The New Landscape in CLL Novel Therapies


      The New Landscape in CLL Novel Therapies

 Dec 2014 article written for CLLSA by Dr. Francesco Forconi (MD, DM, PhD, FRCPath)Associate Professor in  Haematological Oncology - Cancer Science Unit, University of  Southampton.

 Consultant Haematologist - Cancer Care, Haematology Department.  Southampton  University Hospital Trust.


Lay Summary

Chronic lymphocytic leukaemia is a tumour of a type of white blood cells, named B-cells or B lymphocytes, circulating in blood, bone marrow and lymph nodes. These B-cells are defined by the expression of the ‘B-cell receptor’ (BCR). The BCR is a surface immunoglobulin which signals stimuli essential for the survival and proliferation of the tumour cells. New small molecules have now been developed as therapeutical drugs to prevent the tumour BCR from signalling those stimuli. These drugs are commonly called BCR-associated inhibitors, and the results in patients have demonstrated very high and protracted efficacy despite a very low toxicity profile. The results been so exciting, that approvals for commercialisation have been rapidly obtained in the United States and in Europe for the first-in-class compounds (Ibrutinib and idelalisib). However there are other new drugs that clinicians are testing in clinical trials as an alternative to conventional chemotherapy. Among them, inhibitors of molecules that prevent tumour cell death (BCL-2 inhibitors like GDC 0199) and new types of anti-CD20 monoclonal antibodies (obinutuzumab) seem very effective and are also awaited to be used in combinations outside clinical trials.


Over the past two decades, major advances have been achieved in understanding the genetics of Chronic lymphocytic leukaemia (CLL) with a hope to develop a single targeted therapy similar to imatinib used in chronic myeloid leukaemia (CML). However CLL is different from CML in that it lacks a single clonal lesion sufficient to determine tumour transformation and progression, in a fashion similar to the bcr/abl fusion gene translocation. The complexity of CLL with respect to genetic abnormalities has helped stratification of prognostic risks in the chemotherapy era, but it is only through investigating cell signalling and survival mechanisms that novel successful strategies have been developed.

CLL is a neoplasm resulting from the progressive accumulation of functionally ‘anergic’ monotypic B lymphocytes in the blood, bone marrow, lymph nodes, and spleen.1,2 As for any anergic B lymphocyte, CLL express their B-cell receptor (BCR) at levels sufficient to sustain survival of their tumour cells while proliferation is very limited. However CLL cells are different from anergic B-cells in that they express high levels of bcl2 protein which sustains anti-apoptotic mechanisms and consequently survival.1,2

Improved understanding of how cell signals through their BCR, which is essential for normal growth and for tumorigenesis, has led to the development of targeted therapies in CLL, with improved short-term clinical outcomes.1,2 Ibrutinib and idelalisib are two inhibitors targeting BCR-associated signalling pathways. They have been rapidly approved by FDA and EMEA and will hopefully be very soon approved for use outside clinical trials by NICE in the UK.

A second group of molecules which will likely shift therapeutical algorithms away from chemotherapy include BCL2 inhibitors like ABT-199.

A third novel major therapeutical change relies on a new generation of type II anti-CD20 antibodies (e.g. obinutuzumab), which aims to replace the very successful type I anti-CD20 Rituximab.

It is very likely possible that the combination of two or more of these types of drugs together will define the new treatment strategy for CLL. How these or other agents such as other therapeutic antibodies, and chimeric antigen receptor-modified T-cells, will be used in CLL also represents a major question that future clinical trials will answer.

Inhibitors of BCR signalling are ahead in the rapid invasion of the therapeutic scene and will be the topic of this section.

