Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Oncology & Hematology Review, 2017;13(1):34–40 DOI: https://doi.org/10.17925/OHR.2017.13.01.34

Abstract:

Until recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment.
Keywords: CLL, novel agents, targeted therapy
Disclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Acknowledgments: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Received: February 10, 2017 Accepted March 09, 2017
Correspondence: Nishitha M Reddy, 3927 The Vanderbilt Clinic, Vanderbilt University Medical Center, Nashville, Tennessee, US. E: nishitha.reddy@vanderbilt.edu
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with an estimated 18,960 new cases diagnosed in the US in 2016.1 The past few years have witnessed major advances in the treatment of CLL with several new drugs receiving US Food and Drug Administration (FDA) approval in both the frontline and relapsed/refractory setting leading to improvement in overall survival (OS). The availability of several active and relatively well-tolerated agents has raised questions on the optimal drug sequence, duration, and tailoring therapy based on the underlying disease biology. With effective drugs in the previously considered poor prognostic individuals, there is also a need to redefine the prognostic criteria. Several guiding principles have already been established including the management of early asymptomatic disease with observation alone. Indications for treatment of untransformed disease include at least one of the following based on The International Workshop Group on CLL (IWCLL) 2008 guidelines:2
• Progressive marrow failure due to CLL infiltration as evidenced by worsening cytopenias
• Massive (>6 cm below costal margin) splenomegaly with symptoms
• Bulky (>10 cm) or symptomatic lymphadenopathy
• Progressive lymphocytosis
• Autoimmune cytopenias unresponsive to immunosuppressive therapy
• Presence of B symptoms or significant fatigue (Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2 or more related to disease). In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del[17p]). This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general treatment approach in the first-line and relapsed/refractory (R/R) settings are summarized in Figure 1.

Chemoimmunotherapy regimens in CLL—fit patients with no major comorbidities
CIT regimens combine chemotherapeutic agents with a CD20 antibody like rituximab, ofatumumab and obinutuzumab. CIT regimens such as fludarabine, cyclophosphamide, and rituximab (FCR) have been the mainstay of frontline CLL therapy especially in the young, fit individuals. At present, there is no proven benefit to early treatment of patients with CLL. Patients who meet criteria for treatment need to be stratified further based on fitness assessment (age, organ function and performance status) and biological risk (most importantly TP53mutation and /or del[17p]) for treatment decision. Table 1 summarizes the trials comparing different CIT combinations incorporating cytotoxic chemotherapy in combination with a CD20 monoclonal antibody (mAb) that are recommended in the young and elderly fit patients.

FCR is the regimen of choice in young (<65 years), fit patients without evidence of TP53 disruption based on the FCR300 and CLL8 trials. In FCR300,3 a single arm phase II study received FCR as first line treatment. At a median follow up of 6 years, complete remission (CR) was seen in 72% with an overall response rate (ORR) of 95%. Six-year overall survival (OS) rate was 77% and progression free survival (PFS) rate was 51%. Recently updated results at a median follow up of 12.8 years show a median PFS of 6.4 years. Considering unmutated (UM) and mutated (M) immunoglobulin heavy chain variable (IGHV) gene status, IGHV-UM and IGHV-M, 12.8 year PFS was 8.7% and 53.9% respectively. Importantly, in the IGHV-M subgroup there were no relapses after 10.4 years represented by a plateau on the PFS curve.4 A larger phase III study, the CLL8 trial compared FCR with FC. FCR was associated with a superior ORR (90% versus 80%), CR (44% versus 22%), 3-year PFS (65% versus 45%), and 3-year OS (87% versus 83%). FCR was associated with a higher rate of grade 3/4 neutropenia.5 Long-term follow up studies after FCR treatment have revealed durable responses in patients with IGHV-M CLL and those without del(17p) or del(11q).4,6,7

Bendamustine and rituximab (BR) was evaluated in a phase II study with 117 patients in the front-line setting showed an ORR of 88% and a CR rate of 23%. At a median follow up of 27 months, the median (m)-PFS was 33.9 months. A quarter of the patients in this study were >70 years and their m-PFS was similar to younger patients despite a lower ORR in this age group.8 Further in the randomized phase III CLL10 trial, BR was compared with FCR in the front-line setting.9 This was a non-inferiority trial with PFS as primary endpoint and excluded patients with del(17p). The final analysis of 561 patients included 282 patients in the FCR arm and 279 in the BR arm. At a median follow up of 37.1 months, the m-PFS was 55.2 months and 41.7 months in the FCR and BR arms respectively. OS was not different between the two arms. The FCR arm was associated with more grade 3/4 neutropenia and infections especially in patients older than 65 years. There was no difference in PFS in the subgroup of patients >65 years. In addition, post-hoc analysis, favored the use of FCR in patients with IGHV-UM (p=0.017) and del(11q) (p=0.0002) CLL. Due to a lower rate of complications in older patients, BR is a reasonable front-line choice in fit CIT eligible patients >65 years of age. Several additional CIT regimens were tested in the frontline setting and are summarized in Table 1.10–14

References:
