Daniel Greenwald, MD

I always explain to patients that compared to my father’s generation of oncology, and even when I was in medical school, we understand so much more about the immune system and the molecular pathogenesis of cancer in general, but certainly lymphoma. That has resulted in a finer and finer categorization of lymphomas into various subsets. There’s no question that over the next 10 years and 20 years, we will redefine lymphomas into even finer categories that help to tailor our understanding of prognosis, but also therapy. There’s no doubt that the molecular profiling will probably alter our decisions in the future. At the immediate time, it’s not really impacting lymphoma or follicular lymphoma as much as other types of non-Hodgkin’s lymphoma, such as CLL [chronic lymphocytic leukemia]. There are a lot of interesting areas that are rich for potential targets for therapy. Enhancing our ability to use the immune system is going to be key as time goes on and it’ll extend beyond just anti-CD20 antibody therapy to novel forms of antibody-drug conjugates, novel forms of antibodies that lock onto or attack other targets and lymphomas and as I mentioned earlier, cellular therapy that uses either self-made T cells or engineered off-the-shelf T cells. Also, there’s interest in using what are called BiTEs, or bispecific antibodies, that can draw components of one’s immune system more directly into the lymphoma population to treat it. Beyond those immunotherapy approaches, there is still quite a bit of interest in using targeted therapies. We have several of these in use for various forms of non-Hodgkin’s lymphoma that target various pathways and it may be that combining them, although, potentially very costly in terms of the coverage, may be effective in overcoming some of the deficiencies or limitations of single drug approaches.

The key takeaway or clinical pearls I would offer is that follicular lymphoma is a very heterogeneous disease that fortunately for most patients carries a very long survival, and that’s the thing that needs to be emphasized to patients. Obviously, most clinicians understand that historically we view follicular lymphoma as an incurable subtype of lymphoma, but one that can be usually, or often successfully, managed over years to even decades. It’s important that if one requires treatment, that the best attempt at remission be achieved upfront, but understanding the risks of toxicity and taking that into consideration when tailoring a treatment plan for a patient. It’s important to consider options very carefully as some forms of cytotoxic chemotherapy, as well as immunotherapy, can have both short-term and long-term toxicities. But understand that there is support from colleagues in academic medicine who are willing to see patients on a consultative basis, help in a collaborative fashion design a treatment plan, and that can often be implemented in the community. It’s important as a treating clinician to reassure patients that this is an area that is rapidly evolving, rapidly improving, and that survival is often measured in years to decades.

Case: A 45-Year-Old Woman with Follicular Lymphoma

A 45-year-old woman presents with a 2-month history of fatigue and abdominal pain, enlarged lymph nodes in her right neck, and a 5-lb unintentional weight loss

PE: right cervical and axillary lymph nodes palpated ~2 cm; spleen palpable 3 cm below left costal margin

Labs: ANC 1.5 x 10^9, WBC 11.7 x 10^9, lymphocytes 41%, Hb 8.7 g/dL, plt 101 x10^9, LDH 305U/L, 3.6 B2M ug/mL; HBV negative

Excisional biopsy of cervical lymph node on IHC showed CD20+, CD10+, BCL2+, follicular lymphoma grade 2

Bone marrow biopsy showed paratrabecular lymphoid aggregates, 43% involvement

PET/CT showed right axillary, cervical, and mediastinal lymphadenopathy (2.7 cm, 2.5 cm, and 2.6 cm respectively)

Patient was treated with obinutuzumab plus bendamustine chemotherapy. She completed 6 cycles and treatment was well tolerated.

She continued on obinutuzumab maintenance.

30 months later, she complains of fevers, chills, and decreased appetite.

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Treatment advice for community oncologists and hematologists who treat follicular lymphoma based on therapeutic advances occurring rapidly in the field.

