Role of Targeted and Immunotherapy in the Chronic Lymphocytic Leukemia Treatment

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What is the role of targeted therapy in the treatment of CLL?

Chemotherapy with or without immunotherapy has been the mainstay of CLL treatment for many years. The development of targeted therapy (e.g. ibrutinib and idelalisib) has provided a better treatment option in this regard and has transformed the CLL treatment landscape both in first- and second-line settings.

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With the advancements in diagnostic techniques, there has been a significant improvement in the understanding of the disease genetics and various disease prognostication indices have been developed. Various genetic markers have been identified that can modify the disease prognosis independently. This has helped in the development of a variety of targeted agents. Currently, a number of targeted agents have received approved for the treatment for CLL (as discussed below).

Currently, following targeted drugs have received US FDA approval and are being employed for the treatment of CLL:

Ibrutinib:

Ibrutinib is an orally active, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an enzyme involved in the B-cell receptor (BCR) signaling that supports the B-cell survival and proliferation.

Ibrutinib was initially approved for the treatment of patients with relapsed or refractory CLL, but it has now gained approval to be used in first-line settings, especially for patients with del(17p) or TP53 mutation.

Single-agent therapy with Ibrutinib is recommended to be employed for the treatment of patients with significant comorbidity, those who are frail (cannot tolerate chemotherapy), and for patients with age >/=65 years or younger with significant comorbidities.

It is also recommended for the treatment of patients with the relapsed or refractory disease, regardless of patient’s age and comorbidities. It is now considered a standard treatment for patients with del(17p) or TP53 mutation-positive CLL both as first-line therapy or for the relapsed/refractory disease.

Ibrutinib may cause an initial transient increase in absolute lymphocyte count that does not indicate a disease progression and may persist for several weeks. It may cause side effects like bleeding, atrial fibrillation, hypertension, skin rash, diarrhea, fatigue, and invasive fungal infections.

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Acalabrutinib:

Acalabrutinib is a second-generation BTK inhibitor that has been approved for the treatment of patients with relapsed or refractory CLL regardless of age, comorbidities, and adverse prognostic factor like del(17p).

Of note, acalabrutinib is not helpful in the treatment of ibrutinib-resistant CLL with BTK C481S mutations, one of the common reasons for the development of resistance against ibrutinib treatment.

Acalabrutinib is not recommended to be included in the first-line settings. Common side effects associated with the drug include hypertension, atrial fibrillation, and headaches.

Idelalisib:

Idelalisib is an orally active, p110 delta (δ) isoform-selective inhibitor of phosphoinositide-3 kinase (PI3K), an enzyme involved in B-cell activation, proliferation, and survival. As the isoform is specific for B lymphocytes, idelalisib selectively controls the growth of B-lymphocytes, leaving the other blood cells unaffected.

Idelalisib, in combination with rituximab, has been approved by US FDA for the treatment of patients with relapsed or refractory CLL, regardless of patient’s age and comorbidities.

The combination of idelalisib and rituximab was also found effective for the treatment of patients with adverse prognostic factors, like del(17p) or TP53 mutations, ZAP70, CD38 expression, unmutated IGHV, and elevated beta-2 microglobulin (>4 mg/L).

Single-agent therapy with Idelalisib may be helpful for some patients with relapsed/refractory disease and may be employed regardless of age or comorbidities in this setting. Of note, Idelalisib is not included in first-line settings and is only approved for the treatment in second-line settings.

Side effects of idelalisib include liver toxicity, elevated liver function tests, diarrhea or colitis, pneumonia, abdominal pain, intestinal perforation, nausea, fatigue, cough, low blood cells count, and infections including cytomegalovirus (CMV) reactivation.

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Duvelisib:

Duvelisib is an orally active, selective inhibitor of PI3K3γ and PI3Kδ isoforms that suppress B-cell proliferation and promotes apoptosis in CLL cells.

Single-agent therapy with Duvelisib is recommended for the patients with relapsed or refractory CLL irrespective of age, significant comorbidity, or unfavorable prognostic factors like del(17p)/TP53 mutation.

Currently, duvelisib is not indicated in the first-line setting. Side effects associated with the drug include hepatotoxicity, diarrhea, colitis, pneumonia, skin reactions, and infections.

Venetoclax:

Venetoclax is an orally active, selective inhibitor of B-cell leukemia/lymphoma-2 (BCL2) protein, a protein found to be involved in the B-cell apoptosis and cancer development.

Venetoclax has been approved as a single-agent therapy or in combination with rituximab for the treatment of patients with relapsed or refractory CLL who have received prior treatment with ibrutinib or idelalisib, regardless of patient’s age, comorbidities, and del(17p)/TP53 mutation status.

It is not currently included in the first-line treatment settings; however, clinical trials are exploring its utility in combination with other targeted agents for untreated CLL patients.

