Future Management of Waldenstrom Macroglobulinemia

Jorge J. Castillo, MD:In terms of how to move the field forward for Waldenström macroglobulinemia treatment, I think there are a couple of unmet needs. On one hand, we need medications or combinations that can cause and induce a rapid deep response that will be long lasting without having to take a medication indefinitely. I think that’s where we’re trying to hit the sweet spot. In addition to that efficacy, we also need to develop treatments that are probably safer that do not have the risk of neuropathy; the risk of secondary cancers, like chemotherapy does; infusional reactions; or IgM [immunoglobulin M] flares, like the monoclonal antibodies.

We are devising a study in which we are going to be combining ibrutinib and venetoclax. Venetoclax is a BCL-2 [B-cell lymphoma 2] inhibitor that has us very excited. We are running a study now that has not been completed that has shown benefit, even in patients who have been previously exposed to ibrutinib. We are inducing responses, patients are feeling better, and this study has been designed in a way where we will stop the venetoclax within 2 years of starting therapy. Can we use that as a backbone in addition to ibrutinib and use those 2 agents synergistically?

We do have evidence from our laboratory that the combination of a BTK [Bruton tyrosine kinase] inhibitor and a BCL-2 inhibitor is actually synergistic, and they kill cells in a more efficient manner. The next study will give ibrutinib at the standard dose of 420 mg by mouth once daily and venetoclax at the standard dose of 400 mg by mouth once daily. Both agents will be given concurrently for 2 years, and at that moment we will stop therapy and see if we have been able to induce the depth of the response that we wanted—and hopefully the duration of response that we wanted—without causing too much long-term toxicity.

Transcript edited for clarity.

Case: A 65-Year-Old Female With Newly Diagnosed Waldenström Macroglobulinemia

September 2016

• A 65-year old female presented to her PCP with slowly progressing anemia for the last couple of years
• Several months prior to that, she began experiencing drenching night sweats, distended abdomen, and 15 lb weight loss
• SH: Married, exercises regularly, social drinker, non-smoker, no illicit drug use
• FH: Maternal aunt — breast cancer age 51
• Laboratory results:
  • Hemoglobin; 7 g/dL (11-13 g/dL), platelets; 55,000/mm³(155,000-410,000/mm³), and leukocyte count 1,700/mm³(3,800-9,200/mm³).
  • M-protein; 2991.3 mg/dL; IgM 4710 mg/dL (45—281 mg/dL)
  • Serum viscosity; 3.7 centipoise (cP) (1.6—1.9 cP)
  • Beta-2; 3 mg/L (0-2.7 mg/L)
  • IPSSWM: 2 Intermediate
• Bone marrow aspiration and biopsy; 40—50% B cells
• Flow cytometry; Lambda-restricted B cells that expressed CD19 and CD20
• B cells were negative for CD5, CD10, CD43, bcl-1, and bcl-6
• Allele-specific PCR; MYD88^L265Pmutation
• Diagnosis; Waldenström’s macroglobulinemia (WM)

Treatment

• Patient was started on ibrutinib (420 mg) daily with monthly follow-up visits
• After three months, her IgM was 1500 mg/dL and her serum viscosity was 1.5 cP
• Her CBC showed improvements: WBC, 5000/mm³, Hgb 15.5g/dL; platelets 180,000/mm³
• The patient was last seen on follow-up last month and she continues on ibrutinib 2 years after her initial presentation