Combo Rituximab/Ibrutinib for Waldenstrom Macroglobulinemia


Steven P. Treon, MD, PhD:Rituximab [Rituxan] is a drug that seems to segue into almost any other drug and help with its activity. I was very much involved in the development of Rituxan. It was really exciting to see the compatibility with so many drugs. It didn’t surprise me that as a next logical step to the optimization of ibrutinib, the combination with rituximab would have been looked at.

It’s also important to recognize that the standard in the community appears to be rituximab as monotherapy. We know this from the SEER [Surveillance, Epidemiology, and End Results] data. We also know that rituximab monotherapy is what most clinicians tend to use in the community setting from other data. Here, I think the opportunity to be able to optimize Rituxan or optimize ibrutinib with the use of the 2 drugs together seems very appropriate.

In discussing the safety and efficacy of ibrutinib and rituximab therapy, what we saw in the iNNOVATE study—published in theNew England Journal of Medicine—is that the overall response rate was increased, including major responses. This means there was at least a 50% decrease in disease burden. We also saw that the progression-free survival greatly improved with the 2 drugs over rituximab alone. This was true whether the patients were treatment naïve or were previously treated. There were no adverse effects to the combination therapy that were different from what one would have observed with either drug alone.

What was interesting and exciting was that the IgM [immunoglobulin M] flare, which has really dogged us in treating patients with Waldenström, was actually greatly reduced when the 2 drugs were used together. Ordinarily you can see an IgM flare in about half of all patients with Waldenström when you give them rituximab alone. This can be a big problem. You can either induce a patient to go into symptomatic hyperviscosity if their IgM level is high, or they might have morbidities attached to that IgM, like peripheral neuropathy or cryoglobulins, all of which can get worse if you give Rituxan alone if the patient has an IgM flare. So this was actually a very nice thing to see.

The other thing that was really exciting was to see that the infusion-related reactions to rituximab also went down when the drugs were used together. It’s important to keep in mind that a lot of these events are cytokine-driven. Many years ago, we actually presented work that showed that interleukin 6 [IL-6] is induced by bystander cells in response to rituximab and drives the IgM production. This is where a drug like ibrutinib is very important. It can actually bypass those pathways that are important for creating these inflammatory cytokines like IL-6.

Transcript edited for clarity.

A 42-Year-Old Male With Relapsed/Refractory Waldenström Macroglobulinemia

September 2016

  • A 42-year old male presented with blurry vision and nosebleeds.
  • Physical examination revealed retinal hemorrhages, adenopathy, and splenomegaly.
  • Laboratories revealed a hematocrit of 18% (normal 34.8-43.6%)
    • Platelets of 50,000/mm3(normal 155,000-410,000/mm3)
    • Leukocyte count of 1,500/mm3(normal 3,800-9,200/mm3)
  • Serum total protein was high prompting a workup that revealed an IgMλ monoclonal protein and serum IgM level of 12,400 mg/dL.
  • CT scans showed bulky adenopathy (> 5 cm)
  • A bone marrow biopsy revealed that 80% of the intertrabecular space was involved with lymphoplasmacytic lymphoma.
  • Immunohistochemistry demonstrated CD20 expressing bone marrow disease.
  • Molecular diagnostic testing for MYD88 and CXCR4 is pending


  • The patient began several emergent rounds of plasmapheresis, and his vision and energy improved.
  • His retinal exam improved and repeat serum IgM level was 3,892 mg/dL.
  • The molecular diagnostic studies showed MYD88 L265P and CXCR4 nonsense mutations to be present in the tumor cells.
  • The patient received bendamustine alone for two cycles, then rituximab was added to bendamustine for 2 more cycles. He attained a major response.

September 2018

  • Two years later, he relapsed with progressive adenopathy (< 5 cm), symptomatic anemia, and his serum IgM rose to 5,459 mg/dL.
  • Patient was started on rituximab/ibrutinib combination therapy.
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