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Review
. 2020;143(3):217-231.
doi: 10.1159/000501927. Epub 2019 Oct 7.

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

Susanne Saussele  1 , Wilhelm Haverkamp  2 , Fabian Lang  3 , Steffen Koschmieder  4 , Alexander Kiani  5 , Kathleen Jentsch-Ullrich  6 , Frank Stegelmann  7 , Heike Pfeifer  3 , Paul La Rosée  8 , Nicola Goekbuget  3 , Christina Rieger  9 , Cornelius F Waller  10 , Georg-Nikolaus Franke  11 , Philipp le Coutre  12 , Rudolf Kirchmair  13 , Christian Junghanss  14
Affiliations
Review

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

Susanne Saussele et al. Acta Haematol. 2020.

Abstract

Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib's safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit-risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib's efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.

Keywords: Cardiovascular management; Chronic myeloid leukemia; Consensus paper; Philadelphia chromosome-positive acute leukemia; Ponatinib; Tyrosine kinase inhibitor.

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Conflict of interest statement

S.S.: advisory role for Novartis, Bristol-Myers Squibb, Pfizer, and Incyte; received research funding from Novartis, Bristol-Myers Squibb, and Incyte. F.L.: advisory role for Novartis, Ariad, Incyte, Celgene, Sanofi Aventis, and Bristol-Myers Squibb; receives support from the Frankfurter Förderung “Nachwuchswissenschaftler” and the EUTOS funding program; received funding from Novartis. S.K.: advisory board: Pfizer, Incyte, Ariad, Novartis, and Bristol-Myers Squibb; received honoraria from Pfizer, Incyte, Ariad, and Novartis; received research funding from Novartis, Pfizer, and Bristol-Myers Squibb and travel support from Pfizer, Incyte, Ariad, Novartis, and Bristol-Myers Squibb. W.H.: received honoraria for lectures from Ariad. A.K.: received honoraria for lectures and consulting services for Novartis, Bristol-Myers Squibb, and Pfizer. K.J.-U. and C.F.W.: no conflicts of interest to declare. F.S.: advisory board: Incyte, Novartis, and Pfizer; received speaker honoraria from Bristol-Myers Squibb, Novartis, and Pfizer and travel support from Bristol-Myers Squibb and Novartis. H.P.: advisory board: Incyte; received travel support and honoraria from Incyte, Amgen, Novartis, and Jazz Pharmaceuticals. P.R.: advisory board: Novartis, Bristol-Myers Squibb, Incyte, and Pfizer; received research funding and congress/travel support from Novartis and Bristol-Myers Squibb. N.G.: advisory board: Incyte and Novartis; received research support from Incyte and Novartis. C.R.: received honoraria for consulting services from AbbVie, Astellas, Basilea, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline Germany, Incyte, Janssen-Cilag, Pfizer, Merck, Novartis, Roche, Takeda, and Shire. G.-N.F.: received honoraria and research funding from Novartis and honoraria from Incyte and Pfizer. P.C.: received speaker honoraria from Incyte, Novartis, Bristol-Myers Squibb, and Pfizer. R.K.: received research grant from Ariad. C.J.: received financial support for research, honoraria for scientific advisory activity, and speaker honoraria from Incyte.

Figures

Fig. 1
Fig. 1
PACE: 1- and 5-year response at any time in patients with CP-CML, overall, and in patients resistant/intolerant to previous treatment with dasatinib or nilotinib or with T315I mutation (adapted from [6, 10]). R/I resistant or intolerant; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; MMR, major molecular response; MR4.5, 4.5-log reduction or ≤0.0032% BCR-ABL.
Fig. 2
Fig. 2
Forest plots of vascular occlusive events, OS, and MMR in patients with Ph+ ALL treated with new-generation TKIs vs. imatinib (adapted from [40]). MMR, major molecular response; TKI, tyrosine kinase inhibitor; OS, overall survival. Diamonds reflect the summary effect for each TKI. The summary effect size was derived from the following trials: Bosutinib: BELA (NCT00574873); Dasa­tinib: SWOG-S0325 (NCT00070499), START-R (NCT00103844), DASISION (NCT00481247), NordCML006 (NCT­00852566), NCT00320190; Nilotinib: RE-NICE (NCT01400074), ENESTnd (NCT­00471497), ENESTcmr (NCT00760877); Ponatinib: EPIC (NCT01650805). No forest plot contains all available 10 trials because for each analysis (overall survival, major molecular response, and vascular occlusive events), at least one study did not report the event of interest. 95% CI, 95% confidence interval.
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References

    1. Iclusig® Summary of Product Characteristics dated September. 2018.
    1. Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim DW, Nicolini FE, et al. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood. 2016 Feb;127((6)):703–12. - PMC - PubMed
    1. Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014 Sep;26((3)):428–42. - PMC - PubMed
    1. Soverini S, Bavaro L, Martelli M, De Benedittis C, Iurlo A, Orofino N, et al. Compound BCR-ABL1 Kinase Domain Mutants: Prevalence, Spectrum and Correlation with Tyrosine Kinase Inhibitor Resistance in a Prospective Series of Philadelphia Chromosome-Positive Leukemia Patients Analyzed By Next Generation Sequencing [ASH 2018, abstract 789] Blood. 2018;132(suppl 1):789.
    1. Lipton JH, Bryden P, Sidhu MK, Huang H, McGarry LJ, Lustgarten S, et al. Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors. Leuk Res. 2015 Jan;39((1)):58–64. - PubMed

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