From Presentation to the Management of Side Effects, an Overview of DLBCL

Diane Lee

Hi Ashley. I’d like to start by providing a quick overview of diffuse large B-cell lymphoma or DLBCL for any practitioners who are new to lymphoma. DLBCL is an aggressive form of B-cell non-Hodgkin's lymphoma and the most common type of non-Hodgkin's lymphoma. It is a malignancy of the mature B-cell lymphocytes. When patients present to us, they usually come with unilateral, painless adenopathy. They may or may not have what we call constitutional or B symptoms, such as fevers, chills, drenching night sweats, unintentional weight loss, and fatigue that limits their ability to perform their daily activities. I'm not sure if you've seen it in your practice, but about 60% of patients actually present with advanced stage disease, which is stage III or IV. Patients may also present with extranodal disease and that can involve their gastrointestinal tract, testes, thyroid, skin, breast, bone, or central nervous system. Because this is such an aggressive disease, prompt diagnosis is essential. Can you talk about what you do for diagnostic workup for your patients? 

Ashley Ames

Yes, you are absolutely right. Large B-cell lymphoma is a very aggressive form of lymphoma and patients presenting with suspected large cell lymphoma need a diagnosis quickly so that we can treat them appropriately. The gold standard for diagnosis in DLBCL is either a core biopsy or excisional lymph node biopsy. These biopsies provide adequate tissue samples so we can run multiple tests. A fine needle aspiration is another method of performing a biopsy, but we often do not utilize that with large cell lymphoma because with FNA the sample is often very small and we're not able to perform the full testing on that tissue. When we obtain a biopsy, the pathology is key. There are different subtypes of DLBCL and we classify these different subtypes by the immunohistochemistry, or what we call the Hans algorithm. 

Hans algorithm is an algorithm that assesses the immunohistochemistry, which are immunostainings or a process through which antigens or proteins are identified on the cell surfaces of the large B-cell lymphoma. Based on which proteins are identified, we're able to subclassify the large cell lymphoma. For example, we have different subtypes, including germinal center (or GCB) and non-germinal center (or activated B-cell subtypes). Another method of testing that we use is cytology testing. Specifically, we use FISH studies and these evaluate for gene rearrangements. We typically look at rearrangements of C-MYC, BCL6, and/or BCL2. Those with another subclass of lymphoma called high-grade lymphoma have C-MYC rearrangement and/or BCL6 or BCL2 rearrangement and that disease process is much more aggressive. Once we have a diagnosis, the next important step is staging. Diane, can you talk a little about how we stage patients for large cell lymphoma? 

Diane Lee

Yes, and I'm glad you brought up the difference between a core biopsy and a fine needle aspiration because I feel like I see a lot of patients who get an FNA before they come to see us and they typically wonder why we have to get a second biopsy. As you were saying, to be complete with our workup and determine staging, we have to have imaging. We always start with a PET-CT as the PET scan helps evaluate for metabolic activity and active disease within the body. A higher activity level is usually associated with a more aggressive disease and that's usually notated by an SUV value, which stands for standardized uptake value in the PET scan. 

We do a combination of CT scan imaging, which helps us evaluate the size of lymph nodes. For baseline blood work, we get a CBC, comprehensive metabolic panel, LDH, and uric acid. We also check viral serologies HIV, hepatitis B and C, Epstein-Barr virus, and cytomegalovirus, as well as their peripheral blood flow cytometry. To be complete with staging, we usually do a bone marrow biopsy and aspirate because we want to check to see if there's any bone marrow involvement, and we consider doing a lumbar puncture to see if there's any CNS involvement of the lymphoma. 

With all this information we can proceed with the staging of DLBCL. Stage I is when there's a group of lymph nodes that's only in one area. Stage II is when they have two or more groups of lymph nodes that are on the same side of the diaphragm, either above or below it. Stage III is when they have lymph nodes above and below the diaphragm, with or without involvement of their spleen. And stage IV is when there are lymph nodes above and below the diaphragm with or without spleen involvement with bone marrow, peripheral blood, or extranodal disease involvement. Can you explain a little bit about what IPI score is and how the prognosis is determined?

Ashley Ames

Absolutely. Once we have completed full staging assessments and diagnostic assessments, we assess prognosis based off of the International Prognostic Index. This is a tool that we utilize to determine if patients have low-risk, medium-risk, or high-risk disease. We often refer to the International Prognostic Index as the IPI. It's on a scale of zero to five. A higher score is associated with a poorer prognosis. There are five different areas that we assess to determine the prognostic score. One acronym that I've found very helpful is APELS. A is for age; we assign one point for patients who are age 60 or above. P is for performance status; we evaluate how well patients are performing in their everyday lives. Patients with large cell lymphoma who have this diagnosis but are still able to carry out their daily activities do not get a point. But those who are quite sick or ill or unable to carry out their daily activities, they get assigned one point for performance. 

