Targeting BTK in Relapsed/Refractory MZL

John N. Allan, MD:Our patient, in this study, received ibrutinib as third-line treatment. A recent study that was published in 2017 reviewed a relatively large phase II study of patients with marginal zone lymphoma. This was a study whose first author was Dr. Noy. This phase II study enrolled 66 patients with marginal zone lymphoma. All subtypes of marginal zone lymphoma were allowed to enroll. The vast majority of patients, close to 50%, had extranodal marginal zone lymphoma. Another 25% or so had splenic marginal zone lymphoma. The remaining 15% to 20% of patients had nodal marginal zone lymphoma.

What they found was that the drug was active in this disease. There was about a 48% response rate for all patients, with a median progression-free survival of 14 to 15 months and a median overall survival that was not met. In patients who responded, the duration of response was prolonged. The median duration of response was actually not met in this study, which had a median follow-up, at the time of the publication, of about 19 months.

Based on this data, ibrutinib received accelerated approval for patients with marginal zone lymphoma in the relapsed/refractory setting after a prior therapy containing rituximab.

What’s important about the duration of response, as well as the progression-free survival and the response rates, is really looking at this in the context of this being a single agent. The dose that was used was 560 mg—that’s the dose that we use in mantle cell lymphoma. Basically, when we look at this as a single agent and compare it with other drugs that were used in this type of setting, we see very similar response rates. Although this duration of response in the progression-free survival does not necessarily equate to what we see in diseases such as CLL, this is obviously a different disease entity. When we compare it to other drugs that have been studied in smaller patient populations, the response rates are very similar. They’re robust. The drug is well tolerated. At this point in time, many patients, after they’ve had 2 lines of chemoimmunotherapy, are looking for somewhat easier options that might get durable responses and deeper remissions.

Transcript edited for clarity.

A 65-Year-Old Man With Advanced Nodal MZL

November 2014

History & Physical:

• A 65-year-old man presented with multiple lumps in groin, no pain
• PMH: negative for HCV, HBV, HIV
• PE: marked swelling in right axillary and bilateral inguinal lymph nodes
  • ECOG performance status: 0
  • Otherwise healthy, no history of CV disease or diabetes, weight within normal range
• CT revealed lymphadenopathy at multiple nodal sites with multiple involved nodes (each <2 cm) involved at each site; no extranodal involvement or bulky disease
• Biopsies confirmed presence of B cell infiltrate
• IHC: B cell phenotype CD20, CD19

Treatment History:

• He was started on active monitoring with CT, histology, and pathology every 6 mo.

November 2015

• At 12 months following diagnosis, disease progression was shown on imaging, with additional involved axillary nodes
• The patient was started on treatment with bendamustine/rituximab (BR)

November 2017

• Follow-up imaging at 2 years following initiation of BR revealed disease progression in multiple lymph nodes at several sites
  • 2 nodes measuring >3.0 cm
• The patient was started on R-CHOP; he achieved a partial response

June 2018

• 7 months later, the patient developed relapsed disease
• He was started on treatment with ibrutinib 560 mg/day orally
  • He developed mild diarrhea (managed with OTC anti-diarrheal) and bruising on legs from minor bumps
  • Follow-up CBC showed grade 3 neutropenia without fever
• Ibrutinib was discontinued until neutrophils recovered and restarted at same dose without incident