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Zanubrutinib: A Better Medication For Chronic Lymphocytic Leukemias & Small Lymphocytic Lymphomas

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March 13, 2023

Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.

In two large clinical trials, zanubrutinib (tradename Brukinsa) outperformed Ibrutinib and Bendamustine-Rituximab, two common first-line treatments for Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL). This led to its swift approval by the FDA for clinical use in the community.

Zanubrutinib belongs to a class of medications called kinase inhibitors, which are highly targeted medications that can target and eliminate cancer cells while relatively sparing normal tissue, unlike chemotherapy. It inhibits Bruton’s tyrosine kinase (BTK), which are proteins expressed on the surface of certain WBCs. It plays a crucial role in the development and survival of normal WBCs. It additionally promotes the cancer cell growth in leukemias and lymphomas. BTK inhibitors bind to the BTK proteins, preventing them from supporting cancer cell growth.

RELATED: Changing the Way CLL is Treated: What are BTK Inhibitors?

What Is Chronic Lymphocytic Leukemia (CLL)? How is it Different From Small Lymphocytic Lymphoma (SLL)?

RELATED: Chronic Lymphocytic Leukemia (CLL): Overview

CLL and SLL are slow-growing cancers of the white blood cells (WBCs). WBCs are produced by the bone marrow but ultimately circulate within the blood and the lymphatic system. Bone marrow also produces other life-sustaining components of the blood including the red blood cells (RBCs), and platelets. Rarely, the bone marrow can erroneously rev up the production of one or more of its products. This is a recipe for the development of blood cancers. When cancers start in the cells that mature into WBCs, they are termed leukemias or lymphomas. The former term is used when most of the cancer cells occupy the bone marrow and/or the blood. The latter is used when most of the cancer cells populate the lymph nodes.

CLL is the most common leukemia in adults. It starts within the bone marrow, but these cells eventually spill into the bloodstream. In 2023, more than 18,000 cases of CLL will be diagnosed. It will cause more than 4,400 deaths within the same year. Overall, CLL accounts for about 25% of all new cases of leukemias. SLL is essentially the same disease as CLL, with the only distinction being that most SLL cells reside within the nodes of the lymphatic system. It comprises almost 7% of all lymphoma diagnoses.

Symptoms of CLL/SLL:

Many CLL or SLL patients do not show any signs or symptoms of their disease. They are only diagnosed by their physicians incidentally based on routine blood testing. Some patients, however, can experience symptoms that prompt a medical evaluation and workup, and eventually, lead to a diagnosis of CLL or SLL. These symptoms may include:

  • Fatigue
  • Fever
  • Night Sweats
  • Shortness of Breath
  • Easy bleeding and bruising
  • Frequent infections
  • Weight loss
  • Feeling full after eating small amounts of food
  • Swollen glands

Treatment of CLL/SLL:

RELATED: Chronic Lymphocytic Leukemia (CLL): Treatment

The treatment of CLL/SLL depends on the rate of cancer growth as well as the severity of a patient’s symptoms. If a patient has no to minimal symptoms, it is reasonable to defer treatment and pursue watchful waiting. This approach requires a patient to be diligently monitored by a physician through regular visits, laboratory testing, and imaging as indicated.

On the other hand, patients with symptoms or faster-growing cancers may require treatment right away. There are man first-line treatment options for CLL/SLL, such as the following immunotherapy and/or chemotherapy combinations:

  • Irubutinib with or without rituximab
  • Venetoclax with or without rituximab
  • Alemtuzumab

Chemotherapy drugs alone are also less frequently used to treat the disease. These drugs include:

  • Chlorambucil
  • Rituximab
  • Bendamustine

Oftentimes, CLL/SLL may relapse or become refractory to treatment. Such cases often require treatment with a different, novel combination of medications or new drugs altogether.

Clinical Trials Demonstrate Zanubrutinib’s Efficacy

The FDA approval of Zanubrutinib is based on the results of two phase-III clinical trials, the ALPINE and the SEQUOIA trials.

The ALPINE trial enrolled 652 patients with relapsed or refractory CLL or SLL who had received at least one prior course of treatment. These 652 ALPINE patients were randomly assigned to receive either zanubrutinib or ibrutinib. The investigators measured progression-free survival (PFS).The PFS at 24 months was 78.4% for the zanubrutinib and 65.9% for the ibrutinib group, a significant difference.

The SEQUOIA trial enrolled 590 patients with previously untreated CLL or SLL, who were randomly allocated to receive either zanubrutinib or bendamustine–rituximab. 24-month PFS was significantly higher for zanubrutinib than bendamustine–rituximab (85.5% vs. 69.5%).

The Side Effects Of Zanubrutinib

Zanubrutinib is generally well-tolerated and its side effects are usually mild. The most common side effects include:

  • Common cold-like symptoms
  • Constipation
  • Diarrhea
  • Nausea and Vomiting
  • Tiredness
  • Pains in bones, joints, muscles, neck, or back
  • Spasms in muscles
  • Headaches

Although unlikely, some people may experience serious and/or life-threatening side effects, which include but are not limited to:

  • Significantly elevated blood pressure that leads to headaches, dizziness, and changes in vision
  • Blood in bowel movements
  • Bleeding from the gums
  • Easy bruising and bleeding after minor traumas
  • Chest pain or pressure
  • Shortness of breath
  • Serious infections
  • Reactivation of hepatitis B in patients who carry the virus
  • Allergic reaction with symptoms such as rash, hives, swelling, itchiness, wheezing, and trouble breathing, among others.
  • Development of new cancers
  • Harm to unborn babies

Any of these side effects require medical evaluation and management, as indicated.

Key Takeaways:

  • Zanubrutinib is a new, effective drug for CLL or SLL that can significantly prolong progression-free survival for patients. In clinical trials, 78.4% of the patients did not experience any worsening of their disease 24 months after starting the medication.
  • Although generally well-tolerated, zanubrutinib can cause some serious side effects.
  • Patients can experience high blood pressure while taking this drug, especially if they are prone to this condition. It is important to monitor their blood pressure and manage as needed.
  • Zanubrutinib affects the bone marrow and its ability to produce normal, healthy cells required for essential blood function. Patients’ blood cell counts need to be monitored while they are receiving this drug.
  • This medication may cause easy bleeding and bruising, including bleeding from the gums. Therefore, patients should take extra care to avoid injuries. They should use a soft-bristled toothbrush and brush their teeth very gently.
  • Patients may be at an increased risk of contracting an infection while receiving the drug. Therefore, they must practice good personal hygiene and safety precautions.
  • If patients have had Hepatitis B in the past or carry this virus, they may be at an increased risk of the virus becoming active while receiving this medication.
  • Patients should use birth control while taking and for a short while after finishing or discontinuing Zanubrutinib. The medication may cause harm to unborn children.