1. Siegel RL, Miller KD, Jemal A, Cancer statistics, 2016, CA Cancer J Clin, 2016;66:7–30.
2. 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;111:5446–56.
3. 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;112:975–80.
4. 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;127:303–9.
5. 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;376:1164–74.
6. Rossi D, Terzi-di-Bergamo L, De Paoli L et al., Molecular prediction of durable remission after first-line fludarabinecyclophosphamide- rituximab in chronic lymphocytic leukemia, Blood, 2015;126:1921–4.
7. 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, 2015:127:208–15.
8. Fischer K, Cramer P, Busch R, et al., Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group, J Clin Oncol, 2012;30:3209–16.
9. Eichhorst B, Fink A-M, Bahlo J, et al., First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial, Lancet Oncol, 2016;17:928–42.
10. Brown JR, O'Brien S, Kingsley CD, et al., Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial, Blood, 2015;125:2779–85.
11. Foon KA, Mehta D, Lentzsch S, et al., Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia, Blood, 2012;119:3184–5.
12. Kay NE, Geyer SM, Call TG, et al., Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia, Blood, 2007;109:405–11.
13. Wierda WG, Kipps TJ, Durig J, et al., Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia Blood 2011;117:6450–8.
14. Shanafelt T, Lanasa MC, Call TG, et al., Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL), Cancer, 2013;119:3788–96.
15. Goede V, Fischer K, Busch R, et al., Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions, N Engl J Med, 2014;370:1101–10.
16. 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;385:1873–83.
17. Zenz T, Eichhorst B, Busch R, et al., TP53 mutation and survival in chronic lymphocytic leukemia, J Clin Oncol, 2010;28:4473–9.
18. Hillmen P, Skotnicki AB, Robak T, et al., Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia, J Clin Oncol, 2007;25:5616–23.
19. 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;30:1647–55.
20. Stilgenbauer S, Cymbalista F, Leblond V, et al., Alemtuzumab combined with dexamethasone, followed by alemtuzumab maintenance or Allo-SCT in “ultra high-risk” CLL: final results from the CLL2O phase II study, Blood, 2014;124:1991.
21. Castro JE, Sandoval-Sus JD, Bole J, et al., Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia, Leukemia, 2008;22:2048–53.
22. Castro JE, James DF, Sandoval-Sus JD, et al., Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia, Leukemia, 2009;23:1779–89.
23. Pileckyte R, Jurgutis M, Valceckiene V, et al., Dose-dense highdose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia, Leuk Lymphoma, 2011;52:1055–65.
24. Stevenson FK, Caligaris-Cappio F, Chronic lymphocytic leukemia: revelations from the B-cell receptor, Blood, 2004;103:4389–95.
25. Ponader S, Burger JA, Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies, J Clin Oncol, 2014;32:1830–9.
26. Herman SEM, 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;117:6287–96.
27. Satterthwaite AB, The role of Bruton’s tyrosine kinase in B‐cell development and function: a genetic perspective, Immunol Rev, 2000;175:120–7.
28. Pan Z, Scheerens H, Li SJ, et al., Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase, ChemMedChem, 2007;2:58–61.
