Paving the way for new agents; is standard chemotherapy part of the treatment paradigm for chronic lymphocytic leukemia in the future?

References

• Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–1174.
   PubMed Web of Science ®Google Scholar
• Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4070–4078.
   PubMed Web of Science ®Google Scholar
• Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208–215.
   PubMed Web of Science ®Google Scholar
• Stilgenbauer S. Prognostic markers and standard management of chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program. 2015;2015:368–377.
   PubMed Web of Science ®Google Scholar
• Badoux XC, Keating MJ, Wierda WG. What is the best frontline therapy for patients with CLL and 17p deletion? Curr Hematol Malig Rep. 2011;6:36–46.
   PubMed Web of Science ®Google Scholar
• Lin KI, Tam CS, Keating MJ, et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood. 2009;113:3168–3171.
   PubMed Web of Science ®Google Scholar
• Brown JR, Porter DL, O’Brien SM. Novel treatments for chronic lymphocytic leukemia and moving forward. Am Soc Clin Oncol Educ Book; 2014:e317–25. doi:10.14694/EdBook_AM.2014.34.e317.
   Google Scholar
• Pleyer L, Egle A, Hartmann TN, et al. Molecular and cellular mechanisms of CLL: novel therapeutic approaches. Nat Rev Clin Oncol. 2009;6:405–418.
   PubMed Web of Science ®Google Scholar
• Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2:945–956.
   PubMed Web of Science ®Google Scholar
• Chiorazzi N, Ferrarini M. B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu Rev Immunol. 2003;21:841–894.
   PubMed Web of Science ®Google Scholar
• Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107:13075–13080.
   PubMed Web of Science ®Google Scholar
• Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287–6296.
   PubMed Web of Science ®Google Scholar
• Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.
   Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446–5456.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497–2506.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.
   PubMed Web of Science ®Google Scholar
• Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28:1749–1755.
   PubMed Web of Science ®Google Scholar
• O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48–58.
   PubMed Web of Science ®Google Scholar
• Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37.
   PubMed Web of Science ®Google Scholar
• Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114:3382–3391.
   PubMed Web of Science ®Google Scholar
• Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616–5623.
   PubMed Web of Science ®Google Scholar
• Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27:4378–4384.
   PubMed Web of Science ®Google Scholar
• Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101–1110.
   PubMed Web of Science ®Google Scholar
• Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385:1873–1883.
   PubMed Web of Science ®Google Scholar
• Farooqui MZH, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16:169–176.
   PubMed Web of Science ®Google Scholar
• Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. 2014;123:1810–1817.
   PubMed Web of Science ®Google Scholar
• Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15:1090–1099.
   PubMed Web of Science ®Google Scholar
• Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126:842–850.
   PubMed Web of Science ®Google Scholar
• Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125:2915–2922.
   PubMed Web of Science ®Google Scholar
• Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29(26):3559–3566.
   PubMed Web of Science ®Google Scholar
• Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2015; doi:10.1016/S1470-2045(15)00465–9.
   PubMed Web of Science ®Google Scholar
• Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124:3991–3995.
   PubMed Web of Science ®Google Scholar
• Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29:783–787.
   PubMed Web of Science ®Google Scholar
• Lipsky AH, Farooqui MZ, Tian X, et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica. 2015;100:1571–1578.
   PubMed Web of Science ®Google Scholar
• McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829–3830.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Harrington BD, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–32.
   PubMed Web of Science ®Google Scholar
• Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3:317–330.
   PubMed Web of Science ®Google Scholar
• Srinivasan L, Sasaki Y, Calado DP, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009;30;139(3):573–586.
   Web of Science ®Google Scholar
• Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078–2088.
   PubMed Web of Science ®Google Scholar
• Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–594.
   PubMed Web of Science ®Google Scholar
• Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3’-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118:3603–3612.
   PubMed Web of Science ®Google Scholar
• Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–7.
   Web of Science ®Google Scholar
• Furman RR, De Vos S, Leonard JP, et al. A phase 1 study of the selective pi3kδ inhibitor idelalisib (GS-1101) in combination with therapeutic anti-CD20 antibodies (rituximab or ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia. Presented at 55th ASH Annual Meeting; 2013 Dec 7–10; New Orleans, LA.
   Google Scholar
• Barrientos JC, Coutre SE, De Vos S, et al. Long-term follow-up of a phase 1 trial of idelalisib (ZYDELIG®) in combination with bendamustine (B), bendamustine/rituximab (BR), fludarabine (F), chlorambucil (Chl), or chlorambucil/rituximab (ChlR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Presented at 56th ASH Annual Meeting; 2014 Dec 6–9; San Francisco, CA.
   Google Scholar
• Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.
   PubMed Web of Science ®Google Scholar
• O’Brien S, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015;126:2686–94.
   Web of Science ®Google Scholar
• Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Presented at 56th ASH Annual Meeting; 2014 Dec 6–9; San Francisco, CA.
   Google Scholar
• Lampson BL, Tiago M, Kim H, et al. Idelalisib given front-line for the treatment of chronic lymphocytic leukemia results in frequent and severe immune-mediated toxicities. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Porcu P, Flinn I, Kahl BS, et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, in patients previously treated with ibrutinib. Presented at 56th ASH Annual Meeting; 2014Dec 6–9; San Francisco, CA.
   Google Scholar
• O’Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-δ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. Presented at 56th ASH Annual Meeting; 2014 Dec 6–9; San Francisco, CA.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Flinn IW, Cherry M, Maris M, et al. Combination trial of duvelisib (IPI-145) with bendamustine, rituximab, or bendamustine/rituximab in patients with lymphoma or chronic lymphocytic leukemia. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• Davids MS, Kim HT, Gilbert E, et al. Preliminary results of a phase Ib study of duvelisib in combination with FCR (dFCR) in previously untreated, younger patients with CLL. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• McClintock DS, Santore MT, Lee VY, et al. Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death. Mol Cell Biol. 2002;22:94–104.
