Treatment Options in Chronic Lymphocytic Leukemia: A Global Perspective - Episode 2

Guidelines for Chronic Lymphocytic Leukemia

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Dr Brown and Dr Ghia discuss the European Society for Medical Oncology [ESMO] and International Workshop on Chronic Lymphocytic Leukemia [iwCLL] recommended guidelines in assessing and treating chronic lymphocytic leukemia.


Jennifer Brown, MD, PhD: The work-up of a patient with newly diagnosed CLL [chronic lymphocytic leukemia] includes confirming the diagnosis with flow cytometry according to iwCLL [International Workshop on Chronic Lymphocytic Leukemia] guidelines and then assessing their disease status. Patients who have early stage disease and are asymptomatic remain patients who we should observe. None of the new drugs or new trial results suggests that we should change our approach of watching and waiting for patients without active disease. In fact, many patients can go many years without needing therapy.

The criteria for treatment also remain the same. Most commonly, they include cytopenias or large faulty lymphadenopathy that is symptomatic. There are a variety of other indications as well, which includes autoimmune cytopenias that are hard to control.

Paolo Ghia, MD, PhD: In October 2020, the ESMO [European Society for Medical Oncology] guidance was updated, and this was expected because we had a lot of advancements and additions to the treatment in chronic lymphocytic leukemia. Indeed, the whole algorithms as shown in the ESMO Guidelines have completely changed. Now, the first criteria on which we are to base the certification of our patient is entirely genetic testing. On 1 side is the TP53 mutations or division, so that is a FISH [fluorescence in situ hybridization] test for the deletions of the initial 17p and sequencing for the detection of TP53 mutation. On the other side, there is also genetic certification based on immunoglobin and gene status. This is the first level. Based on this, we can choose who the patients are who can still benefit from immunochemotherapy. At the end, a minor portion of the patients are those with mutated immunoglobin genes. On the other side, the patient with unmutated immunoglobin genes, or TP53 and deletion, should be treated with novel therapies.

At that point, for this patient, we should evaluate the fitness of the patient. The fitness is a different concept from what we were using in the era of immunochemotherapy. It is more about comorbidities, such as the age of the patient. The possibility to better tolerate 1 or another novel treatment is probably based mostly on the comorbidities and polypharmacy: other drugs that patients are taking.

In the ESMO Guidelines, there is a much higher number of drugs and alternatives for our patients since a number of novel drugs have been approved or are on the way to being approved. Besides continuous treatment with ibrutinib, we also have the second-generation BTK [Bruton tyrosine kinase] inhibitor acalabrutinib, and for the first time we have a fixed-duration treatment like venetoclax with obinutuzumab. It is approved in the first-line setting for 12 months of treatment or venetoclax plus rituximab, which is approved for 24 months in the relapsed/refractory setting. In the relapsed/refractory setting, these are all first-line treatments.

In the relapsed/refractory setting, the ESMO Guidelines have also been updated. Not much is new; the major criterion to decide therapy in the relapsed/refractory setting is still based on the length of response to the first-line treatment. We can see patients who carried the division 17p or PC3 mutations, and these patients should avoid being treated with immunochemotherapy. We then have patients who responded for less than 36 months, and these patients are considered refractory to the previous lines and not well responding; therefore, they should again avoid the use of immunochemotherapy.

A portion of patients have a long remission: a longer response of more than 36 months. These patients are probably the only subset of patients for whom we can propose a second-line treatment based on immunochemotherapy with a minimal exception. First, FCR [fludarabine, cyclophosphamide, rituximab] should not be repeated. It is now well defined in the ESMO Guidelines that FCR [fludarabine, cyclophosphamide, rituximab] is not advisable to be repeated because it is too toxic for bone marrow function. Therefore, if we consider a patient who has more than 36 months of response to the first-line chemotherapy, we remain with few options because this is not achievable with chlorambucil-based treatment; with bendamustine, that is quite rare. In the setting of a patient who achieves a longer remission with immunochemotherapy, the option of novel therapy remains to be considered strong.

The iwCLL guidelines are different because they refer how to diagnose CLL where it indeed strongly recommends that we have to perform an immunophenotype. Of course, we have known for many years if not decades that the diagnosis of CLL should be made only after looking at the immunophenotype to see the expression of the typical markers. It is not based only on the white blood cell count any more.

Second, we do not need to do a bone marrow biopsy for diagnosis because it is not adding anything to the diagnosis by definition. Leukemic cells from CLL are already present in the bone marrow. Third, we can follow that, and we do not need the radiologic assessment. In fact, we could use physical exam only. In addition, you can use a chest x-ray or abdominal ultrasound because this is enough to assess if lymph nodes are present.

It is for this simple reason that the iwCLL guidelines tell us how and when to treat the patient. It is not only when the disease is progressing. We also have a clear criterion that tells us when the moment to start initiating the treatment is. These are clear criteria, with the major 1 being either the presence of anemia or thrombocytopenia due to the invasion of the bone marrow by the leukemic cells. Second is having bulk lymph nodes, which in the chronic lymphocytic leukemia are those more than 10 cm in size. The third is being refractory to corticosteroids when having an autoimmune manifestation like hemolytic anemia or autoimmune thrombocytopenia.

In addition, we can also have other criteria—usually a companion anemia, thrombocytopenia, or bulk lymphadenopathy, symptoms like fatigue, weight loss, night fever, and night sweats. On the other side, there is also the increasing lymphocyte count, in particular the doubling of the lymphocyte count, which is again a criteria that should be considered only when the major criteria are present. In any case, in the presence of these symptoms or lymphocyte doubling, we always have to think about other reasons and causes, particularly when they are isolated.

The iwCLL guidelines also provide the criteria for how to treat the patient and the time of treatment needed. In this case, they underscore the relevance of the mutation metastasis or the immunoglobin genes as well as the status of the TP53 gene, either the deletion or mutation, to decide and define the best therapy for our patient. The iwCLL is also indicating the strategy for the treatment, but we have to consider the iwCLL guidelines more as a general overview for how to manage patients with chronic lymphocytic leukemia.

Another important point is that the iwCLL guidelines underscore that, for the vast majority of patients—not all patients—a period of wait and watch is strongly recommended. It is rare that the patient needs the treatment and the therapy right at diagnosis. In addition, at the moment, there is no evidence that preemptive treatment can be more beneficial for patient compared with the wait-and-watch approach.

Transcript Edited for Clarity