29. 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.
30. Byrd JC, Furman RR, Coutre SE, et al., Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib, Blood, 2015;125:2497–506
31. 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.
32. 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;16:169–76.
33. 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.
34. 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;123:1810–7.
35. 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, 2016;17:200–11.
36. Byrd JC, Harrington B, O’Brien S, et al., Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia, N Engl J Med, 2016;374:323–32.
37. Fegan C, Bagshawe J, Salles G, et al., The Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059: promising single agent activity and well tolerated in patients with high risk chronic lymphocytic leukaemia (CLL), Blood, 2014;124:3328.
38. Harb WA, Hill BT, Gabrilove J, et al., Phase 1 study of single agent CC-292, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, in relapsed/refractory chronic lymphocytic leukemia (CLL), Blood, 2013;122:1630.
39. Anderson MA, Huang D, Roberts A, Targeting BCL2 for the treatment of lymphoid malignancies, Semin Hematol, 2014;51:219-27.
40. 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.
41. Stilgenbauer S, Eichhorst B, Schetelig J, et al., Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study, Lancet Oncol, 2016;17:768–78.
42. Cervantes-Gomez F, Lamothe B, Woyach JA, et al., Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia, Clin Cancer Res, 2015;21:3705–15.
43. Herman SEM, 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;116:2078–88.
44. Furman RR, Sharman JP, Coutre SE, et al., Idelalisib and rituximab in relapsed chronic lymphocytic leukemia, N Engl J Med, 2014;370:997–1007.
45. 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, Blood, 2014;124:3334.
46. 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;29:1811–22.
47. Dong S, Guinn D, Dubovsky JA, et al., IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells, Blood, 2014;124:3583–6.
48. 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, Blood, 2014;124:3335.
49. Burris HA, Patel MR, Brander DM, et al., TGR-1202, a novel once daily PI3Kδ inhibitor, demonstrates clinical activity with a favorable safety profile, lacking hepatotoxicity, in patients with chronic lymphocytic leukemia and B-cell lymphoma, Blood, 2014;124:1984.
50. Lunning MA, Vose J, Fowler N, et al., Ublituximab+ TGR-1202 Demonstrates Activity and a Favorable Safety Profile in Relapsed/ Refractory B-Cell NHL and High-Risk CLL: Phase I Results, Blood, 2015;126:1538.
51. Chanan-Khan A, Miller KC, Musial L, et al., Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study, J Clin Oncol, 2006;24:5343–9.
52. Ferrajoli A, Lee B-N, Schlette EJ, et al., Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia, Blood, 2008;111:5291–7.
53. Salihoglu A, Ar MC, Soysal T, Novelties in the management of B-cell malignancies: B-cell receptor signaling inhibitors and lenalidomide, Expert Rev Hematol, 2015;8:765–83.
54. Badoux XC, Keating MJ, Wen S, et al., Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia, Blood, 2011;118:3489–98.
55. Chen CI, Paul H, Wang T, et al., Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia, Br J Haematol, 2014;165:731–3.
56. Chen CI, Bergsagel PL, Paul H, et al., Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia, J Clin Oncol, 2010;29:1175–81.
57. Chanan-Khan A, Miller KC, Lawrence D, Padmanabhan S, Miller A, Hernandez-Illatazurri F, et al. Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response, Cancer, 2011;117:2127–35.
58. Fink AM, Bahlo J, Sandra R, et al., Lenalidomide Maintenance after Front Line Therapy Substantially Prolongs Progression Free Survival in High Risk CLL: Interim Results of a Phase 3 Study (CLL M1 study of the German CLL Study Group), Presented at: 58th Annual Meeting of the American Society of Hematology, San Diego US, December 3, 2016.
59. Ramsay AG, Clear AJ, Fatah R, Gribben JG, Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer, Blood, 2012;120:1412–21.
60. Kater AP, Tonino SH, Egle A, Ramsay AG, How does lenalidomide target the chronic lymphocytic leukemia microenvironment?, Blood, 2014;124:2184–9.
61. Brusa D, Serra S, Coscia M, et al., The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia, Haematologica, 2013;98:953–63.