Tumor lysis syndrome (TLS), a syndrome caused by the mass destruction of leukemia cells that release their constituents in the blood leading to kidney failure, was observed in some patients treated with venetoclax. Other side effects associated with the drug include low blood cells count, nausea, diarrhea, and upper respiratory tract infection.

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What is the role of immunotherapy in the treatment of CLL?

Immunotherapy works by stimulating the body’s immune system to identify and kill cancer cells. Immunotherapy employing a number of monoclonal antibodies in conjunction with several chemotherapeutic agents has been standard of care for the treatment of CLL for many years. With the development of newer immunotherapeutic agents, the treatment landscape of many cancer types including CLL has been revolutionized.

Following is the list of various immunotherapeutic agents currently approved for the treatment of CLL:

Rituximab:

Rituximab is a CD20 targeted monoclonal antibody that binds to and inactivates CD20, a protein expressed on the surface of B cells. The CD20-protein does not have a natural ligand and its exact function is unknown. However, monoclonal antibodies directed towards CD20-protein cause reduction in the number of malignant B-cells.

Rituximab was one of the first targeted monoclonal antibody approved by the US FDA (in 1998) for any cancer. Initially, it was approved for the treatment of CD20-positive non-Hodgkin lymphomas (NHLs).

It was subsequently approved (in 2010) as the first-line treatment for CLL in combination with chemotherapy. Since then, rituximab in combination with chemotherapy has become standard of care for the management of patients with CLL, irrespective of age or presence of comorbidities, and del(17p)/TP53 mutation status.

It has also been approved for the treatment patients with relapsed or refractory disease in combination with targeted agents or chemotherapeutic agents. The wide application of this drug marked the initial shift of the CLL treatment landscape from chemotherapy to chemoimmunotherapy.

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Obinutuzumab:

Obinutuzumab is a type II monoclonal antibody that works differently than rituximab for blocking CD20 receptor expressed on the surface of B-cells resulting in greater destruction of CLL cells.

Due to its superior efficacy, it is now preferred over rituximab (in combination with chemotherapy) for the first-line treatment of patients with CLL, irrespective of age or presence of comorbidities, and del(17p)/TP53 mutation status. Also, it may be used as a single-agent treatment for selected patients who cannot tolerate chemotherapy in both first-line or second-line therapy.

Ofatumumab:

Ofatumumab is a second generation, type I anti-CD20 monoclonal antibody with increased efficacy (compared to rituximab) in some patients who have not responded to rituximab and in patients who have low CD20 expression level for their CLL cells.

Similar to rituximab and obinutuzumab, it can be employed (in combination with chemotherapy) for the first-line treatment of patients with CLL, irrespective of age or presence of comorbidities. It can also be employed as a single-agent treatment for the management of relapsed or refractory disease irrespective of del(17p)/TP53 mutation status.

Recently, ofatumumab was also approved as the maintenance treatment for patients with relapsed or refractory CLL who achieved complete or partial response after at least two prior lines of therapy. Common side effects of ofatumumab include low blood cell counts, infections, infusion reactions, and pneumonia.

Alemtuzumab:

Alemtuzumab is a monoclonal antibody that targets the CD52 antigen found on the surface of B-cells, T-cells, natural killer cells, eosinophils, dendritic cells, and macrophages.

Alemtuzumab may be employed as a single agent or in combination with rituximab for the treatment of relapsed or refractory CLL with or without del(17p)/TP53 mutation. In combination with rituximab, it can be employed for the treatment of del(17p)/TP53 mutation-positive CLL in the first-line setting.

The most common side effects associated with alemtuzumab are chills, fever, nausea, very low white blood cell counts, infection (especially with CMV), and infusion reactions.

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Lenalidomide:

Lenalidomide is a second-generation thalidomide-analog that has immuno-modulatory properties. It can reverse the T-cell dysfunction associated with CLL. Also, it causes the reduction in T-cell checkpoint protein (PD-1) and its ligand (PDL-1) expressed on the surface of the CLL cells.

It has been approved in combination with rituximab for the treatment of patients with relapsed or refractory CLL irrespective of patient’s age, comorbidities, and del(17p)/TP53 mutation status. It can also be employed as maintenance therapy in high-risk patients who have received prior single line chemo-immunotherapy or have achieved CR or PR after two line of treatment.

The most common adverse event associated with the drug is “tumor flare”– an acute swelling of lymph nodes and in the overlying skin, rash, and fever. Other common side effects include skin problems, gastrointestinal disorders, and infections.

Immune Checkpoint Inhibitors like pembrolizumab and nivolumab have shown activity in patients with Richter’s transformation refractory to chemotherapy or targeted therapy.

Similarly, adoptive T-cell therapy, directed towards CD19-surface protein and/or other proteins expressed on the surface of CLL cells, have demonstrated exciting results in different clinical trials. Additionally, the genetically modified CART cells persist for many years that is advantageous to eradicate the minimum residual disease (MRD) in patients with high-risk features. Considering the potential clinical application of CART therapy for the treatment of leukemia it may soon be incorporated into clinical practice for the treatment of CLL.

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