Treatment Plans for Relapsed/Refractory Patients with DLBCL

Diane Lee

Hi Ashley, we discussed the background and overview of DLBCL and first line therapies in our first conversation. I’d like to talk about the treatments that are available for patients who unfortunately relapse or are refractory to their first line therapies.

Ashley Ames

First and foremost, when we have a patient who has either primary refractory disease, meaning that they don't have an adequate response to treatment, or relapsed disease, meaning the disease comes back after they achieve a complete remission, we need to obtain a biopsy to confirm pathology. At first relapse or primary refractory disease, it’s always important to make sure that we are in fact dealing with large-cell lymphoma and that this does not represent a second primary lymphoma or other malignant process. Once we have pathology confirming the diagnosis of large-cell lymphoma, we look at the time frame of relapse.  

For those who relapse in less than a year after completing treatment, or for those who have primary refractory disease, we utilize consolidative therapy with chimeric antigen receptor (CAR) T-cell therapy. We're going to talk a little bit more about that shortly. But first, with those who relapse over a year after completion of treatment, we utilize high-dose chemotherapy and autologous stem cell rescue as consolidative therapy. So, it's important to recognize which patients will receive what consolidative therapy. When we're talking about second line treatment, standard of care utilizes salvage chemotherapy with platinum-based therapy. We have several different regimens. For example, RICE (rituximab, ifosfamide, carboplatin, and etoposide), R-DHAOx (rituximab, dexamethasone, cytarabine, and oxaliplatin), R-GemOx (rituximab, gemcitabine, and oxaliplatin), and of course, if appropriate, clinical trial.

Diane Lee

So, how do you determine who is a good candidate for high-dose therapy and autologous stem cell transplant?

Ashley Ames

When we look at candidates, we look to see how physically fit they are, their performance status, and we also want to take into account comorbidities and age. Unfortunately, age does play a role in high-dose therapy and autologous stem cell rescue. Sometimes we are able to safely transplant elderly patients, but other times, if the patient has poor performance status and multiple comorbidities, we're not able to proceed with autologous stem cell rescue. We sometimes refer these patients for CAR T-cell therapy. So, the decision to proceed with high-dose therapy and stem cell rescue is individualized. We review potential benefits versus risks, we take into account comorbidities, and status of the underlying disease. When we determine that a patient is in remission (from salvage therapy),medically fit with the goal of achieving long-term remission and still curative intent, those patients are then referred to our colleagues on the bone marrow transplant service for further discussions about proceeding with transplant.

Diane Lee

We’re really fortunate here at MSK to have a geriatric consult service. The consultation is very helpful  when we have elderly patients who we're on the fence about and just in general when we’re caring for them. We get their expert weigh-in on how they think a patient will fare during a transplant or CAR-T.

Ashley Ames

Absolutely. Once we determine that a patient is going to proceed with transplant, we then have to go through with what we call apheresis. Diane, can you tell me a little bit about apheresis?

Diane Lee

An apheresis machine is very similar to a dialysis machine, where an IV is placed in the patient either centrally or peripherally, and it's used to collect the patient's whole blood. The apheresis machine then separates the stem cells from the whole blood, and that's when the stem cells are collected. The whole blood is then returned and reinfused into the patient through another IV line. The process can take between one and five days. We need to collect a minimum of 5-7 million cells which are then preserved in a lab. 

While patients are also undergoing a pre-transplant workup, we also send them for a dental evaluation because they need to evaluate for any dental work that might be needed prior to transplant, such as a tooth extraction. We also evaluate for appropriate organ function, so our patients get pulmonary function tests as well as echocardiograms. Our patients also go through another bone marrow biopsy and aspirate to ensure that there is no bone marrow involvement prior to undergoing transplant. Another very important aspect is having social work involved with these patients because we need to ensure that they have psychosocial support and are assessed for any needs that they may have during and after transplant. Ashley, what are the next steps after going through the pre-transplant workup? What are patients to expect?

Ashley Ames

Once we have the cells collected and patients complete their pre-transplant clearance where they're deemed appropriate for the transplant, we move on to a conditioning regimen. This is that high dose chemotherapy portion that we talked about earlier. One of the most commonly utilized regimens is BEAM (BCNU [Carmustine], etoposide, aracytin, and melphalan) chemotherapy. Again, we utilize different chemotherapies because we attack cells at different points of cell growth. Patients will receive the BEAM regimen for several days before their stem cells are re-infused. The day that the stem cells are re-infused is considered day zero. 

The stem cell infusion is very similar to a blood transfusion. There are different safety checks depending on your institution. Patient's vital signs are monitored very closely. Sometimes depending on insurance, or sometimes depending on the patient and their performance status, they are either admitted to the hospital or they receive their stem cell transplant in the outpatient setting with very close follow-up. And once we reinfuse the stem cells, it's really just waiting for count recovery and assessing potential toxicities. 

One of the toxicities that we see is pancytopenia. A lot of these patients require blood transfusions and blood products because the chemotherapy is so potent. Patients are at higher risk for infection, so they are monitored very closely. Patients can also have gastrointestinal side effects. Some patients have very bad mucositis, sometimes requiring IV pain control. Other times patients have GI distress such as nausea, vomiting, and/or diarrhea. Patients who experiencing these symptoms are often hospitalized or remain hospitalized in order to receive appropriate care and close monitoring. 

Diane Lee

One of the major misconceptions from our patients is that they think the transplant is their treatment, when in fact it is the high-dose therapy that they receive prior that is actually the treatment for the lymphoma and the transplant is the rescue to help them recover from the high-dose chemotherapy.

