CONCLUSION
Continue Reading
In conclusion, idelalisib is a highly efficacious new targeted therapy for the treatment of patients with iNHL and CLL/SLL, producing high rates of durable responses, with favorable PFS and OS. Combinations with BR chemotherapy in the relapsed/refractory CLL population demonstrate safety with both a PFS and OS benefit. The somewhat unique toxicity profile requires careful monitoring of patients treated with this agent. Targeted therapies such as idelalisib already play a pivotal role in the current treatment of CLL/iNHL, and this role is expected to expand as many clinical trials are ongoing.
Disclosure
AA was supported by the CA127264 research grant from National Institutes of Health. BTH has served on an advisory boards with both Genentech and Pharmacyclics. MRS has served on advisory boards with Genentech, Spectrum, and Celgene. The authors report no other conflicts of interest in this work.
Yazan F Madanat,1 Mitchell R Smith,2 Alexandru Almasan,3 Brian T Hill2
1Department of Internal Medicine, 2Department of Hematology and Medical Oncology, Taussig Cancer Institute, 3Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
References
1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the united states, 1992–2001 Blood. 2006;107:265–276.
2. Gribben JG. How I treat indolent lymphoma Blood. 2007;109:4617–4626.
3. Junlen HR, Peterson S, Kimby E, et al. Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish lymphoma registry study Leukemia. 2015;29:668–676.
4. Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and epidemiological burden of chronic lymphocytic leukaemia Eur J Cancer Care (Engl). 2004;13:279–287.
5. Diehl LF, Karnell LH, Menck HR. The American college of surgeons commission on cancer and the American cancer society. The National Cancer Data Base report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia Cancer. 1999;86:2684–2692.
6. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia Blood. 2008;112:975–980.
7. Goede V, Hallek M. Pharmacotherapeutic management of chronic lymphocytic leukaemia in patients with comorbidities: new agents, new hope Drugs Aging. 2015;32(11):877–886.
8. Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R)(FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the german CLL study group (GCLLSG)(CLL10 study) [abstract 19]. Abstract presented at: 56th American Society of Hematology (ASH) Annual Meeting and Exposition, December 6–9, 2014, San Francisco, CA.
9. Lunning MA, Vose JM. Management of indolent lymphoma: where are we now and where are we going Blood Rev. 2012;26:279–288.
10. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial Lancet. 2013;381:1203–1210.
11. Stevenson FK, Caligaris-Cappio F. Chronic lymphocytic leukemia: revelations from the B-cell receptor Blood. 2004;103:4389–4395.
12. Davids MS, Brown JR. Targeting the B cell receptor pathway in chronic lymphocytic leukemia Leuk Lymphoma. 2012;53:2362–2370.
13. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia N Engl J Med. 2013;369:32–42.
14. Wang Y, Zhang LL, Champlin RE, Wang ML. Targeting Bruton’s tyrosine kinase with ibrutinib in B-cell malignancies Clin Pharmacol Ther. 2015;97:455–468.
15. Markham A. Idelalisib: first global approval Drugs. 2014;74:1701–1707.
16. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling Nat Rev Mol Cell Biol. 2010;11:329–341.
17. Puri KD, Gold MR. Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies Front Immunol. 2012;3:256.
18. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells Blood. 2014;124:3583–3586.
19. Sciavolino PJ. A tale of two isoforms: PI3K delta and gamma. Targeted Oncology [serial online, cited December 1, 2015] April 30, 2015. Available from: http://www.targetedonc.com/publications/targeted-therapies-cancer/2015/april-2015/a-tale-of-two-isoforms-pi3k-delta-and-gamma. Accessed November 10, 2015.
20. Bernal A, Pastore RD, Asgary Z, et al. Survival of leukemic B cells promoted by engagement of the antigen receptor Blood. 2001;98:3050–3057.
21. Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies Nat Rev Drug Discov. 2013;12:229–243.
22. Ramanathan S, Jin F, Sharma S, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of idelalisib Clin Pharmacokinet. Epub August 15, 2015.
23. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia Blood. 2014;123:3390–3397.
24. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia N Engl J Med. 2014;370:997–1007.
25. O’Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia Blood. 2015;126(25):2686–2694.
26. Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double-blind placebo-controlled study [late breaking abstract 5]. Abstract presented at: 57th American Society of Hematology (ASH) Annual Meeting and Exposition, December 5–8, 2015, Orlando, FL.
27. Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma N Engl J Med. 2014;370:1008–1018.
28. Zyledig® [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2014. Available from:http://www.gilead.com/~/media/Files/pdfs/medicines/oncology/zydelig/zydelig_pi.pdf. Accessed November 28, 2015.
29. Lampson BL, Matos T, Kim HT, et al. Idelalisib given front-line for the treatment of Chronic lymphocytic Leukemia Results in frequent and severe immune-mediated toxicities [abstract 497]. Abstract presented at: 57th American Society of Hematology (ASH) Annual Meeting and Exposition, December 5–8, 2015, Orlando, FL.
30. Weidner AS, Panarelli NC, Geyer JT, et al. Idelalisib-associated colitis: histologic findings in 14 patients Am J Surg Pathol. 2015; 39(12):1661–1667.
31. Butler T, Maravent S, Boisselle J, Valdes J, Fellner C. A review of 2014 cancer drug approvals, with a look at 2015 and beyond P T. 2015; 40:191–205.
32. Blunt MD, Steele AJ. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia Leuk Res Rep. 2015;4:60–63.
33. Balakrishnan K, Peluso M, Fu M, et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL Leukemia. 2015;29:1811–1822.
34. Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies Cell Death Dis. 2015;6:e1593.
Source: Blood and Lymphatic Cancer: Targets and Therapy
Originally published March 15, 2016.
