Second-Line Treatment Options for Patients With MZL

John N. Allan, MD:The prognosis for patients in the relapsed setting can vary. What’s really important is the duration of remission to the first-line treatment. If a patient were to have a prolonged remission—let’s say 5 to 7 years, which is very possible—potential retreatment with chemoimmunotherapy and/or single-agent anti-CD20 therapy may have an additional relatively prolonged remission.

If a patient relapses on a relatively short order—2 years or less—there’s something about the biology of the disease that is typically displaying a more aggressive tendency. For these patients, we may need to think of alternative therapies going forward. In general, looking at most relapsed/refractory studies that typically enroll patients who have had either 1 or 2 prior therapies, the median progression-free survival is on the order of a little over 2 years. Overall, patients do relatively well going forward.

We are now fortunate enough to have access to many targeted treatments. Additionally, we have newer antibodies that we can combine with chemoimmunotherapy that have proven effective and achieve responses in rituximab-refractory disease. For patients being treated with this disease, the future is bright. We are fortunate to be able to deliver these therapies.

Really, there are 3 approaches. You can rechallenge a patient who may have had a durable remission with single-agent anti-CD20 therapy. If it’s 2 or 3 years, they feel relatively well, and they’re relatively happy and robust without too many symptoms and want to remain active, you can rechallenge with anti-CD20 therapy. Several patients may get 2 or 3 rounds of single-agent monotherapy for marginal zone lymphoma.

Obviously, if they get chemoimmunotherapy up front, many times patients will be rechallenged with the same chemoimmunotherapy regimen in the second-line, second round of treatment. This depends on how durable that initial remission is. If the initial remission is durable, a patient may go 5 or 6 years without relapsing. It’s very likely that they will still have very responsive disease, and you might get away with another durable remission with a chemoimmunotherapy approach. Again, if that remission is short—2 years or shorter—we know from follicular lymphoma that those patients have worse outcomes, and we start to talk about more advanced therapies, or nonchemoimmunotherapy approaches, and/or chemoimmunotherapy approaches with consolidation of stem cell transplants.

Obviously, if they have a short remission, or there are many comorbidities and the patient may not have a great outcome with a repeated chemoimmunotherapy approach, we now have many targeted options that we can choose from. These include PI3 kinase inhibitors, which have established decent data and response rates in relapsed/refractory settings. We have BTK inhibitors, such as ibrutinib, which our patient, in this case study, received in a third-line setting. We have drugs, such as lenalidomide, that are third-generation IMiDs that can have durable responses and can achieve response rates in refractory patients.

We also have obinutuzumab, which is a third-generation anti-CD20 antibody that is glycoengineered to have increased ADCC activity, which we believe may lead to more increased effectiveness. Combined with bendamustine, this has been shown to improve outcomes in patients with follicular lymphoma. Patients with marginal zone lymphoma were also enrolled in that study, and so that remains an option—as a single agent or in combination with chemoimmunotherapy.

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