Ashley Ames

Absolutely, that's a great point and I think that's also a really good learning point for our providers. 

Diane Lee

As you mentioned, some of the follow-up care that the patients need due to these side effects and effects from the transplant include frequent follow-up in an outpatient clinic setting and frequent physical examinations including lab tests. At day 100 they get a PET scan. If the patient is in complete response, they are then followed once every three months for two years with a scan every six months. If a patient remains in complete response after two years post completion of their transplant, then the interval between follow up visits is increased to every six months. And at that point we no longer get standard surveillance imaging. It's only done if clinically indicated. We follow patients for 10 years post-transplant.

Ashley Ames

I think one of the really important things to talk about is that someone might ask, "Why do we monitor them for so long? Ten years is a really long time." One of the reasons that we monitor patients for that long is because there are long-term toxicities and there is a significantly increased risk for developing a secondary malignancy such as myelodysplastic syndrome. These can develop 8 to 10 years post-transplant and that's why it's so important to follow these patients for the full 10 years post stem cell transplant. 

Switching gears, we talked a little bit about CAR T-cell therapy. This is a little bit different. It’s a form of genetically modified immunotherapy that uses a patient's own T lymphocytes to attack and kill cancer cells. Back in 2017, the FDA approved CAR T-cell therapy as third-line treatment for patients with large-cell lymphoma. However, through vigorous clinical trials and research, CAR T-cell is actually approved in second-line therapy for large-cell lymphoma for those who either have primary refractory disease or for those who have relapsed within a year of completing frontline therapy. Diane, can you tell us a little bit about the role that CAR T-cell therapy plays in large-cell lymphoma?

Diane Lee

Yes, CAR T-cell therapy is quite exciting because it fits the unmet need of our patient population. About 24% of these patients relapse, as you were saying, following high-dose therapy in autologous stem cell transplant. Approximately half of these patients with refractory B-cell lymphoma achieve complete remission in response to CAR-T, which is directed against CD19. And while the overall durability of these responses remains to be determined since it's still a relatively new therapy, some patients have remissions that have been sustained for at least three years at this point, which is very exciting. There are various CAR-T products, as there are different drugs that are used in the same drug class, and each CAR-T product has subtle structural differences, although they're all directed against the same antigen of CD19. Ashley, how do you determine what patients are eligible for CAR-T therapy?

Ashley Ames

It is somewhat similar to the process that we utilize for high-dose therapy and autologous stem cell rescue, but we know that we are able to safely utilize CAR-T cells in our geriatric patients. While there are side effects, because we are not using high-dose therapy, we are able to administer this quite safely in our geriatric patients and provide curative intent. I think one important thing that is quite different with CAR T-cell therapy as opposed to high-dose therapy and stem cell rescue is that we know those patients with large-cell lymphoma don't have to be in a complete remission to proceed with CAR T-cell therapy. Whereas with high-dose therapy and stem cell rescue, you absolutely need to be in remission before proceeding. 

The collection process of CAR-T cells is quite similar to the apheresis process with stem cell therapy. However, instead of collecting stem cells, we collect T lymphocyte cells. When we utilize CAR-T cells, we have to think about potential side effects. The biggest side effect that we are most familiar with is cytokine release syndrome which is a constellation of various symptoms that occur when there's inflammation caused by the T-cells. Patients can present with fevers, chills, fluctuations in their blood pressure, and have abnormal labs. So, cytokine release syndrome is often treated with a combination of tocilizumab, which inhibits IL-6 activity, as well as dexamethasone. There’s higher risk for cytokine release syndrome when there's a high burden of disease, but most patients were able to effectively treat cytokine release syndrome. Diane, can you talk a little bit about some of the neurologic toxicities we can see with CAR-T cells?

Diane Lee

Yes, another major side effect that we have to monitor closely for is neurotoxicity and the mechanism of the neurotoxicity is not entirely clear. We do know that CAR-T cells cross the blood-brain barrier and potentially infiltrate the CNS, or the central nervous system. But interestingly, clinical trials have shown that those with CNS involvement are not necessarily at higher risk of neurotoxicity compared to those without CNS involvement. So, with neurotoxicity we monitor for symptoms including headache, any mental status changes or confusion, encephalopathy, and seizures. And we have seen cerebral edema, which has been fatal in some patients. The majority of these symptoms are reversible, and management can include steroids and anti-seizure prophylaxis during hospitalization. Some of the other challenges that we face with CAR-T, which I think is worth noting, is access to care and availability of CAR-T therapy. It is limited to qualified institutions and therefore it's not readily available to patients in rural areas. Also, CAR T-cell therapy is quite expensive. Axi-cel (axicabtagene ciloleucel) is about $373,000 and tisa-gel (tisagenlecleucel) is about $475,000.

Ashley Ames

One of the other issues that we run into is production of the CAR-T cells. The CAR T-cell production can take anywhere from three to four weeks. That being said, we sometimes can run into issues when the CAR T-cell product is being manufactured. And obviously we know that lymphoma is very aggressive, so we have to incorporate bridging therapy or some form of chemo-immunotherapy treatment after the patients have their T-cells collected and we wait for the product to be finalized. So that's always something to keep in mind when we're referring patients for CAR T-cell therapy. 

Diane Lee

Thanks, Ashley. There are so many new advances in the treatment of DLBCL, it's quite exciting.

Ashley Ames

It really is. Thanks for chatting today, Diane. I look forward to our next conversation.