Ibrutinib For Mantle Cell Lymphoma

What is a Lymphoma?

A lymphoma is a type of cancer that starts with the body’s white blood cells (WBCs), also called lymphocytes. WBCs are produced in the bone marrow, which is the tissue that lines the insides of many of our long bones, including the hip bones and the vertebral column.

Broadly, cancers of the WBCs are termed leukemias or lymphomas. Their names signify the location of the involved cancer cells. In leukemia, the cancer cells occupy the bone marrow and the blood. In lymphoma, the errant cells take up residence within the lymph nodes and the lymphatic system. They can often form masses that can be seen or felt in lymphoma patients.

The lymphatic system or tissue is an extensive network within the body. It consists of lymph nodes, which are rounded, bean-shaped collections of WBCs. These nodes are extensively interconnected through lymphatic channels. Lymph tissue is also found in the spleen, bone marrow, thymus gland, and gastrointestinal tract, among other locations. Lymphomas can start in any of these locations.

Mantle Cell Lymphoma: A Type of Non-Hodgkin Lymphoma

Non-Hodgkin Lymphoma (NHL) is a collection of lymphomas that share some common features and are treated similarly. About 5-6% of all lymphomas are mantle cell lymphomas (MCLs). MCL starts within the outer rim or the so-called mantle zone of a lymph node. Unfortunately, MCL is one of the more aggressive types of NHL. It is, however, a rare disease, affecting only 1 in 200,000 individuals per year. Men in their 60s and 70s are most at risk.

MCL tends to be diagnosed at later stages, when it is widespread within the lymphatic system and involves other organs, such as the spleen and the bone marrow. It tends to progress more quickly than other lymphomas. These factors make it a challenge to treat. Oftentimes, it can be resistant to traditional treatments, which further exacerbates the challenge. It has traditionally been treated with chemotherapy followed by an ASCT and maintenance therapies, usually consisting of an immunotherapy drug, such as rituximab. It can be a toxic course of action, which can significantly worsen patients’ quality of life. Newer, more effective treatment strategies for MCL are, thus, the need of the hour.

“ASCT is a procedure where your own [healthy bone marrow cells] are taken out of your body, you receive high-dose chemotherapy [to kill off the cancer cells], and you are rescued by having your cells given back to you,” explains Dr. Catherine Diefenbach, Director of the Clinical Lymphoma program at Perlmutter Cancer Center. She continues, “For this procedure, you stay in the hospital for 10-14 days and you have toxicities related to the high-dose chemotherapy. This carried the highest and best chance for long-term disease-free control.”

A Potential Gamechanger: The Triangle Study

The Triangle study is a phase 3 clinical trial. Phase 3 clinical trials pit new treatment strategies against standard therapies to see which one is better. It is the most rigorous litmus test for any new treatment option. The primary goal of this study was to measure failure-free survival, which is defined as survival without disease or disease progression at the end of treatment.

The study recruited almost 900 patients from 14 different primarily European countries. These patients were randomly assigned to receive one of three treatments: A, standard chemotherapy followed sequentially by ASCT and rituximab maintenance therapy; B, standard chemotherapy with ibrutinib followed by ASCT and 2 years of maintenance ibrutinib; C, induction chemotherapy with ibrutinib followed by 2 years of ibrutinib maintenance.

The addition of ibrutinib to ASCT (arm B) had a failure-free survival of 88% at 3 years, significantly better than the standard chemotherapy, ASCT, and rituximab maintenance arm (failure-free survival: 72%). More surprisingly, patients who omitted ASCT (arm C) had a similarly superior failure-free survival at 3 years as well (FFS: 86%). All in all, patients who received ibrutinib in addition to standard treatment and as a substitute for ASCT did better than those who received standard care. This is a highly significant finding.

“What’s so interesting about this study is that the two arms that contained ibrutinib were superior to the arm that was just standard of care therapy,” Dr. Diefenbach proclaims. “We must temper this [finding] with some degree of patience [because] for the patients who were on ibrutinib, they stayed on this drug for two years… For this reason, even though we are seeing superior signal in the ibrutinib arms, we do not know what the next two years when these patients are off ibrutinib are going to be.”

Ibrutinib: How Does it work?

Ibrutinib belongs to a class of medications called kinase inhibitors, which are highly targeted medications that can find and eliminate cancer cells while relatively sparing normal tissue, unlike chemotherapy.

It inhibits Bruton’s tyrosine kinase (BTK), which are protein enzymes expressed on the surface of certain lymphocytes. It plays a crucial role in the development and survival of normal WBCs. It, additionally, promotes cancer cell growth in MCL. BTK inhibitors bind to the BTK proteins, which in turn prevents them from supporting cancer cell growth.

What are the Side Effects?

Like all medications, Ibrutinib carries side effects. Although most side effects are minor and easily managed, some can be serious. The most common side effects include:

Low platelet count
Low white blood cell count
Low red blood cell count
Muscle and bone pain
Fatigue
Bruising
Nausea
Diarrhea
Skin rashes

Some of the more serious side effects include, among others:

Increased risk of infections
High blood pressure
Problems with the heartbeat (arrhythmias)
Development of other cancers

In the Triangle study, the addition of Ibrutinib to any of the treatment arms did not cause any new or worse toxicity compared to the other arms.

Putting it into Context

Mantle Cell Lymphoma (MCL) is a type of cancer of the white blood cells. It is aggressive, usually diagnosed later in the disease course, and often resistant to treatment.
Traditional treatment with the best chance for long-term disease control for MCL requires high-dose chemotherapy, followed by autologous stem cell transplant (ASCT) and maintenance rituximab. This treatment sequence can be highly toxic to patients.
The Triangle study is a revolutionary study that showed that the addition of ibrutinib to the traditional treatment or using this drug in lieu of ASCT may offer patients better disease control.
However, we should await updates from the study patients over the next years to see whether they continue to do better than those who receive traditional care.
Dr. Diefenbach hails these study findings with some “tempered optimism.” “Patients with MCL may be able to receive maintenance therapy with [ibrutinib] for 2 years and not have to go through [toxic] ASCLT to have an equivalent or better outcome than those [who receive standard therapies].”
“For patients who are not candidates for ASCT… it would be very reasonable [to use ibrutinib] based on this study,” notes Dr. Diefenbach. Such patients would have previously received suboptimal therapies with less-than-desirable outcomes.

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