PROGNOSIS AND NEW THERAPEUTIC APPROACHES IN CHRONIC LYMPHOCYTIC LEUKEMIA TREATMENT
Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, comprising about 30% of all leukemias in Europe and United States. Also, it represents one of the most active hematological disease regarding clinical trials. Nearly 80% of CLL patients have some chromosomal aberration, with following being emphasized due to its frequency and importance: 13q14 deletion (del13q14), 11q22-q23 deletion (del11q), chromosome 12 trisomy, 17p deletion (del17p) or/and tumor suppressor gene TP53 mutation. The use of new therapeutic agents in CLL treatment has markedly improved survival and quality of life of CLL patients. Ibrutinib, Bruton’s kinase inhibitor (BTK), is approved for first line therapy for CLL patients with del17p or TP53 mutation, as well for relapsed/refractory CLL patients (R/R CLL). The use of venetoclax, antiapoptotic protein bcl-2 inhibitor, is indicated for R/R CLL patients who are resistant to ibrutinib or for whose ibrutinib is contraindicated (use of anticoagulant therapy; increased bleeding risk). Phosphoinositide 3-kinase (PI3K), idelalisib (in combination with rituximab) and duvelisib (monotherapy), are approved for treatment of R/R CLL patients. The PI3K inhibitors are rarely used in treatment of R/R CLL patients before ibrutinib or venetoclax, primarily because of unfavourable safety profile of these drugs. New therapeutic agents are providing CLL patients longer overall survival and progression free survival, especially for CLL patients with adverse prognostic factors.
References
Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2017;92(9):946–65.
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41.
Scarfo L, Ferreri AJM, Ghia P. Chronic lymphocytic leukaemia. Crit Rev Oncol Hematol. 2016;104:169–82.
Hallek M. On the architecture of translational research designed to control chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Progr. 2018;2018(1):1–8.
Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd PJ, et al. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet. 1999;353(9146):26–9.
Tees MT, Flinn IW. Chronic lymphocytic leukemia and small lymphocytic lymphoma: two faces of the same disease. Expert Rev Hematol. 2017;10(2):137–46.
Ma ESK. Recurrent Cytogenetic Abnormalities in Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia. Methods Mol Biol. 2017;1541:279–93.
Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–6.
Autore F, Strati P, Laurenti L, Ferrajoli A. Morphological, immunophenotypic, and genetic features of chronic lymphocytic leukemia with trisomy 12: a comprehensive review. Haematologica. 2018/05/10. 2018;103(6):931–8.
Puiggros A, Blanco G, Espinet B. Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go. Biomed Res Int. 2014/05/22. 2014;2014:435983.
Amaya-Chanaga CI, Rassenti LZ. Biomarkers in chronic lymphocytic leukemia: Clinical applications and prognostic markers. Best Pract Res Clin Haematol. 2016;29(1):79–89.
Liu Y, Wang Y, Yang J, Bi Y, Wang H. ZAP-70 in chronic lymphocytic leukemia: A meta-analysis. Clin Chim Acta. 2018;483:82–8.
Parikh SA, Shanafelt TD. Prognostic factors and risk stratification in chronic lymphocytic leukemia. Semin Oncol. 2016;43(2):233–40.
An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779–90.
Molica S, Giannarelli D, Mirabelli R, Levato L, Shanafelt TD. Chronic lymphocytic leukemia international prognostic index (CLL-IPI) in patients receiving chemoimmuno or targeted therapy: a systematic review and meta-analysis. Ann Hematol. 2018;97(10):2005–8.
Danilov A V. Targeted Therapy in Chronic Lymphocytic Leukemia: Past, Present, and Future. Clin Ther. 2013;35(9):1258–70.
Gomes LC, Ferrao ALM, Evangelista FCG, de Almeida TD, Barbosa RC, Carvalho M das G, et al. Advances in chronic lymphocytic leukemia pharmacotherapy. Biomed Pharmacother. 2018;97:349–58.
Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193–205.
Ferrer G, Montserrat E. Critical molecular pathways in CLL therapy. Mol Med. 2018;24(1):9.
