Utilizing Ibrutinib for Mantle Cell Lymphoma

Michael L. Wang, MD:I would predict the patient will relapse within 5 years, because of his high MIPI score and because of the fact that his tumor was 9 cm in the abdomen. So, it does not surprise me at all that the patient relapsed about roughly 4 years after initial therapy. Then the patient, in this case, was treated with ibrutinib. I really love this option. I think it is absolutely the right thing the oncologist in this case did. Ibrutinib is a small molecule targeting a protein called the Bruton’s tyrosine kinase, which is an important component of the B-cell receptor pathway, all the way from the surface of the B cell to the nucleus of the B cell. And BTK, Bruton’s tyrosine kinase, is in the cytosol part of that pathway, and once it’s blocked with ibrutinib or you knock the gene out, the cell dies. So, ibrutinib was approved in November of 2013 by the United States FDA through a breakthrough mechanism based on only a phase II clinical trial that was not intentionally meant for FDA approval.

They were just doing a phase II clinical trial, but it is unprecedented in efficacy with a 68% overall response rate and a CR rate over 20%. You may not think that this is impressive, but let me tell you, if you use ESHAP [etoposide, methylprednisolone, cytarabine, and cisplatin] or all these chemotherapy combinations—with ESHAP, you need to admit the patient to the hospital for their therapy, the patient will lose their hair, and their blood count goes down. They need transfusions. They needed to fight infections. And now, their response rate is about 65% to 70%. Now we can achieve this without giving the patient all of these chemically toxic combinations. We do not have to use intravenous catheter. We can just give the patient a pill once a day and achieve the same purpose. So, this was a milestone in the therapy of mantle cell lymphoma. I’m very proud and very happy from the inside that I actually led the clinical trial that lead to the FDA approval.

I might be 1 of the top 10 people who prescribe ibrutinib in the field of mantle cell lymphoma. Ibrutinib is given at 560 mg, which is 4 tablets—4 capsules. Each capsule is 140 mg. The patient will take 4 capsules in the morning on an empty stomach. So, after that, with ibrutinib, the most common side effects are fatigue, loose stools not qualifying for diarrhea, and sometimes a little petechiae. Like aspirin, there are very common bleeding issues, but nothing severe. If you do not use it with other blood thinners, such as warfarin, Xarelto [rivaroxaban], or aspirin—if you don’t use it with this medicine together—the bleeding is really not very heavy, not very risky. However, you need to caution all of the patients who take ibrutinib: try not to fall, avoid contact sports, avoid riding a bicycle. In that clinical trial, about 4 patients had subdural hematoma, intracranial bleeding. Each of the 4 patients had 1 of 2 things. They were taking either aspirin or warfarin. They were also associated with trauma, such as a fall.

So, avoid trauma, and be aware that ibrutinib is a bleeder. The other issue is that ibrutinib sometimes can cause a rash, especially in young people. Don’t panic. It’s not an allergy. If you stop the drug for a few days and use a Medrol Dosepak, it goes away almost all of the time. Don’t be afraid of the rash, but be aware of the severe bleeding risk. The most dreaded side effect is atrial fibrillation. For about 6% of people, especially elderly people who are above 70 years old and have a history of long-term hypertension, who have a history of a cardiac disease—any cardiac disease—ibrutinib could induce atrial fibrillation. The most dynamic organ of our body is the heart, and the heart can decide the patient’s life in minutes or seconds.

Therefore, when the patient has atrial fibrillation, according to my experience, I would avoid using ibrutinib. This is not the general guideline you would hear, but I become very cautious when the patient has atrial fibrillation. I often ask the patient to have a nodal ablation from the cardiologist. Well, nodal ablation is not a regular indication for this kind of atrial fibrillation, but an oncology is changing the protocol for cardiology. And many, many cardiologists are collaborating with us to put the patient into normal sinus through nodal ablation so we can resume ibrutinib.

I once treated an 85-year-old lady from Texas. In Houston, there’s a much-traveled local road called the Buffalo Speedway. She lived on that Buffalo Speedway, which is 5 minutes away from The University of Texas MD Anderson Cancer Center. She received stem cell transplant and hyper-CVAD. Everything under the sunshine, she got it, and then she came to me in around 2015 and was put on this clinical trial that led to the approval of ibrutinib by the FDA. I remember she had a tumor on the right side of the cervical, a big tumor, like an apple. Within a week, the apple became a golf ball, and within 2 weeks, the apple disappeared. So, a good complete remission occurs in 20%, according to the old Cheson criteria. If you use the new, updated Lugano criteria, the CR rate will be much higher. It will be in about 30% to 40% to the best of my knowledge. Complete remission does happen if you use PET scan. With PET scan negativity, we call that complete metabolic response. The response is about 70%, and if you are able to steer the patient away from those toxicities, the patient could stay on the drug for as long as 5 years. My record is 6 years.

Transcript edited for clarity.

March 2013

• A 55-year-old male presents to his physician complaining of fatigue, unexplained weight loss, and neck swelling
• PMH: unremarkable
• Physical exam:
  • Bilateral cervical lymphadenopathy
• Laboratory findings:
  • Leukocytes, 9.0 X 10⁹/L
  • Hb, 9.8 g/dL
  • LDH, 520 U/L
  • Beta2-microglobulin; 6.4 mg/L
  • AST, 167 U/L; ALT 202 U/L
• Excisional biopsy of the right cervical node:
  • Immunophenotyping: IgM+, CD5+, CD10-, CD19+, CD20+, CD22+, CD23-, cyclin D1+
  • Cytogenetics: t(11;14)(q13;q32)
• CT imaging of the neck, chest, abdomen, pelvis: marked¹⁸F-FDG uptake and enlargement of bilateral cervical lymph nodes (right, 4.6 cm; left, 3.1 cm) and mesenteric lymph node (9.2 cm)
• Diagnosis: Mantle-cell lymphoma, Ann Arbor stage III
• The patient was started on induction therapy with R-hyper-CVAD and achieved significant reduction in tumor burden
• Consolidation with autologous stem cell transplant resulted in complete remission

March 2017

• The patient reports having symptoms of fatigue and weight loss
• PET/CT shows diffuse uptake of¹⁸F-FDG in the right lung and mediastinal lymph nodes
• The patient was started on therapy with ibrutinib