This is the case of a 65-year-old gentleman who was diagnosed with a nodal marginal zone lymphoma in November of 2014. When he presented, he presented with diffuse adenopathy. He came to his doctor because of lymph nodes in his groin. Upon initial exam, his physician found that he had diffuse adenopathy not just in his groin but also in his axillain his right axilla, as well as in the bilateral groin. Overall, he was noted to feel generally well, without too many symptoms. His past medical history was negative for any significant medical conditions, such as cardiovascular disease or diabetes. He was an otherwise generally healthy gentleman.

Upon initial lab work, he was found to be negative for HIV. He was also negative for hepatitis C and hepatitis B. Initial lab work showed a mild neutropeniaabout 900 ANC. No other significant or major abnormalities showed up on his blood work.

He was recommended for a biopsy, at which point biopsies of the groin node revealed that it was a B-cell malignancy. It really just expressed CD19 and CD20 and was negative for other common markers that were evaluated. Baseline imaging revealed diffuse adenopathy, as well. That was confirmed in multiple nodal sites, but it was noted that most of these nodal sites were less than 2 cm. Given that he was feeling well, the recommendation from his physician was to continue to monitor him and observe him with physical exams and imaging going forward.

In November of 2015, he was noted to have disease progression. He felt lymph nodes growing in his arms, axilla, and groin. At that point, his physician had discussions with him about treatment options. The decision to initiate chemoimmunotherapy with bendamustine and rituximab was made.

The patient did relatively well. He had a decent response. Unfortunately, 2 years later, he did have a relapse. Again, he was noted to have enlarging lymphadenopathy. Given that he had relapsed in a short amount of time, within about 2 years, it was decided not to rechallenge him with bendamustine/rituximab. His physician recommended a more aggressive regimenR-CHOP.

He received all 6 cycles of R-CHOP. At the end of treatment, he was noted to only have a partial remission. At that point, given that he&rsquo;d just gotten chemotherapy, was in a remission, and was feeling a little better, he was recommended for observation. Unfortunately, this remission was also shorter than the previous one. Seven months later, he came back to his physician and, again, noted disease progression with enlarged lymphadenopathy and a return of symptoms of fatigue.

At this point, the patient and his physician had several decisions to make. The recommendation was to initiate third-line treatment with a drug called ibrutinib. The drug was initiated. He tolerated it relatively well but had some complications with diarrhea that resolved with over-the-counter therapy. He had noticeable bruising throughout the treatment but no significant major bleeding. His course was complicated by neutropenia, at which point the drug had to be held. The neutropenia resolved within a short amount of time, and then he was rechallenged at the same dose. The patient continues on this therapy.

Case Overview: Advanced MZL With Disease Progression

Nodal marginal zone lymphoma is a relatively rare subtype of a non-Hodgkin lymphoma. Marginal zone lymphoma, in general, is a relatively rare subtype representing somewhere around 10% of non-Hodgkin lymphomas. There are basically 3 types of marginal zone lymphomas. There are extranodal marginal zone lymphomas, which are called MALT lymphomas, or mucosa-associated lymphoid tissue lymphomas. There is an entity described and known as splenic marginal zone lymphoma. Then, the third entity is a nodal marginal zone lymphoma.

Essentially, this is a diagnosis of exclusion. When you believe you&rsquo;re dealing with a marginal zone lymphoma, you essentially have to exclude extranodal sites. If there is any involvement of the gut, ocular adnexa, skin, or any other area that would be extranodal, outside of the lymph nodes, the diagnosis typically gets lumped into the category as an extranodal marginal zone lymphoma. Essentially, you have to rule out an extranodal source. Again, splenic marginal zone lymphoma is a relatively straightforward diagnosis. It literally just involves the spleen and the bone marrow. If you have a patient presenting without extranodal sites, without an isolated enlarged spleen and predominantly enlarged lymph nodes, you then get diagnosed with what&rsquo;s called a nodal marginal zone lymphoma.

When we talk about nodal marginal zone lymphoma, a lot of our data that we extrapolate from is from our patients with follicular lymphoma. These 2 disease entities are similar in their outcomes. Because nodal marginal zone lymphomas are relatively rare, they are less represented in clinical trialstypically, at smaller numbers to where the power isn&rsquo;t there to really know how these subgroups do long term, respectively, with treatments.