Burger JA, O’Brien S. Evolution of CLL treatment - from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510–27.
Robak P, Robak T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26(11):1249–65.
Jamroziak K, Pula B, Walewski J. Current Treatment of Chronic Lymphocytic Leukemia. Curr Treat Options Oncol. 2017;18(1):5.
Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018;131(4):379–86.
Davids MS. How should we sequence and combine novel therapies in CLL? Hematol Am Soc Hematol Educ Progr. 2017;2017(1):346–53.
Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43–56.
Yeung CCS, Shadman M. How to Choose the Best Treatment and Testing for Chronic Lymphocytic Leukemia in the Tsunami of New Treatment Options. Curr Oncol Rep. 2019;21(8):74.
Hallek M, Furstenau M. How to approach CLL in clinical practice. Hematol Oncol. 2019;37 Suppl 1:38–42.
Kamel S, Horton L, Ysebaert L, Levade M, Burbury K, Tan S, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29(4):783–7.
Marini BL, Samanas L, Perissinotti AJ. Expanding the armamentarium for chronic lymphocytic leukemia: A review of novel agents in the management of chronic lymphocytic leukemia. J Oncol Pharm Pract. 2017;23(7):502–17.
Lampson BL, Davids MS. The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep. 2017;12(1):11–9.
Khan M, Siddiqi T. Targeted Therapies in CLL: Monotherapy Versus Combination Approaches. Curr Hematol Malig Rep. 2018;13(6):525–33.
Olin JL, Griffiths CL, Smith MB. Venetoclax: A novel B-cell lymphoma-2 inhibitor for chronic lymphocytic leukemia and other hematologic malignancies. J Oncol Pharm Pract. 2018;24(7):517–24.
Fischer K, Al-Sawaf O, Bahlo J, Fink A-M, Tandon M, Dixon M, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019;380(23):2225–36.
Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019;380(22):2095–103.
Hillmen P, Rawstron AC, Brock K, Munoz-Vicente S, Yates FJ, Bishop R, et al. Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study. J Clin Oncol. 2019;JCO1900894.
Fowler N, Davis E. Targeting B-cell receptor signaling: changing the paradigm. Hematol Am Soc Hematol Educ Progr. 2013;2013:553–60.
Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19(6):715–27.
Burger JA. Bruton’s tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL) AU - Thompson, Philip A. Expert Opin Investig Drugs. 2018;27(1):31–42.
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2014;370(11):997–1007.
Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J. 2018;8(10):93.
Coutre SE, Burger JA, Pagel JM. Discussion: Managing Risk When Using Idelalisib. Vol. 14, Clinical advances in hematology & oncology : H&O. United States; 2016. p. 13.
Mato AR, Hill BT, Lamanna N, Barr PM, Ujjani CS, Brander DM, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050–6.
O’Brien S, Patel M, Kahl BS, Horwitz SM, Foss FM, Porcu P, et al. Duvelisib (IPI-145), a PI3K-δ,γ Inhibitor, Is Clinically Active in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Blood. 2014;124(21):3334 LP – 3334.
Patel MR, Kahl BS, Horwitz SM, Younes A, Foss FM, Oki Y, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory CLL. J Clin Oncol. 2013;31(15_suppl):7070.
Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018/10/04. 2018;132(23):2446–55.
Vangapandu H V, Jain N, Gandhi V. Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017/04/13. 2017;26(5):625–32.
Mato AR, Thompson MC, Nabhan C, Svoboda J, Schuster SJ. Chimeric Antigen Receptor T-Cell Therapy for Chronic Lymphocytic Leukemia: A Narrative Review. Clin Lymphoma Myeloma Leuk. 2017;17(12):852–6.
Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives. Curr Res Transl Med. 2017;65(3):93–102.
Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X, et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. J Clin Oncol. 2017;35(26):3010–20.
Lemal R, Tournilhac O. State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019. J Immunother Cancer. 2019;7(1):202.
Gill S, Frey N V, Hexner EO, Lacey SF, Melenhorst JJ, Byrd JC, et al. CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL. J Clin Oncol. 2017;35(15_suppl):7509.