Chronic Lymphocytic Leukemia: 5 Things to Know

Kate M. O'Rourke


September 24, 2019

B-cell chronic lymphocytic leukemia (CLL)—characterized by the accumulation of small, mature-appearing lymphocytes in the blood, bone marrow, and lymphoid tissues—is the most common form of leukemia affecting adults, representing up to 30% of cases worldwide.[1,2,3]

CLL involves signaling via surface immunoglobulin (the major part of the B-cell receptor), genetic alterations, and interactions between CLL cells and other cell types, such as stromal cells, T cells, and nurse-like cells in the lymph nodes.[3,4] CLL can be preceded by a precursor phase, monoclonal B-cell lymphocytosis, where low levels of cells phenotypically identical to CLL are found in the circulation.[4]

Here are five things to know about this malignancy, from its pathogenesis and progression to emerging treatments and remaining causes for concern.

1. Although the cause of CLL is unknown, genetic factors contribute to it.

Roughly 10% of patients with CLL will have a relative with the disease, and first-degree relatives of patients with CLL have an 8.5-fold increased risk of developing the malignancy.[3]

CLL is rare in Asians, a currently mysterious finding that may one day reveal important facets of this disease's etiology and biology.[5]

Genomic alterations in CLL can include chromosomal alterations, mutations, alterations in the expression of microRNAs, and epigenetic modifications, some of which can be used to determine prognosis and guide management strategies.[3] Single nucleotide polymorphisms in nearly 30 loci have been associated with familial CLL.[3] Patients with mutations in the 3' untranslated region of NOTCH1 and those with nonsynonymous mutations that alter the amino acid sequence of NOTCH1 have worse overall survival.[3]

2. CLL's clinical progression is variable and aided by new treatments.

Some patients with CLL require treatment soon after diagnosis, others do not require it for years, and 30% never require therapy.[3,6]

The degree of mutation of the genes encoding the immunoglobulin heavy chain clonotype of the B-cell receptor is one of the most robust prognostic tools for the disease. Unmutated CLL has a more aggressive disease course, and mutated CLL is more indolent.[4] Patients with asymptomatic early-stage CLL and those with disease unlikely to progress are usually not offered treatment, but as new, relatively low-toxicity drugs become available, the time to first treatment for early-stage disease is likely to change.[7,8]

Combination chemoimmunotherapy regimens are frontline therapy for CLL, with chlorambucil the standard for patients older than 65 years, but frontline therapy is shifting to chemotherapy-free regimens.[9]

Additional treatments for CLL include the monoclonal antibodies rituximab, ofatumumab, and obinutuzumab; the PI3K-delta small-molecule inhibitor idelalisib and dual PI3K-delta and PI3K-gamma inhibitor duvelisib; targeted therapies aimed at Bruton tyrosine kinase, such as ibrutinib and the investigational agent acalabrutinib; and the BCL2 selective inhibitor venetoclax.[9,10]

A number of approvals granted by the US Food and Drug Administration (FDA) have also changed the treatment landscape for CLL in recent years. Idelalisib was approved by the FDA in 2014 for relapsed CLL.[11] Ibrutinib monotherapy, a once-daily oral pill, was approved in 2014 in patients with CLL who have received at least one previous therapy and in 2016 for frontline CLL therapy.[12] In 2018, duvelisib was approved for refractory CLL.[13] Early in 2019, the FDA approved the first nonchemotherapy combination regimen for treatment-naive patients with CLL: ibrutinib plus obinutuzumab.[8]

3. Encouraging results have been noted with CAR-T cells.

Therapy with genetically engineered chimeric antigen receptor T (CAR-T) cells is rapidly migrating to clinical applications and showing promise, particularly for patients with a poor prognosis.[14,15] A recent prospective clinical trial demonstrated that in patients not achieving a complete response despite at least 6 months of ibrutinib, anti-CD19 CAR-T-cell therapy achieved a complete response rate of 43% and a bone marrow remission rate of 94%.[15]

The therapeutic association of CAR-T cells with ibrutinib appears to be particularly promising.[14] In patients who do not respond to newer CLL agents, CAR-T therapy provides a new opportunity that could not only replace allogeneic hematopoietic cell transplantation in patients who would have been eligible but also be extended to older patients with limited comorbidities.[14]

In the future, CAR-T therapy may also directly compete with targeted therapies, which must be administered over the long term and come with the barriers of toxicity, cost, and compliance.[14]

4. Fatigue is a major concern for patients with CLL.

Fatigue, which predicts worse physical and mental health, affects 20%-70% of CLL survivors.[16,17,18,19] Although fatigue is one of the most common symptoms of CLL, it is also one of the most commonly overlooked and undertreated.[19]

In patients with CLL, fatigue may be related to the cytokines and enzymes that are released by white blood cells in response to inflammation.[20]

5. CLL can transform into more aggressive diseases.

CLL can transform into clonally related or unrelated diffuse large B-cell lymphoma (Richter syndrome), Hodgkin lymphoma, or rare interdigitating dendritic cell sarcoma, all of which have an aggressive disease course that does not respond well to therapy.[21,22]

Transformation to Hodgkin lymphoma is observed in roughly 0.5% of patients. Interdigitating dendritic cell sarcoma is even rarer.[21,22] Transformation to Richter syndrome, seen in 5%-10% of patients with CLL, may be caused by viral infections, such as Epstein-Barr virus infection, which is common in immunosuppressed patients.[23,24]

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