BCR-associated kinase inhibitors


BCR signalling is essential to the survival and/or proliferation of normal and tumour B-cells and it is composed of a cascade of molecules and enzymes including LYN, SYK, BLNK, BTK, PLC-g2 and PI3K that can all be targeted therapeutically.1,2 Ibrutinib is an orally bioavailable irreversible inhibitor of BTK. It covalently binds to Cys-481 in the ATP binding domain of the BTK molecule and suppresses BCR mediated survival signals. In early phase clinical trials in patients with relapsed or chemo-resistant CLL, ibrutinib showed an overall response (OR) rate of 91% (including 20% of patients obtaining a partial response with persistent lymphocytosis (PR+L)).3The patients in these early studies were rich in conventional clinical and genetic factors poor prognosis, but responses appeared independent of those factors and resulted in progression free survival of ~75% after more than two years from commencement of treatment.3 Very similar results were obtained in elderly patients who had not received prior treatments, where treatment with ibrutinib associated with an OR rate of 84% (including 13% PR+L). Responses maintained over time and 96% patients had not progressed at 2–years.4 Interestingly the majority of patients treated with ibrutinib have a paradoxical increase of the lymphocyte counts in the blood, and this can be prolonged for months but it does not appear to predict inferior efficacy or shorter duration of response.5Another remarkable feature is the very good tolerability profile of Ibrutinib and the most common side effects (diarrhoea, nausea and fatigue) are generally very mild.


PI3K are a family of enzymes involved in a wide array of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking.6 The p110δ isoform regulates different aspects of cellular proliferation and survival and is constitutively over-expressed in CLL B-cells. Idelalisib is an orally bioavailable selective PI3K-δ inhibitor that promotes apoptosis of CLL B-cells in vitro and that can abrogate the survival signal provided by the microenvironment.7 In a phase I trial of patients with relapsed/refractory high-risk CLL patients requiring new treatment, idelalisib treatment resulted in an OR rate of 72%.8 Median PFS was 15.8 months. Therapy was generally well-tolerated and most common Grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%) and diarrhoea (6%).

Benefits of BCR-associated kinase inhibitors over chemotherapy

The BCR tyrosine kinase inhibitors ibrutinib and idelalisib appear to have several advantages over current chemotherapy regimens, although longer follow ups and results from more clinical trials are needed to validate the benefits.

Outcome – Although long term long term data are still lacking and multiple questions are still unanswered about durability and consequences of treatment, results currently published indicate that in patients with treatment naïve CLL, PFS was >95% at 2-years.4 This results are dramatically superior to those of patients treated with FCR, of whom ~25% progress at 2-years and 51% at 6 years.9

Mitigating the poor prognosis of defined genetic lesions – BCR-associated kinase inhibitors appear to markedly mitigate the risks associated with genetic lesions such those of TP53 gene. FCR treatment determines an OR of 33% with a median PFS of less than 2-years in this group of patients.10 Other treatments including alemtuzumab, and rituximab alone or with heavily cytotoxic and immunosuppressive combinations (CFAR), flavopiridol and lenalidomide based combinations also result in mediocre responses.11 Conversely, the early data from patients with del(17p) treated with ibrutinib documented an OR rate of 56% and a median PFS of more than 2 years.4 Similar positive results have been documented in patients treated with idelalisib combined to rituximab with 80% OR and more than 75% patients not progressing after 1 year.12

However, the outcomes of patients with these high-risk mutations are still inferior to patients without these abnormalities. This suggests that kinase inhibitors are not able to completely overcome the adverse prognosis conferred by the presence of these factors, various combinations are being tested in clinical trials with the effort to further improve outcomes in these type of patients.

Infections - treatments with immunochemotherapy regimens often result into a variable but significant incidence of infectious complications. Regimens like FCR result in infectious complications ranging from 35% at 3 months to 12% at 9 months, and are poorly tolerated in patients older than 65-70 years.13 Ibrutinib trials are currently showing a lower incidence of infectious complications and this progressively declines with continuation of therapy.3

Expanding the CLL population to treat actively - Efforts are currently underway to evaluate the role of kinase inhibitors in patients with poor prognostic markers prior to meeting the conventional criteria for initiating therapy. The potentials are that early disease control might limit immune dysfunction and infectious complications, which remain the main cause of morbidity and mortality in CLL.14 Also, a large group of patients with advanced age and comorbidities are often not eligible for treatment with any (immuno)chemotherapy patients despite indication for treatment according to the current guidelines, because the complications secondary to the treatments might be superior than the benefits.15 Given the excellent tolerability and impressive responses observed in patients treated with kinase inhibitors, trials are underway to evaluate their role in patients who would be otherwise classified as ‘no go’.