In general, we do believe that they respond well to rituximab-based therapies. Overall, several different studies have shown 5-year overall survival rates that range from 60% to upward of 80% to 90%. It is a mixture. There is some evidence that nodal marginal zone lymphomas may have a slightly worse prognosis than other marginal zone lymphomas, such as extranodalMALTs&mdash;and splenic marginal zone lymphomas.

Marginal zone lymphoma is a diagnosis that is relatively difficult to come to an agreement on. It lacks many features of other B-cell malignancies, such as specific immunophenotypes, and differs from follicular lymphoma in that it is predominately a CD10-negative disease. It differs from CLL, SLL, and mantle cell lymphoma in that it&rsquo;s typically a CD5-negative disease. Really, it comes down to a histopathologic diagnosis.

The frustrating part, for physicians and pathologists alike, is that the histology can vary dramatically. It can have lymphoplasmacytoid differentiation, plasmacytic differentiation, and can sometimes mimic lymphoplasmacytic lymphoma or Waldenstr&ouml;m macroglobulinemia, which are typically CD5 and CD10 negative.

It really comes down to experiencefor an experienced pathologist to really hone in on the subtleties for making the diagnosis. We are now using more molecular features to try to understand and differentiate these entities&mdash;marginal zone lymphomas from other ones such as follicular lymphoma, Waldenstr&ouml;m macroglobulinemia, CLL, mantle cell lymphoma, and such.

Marginal zone lymphomas are noted to involve some type of antigen stimulation or some type of chronic inflammation. The most common marginal zone lymphomas, which are extranodal marginal zone lymphomas, are typically found in settings of infections such has

. Certain bacteria are involved with skin and nodal marginal zone lymphomas, as well as ocular extranodal marginal zone lymphomas.

What we have found is that these nodal marginal zone lymphomas also have a relatively common background of patients with chronic antigen stimulation. Sometimes they&rsquo;re involved with hepatitis, such as in splenic marginal zone lymphomas. In nodal marginal zone lymphomas, although no specific infection has necessarily been associated with them, they do note relatively common associations with autoimmune disorders such as lupus, Sj&ouml;gren syndrome, and other kinds of chronic inflammatory conditions.

Appropriately Diagnosing and Classifying MZL

When we&rsquo;re dealing with first-line treatment options for marginal zone lymphoma, we typically put patients into 2 categories. We look for patients who might respond to single-agent rituximab, or anti-CD20 therapy, and then we try to identify patients who might benefit from more aggressive chemoimmunotherapy approaches. In general, we extrapolate how we treat patients in the frontline setting from how we manage our follicular lymphoma patients. These are both considered indolent diseases. They both can possibly be monitored and observed for periods of years before any treatment is indicated. We really look for those treatment indications that are commonly used in follicular lymphoma, such as bulky adenopathy, progressive adenopathy, cytopenia, and B symptoms. Things that are common among indolent lymphomas as treatment indicationswe look for those before we initiate.

If you have a low tumor burden or an older patient with comorbidities who may not tolerate chemoimmunotherapy, you may back off and use single-agent anti-CD20 therapy. If you have a younger patient who has bulky disease and/or is symptomatic, in which you need to get a more rapid and durable response, that&rsquo;s where we employ our chemoimmunotherapy options, of which there are several.

When we determine how we want to treat and approach a patientwhether we observe them or we treat them at diagnosis&mdash;we really look into several factors. One is, how is the patient feeling? It&rsquo;s a clinical assessment. Are they having symptoms? Are they bothered by the lymph nodes? Did they arise rapidly, or was this something that has slowly grown over time? Again, looking at their blood counts and their lab work will help determine the need and whether or not there are clear-cut treatment indications for whether or not to initiate. If the patient has a normal blood count, feels well, and has some lymphadenopathy that is relatively small, you can typically observe him or her and try to understand the pace of the disease prior to initiating treatment at diagnosis.

With nodal marginal zone lymphoma, many patients do present with bulky adenopathy and typically require treatment at diagnosis. However, that&rsquo;s not always the case. Again, you&rsquo;d look at the clinical scenario of this specific patient and what would meet their needs.

Frontline Treatment Considerations for Patients With MZL

When we&rsquo;re thinking about treatment with single-agent anti-CD20 antibodies such as rituximab versus chemoimmunotherapy approaches such as bendamustine/rituximab or R-CHOP, we look at whether or not the patient is symptomatic. What are their comorbidities? What are their treatment goals? Do they want to avoid more aggressive regimens? We really have to make it a patient-centered decision.