62. Riches JC, Davies JK, McClanahan F, et al., T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production, Blood, 2013;121:1612–21.
63. Jain N, Basu S, Thompson PA, et al., Nivolumab Combined with Ibrutinib for CLL and Richter Transformation: A Phase II Trial. Presented at: 58th Annual Meeting of the American Society of Hematology, San Diego US, December 3, 2016.
64. Porter DL, Hwang W-T, Frey NV, et al., Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia, Sci Transl Med, 2015;7:303ra139.
65. Mato A, Porter DL, A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs, Blood, 2015;126:478–85.
66. Buchner M, Baer C, Prinz G, et al., Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia, Blood, 2010;115:4497–506.
67. Lapalombella R, Sun Q, Williams K, et al., Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia, Blood, 2012;120:4621–34.
68. Quiroga MP, Balakrishnan K, Kurtova AV, et al., B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406, Blood, 2009;114:1029–37.
69. Suljagic M, Longo PG, Bennardo S, et al., The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu- TCL1 transgenic mouse model of CLL by blocking antigendependent B-cell receptor signaling, Blood, 2010;116:4894–905.
70. Ward E, Mittereder N, Kuta E, et al., A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo, Br J Haematol, 2011;155:426–37.
71. Herbst R, Wang Y, Gallagher S, et al., B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody, J Pharmacol Exp Ther, 2010;335:213–22. 72. Herman SE, Barr PM, McAuley EM, et al., Fostamatinib inhibits B-cell receptor signaling, cellular activation and tumor proliferation in patients with relapsed and refractory chronic lymphocytic leukemia, Leukemia, 2013;27:1769–73.
73. Zhong Y, El-Gamal D, Dubovsky JA, et al., Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells, Leukemia, 2014;28:1158–63.
74. Robak T, Robak P, Anti-CD37 antibodies for chronic lymphocytic leukemia, Expert Opin Biol Ther, 2014;14:651–61.
75. Currie KS, Kropf JE, Lee T, et al., Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase, J Med Chem, 2014;5:3856–73.
76. Sharman J, Hawkins M, Kolibaba K, et al., An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia, Blood, 2015;125:2336–43.
77. Maddocks KJ, Pagel J, Byrd JC, et al., Phase 1b study of otlertuzumab (TRU-016), an Anti-CD37 ADAPTIRTM protein, in combination with rituximab in patients with chronic lymphocytic leukemia (CLL), Blood, 2014;124:4671.
78. Byrd JC, Pagel JM, Awan FT, et al., A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 monospecific ADAPTIR therapeutic protein in chronic lymphocytic leukemia, Blood, 2014;123:1302–8.
79. Beckwith KA, Frissora FW, Stefanovski MR, et al,. The CD37- targeted antibody–drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model, Leukemia, 2014;28:1501–10.
80. Heider KH, Kiefer K, Zenz T, et al., A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies, Blood, 2011;118:4159–68.
81. Awan FT, Hillmen P, Hellmann A, et al., A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia, Br J Haematol, 2014;167:466–77.
82. Woyach JA, Awan F, Flinn IW, et al., A phase 1 trial of the Fcengineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL, Blood, 2014;124:3553–60.
83. Hing ZA, Mantel R, Beckwith KA, et al., Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia, Blood, 2015;125:3128–32.
84. Andritsos L, Byrd JC, Jones JA, et al., Preliminary results from a phase I dose escalation study to determine the maximum tolerated dose of plerixafor in combination with rituximab in patients with relapsed chronic lymphocytic leukemia, Blood, 2010;116:2450.
85. Alsagaby SA, Brennan P, Pepper C, Key Molecular Drivers of Chronic Lymphocytic Leukemia, Clin Lymphoma Myeloma Leuk, 2016;16:593–606.
86. Jain N, Chen Q, Ayer T, et al., Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies, Blood, 2015;126:871.
87. Shanafelt TD, Borah BJ, Finnes HD, et al., Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels,J Oncol Pract, 2015;11:252–8.
Keywords: CLL, novel agents, targeted therapy