Tailored Treatment Approaches for Newly Diagnosed Follicular Lymphoma

 To review our case, our patient achieved 30 months of freedom from trouble, as I say, but now she has relapsed after a cytotoxic chemotherapy and a monoclonal antibody. Considering that she was treated with maintenance therapy, it is suggested that she has a refractory to both of these modalities of therapy. In general, we don’t like to go back to a cytotoxic chemotherapy of the same mechanism that is close to the initial therapy, particularly 1 that can be harsh on the bone marrow, like bendamustine [Treanda]. It’s important to understand that not all patients with a relapse necessarily require treatment. Some can be monitored depending on the same factors that we considered during initial therapy. However, in this case, she’s having considerable symptoms. My first priority would be to establish whether there’s evidence of transformation. Again, repeating a PET [positron emission tomography] scan with a low threshold to rebiopsy an area of intense FDG [fluorodeoxyglucose] uptake. For the majority of patients, I look for an investigational protocol if 1 is available, and if it’s not available, I would certainly consider 1 of the many approved treatments utilized in the second-line setting. This might include lenalidomide [Revlimid] and rituximab [Rituxan], a PI3 [phosphoinositide 3] kinase inhibitor, or EZH2 [enhancer of zeste 2 polycomb repressive complex 2 subunit] inhibitor. Occasionally, I will use some of the older radiotherapies, but again, my focus is always looking for a clinical trial if available.

We know from lymphoma care and many registrational studies, as well as cohort studies, that patients who progress within 24 months of diagnosis tend to do more poorly. And that’s been supported by again, prospective studies following patients, but also retrospective analysis of patients undergoing therapy and study. Although this patient progressed at 30 months, it’s concerning that she’s progressed this early following this therapy and at this young age. It’s another reason to consider a full restaging, a full assessment for transformation, and, when indicated, assessment by a center with excellence for treatment in lymphoma that has access to not only investigational studies but, if necessary, cellular immunotherapy approaches, as well as a stem cell transplant.

Treatment options and variables that need to be considered when managing patients with follicular lymphoma who relapse early after first-line chemoimmunotherapy.

Managing Early Progression in Follicular Lymphoma

Maintenance therapy refers to prolonged administration of an agent, usually with low toxicity to either delay or prevent recurrence or progression. Maintenance therapy is something that has been used and studied in the treatment of follicular lymphoma with rituximab [Rituxan] and obinutuzumab [Gazyva] and other anti-lymphoma approaches. In general, I do consider maintenance because I follow the clinical evidence and maintenance therapy for follicular lymphoma is certainly an option. In the GALLIUM trial, it was built into the study that maintenance would be utilized in each arm. It is supported by data that it delays progression-free intervals or improves progression-free survival. However, it’s never been clearly demonstrated to improve overall survival, so I take maintenance consideration on a case-by-case basis. It really depends on the depth of remission. For patients who achieve partial remission, there’s a possibility it can be converted to a complete remission with the continuation of therapy on maintenance. For patients who achieve a complete remission and, for example, have a toxicity of therapy such as protracted or severe neutropenia, I will often not use maintenance. It really depends on how well the patient has done, and if they have suffered any toxicities, as well as what their personal preferences are. What their tolerance is, meaning their emotional tolerance to continue with therapy vs their eagerness to continue with therapy, to keep the disease controlled. Sometimes there are practical considerations with payer coverage for maintenance, where it is not always approved, even though it’s perhaps supported by evidence or even label.

Any patient who’s on maintenance is going to be assessed regularly. There are different maintenance schedules, but if we follow the maintenance schedule described by GALLIUM, patients are treated every 2 months. Typically, they’re assessed at those intervals with a complete set of laboratory studies, including blood count, assessment of symptoms, and a physical exam. On occasion, they also undergo imaging to confirm a sustained or assess for remission. We’re always assessing whether they’re fit enough to continue with therapy and understanding, are they still responding to therapy, do they remain in remission, are they perhaps relapsing? Obviously, a patient who relapses during maintenance therapy requires attention and likely a change in therapy.