If they are older and have more comorbidities, I feel more comfortable backing off and using single-agent anti-CD20 therapy. Additionally, if they have low burden but are somewhat symptomatic, and we&rsquo;re potentially trying to prevent needing to use more chemoimmunotherapy, and if we simply observe and the lymph nodes grow to be bulkiermore than 5 cm; closer to 7 cm&mdash;I may decide to treat with anti-CD20 therapy to try to capture the patient in a low tumor burden situation.

When a patient is symptomatic, when they have bulky adenopathy, and when they are in need of a response that&rsquo;s going to be more rapid and durable, I start to think of our acute chemoimmunotherapy options.

When we&rsquo;re looking at which type of anti-CD20 therapy we want to use, we are fortunate to now have several antibodies currently FDA approved for different indications. Although there&rsquo;s not currently an FDA approval for third-generation antibodies such as obinutuzumab, we are able to access these drugs because the marginal zone lymphomas have been studied in randomized phase III protocols. In an up-front setting, I typically don&rsquo;t use obinutuzumab. I&rsquo;ll typically use rituximab. But in a second-line setting or in any patient who demonstrates that they are rituximab refractory, I will employ&hellip;something that is potentially considered to be a better or more effective antibody and may use obinutuzumab.

Anti-CD20 Antibody Therapy in First-Line MZL

The prognosis for patients in the relapsed setting can vary. What&rsquo;s really important is the duration of remission to the first-line treatment. If a patient were to have a prolonged remissionlet&rsquo;s say 5 to 7 years, which is very possible&mdash;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&mdash;there&rsquo;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&rsquo;s 2 or 3 years, they feel relatively well, and they&rsquo;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&rsquo;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&mdash;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.

Second-Line Treatment Options for Patients With MZL

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&rsquo;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&rsquo;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&rsquo;re robust. The drug is well tolerated. At this point in time, many patients, after they&rsquo;ve had 2 lines of chemoimmunotherapy, are looking for somewhat easier options that might get durable responses and deeper remissions.

Targeting BTK in Relapsed/Refractory MZL

When we&rsquo;re thinking about a patient who might be eligible for ibrutinib-based treatment, we really take some patient considerations into account. Overall, the drug is well tolerated. There are some complications that are associated with it that should be recognized. Some of the major complications that we note with this drug are atrial fibrillationAFIB&mdash;which is noted in 10% to 15% of patients in quoted studies, as well as bleeding. It has an antiplatelet effect that is similar to aspirin. Patients may have bruising, and significant bleeds have also been noted, although at very low percentages.

Bruising and AFIB are the major things that we think about. If we have an older patient with cardiovascular disease, who might already have AFIB and might be on a blood thinner and is a fall-risk patient, you have to take that into consideration when you&rsquo;re considering initiating ibrutinib. Otherwise, if the patient is relatively healthy or relatively robust, ibrutinib is a very good option. It&rsquo;s well tolerated and can be used safely and effectively.

That&rsquo;s not to say that if there are complications in a patient who has comorbidities of AFIB or cardiovascular disease that this drug cannot be used. It absolutely can be used, and we use it in the clinic and in practice. For these patients, you just have to consider potential alternatives if you potentially see that they may not tolerate the drug well.

When managing toxicities of ibrutinib, you really have to be aware of what the symptoms of AFIB are. Many times, patients will talk about palpitations and fluttering and things like that. When you talk to them, it&rsquo;s very brief. And so, it&rsquo;s kind of hard to decipher. So, when your patient is on these types of drugs, any of those types of complaints need to be taken very seriously. At that point, you need to do your workup appropriately, do EKGs, and monitor and ask about them. Sometimes patients aren&rsquo;t so forthright in bringing up their symptoms. Ask about bleeding. Ask about diarrhea. Ask about joint aches. You really have to monitor them. You really need to inquire about these types of things. Typically, we&rsquo;re seeing patients on an every-couple-of months basis or so. When they come back, these are the things to be aware ofto look for and discuss with the patient. I try to identify these things before they become more problematic and/or uncontrolled.

Using Ibrutinib in Relapsed/Refractory MZL

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&rsquo;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&rsquo;ve had prolonged remissions, you&rsquo;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&rsquo;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&rsquo;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 &mdash;are a choice for treatment.

In marginal zone lymphoma, we&rsquo;re really looking forward to the future of these targeted agents and potential immunotherapies as they start to come around. In the future, what&rsquo;s going to be important will be learning how to use these monotherapies that we&rsquo;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.

Perspective on Treating Advanced Marginal Zone Lymphoma