Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib

Cecelia R. Miller, Amy S. Ruppert, Nyla A. Heerema, Kami J. Maddocks, Jadwiga Labanowska, Heather Breidenbach, Gerard Lozanski, Weiqiang Zhao, Amber L. Gordon, Jeffrey A. Jones, Joseph M. Flynn, Samantha M. Jaglowski, Leslie A. Andritsos, Kristie A. Blum, Farrukh T. Awan, Kerry A. Rogers, Michael R. Grever, Amy J. Johnson, Lynne V. Abruzzo, Erin K. HertleinJames S. Blachly, Jennifer A. Woyach, John C. Byrd

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P 5 .03), deletion 17p (P 5 .03), and complex karyotype (P 5 .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P, .0001), but not due to progressive CLL (P 5 .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P, .0001) and complex karyotype (HR, 4.77; 95% CI, 1.42-15.94; P 5 .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.

Original languageEnglish (US)
Pages (from-to)1584-1588
Number of pages5
JournalBlood Advances
Volume1
Issue number19
DOIs
StatePublished - Aug 22 2017
Externally publishedYes

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Tetraploidy
B-Cell Chronic Lymphocytic Leukemia
Confidence Intervals
Karyotype
Lymphoma
Lymphoma, Large B-Cell, Diffuse
PCI 32765
Fluorescence In Situ Hybridization
Therapeutics
Chromosomes
Clinical Trials
Incidence

ASJC Scopus subject areas

  • Hematology

Cite this

Miller, C. R., Ruppert, A. S., Heerema, N. A., Maddocks, K. J., Labanowska, J., Breidenbach, H., ... Byrd, J. C. (2017). Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Advances, 1(19), 1584-1588. https://doi.org/10.1182/bloodadvances.2017007302

Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. / Miller, Cecelia R.; Ruppert, Amy S.; Heerema, Nyla A.; Maddocks, Kami J.; Labanowska, Jadwiga; Breidenbach, Heather; Lozanski, Gerard; Zhao, Weiqiang; Gordon, Amber L.; Jones, Jeffrey A.; Flynn, Joseph M.; Jaglowski, Samantha M.; Andritsos, Leslie A.; Blum, Kristie A.; Awan, Farrukh T.; Rogers, Kerry A.; Grever, Michael R.; Johnson, Amy J.; Abruzzo, Lynne V.; Hertlein, Erin K.; Blachly, James S.; Woyach, Jennifer A.; Byrd, John C.

In: Blood Advances, Vol. 1, No. 19, 22.08.2017, p. 1584-1588.

Research output: Contribution to journalArticle

Miller, CR, Ruppert, AS, Heerema, NA, Maddocks, KJ, Labanowska, J, Breidenbach, H, Lozanski, G, Zhao, W, Gordon, AL, Jones, JA, Flynn, JM, Jaglowski, SM, Andritsos, LA, Blum, KA, Awan, FT, Rogers, KA, Grever, MR, Johnson, AJ, Abruzzo, LV, Hertlein, EK, Blachly, JS, Woyach, JA & Byrd, JC 2017, 'Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib', Blood Advances, vol. 1, no. 19, pp. 1584-1588. https://doi.org/10.1182/bloodadvances.2017007302
Miller, Cecelia R. ; Ruppert, Amy S. ; Heerema, Nyla A. ; Maddocks, Kami J. ; Labanowska, Jadwiga ; Breidenbach, Heather ; Lozanski, Gerard ; Zhao, Weiqiang ; Gordon, Amber L. ; Jones, Jeffrey A. ; Flynn, Joseph M. ; Jaglowski, Samantha M. ; Andritsos, Leslie A. ; Blum, Kristie A. ; Awan, Farrukh T. ; Rogers, Kerry A. ; Grever, Michael R. ; Johnson, Amy J. ; Abruzzo, Lynne V. ; Hertlein, Erin K. ; Blachly, James S. ; Woyach, Jennifer A. ; Byrd, John C. / Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. In: Blood Advances. 2017 ; Vol. 1, No. 19. pp. 1584-1588.
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abstract = "Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0{\%}; 95{\%} confidence interval [CI], 1.4{\%}-5.7{\%}). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P 5 .03), deletion 17p (P 5 .03), and complex karyotype (P 5 .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P, .0001), but not due to progressive CLL (P 5 .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95{\%} CI, 3.83-19.59; P, .0001) and complex karyotype (HR, 4.77; 95{\%} CI, 1.42-15.94; P 5 .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.",
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T1 - Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib

AU - Miller, Cecelia R.

AU - Ruppert, Amy S.

AU - Heerema, Nyla A.

AU - Maddocks, Kami J.

AU - Labanowska, Jadwiga

AU - Breidenbach, Heather

AU - Lozanski, Gerard

AU - Zhao, Weiqiang

AU - Gordon, Amber L.

AU - Jones, Jeffrey A.

AU - Flynn, Joseph M.

AU - Jaglowski, Samantha M.

AU - Andritsos, Leslie A.

AU - Blum, Kristie A.

AU - Awan, Farrukh T.

AU - Rogers, Kerry A.

AU - Grever, Michael R.

AU - Johnson, Amy J.

AU - Abruzzo, Lynne V.

AU - Hertlein, Erin K.

AU - Blachly, James S.

AU - Woyach, Jennifer A.

AU - Byrd, John C.

PY - 2017/8/22

Y1 - 2017/8/22

N2 - Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P 5 .03), deletion 17p (P 5 .03), and complex karyotype (P 5 .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P, .0001), but not due to progressive CLL (P 5 .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P, .0001) and complex karyotype (HR, 4.77; 95% CI, 1.42-15.94; P 5 .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.

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