Using Novel Therapies in MZL

John N. Allan, MD:In this patient, ibrutinib technically could have been started earlier. Its current label is after a prior therapy with rituximab or with an anti-CD20—containing regimen. This patient received it in a third-line setting. Technically, he could have received this drug in a second-line setting. He could have received it earlier. Right now, there are no real good data demonstrating that it would be that effective or more effective over a chemoimmunotherapy approach in the frontline setting. There’s no indication for that, but this patient may have received it slightly earlier.

Whether or not you do that comes down to the disease characteristics. If you’ve had prolonged remissions, you’re likely to get really deep responses. Even in second-line settings with bendamustine, the response rates are known to be higher. Bendamustine and obinutuzumab seem to be more durable, but these have not been compared head-to-head. When I’m thinking about going to targeted agents, I really want to know that the disease is refractory to chemotherapy. These drugs are still effective and can be used to gain deep, durable remissions. Obviously, these marginal zone lymphomas will sometimes transform into a diffuse large B-cell lymphoma, at which point ibrutinib is not going to manage that. If there’s any clinical concern of a potential for transformation at that second progression, more aggressive regimens such as the one that this patient had—R-CHOP —are a choice for treatment.

In marginal zone lymphoma, we’re really looking forward to the future of these targeted agents and potential immunotherapies as they start to come around. In the future, what’s going to be important will be learning how to use these monotherapies that we’re currently employing, as well as how they can be combined with each other, and what the safety and toxicity profiles are. In the future, I hope to see combination studies with PI3 kinase inhibitors and novel anti-CD20 antibodies, as well as studies that look into combinations of ibrutinib and Revlimid (lenalidomide). Some of these studies are currently being done. We have immunotherapies, such as PD-1 inhibitors, that have shown some effectiveness in diseases like follicular lymphoma.

Obviously, doing large studies in marginal zone lymphoma will be difficult. But even bispecifics and CAR T cells—these things are potentially on the horizon and may be able to salvage some of these chemorefractory patients. Learning how to combine these targeted agents, learning how to employ immunotherapy-based treatments, and understanding their effectiveness in this specific disease entity will be important. Those studies are on the horizon, and we look forward to the future.

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