, William; Sasaki, Koji; Short, Nicholas J.; Ravandi, Farhad; Kadia, Tapan; Patel, Keyur; Luthra, Raja; Ferrajoli, Alessandra; Garcia-Manero, Guillermo; Rios, Mary Beth; Dellasala, Sara; Jabbour, Elias; Cortes, Jorge E.

In: Blood, Vol. 130, No. 19, 09.11.2017, p. 2084-2091.

Research output: Contribution to journalArticle

Issa, GC, Kantarjian, HM, Gonzalez, GN, Borthakur, G, Tang, G, Wierda, W, Sasaki, K, Short, NJ, Ravandi, F, Kadia, T, Patel, K, Luthra, R, Ferrajoli, A, Garcia-Manero, G, Rios, MB, Dellasala, S, Jabbour, E & Cortes, JE 2017, 'Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment', Blood, vol. 130, no. 19, pp. 2084-2091. https://doi.org/10.1182/blood-2017-07-792143
Issa GC, Kantarjian HM, Gonzalez GN, Borthakur G, Tang G, Wierda W et al. Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. Blood. 2017 Nov 9;130(19):2084-2091. https://doi.org/10.1182/blood-2017-07-792143
Issa, Ghayas C. ; Kantarjian, Hagop M. ; Gonzalez, Graciela Nogueras ; Borthakur, Gautam ; Tang, Guilin ; Wierda, William ; Sasaki, Koji ; Short, Nicholas J. ; Ravandi, Farhad ; Kadia, Tapan ; Patel, Keyur ; Luthra, Raja ; Ferrajoli, Alessandra ; Garcia-Manero, Guillermo ; Rios, Mary Beth ; Dellasala, Sara ; Jabbour, Elias ; Cortes, Jorge E. / Clonal chromosomal abnormalities appearing in Philadelphia chromosome–negative metaphases during CML treatment. In: Blood. 2017 ; Vol. 130, No. 19. pp. 2084-2091.
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abstract = "Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10{\%}); the most common were 2Y in 25 (43{\%}) and trisomy 8 in 7 patients (12{\%}). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which –Y was the only clonal abnormality, and all others. We found that patients with non –Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52{\%} vs 70{\%}, P 5 .02), EFS (68{\%} vs 86{\%}, P 5 .02), TFS (76{\%} vs 94{\%}, P < .01), and OS (79{\%} vs 94{\%}, P 5 .03). In a multivariate analysis, non –Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95{\%} confidence interval, 1.15-6.89; P 5 .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10{\%} at 3 months was included in the analysis. In conclusion, non –Y CCA/Ph- are associated with decreased survival when emerging in patients with chronic-phase CML across various TKIs. This trial was registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, and #NCT00050531 (imatinib); #NCT00254423 (dasatinib); #NCT00129740 (nilotinib); and NCT01570868 (ponatinib).",
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AU - Issa, Ghayas C.

AU - Kantarjian, Hagop M.

AU - Gonzalez, Graciela Nogueras

AU - Borthakur, Gautam

AU - Tang, Guilin

AU - Wierda, William

AU - Sasaki, Koji

AU - Short, Nicholas J.

AU - Ravandi, Farhad

AU - Kadia, Tapan

AU - Patel, Keyur

AU - Luthra, Raja

AU - Ferrajoli, Alessandra

AU - Garcia-Manero, Guillermo

AU - Rios, Mary Beth

AU - Dellasala, Sara

AU - Jabbour, Elias

AU - Cortes, Jorge E.

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N2 - Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%); the most common were 2Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which –Y was the only clonal abnormality, and all others. We found that patients with non –Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P 5 .02), EFS (68% vs 86%, P 5 .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P 5 .03). In a multivariate analysis, non –Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P 5 .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10% at 3 months was included in the analysis. In conclusion, non –Y CCA/Ph- are associated with decreased survival when emerging in patients with chronic-phase CML across various TKIs. This trial was registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, and #NCT00050531 (imatinib); #NCT00254423 (dasatinib); #NCT00129740 (nilotinib); and NCT01570868 (ponatinib).

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