Stephan Stilgenbauer, MD: The treatment options for chronic lymphocytic leukemia, or CLL, have dramatically changed in recent years. In the past, we had only chemoimmunotherapy, which is rather nonspecific and has several toxicities. In recent years, there has been the development of more targeted treatment options, which provide very high efficacy and good tolerability to patients. There are certain patient profiles that we must consider when selecting treatment. We must look at any comorbidities, comedications, and disease characteristics, such as genetic parameters of the leukemia cells.

With new treatment options available, the fitness of the patients, defined by renal function or other comorbidities, becomes less and less relevant. These treatments can be delivered safely and can also be used in older patients who have comorbidities.

Risk stratification is mainly based on genetic disease characteristics, such as the mutational status of the immunoglobulin genes; the IGHV mutational status, with unmutated IGHV genes conferring a worse prognosis; and other things such as 17p deletions or TP53 mutations. We know that patients with these abnormalities do not benefit at all from chemotherapy. Rather, they are prime candidates for novel treatment options that target BTK [Bruton tyrosine kinase] or BCL2. These options are particularly well suited for patients with high-risk genetic disease features such as an unmutated IGHV status, 17p deletion, or TP53 mutations.

Paolo Ghia, MD, PhD: When I consider treatment for patients who have high-risk features, I first identify what those high-risk features are.

When we consider how to care for a patient, we have to look for any TP53 aberrations, and it can be either a deletion or the 17p chromosome or mutation in the TP53 gene. Those are definitely the types of patients who we want to avoid giving immunochemotherapy to, because we know that these patients are resistant to immunochemotherapy. These patients should be treated with novel therapies only, either BTK inhibitors or BCL2 inhibitors.

On the other side, we may have a patient with unmutated immunoglobin genes, when we know that immunochemotherpy is not so effective. We know this patient doesn’t achieve longer remissions and continues to relapse after immunochemotherapy. For this type of patient, we prefer to use a novel therapy—a BTK or BCL2 inhibitor. The approach for this type of patient is less stringent, and it really depends on access to therapies. In Italy, for example, we don’t have access. The only therapy we can propose is immunochemotherapy. But for the unmutated patient, we tend to propose that the patient be enrolled in a clinical trial.

We know that patients with mutated immunoglobin genes have much better outcomes, even when treated with immunochemotherapy. For these patients, we discuss the pros and cons of chemotherapy. If they are young and fit, they can be treated with FCR [fludarabine, cyclophosphamide, rituximab]. On the other side they can be treated with novel therapies. We know that patients with mutated immunoglobin genes who are treated with FCR [fludarabine, cyclophosphamide, rituximab] can achieve a long, stable remission—up to 10 years—without progression. This is true in 3 of 4 patients with mutated immunoglobin genes. We don’t expect 100% of patients to respond. We know that immunochemotherpy is a fixed duration treatment. They are given 6 cycles of therapy, and then the patient can enjoy a treatment holiday. However, we also know the long-term consequences of immunochemotherapy, like acute leukemia, MDS [myelodysplastic syndrome], or the long-standing risk for infections.

On the other side, we have novel therapies, in particular BTK inhibitors. Continuous treatment can be a disadvantage, in particular for young patients, but we also know we can achieve long-term remissions and responses. We see that 70% of patients are free of relapse after 5 years of follow-up.

Transcript Edited for Clarity