   PubMed Web of Science ®Google Scholar
• Tsujimoto Y, Shimizu S. Bcl-2 family: life-or-death switch. FEBS Lett. 2000;466(1):6–10.
   PubMed Web of Science ®Google Scholar
• Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281(5381):1322–1326.
   PubMed Web of Science ®Google Scholar
• Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395–419.
   PubMed Web of Science ®Google Scholar
• Robertson LE, Plunkett W, McConnell K, et al. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 1996 Mar;10(3):456–459.
   PubMed Web of Science ®Google Scholar
• Van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–399.
   PubMed Web of Science ®Google Scholar
• Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488–496.
   PubMed Web of Science ®Google Scholar
• Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–208.
   PubMed Web of Science ®Google Scholar
• Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–22.
   PubMed Web of Science ®Google Scholar
• Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303–309.
   PubMed Web of Science ®Google Scholar
• Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126:1921–1924.
   PubMed Web of Science ®Google Scholar
• Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. Cancer. 2013;119(21):3805–3811.
   PubMed Web of Science ®Google Scholar
• Ferrajoli A, O’Brien S, Wierda WG. Treatment of patients with CLL70 years old and older: a single center experience of 142 patients. Leuk Lymphoma. 2005;46:46–48.
   Google Scholar
• Pettitt AR, Jackson R, Carruthers S, et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol. 2012;30:1647–1655.
   PubMed Web of Science ®Google Scholar
• Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99(10):3554–3561.
   PubMed Web of Science ®Google Scholar
• Hill BT, Caimi P, Kindwall-Keller T, et al. Bendamustine plus alemtuzumab is safe and feasible treatment for fludarabine refractory chronic lymphocytic leukaemia (CLL). Br J Haematol. 2014;164:297–299.
   PubMed Web of Science ®Google Scholar
• Montillo M, Tedeschi A, Petrizzi VB, et al. An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia. Blood. 2011;118:4079–4085.
   PubMed Web of Science ®Google Scholar
• Zent CS, Taylor RP, Lindorfer MA, et al. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells. Am J Hematol. 2014;89:757–765.
   PubMedGoogle Scholar
• Badoux XC, Keating MJ, Wen S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2013;31:584–591.
   PubMed Web of Science ®Google Scholar
• Pettitt AR, Matutes E, Oscier D. Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia. 2006;20:1441–1445.
   PubMed Web of Science ®Google Scholar
• Thompson PA, O’Brien SM, Wierda WG, et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer. 2015;121:3612–3621.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Jaglowski S, O’Brien S, et al. Analysis of prognostic factors predictive of complete response (CR) to ibrutinib in patients with CLL/SLL. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• Jones J, Hillmen P, Coutre S, et al. Pattern of use of anticoagulation and/or antiplatelet agents in patients with chronic lymphocytic leukemia (CLL) treated with single-agent ibrutinib therapy. Presented at 56th ASH Meeting; 2014 Dec 6–9; San Francisco, CA.
   Google Scholar
• Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30:980–988.
   PubMed Web of Science ®Google Scholar
• Strati P, Keating MJ, O’Brien SM, et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood. 2014;123:3727–3732.
   PubMed Web of Science ®Google Scholar
• Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123:1957–1960.
   PubMed Web of Science ®Google Scholar
• Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100(1):77–86.
   PubMed Web of Science ®Google Scholar
• Ysebaert L, Klein C, Quillet-Mary A. Ibrutinib exposure and B-cell depletion induced by antiCD20 monoclonal antibodies rituximab and obinutuzumab: is there a rationale for combination studies? Blood. Presented at 56th ASH Meeting; 2014 Dec 6–9; San Francisco, CA.
   Google Scholar
• Davis C, Stepanchick E, Syed K et al. Effects of ibrutinib on rituximab and GA-101 induced antibody-dependent cell cytotoxicity (ADCC) in lymphoma cells in vitro. Presented at 56th ASH Meeting; 2014 Dec 6–9; San Francisco, CA.
   Google Scholar
• Ysebaert L, Klein C, Quillet-Mary A CLL cells from ibrutinib-induced lymphocytosis of relapsed/refractory chronic lymphocytic leukemia patients are responsive to obinutuzumab, but not rituximab, ex vivo. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• 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. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–2549.
   PubMed Web of Science ®Google Scholar
• Woyach JA, Furman RR, Liu T-M, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370(24):2286–2294.
   PubMed Web of Science ®Google Scholar
• Cheng S, Guo A, Lu P, et al. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015;29:895–900.
   PubMed Web of Science ®Google Scholar
• Zhou Q, Lee G-S, Brady J, et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012;91:713–720.
   PubMed Web of Science ®Google Scholar
• Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–87.
   PubMed Web of Science ®Google Scholar
• Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015 Mar 26;125(13):2062–2067.
   PubMed Web of Science ®Google Scholar
• Barrientos JC, Kaur M, Mark A, et al. Outcomes of patients with chronic lymphocytic leukemia (CLL) after idelalisib therapy discontinuation. Presented at 57th ASH Annual Meeting; 2015 Dec 5–8; Orlando, FL.
   Google Scholar
• Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022–1035.
   PubMed Web of Science ®Google Scholar
• De Rooij MF, Kuil A, Kater AP, et al. Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for combination therapy. Blood. 2015;125:2306–2309.
   PubMed Web of Science ®Google Scholar