Micrograph showing CLL
Recent advances in chronic lymphocytic leukemia (CLL) have prompted an update to the 2008 International Workshop in Chronic Lymphocytic Leukemia (iwCLL) consensus guidelines.
The updated iwCLL guidelines include new information on genomic alterations, the use of clinical staging and prognostic markers/scores, response assessment, minimal residual disease (MRD), and viral diseases in CLL patients.
The update was recently published in Blood.
Diagnosis, prognosis, and staging
To verify CLL diagnosis, the iwCLL guidelines recommend obtaining complete blood counts and differential counts as well as immunophenotyping of peripheral blood lymphocytes. A panel of CD19, CD5, CD20, CD23, κ, and λ typically suffices to establish a diagnosis.
Other tests that may help in prognosis or assessing tumor burden include molecular cytogenetics for del(13q), del(11q), del(17p), and add(12) in peripheral blood lymphocytes and determining TP53 and IGHV mutational status.
These tests can help identify poor-prognosis patients who are not likely to benefit from standard chemotherapy but are likely to benefit from small-molecule inhibitors of BTK, PI3K, or BCL2.
In addition, serum markers such as β2-microglogulin provide insight into overall survival and progression-free survival.
With regard to clinical staging, the guidelines highlight the Binet and Rai systems, which are routinely used in clinical practice and clinical trials.
However, the guidelines also note that “there are a large number of biomarkers that can provide additional prognostic information,” and, recently, “several prognostic scores and stratification systems have been proposed based on multivariate analyses.”
For example, the CLL international prognostic index (CLL-IPI) provides a weighted score that uses clinical stage, age, IGHV mutational status, β2-microglogulin, and the presence of del(17p) and/or TP53 mutations.
Indications for treatment
The guidelines note that active disease must be documented to initiate therapy. At least 1 of the following criteria must be met:
- Evidence of progressive marrow failure
- Massive, progressive, or symptomatic splenomegaly
- Progressive/symptomatic lymphadenopathy or massive nodes
- Progressive lymphocytosis
- Autoimmune complications
- Extranodal involvement
- Disease-related symptoms (unintentional weight loss, significant fatigue, fevers, night sweats for over a month without evidence of infection).
Following relapse, subsequent lines of treatment should follow the same principles as those used for initial treatment decisions.
Response, MRD, and more
The guidelines say 2 groups of parameters must be assessed to determine response to therapy:
- Group A: lymphoid tumor load and constitutional symptoms, including liver and/or spleen size, lymph node evaluation, and circulating lymphocyte count
- Group B: the hematopoietic system (platelet count, hemoglobin, and marrow).
For therapies with a defined treatment duration, response should be assessed at least 2 months after treatment is completed. For continued therapies or maintenance, response should be assessed at a predefined time point or at least 2 months after patients achieve their maximum response.
The guidelines also say MRD should be assessed in clinical trials aimed at maximizing the depth of remission. Furthermore, it “may be important” to confirm MRD negativity in the blood and marrow, as there are therapies that preferentially clear the blood but not the marrow (such as monoclonal antibodies).
In addition to the aforementioned recommendations, the updated iwCLL guidelines also include information on patient eligibility for clinical trials, guidance regarding treatment-related toxicities, and recommendations for supportive care and managing complications.