CLL: When to Initiate Frontline Therapy

Javier Pinilla-Ibarz, MD, PhD: In chronic lymphocytic leukemia, there is a specific situation—very well documented by iwCLL criteria described years ago in a Blood paper, as well also containing the NCCN guidelines—that will really describe the situation where a patient should receive therapy for chronic lymphocytic leukemia. In general, we summarize this condition as the presence of anemia, low platelets, enlargement of the lymph nodes to really, really bulky size, or enlargement of the spleen, and we also can be including patients who have an autoimmune hemolytic anemia refractory to treatment with steroids. Finally, the presence of B-cell symptomatology, very common in lymphomas in general, such as weight loss, low-grade fevers, extreme fatigue, and drenching night sweats also will be reason for which sometimes patients require therapy.

In the past 5 years, there are many more alternatives for the frontline treatment of patients with chronic lymphocytic leukemia. We went from chemotherapy to chemoimmunotherapy to, these days, the availability of targeted drugs. The question is how we decide and how we stratify patients to really receive the best therapy in each case. And in this case, what is very important is also very well pointed out in NCCN guidelines. No. 1 is the presence or absence of 17p deletion. The presence of 17p deletion, today in current NCCN guidelines, would prompt the administration of targeted therapies with a BTK inhibitor, in this case, ibrutinib. If the patient presents with a non-17p deletion, I think IGHV mutational status plays a very important role on how we’re going to really manage this patient in the future.

At this point, another important factor will be the age, younger age or older age. Obviously, younger age, most of the time, is fit patients, while older age has multiple comorbid conditions. In this case, in younger patients with no comorbid conditions and with the presence of IGHV-mutated disease, we still discuss with them the chemoimmunotherapy treatment with a classical regimen of fludarabine/Cytoxan/Rituxan. However, and in general, when a patient has unmutated IGHV mutational status, more and more they can be offered treatment with a Bruton tyrosine kinase, or BTK inhibitor. In this case, that’s ibrutinib.

However, in this discussion of older patients or younger patients with unmutated immunoglobulin, another important factor is the duration of therapy. Today, ibrutinib, a BTK inhibitor, is being given until disease progression or unacceptable toxicity. In some patients, for different reasons, it could be finance and toxicity, side effects; they are not really likely to really stay on drug for life, so they may opt, in some cases, to even have chemoimmunotherapy or in older cases, a classical combination of monoclonal antibodies, anti-CD20, such as obinutuzumab, ofatumumab, or rituximab with chlorambucil that is also a category 1 NCCN for therapy of older patients, more than 65 years of age with multiple comorbid abnormalities.

Finally, the use of bendamustine/Rituxan (BR) also can be discussed in patients more than 65 years of age who may not have many comorbid conditions but they are really interested in a limited therapy for the control of this condition, even though we know the progression-free survival of this regimen included in the monoclonal antibody with chlorambucil and BR is significantly shorter than patients who really take ibrutinib in the long run.