Exploring Use of Ibrutinib/Rituximab Combination for Waldenström Macroglobulinemia

A type of non-Hodgkin lymphoma, Waldenström macroglobulinemia is a rare, slow-growing lymphoproliferative disorder that is estimated to affect only 1,000 to 1,500 individuals each year in the United States.

The 2 ways to treat the disorder is through the use of chemotherapy or immunotherapy; sometimes, depending on the case, both are needed. Over the past few years, many advances have been made in developing new drugs to treat the disorder, but because there have only been a few studies conducted to assess which drugs are best, a single treatment standard does not exist.

At the 2018 American Society of Clinical Oncology (ASCO 2018) Annual Meeting, Rare Disease Report^® sat down with Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, to delve into a newer drug combination for the treatment of patients with Waldenström macroglobulinemia which was recently assessed in a phase 3 trial.

Rare Disease Report^®: Can you tell us about the phase 3 INNOVATE trial evaluating the use of ibrutinib (Imbruvica) in combination with rituximab (Rituxan) as a treatment option for these patients?

Dimopoulos: The INNOVATE trial is a prospective placebo-controlled randomized trial which included 150 patients with Waldenström macroglobulinemia; both newly diagnosed symptomatic patients and previously treated patients were [eligible for enrollment].

The trial had two arms: the control arm included rituximab with placebo, and the investigational arm included rituximab with ibrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor. The primary endpoint was progression free survival (PFS). At the interim analysis, this endpoint was met; the difference was highly statistically significant with a hazard ratio of 0.22. With a median follow up of 29 months the median PFS for the control arm was 22 months, whereas it has not been reached for the investigational arm. Furthermore, there was a significant increase in the response rate in the investigational arm.

RDR: Can you tell us more about the trial’s findings?

Dimopoulos: We know that in Waldenström macroglobulinemia there is a minority of patients who harbor mutations at MYD88 and CXCR4 and we know that treatment with ibrutinib in these patients is associated with lower responses and with shorter PFS. In our trial, we observed that when we combined ibrutinib with rituximab we were able to overcome these adverse features and these patients did as well as patients without these mutations.

Furthermore, there was a significant improvement of the anemia, with increases of the hemoglobin in 95% of the patients treated with the combination. The combination was relatively well tolerated, with the combination of ibrutinib and rituximab we did not see infusion-related reactions that we see with rituximab alone; we did not see an immunoglobulin (IGM) flare, which is an increase of the IGM a few weeks after initiation of treatment. We had some patients who developed hypertension and atrial fibrillation, these are well-established complications associated with the administration of BTK inhibitors.

However, we have to note that our patient population was older; one-third of the patients were above the age of 75 and these patients have a frequent history of atrial fibrillation. The episodes of hypertension and atrial fibrillation were usually controlled and in only 4% of the patients treated with the combination of ibrutinib and rituximab, there was a discontinuation because of the complication of atrial fibrillation.

RDR: What are the implications of these findings?

Dimopoulos: The combination of ibrutinib and rituximab is becoming a new standard of care that will allow a higher percentage of patients with Waldenström macroglobulinemia to respond to treatment and to have a prolonged progression-free survival. So, I believe these results are very relevant for the treatment of these patients with this rare disease.

RDR: What are the next steps for this research?

Dimopoulos: Both ibrutinib and rituximab are approved single agent for the treatment of Waldenström macroglobulinemia, so especially in the United States, it shouldn’t be a problem to administer the combination of the drugs.

We still have challenges in treating this disease and we would like to improve upon the depth of response because still, we have few patients who have seen a very good partial response or better. Also, we would like to develop regimens that will allow for patients to have a fixed duration treatment and to give them the opportunity for long treatment-free intervals because we know that treatment-free intervals are associated with an improved quality of life.

The US Food and Drug Administration has granted a priority review to the supplemental new drug application ibrutinib for use in combination with rituximab as a treatment option across all lines of therapy for patients with Waldenström macroglobulinemia.