Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by the clonal expansion of small mature-looking CD19+, CD23+, and CD5+ B cells that accumulate in the blood, bone marrow, and lymphoid organs.1 It is the most common form of leukemia found in adults in Western countries. In 2022, the estimated new number of CLL cases in adults and children was 20,160 (12,630 in males; 7530 in females).2 Patients with CLL present with a wide range of signs and symptoms and the course of the disease is highly variable, ranging from a slow, indolent course to rapid disease progression. Onset may be insidious and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason.3 In fact, most patients are diagnosed with CLL incidentally after routine blood work shows absolute lymphocytosis, while others may experience painless lymphadenopathy or present with symptoms caused by splenomegaly or cytopenias.  

Counseling patients diagnosed with CLL poses a unique challenge for clinicians because of the variability of its course and the growing array of treatment options. Even though mortality rates have been declining, CLL is estimated to have caused 4320 deaths in 2021. The 5-year relative survival of patients with CLL has dramatically improved in the past 4 decades, from 65.1% in 1975 to an estimated 87.2% in 2021.4 This leukemia remains a chronic disease and most patients will eventually relapse on or after treatment and will require multiple lines of therapy.5 While treatment has dramatically improved and survival has been prolonged, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been declining in CLL.6 Combinations of targeted agents are now being investigated to create efficient, potentially curative therapies for CLL with fixed duration.7

When to Treat

The goal of CLL management is to maintain the best quality of life and treat only when patients become symptomatic from their disease.7,8 Unlike other hematologic malignancies, CLL is a long-term, slowly developing leukemia. Thus, the emphasis on a risk-stratified approach to treatment: those at high risk are treated promptly and those at lower risk are not unnecessarily exposed to toxicity. A number of prognostic factors have been identified that can help clinicians predict time from initial diagnosis to time of treatment initiation as well as help identify patients more likely to require early treatment.7

Two widely accepted clinical staging systems, the Rai and Binet staging systems, have been previously used. Similar to one another, these systems were developed 30 to 35 years ago and are simple and inexpensive and do not require the use of imaging. They use modalities such as blood counts and physical examination to identify 3 major prognostic subgroups.9 The drawback is that these staging systems do not fully reflect the high variability of CLL or the known biologic characteristics of CLL cells that are predictive of survival and treatment response.7 In addition, during the past 3 decades, a rapidly growing number of potential biomarkers have been identified that provide prognostic information independent of the clinical stage.

As a result, new comprehensive prognostic scores have been developed that combine clinical, biologic, and genetic information, with the most relevant currently being the CLL International Prognostic Index (CLL-IPI, Table 1).10 It uses a weighted grading of 5 independent prognostic factors — TP53 deletion and/or mutation (TP53 dysfunction), immunoglobulin heavy-chain variable (IGHV) gene mutational status, serum β2-microglobulin, clinical stage, and age — and then identifies 4 risk groups defined by significantly different overall survival at 5 years. The prognostic value of the CLL-IPI will need to be revisited as the number of clinical trial results with targeted agents continues to increase and studies with longer follow-up periods become available.7

Initiating CLL Treatment

Treatment should be initiated when patients progress or present with progressive or symptomatic/active disease.7 The International Workshop on CLL (iwCLL) updated its guidelines in 2018 and offered parameters on treatment initiation.11,12

Any of the following criteria should be met to initiate CLL therapy11,12:

  • Progressive marrow failure, hemoglobin <10 g/dL or platelet count of <100 x 109/L
  • Massive (≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly
  • Massive (≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
  • Autoimmune complications of CLL that are poorly responsive to corticosteroids
  • Symptomatic extranodal involvement (eg, skin, kidney, lung, spine)
  • Disease-related symptoms, including unintentional weight loss of ≥10% within the previous 6 months, significant fatigue, fever ≥100.5 ⁰F for 2 or more weeks without evidence of infection, night sweats for ≥1 month without evidence of infection

With an ever-widening array of treatments and combinations, the selection of first-line therapy is being increasingly individualized based on the patient’s individual profile. The disease is primarily diagnosed in older adults, with a median age of 72 years, and comorbidities are frequently present in older patients. The presence of multiple comorbidities (≥2 comorbidities) is an independent predictor of clinical outcome, independent of age or disease stage.13 However, age, performance status, comorbidities, and the presence or absence of deletion of the long arm of chromosome 17p — del(17p) — or TP53 mutation will all help direct treatment planning.

These parameters should be considered before recommending a treatment regimen for CLL14:

  1. The clinical stage of the disease
  2. The patient’s presenting symptoms
  3. Patient fitness and comorbidities; especially in regard to the toxicity profiles of the newer, targeted agents
  4. The genetic risk of the leukemia
  5. The treatment situation (first- vs second-line, response vs nonresponse to the last treatment)

In addition to clinical parameters, molecular biomarkers have been identified that can provide insight into the underlying pathogenesis of the disease as well as serve as predictors of time to progression, time to need for therapy, and overall survival. Prior to initiating therapy, both fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) panels should be performed. Molecular and cytogenetic results are becoming increasingly relevant for prognosis and therapy selection.8,12,15

High-risk features predictive of disease progression include del(11q) and del(17p), TP53 mutations, IgVH unmutated status, use of the IGHV3-21 gene segment, and expression of ZAP70 or CD38.7,15,16 For example, del(17p)/TP53 alterations are the most important prognostic and predictive markers for treatment decisions in CLL as they have been shown to demonstrate resistance to standard chemoimmunotherapy such as fludarabine, cyclophosphamide, and rituximab.7,13

The toxicity profile of the different therapies and the duration of treatment (continuous vs fixed duration) also need to be considered when selecting first-line therapy. For example, Bruton tyrosine kinase inhibitors (BTKis) are given continuously until disease progression while venetoclax-based combination regimens have a specific course of treatment.7,13 Patient preference needs to be taken into consideration; in this case, BTKi therapy could continue for years, raising the risk of adverse events and financial burden.

Second-Line Therapy

The options for managing patients after initial treatment is again dependent on many factors such as the duration of remission and the patient’s physical fitness. One rule is that first-line therapy may be repeated if the duration of the first remission exceeds 36 months.7 However, for treatment-refractory CLL, defined by an early relapse within 6 months, the initial regimen should be changed and more potent therapies used.

As with first-line therapy, the choice of second-line therapy may also depend on the molecular risk profile and the fitness and comorbidity of the patient, especially in regard to the potential side effects of some of the newer agents.7 Transplantation may also be an option for physically fit patients with refractory CLL or with del(17p). Participation in clinical trials should also be encouraged if possible to patients with refractory disease. Table 2 lists currently available therapy for CLL.7,3

Treatment Side Effects

The management of treatment side effects is a key component of the treatment plan. In addition to managing nausea, vomiting, fatigue, and hair loss, many of the newer agents used in the treatment of CLL have the potential to cause neutropenia, thrombocytopenia, anemia, organ toxicity, and other adverse reactions.1 Therefore, the choice of first-line treatment for patients with CLL, including those with high-risk features, is largely patient-specific including appropriate management of treatment-emergent adverse events.

Is allo-HSCT still relevant? Allo-HSCT has been considered the treatment of choice for high-risk patients with CLL and traditionally was the only strategy that could produce a cure.8 However, with the advent of novel agents and new treatment combinations, allo-HSCT is rarely performed.17,18 Novel agents are being increasingly used in combination and earlier in the disease course; allo-HSCT may continue to have a role for patients who become resistant/refractory and are intolerant to or do not have access to these agents.7,8


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