We then look at E for extranodal sites of disease; if there are one or more extranodal sites of disease, we assign a point. L is for LDH; when we see an elevated LDH a patient gets a point. Last but not least, S is for stage; those with stage III or IV disease get assigned a point. The lower the IPI score, the more favorable prognosis a patient has, and the higher the score, the poorer the prognosis. Once we have all this diagnostic information and risk stratification is performed, it's really important that we start treatment urgently. We know that if patients go untreated, the lymphoma will continue to grow. It can spread into vital organs and cause organ failure and can even lead to death if untreated. Diane, can you tell me a little bit about what frontline treatment we use for large cell lymphoma?

Diane Lee

Sure, I have to say I love the acronym APELS. I never heard that before. Another way to figure out the IPI score if you don't remember the APELS acronym is the scoring calculator at mdcalc.com. And as you said, DLBCL is a very aggressive cancer, but we do treat with curative intent. The backbone of standard of care treatment has been R-CHOP for many, many years. It's a combination of five medications. The R is for rituximab, which is an anti-CD20 monoclonal antibody, in combination with C for cyclophosphamide, H for doxorubicin hydrochloride or hydroxydaunomycin, O for vincristine or oncovin, and P for prednisone. 

We use multiple agents at the same time because we've seen that it actually helps kill the cells during various cycles of cell growth. I have a lot of patients who ask why we use prednisone. It helps induce apoptosis of the lymphoma cells. That's a pill that the patients take for five days following their infusion of R-CHOP therapy. When patients are starting treatment it's really important for us to discuss the common and potential side effects. The things that we see commonly are gastrointestinal side effects, including nausea and vomiting. Constipation is a very big side effect and it's important to have an aggressive bowel regimen for our patients. They must have a bowel movement at least once every one to two days. They need to call us if they do not have a bowel movement in 48 hours. We explain that not having a bowel movement or having very bad constipation can lead to a medical emergency if it causes a bowel obstruction and, worst case, a bowel perforation. Patients don't realize that chemotherapy, in this case vincristine, can cause constipation. We reiterate that we’re not talking about your normal, "I haven't gone to the bathroom for a few days" prior to treatment, this is actually being caused by the chemotherapy and it's very, very important for them to contact us and let us know if it’s happening. If a patient is having diarrhea on the other hand, we stress that they contact us because diarrhea will have us concerned for dehydration and possible electrolyte imbalances. We would also consider stool studies in the right clinical situation to rule out an infectious cause. Another common side effect can be neutropenia. So based on age, sometimes we'll use growth factor with treatment. We’re always concerned about a fever, so if a patient has a fever of 100.4 or greater, they have to call us. If they have neutropenic fever, they need to be admitted into the hospital for IV antibiotics. 

Another common side effect is paresthesia from vincristine. It's important for us to constantly monitor patients for peripheral neuropathy; we can always dose-reduce or omit the vincristine in certain appropriate clinical scenarios. When we are discussing treatment, we must obtain a good social history, especially with regard to their occupation. We need to know and be familiar with whether it's an occupation that requires them to use their fine motor skills. Like with a police officer, we want to make sure they are able to use firearms appropriately. Or if you have a patient who's a surgeon or artist, you want to be careful because they need to maintain their fine motor skills. Or if you have a singer, you want to be aware of rare but possible vocal cord paralysis. These are things that we keep in mind when we're treating our patients because we want to maintain their quality of life after treatment.

Ashley Ames

That's a lot of great information. Regarding treatments, we know that for decades R-CHOP has been the standard of care. However, more recently the FDA approved a newer regimen, pola-R-CHP, based off data from the POLARIX trial¹, a phase three double-blind placebo-controlled trial that compared R-CHOP, the standard of care, with a newer combination of drugs. One of the investigational agents was polatuzumab vedotin. This is an antibody drug conjugate that targets CD79b, which is expressed on the surface of malignant B cells. 

The trial evaluated R-CHOP against rituximab, cyclophosphamide/doxorubicin/prednisone, and polatuzumab. After the median follow-up of 28.2 months, patients in the investigational arm had a significantly higher progression-free survival compared to those on the standard of care arm. In April 2023, the FDA approved the pola-R-CHP regimen, and we're utilizing it quite frequently in those with intermediate- or high-risk large cell lymphoma. The side effect profile is quite similar to R-CHOP. Polatuzumab vedotin's side effects are very similar to vincristine. What I find really exciting is that for decades we've been using the same regimen but now we have a more efficacious regimen, which is particularly helpful in those patients with intermediate- and high- risk large cell lymphoma.

Diane Lee

I agree, this is an exciting development in the treatment of DLBCL patients.