Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries with an annual incidence of 4–5 new cases per 100,000 people. The disease typically presents in elderly people, with a male predominance and a median age at diagnosis of 72 years .
In this current special issue of Acta Haematologica, which is dedicated to the topic of CLL, we present a series of review articles that highlight recent innovations and current challenges in the field. For decades, clinical research in CLL moved forward slowly, like an older dog, with chlorambucil therapy remaining the most widely used standard therapy. However, the introduction of rituximab and the development of chemo-immunotherapy awakened the field from hibernation, and in 2010, CLL suddenly became a hotbed for development of innovative new targeted drugs, which have now transformed CLL therapy. Over the last decade, these targeted therapies became the new therapy standard, based on a series of phase 3 trials that consistently demonstrated major progression-free survival advantage with the new agents as compared with the prior standard, chemo-immunotherapy. This special issue discusses the innovations in CLL, the new tricks that we were taught about CLL by the introduction of the new targeted therapies, which swept away chlorambucil and other aged treatments and concepts. Here, we summarize the content of this special CLL issue and put a spotlight on the progress and major remaining changes.
Major progress has been made in understanding CLL disease biology, pathogenesis, and genetic influences in CLL over the last two decades, especially recognizing the key role of B-cell receptor (BCR) activation and signaling in CLL pathogenesis. The importance of BCR signaling for normal B-cell development and adaptive immunity was already well established, before realizing that BCR signaling is also a crucial CLL cell growth and survival pathway. BCR signaling and other signaling cues are being activated in CLL cells by cross-talk with the tissue microenvironment within the secondary lymphatic tissues (lymph nodes, spleen), where proliferating CLL cells form characteristic “proliferation centers,” also termed “pseudo-follicles” . An update about the topic of CLL disease biology with a focus on the role of the tissue microenvironment and BCR signaling is covered in this special issue by Koehrer and Burger.
Yet, the most significant and dramatic progress in the CLL field over the last 10 years has been the development of new targeted therapies, resulting in a transition from chemotherapy-based regiment to “chemotherapy-free” targeted treatment as the new standard of CLL therapy in the frontline and relapsed disease settings . With this development, the prior standard chemo-immunotherapy regimen is now transitioning to retirement. Three families of drugs currently constitute the preferred therapies in CLL: Bruton tyrosine kinase inhibitors (BTKi), venetoclax, an antagonist of the antiapoptotic protein BCL-2, and monoclonal antibodies targeting CD20, which can be used in combination with the BTKi and/or venetoclax.
Integrating data involving phase 3 clinical trials which involve single agent or combination approach of these molecular/biological target drugs taught us several lessons regarding treatment approach. Several studies compared the use of two different anti-CD20 antibodies in CLL: rituximab and the newer antibody, obinutuzumab. Phase 3 clinical trials consistently demonstrated higher efficacy with use of obinutuzumab in combination with chemotherapy, venetoclax, or BTKi  in comparison to rituximab-based combinations. On the other hand, increased toxicity, i.e., infusion-related reactions and associated cytopenias is more commonly seen with obinutuzumab.
Ibrutinib is the first in class oral BTKi approved for patients with CLL . Ibrutinib fundamentally changed our treatment approach in CLL, from time-limited treatment with chemo-immunotherapy to long-term kinase inhibitor therapy. Currently, there are two newer “second generation” BTKi that are FDA approved: acalabrutinib  and more recently zanubrutinib . The cardiac safety profile favors the 2nd generation BTKi, based on randomized trials against ibrutinib. Despite these differences, long-term therapy data with ibrutinib are very favorable, demonstrating that CLL patients who receive first-line ibrutinib therapy have on overall survival that matches the survival of the age-matched normal population .
The development of the BCL-2 inhibitor venetoclax in CLL has brought time-limited therapy back to CLL in the era of the novel agents. Indeed, the use of venetoclax, normally in combination with anti-CD20  or, more recently, in combination with BTKi (not FDA approved) is generally administered for a limited period of time, often for 12–24 months .
The current challenge, with the new emerging drugs and the combinations, is to determine which therapy regimen is best for CLL subgroups, or even for all patients. Comparative phase 3 clinical trials, such as the CLL17 trial which compares ibrutinib long-term monotherapy with time-limited therapy with venetoclax plus obinutuzumab versus venetoclax plus ibrutinib, are in process and will help answer this key challenge.
Given the early success of venetoclax-based combination therapy as time-limited treatment, i.e., high rates of patients achieving deep remissions, the importance of testing for minimal residual disease, which has no significant role with BTKi monotherapy, came back to life, functioning as a marker for predicting remission duration after stopping therapy. Achievement of minimal residual disease-negative remission can be tested by different methods and sensitivity  and is a desirable endpoint with venetoclax-based time-limited combination therapy. This important topic is reviewed in this special issue by Dr. Al Sawaf.
Despite all progress with the new targeted agents in CLL, none of the current regimen has been demonstrated to be curative, and development of resistance to the BTKi and/or venetoclax is a growing clinical problem and topic of intense research. Resistance to the novel agents, in general, is much more frequent in patients who have had prior exposure to chemo-immunotherapy and TP53 alterations. The topic of drug resistance and the underlying mechanism as well as novel prognostic markers are discussed by Dr. Inhye.
Besides the issue of drug resistance in high-risk CLL, we also continue to see infections, complications, and secondary malignancies in our patients with CLL, and new methodologies such as machine learning may help us predicating these complications . Accelerated CLL and Richter’s transformation (RT), although rare and probably less frequent nowadays, with the decline in use of chemo-immunotherapy, continue to be an “unmet need” which requires our special attentions .
For patients who develop resistance to the targeted therapies or who develop disease transformation, cellular therapy remains the only therapy option with a chance of long-term survival. Therefore, new immunotherapies, especially autologous CAR T-cell therapy and also novel bispecific antibodies are being developed for CLL. Although the first reported successful use of CAR T-cell therapy in patients with relapse-refractory CLL occurred more than 10 years ago , development of this exciting approach in CLL has been challenging, and CAR T-cell therapy is not yet approved in CLL. Hence, allogeneic stem cell transplantation remains the standard cellular therapy in CLL. Cellular therapy options for CLL and RT are discussed by Dr. Beyar.
Last, but not least, is the SARS COVID-19 pandemics, which over the last 3 years have been the most important health challenge worldwide. This pandemic was particularly challenging for patients with CLL, who were at high risk for complications, hospitalizations, and death due to their immunosuppressive state . The challenges faced by CLL patients during the COVID-19 pandemic are summarized by Dr. Itchaki. This difficult era for our CLL patients taught us once again how vulnerable CLL patients are, and that we need to combine forces together with specialists from other areas, such as infectious disease, to improve supportive care and outcome. We can conclude that last decade has revolutionized our approach in the field of CLL therapy, with major improvements in long-term outcome and tolerability of treatments, but we still face important challenges that continued research to overcome immunosuppression and associated complications, drug resistance, and more effective therapies for high-risk CLL and especially patients with RT.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
There were no funding sources for the manuscript.
J.B. and T.T. participated in literature review and manuscript writing.
Editorial to the special topic issue “Chronic lymphocytic leukaemia (CLL) in the era of new targeted therapies” of Acta Haematologica.