I tend to use the FLIPI [Follicular Lymphoma International Prognostic Index] score in the initial assessment. Subsequently, I use some features of the FLIPI score, for example, the LDH [lactate dehydrogenase] level, as well as the hemoglobin, to understand how well patients are doing. But in general, I rely on the assessment of symptoms, physical exam, and imaging, as well as laboratory studies to determine if a patient remains in remission. When indicated they need to undergo bone marrow biopsy and all of these factors are taken into consideration and understanding are they still benefiting from treatment or is maintenance therapy somehow no longer working. As I’ve mentioned, it’s important to assess for toxicity as well. Cytopenias can occur late with maintenance antibody therapy, and it’s important to understand not only the mechanism but also the means of treating that when it occurs.

Factors that affect the use of maintenance therapy, including anti-CD20 maintenance therapy, for newly diagnosed follicular lymphoma, and recommendations for assessing response to therapy.

Maintenance Therapy for Newly Diagnosed Follicular Lymphoma

CD20 is an attractive target for the treatment of lymphoma because it’s so highly expressed in lymphoma. We’ve known since the late 1990s that we can target CD20 using monoclonal antibodies except for normal B cells, which we acknowledge we will get rid of as we treat with an anti-CD20 antibody. This is a fairly specific treatment for lymphoma. We’ve also long recognized that there’s a synergy between treatment with the anti-CD20 antibodies and cytotoxic chemotherapy. I will often explain to patients that even though we’re suppressing their normal B cells, in most adults they can do well for a period of time without those B cells. There, of course, has to be vigilance for infection as there is an increased risk of opportunistic infections, but over the short-term, most adults will do well even when we target CD20. It has also been recognized that targeting CD20 can vary from 1 person to another. There are factors for the host or the patient’s immune system that influence the ability to respond to therapy against their lymphoma using an antibody. Newer generations of anti-CD20 antibodies have capitalized on our understanding of how the immune system functions. For example, newer versions may have an altered structure where they’re fully humanized rather than containing mouse components. They may have removal of sugar residues on the protein on the antibody, which enhances the immunologic function of the antibody. In other words, newer versions of anti-CD20 antibodies are engineered, we hope to work better and the clinical evidence has supported that.

The GALLIUM trial was a very large prospective study evaluating the treatment of frontline follicular lymphoma. This was a study of over 1200 patients and they were randomized to receive obinutuzumab [Gazyva] and chemotherapy vs rituximab [Rituxan] and chemotherapy, followed by respective maintenance schedules for each antibody. The treating oncologist could select the chemotherapy, but there was randomization to balance that factor. Many patients received bendamustine [Treanda], some patients CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], some patients CVP [cyclophosphamide, vincristine, prednisone]. What it demonstrated was that there was a superior progression-free survival compared with rituximab chemotherapy, with medians not yet reached for either arm. The adverse events for obinutuzumab-based therapy are well described and can be mitigated with several measures. There was a slight increase in toxicity versus rituximab.

The rationale for treating newly diagnosed follicular lymphoma with the anti-CD20 monoclonal antibody, obinutuzumab, in the first-line setting.

Newly Diagnosed Follicular Lymphoma: First-Line Anti-CD20 Therapy

When deciding between available options, treatment considerations involve medical comorbidities and any appreciable contraindications, as well as the patient’s preference for mode of treatment, for example, IV vs oral, as well as the desire to achieve a disease-free interval off of active therapy. In the context of patient discussion around these factors, we almost always consider some form of anti-CD20 therapy as the backbone, and typically with chemotherapy in the frontline setting. Historically, various forms of cytotoxic chemotherapy have been utilized. I think in the majority of centers, bendamustine [Treanda] in combination with an anti-CD20 antibody, like obinutuzumab [Gazyva] remains the mainstay of therapy in the frontline setting outside of the clinical trial. In the frontline setting, the goal of therapy is to achieve a deep remission and to have as long a remission interval as possible. We know that with follicular lymphoma, subsequent rounds of therapy tend to lead to shorter durations of remission, and our expectation, and we believe that if we can achieve a deep and durable remission patients are likely to do better over the long run. I would argue that in the present era we have to consider, for example, COVID-19 infection in deciding when to initiate therapy. For patients who require treatment unequivocally, we give therapy, but if there is some consideration to watch and evaluate or follow expectantly, we will occasionally consider delaying therapy to allow for, for example, response to a vaccine or to minimize the risk of infection. There are practical considerations that come into play or consideration when deciding when to initiate therapy.