Possible pitfalls of BCR-associated kinase inhibitors over chemotherapy

Cost-effectiveness – despite the extremely exciting results, kinase inhibitors are very expensive and meant for long term treatments. This is different from immunochemotherapy regimens, during which patients are treated within a period of around ½ year. This raises the question of who is in real need for the novel treatments or for whom the conventional treatments may ‘just be sufficient’.

Ongoing clinical trials are addressing these questions and the UK-based FLAIR study is one of them. However, long term data from the initial cohort of patients treated with FCR at MD Anderson Cancer Enter indicate that patients with mutated tumour IGHV and isolated 13q deletion have extremely prolonged PFS with no relapses reported after 10-years.16

New complications - while the infectious complications are lower than in patients treated with (immuno)chemotherapies, other complications are important to be monitored during kinase inhibitors. Patients treated with ibrutinib have a relatively high incidence of atrial fibrillation and bleeding diathesis possibly due to collagen-mediated platelets aggregation defect.3,17,18 Patients treated with idelalisib have frequent transaminase elevations, diarrhoea with colitis and pneumonitis during continued drug exposure.8

Duration of therapy – need of combinations to eradicate CLL? one of the unanswered questions is how long treatment with the kinase inhibitors should last. With (immuno)chemotherapies the ideal goal has been eradication of minimal residual disease, which predicts longer survivals. However, kinase inhibitors do not seem to achieve eradication of disease, despite prolongation of time free of progressive disease. 3,8 Hence the current attitude is to consider other molecules in combinations that may induce eradication of disease and/or to continue treatments until the new trials become informative on the consequences of discontinuation and/or on the effect of the various combinations.

Resistance to ibrutinib – In some patients who had relapsed CLL while on ibrutinib, mutations in BTK at the binding site of ibrutinib and in PLCγ2 have been found, resulting in Ibrutinib unable to block BCR signalling and in constitutive activation of the pathway.19 Although these events are very infrequent, there are efforts already in the scientific community to develop specific agents that have the ability to overcome these resistance pathways.

Conclusions and other drugs

A big proportion of patients now come to clinic already keen to consider oral kinase inhibitors if treatments are proposed. They have the great advantage of being oral tablets, which is more acceptable in the oncology community. However many questions remain yet unanswered and these novel drugs are more likely to be used in combination with other targeted therapies. These include antibodies targeting various surface antigens on CLL B-cells including CD20, CD19 and CD37, molecules specifically designed either to directly target CLL B-cells or overcome the micro-environmental signals that provide the CLL B-cells a survival advantage, e.g. ABT-199, or lenalidomide.20 However alternative kinase inhibitors like spleen tyrosine kinase (SYK), cyclin dependent kinase (CDK) and other systems like autologous chimeric antigen receptor modified T-cells directed towards the CD19 antigen are still under intensive investigation.20


1. Stevenson FK, Forconi F, Packham G. The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukaemia. Semin Hematol. 2014;51(3):158-167.

2. Packham G, Krysov S, Allen A, et al. The outcome of B-cell receptor signalling in chronic lymphocytic leukaemia.: proliferation or anergy. Haematologica. 2014;99(7):1138-1148.

3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukaemia. N Engl J Med. 2013;369(1):32-42.

4. 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, multi-centre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58.

5. 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(12):1810-1817.

6. So L, Fruman DA. PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem J. 2012;442(3):465-481.

7. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukaemia. by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-2088.

8. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukaemia. Blood. 2014;123(22):3390-3397.

9. 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 leukaemia. Blood. 2008;112(4):975-980.

10. Strati P, Keating MJ, O'Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukaemia. with 17p deletion. Haematologica. 2014;99(8):1350-1355.

11. 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(1):36-46.

12. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukaemia.N Engl J Med. 2014;370(11):997-1007.

13. 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(9747):1164-1174.

14. Morrison VA. Infectious complications in patients with chronic lymphocytic leukaemia.: pathogenesis, spectrum of infection, and approaches to prophylaxis. Clin Lymphoma Myeloma. 2009;9(5):365-370.

15. Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M, Group EGW. Chronic lymphocytic leukaemia.: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 6:vi50-54.

16. 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(24):3727-3732.

17. Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukaemia. 2014.

18. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukaemia. N Engl J Med. 2014;371(3):213-223.

19. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294.

20. Awan FT, Byrd JC.Clin Cancer Res. 2014.