Waldenstrom Macroglobulinemia: Ibrutinib Monotherapy

Jorge J. Castillo, MD:Recently, one of our studies—a phase II, single-agent, single-arm study evaluating ibrutinib in about 30 patients with previously untreated Waldenström macroglobulinemia—was published in theJournal of Clinical Oncology. This was a very interesting study. We felt that it was necessary to do this study because the approval by the FDA that was given in 2015 for ibrutinib in Waldenström macroglobulinemia didn’t really have any regard for if the patient needed to be previously treated or untreated to begin ibrutinib. There was also no data on previously untreated patients. We felt it was a scientific gap, and we designed a study to be able to identify these patients, treat them, and see how they did. We put about 30 patients on this study. Based on our previous experience that patients withoutMYD88mutations did not benefit much from ibrutinib, we did not include anyMYD88-negative patients in the study. So all our patients hadMYD88-positive disease.

What we saw in this study has been very beneficial to patients. We did not see any difference in terms of how well patients did compared to studies on patients who were previously treated. There were 2 previous studies in patients who were previously treated. One of them is from our group, the one that actually got ibrutinib approved by the FDA, and the other was a multinational study in patients who were cetuximab-refractory. Those 2 studies were in previously treated patients, so the iNNOVATE study was done in patients who were previously untreated.

The reason we decided ibrutinib was an important molecule to test in Waldenström macroglobulinemia is because of theMYD88mutation. When a normal patient gets infected by a virus or bacteria, the MYD88 receptor gets activated, couples with itself in the membrane of the cell, and activates a series of reactions in the cell. One of them is the activation of BTK [Bruton tyrosine kinase]. It y occurred to us that a BTK inhibitor would actually be very important in patients with Waldenström macroglobulinemia because in patients with Waldenström macroglobulinemia, the mutation inMYD88allows MYD88 to activate itself, even in the absence of any kind of trigger. Those cells are activated inherently all the time. That was the reason. Ibrutinib is a BTK inhibitor and by blocking BTK, we are able to show, at least in the laboratory, that all the reactions downstream—in terms of activation of survival signaling pathways, nuclear factor kappa B, and other factors—were clearly blunted by this inhibition. That gave us the idea that in the clinic, this could potentially work.

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