I would agree with the approach taken in this patient. She received appropriate therapy with a combination of chemotherapy that has documented activity and an antibody, obinutuzumab. These have been demonstrated in combination to evoke a very deep remission that’s durable for the frontline treatment of follicular lymphoma. There are other considerations. If at all possible, I look for an investigational trial if available. There are trials comparing antibody-based therapy alone to antibody-based therapy with a targeted inhibitor. So when, and if at all possible, I explore the option of a clinical trial. There are patients who have a low bulk or low volume disease who may be able to be treated without chemotherapy as we have utilized in some studies in the past. Again, challenges that can occur are related to the patient’s overall health and their comorbidities. In our hypothetical example here, we’re dealing with a younger patient who had otherwise been healthy, but in a much older patient who may have cardiac problems, renal problems, pulmonary problems, or a history of infection, there has to be tailoring of the approach and that sometimes means altering the chemotherapy schedule or adjusting the treatment in some fashion.

Goals of therapy and variables that affect how patients with newly diagnosed follicular lymphoma are managed with chemoimmunotherapy in the frontline setting, including during COVID-19.

Newly Diagnosed Follicular Lymphoma: Frontline Treatment Decisions

: For risk stratification, I follow current guidelines as well as get a general clinical assessment of the patient. The primary question always is, does this patient have symptoms or objective findings that would warrant treatment as opposed to expecting observation or as many of us call it, watch and wait? The other question is, are there features that concern occult transformation? This is an instance where a PET [positron emission tomography] scan can be quite helpful as was used in this case. And if there’s an area of intense FDG [fluorodeoxyglucose] uptake, where we suspect there may be transformation gene aggressive lymphoma, we’ll often pursue that with a biopsy to evaluate that. I do calculate the FLIPI [Follicular Lymphoma International Prognostic Index] because I think it’s helpful in understanding the burden of disease and the overall prognosis. And of course, that includes the age, the stage, the baseline hemoglobin, the DLDH [dihydrolipoamide dehydrogenase], and the number of noble sites. When deciding whether a patient needs treatment, we’re keen on their symptoms. Is there any obvious organ function that might be threatened, do they have cytopenias, do they have bulky disease, and are they progressing rapidly? When patients are considered for enrollment in clinical trials, we use objective criteria like the GELF [Groupe d'Etude des Lymphomes Folliculaires] criteria, which define bulk as 3 sites greater than 3 centimeters or a single site or more than 1 site greater than 7 centimeters, B symptoms splenomegaly, effusions, cytopenias, or leukemia. In this hypothetical case, the patient has several features that warrant initiation of therapy. We have learned from registration and observational studies that the FLIPI, while important, doesn’t tell the entire story. There are patients who can have a low FLIPI score who do poorly and patients who have a high or aggressive FLIPI score who may in fact do well. So there have been attempts at looking at other molecular measures, such as the TMTV [total metabolic tumor volume], the M7-FLIPI [M7-FLIPI incorporates the FLIPI score and mutational status from 7 genes], and other multigene models. But at the present time, I don’t use these in deciding initial therapy for patients with follicular lymphoma. As far as molecular features, I rely on the baseline and basic features that are required for diagnosis. This includes the hemostatic chemistry performed by the pathologist as well as translocation studies, and in some cases molecular studies to confirm we in fact have follicular lymphoma.

Recommendations for assessing and risk stratifying patients with newly diagnosed follicular lymphoma, with special considerations regarding the current role of molecular testing.

Daniel Greenwald, MD | Authors

Articles

Tailored Treatment Approaches for Newly Diagnosed Follicular Lymphoma

Managing Early Progression in Follicular Lymphoma

Maintenance Therapy for Newly Diagnosed Follicular Lymphoma

Newly Diagnosed Follicular Lymphoma: First-Line Anti-CD20 Therapy

Newly Diagnosed Follicular Lymphoma: Frontline Treatment Decisions

Criteria Used in the Initial Diagnosis of Follicular Lymphoma