Fakhri Reviews Considerations for Second-Line Therapy in DLBCL

Bita Fakhri, MD, MPH, is a hematologist-oncologist who is an assistant professor, Division of Hematology and Blood Marrow Transplant, University of California San Francisco School of Medicine. Fakhri cares for adult patients with Hodgkin's lymphoma, non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL).

Five years ago this month, FDA approved the first chimeric antigen receptor (CAR) T-cell therapy, in which a patient’s own cells are modified and then infused back into the body to help the immune system attack cancer. Today, many of Fakhri’s patients receive CAR T-cell therapy for diffuse large B-cell lymphoma (DLBCL), and recent advances have seen the treatment used earlier in the course of a patient’s care.

Fakhri spoke to The American Journal of Managed Care® (AJMC®) about the many treatment options for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma.

This interview has been edited lightly for clarity.

AJMC®: The treatment landscape for R/R DLBCL has evolved, with many new therapies now available. Can you discuss the current treatment landscape? What clinical or patient-specific factors should be considered when selecting therapy?

Fakhri: As you said, the treatment for relapsed/refractory DLBCL has significantly changed in the past year with 2 large positive trials. The ZUMA-7 trial involved randomized patients with early relapsed or primary refractory diffuse large B-cell lymphoma to receive axicabtagene ciloleucel (axi-cel) CAR T-cell therapy versus the standard of care, which was autologous stem cell transplant. It was a positive study, which resulted in the approval of CAR-T therapy, the axi-cel product, in primary refractory or early relapse patients as a second-line of therapy. And the other trial, the TRANSFORM trial, randomized patients with early relapsed or primary refractory diffuse largely B-cell lymphoma, to receive the lisocabtagene maraleucel (liso-cel) CAR-T product, versus autologous stem cell transplantation. And that was also a positive study. So, now high-risk, relapsed/refractory patients that are defined as early relapse or primary refractory have the option of getting a CAR-T product in the second line.

There are also some palliative options available, including tafasitamab and lenalidomide, which are based on the L-MIND trial. This presents an option for transplant-ineligible patients in the second-line setting—or for patients who have failed an autologous stem cell transplantation or CAR-T-cell therapy, as a later line of therapy, with really good results. And then we also have the CD-19 antibody-drug conjugate, the loncastuximab tesirine, which was also approved in the third-line setting for patients with relapsed/refractory diffuse large B-cell lymphoma. And, last but not least, the combination of chemoimmunotherapy, bendamustine and rituximab (BR) plus C-79 antibody-drug conjugate polatuzumab vedotin, was also approved in Europe in the second-line setting and in the United States in the third-line setting.

So, to summarize, we have the CAR-T product in the second line setting and, of course, as a later line of therapy; and then tafasitamab-lenalidomide, loncastuximab, and BR+polatuzumab (pola) are all options that have made their way to the treatment armamentarium for patients with relapsed-refractory diffuse large B-cell lymphoma.

In terms of clinical or patient-specific factors, it matters which line of therapy we are considering. Is it the second line of therapy or the third line of therapy? In the second line of therapy with high-risk disease, early relapse, or primary refractory setting, CAR-T makes perfect sense if a patient has the performance status to go through CAR-T therapy. And other treatments, a lot of it depends on the side effect profile of the treatment combination that we are using and patient comorbidities. Basically, reconciling the side effect profile and patient comorbidities, to make sure that patients are going to, not only respond to these treatments but also tolerate these treatments. Unfortunately, with the growing options, patients should have a say. So, it is also important for patients to express their preferences when choosing a treatment option.

AJMC®: Treatment emergent adverse events (TEAE) are quite common among some of the novel agents for DLBCL and can lead to discontinuation. What are the most common TEAEs seen in practice and how are they managed?

Fakhri: That’s a great question, because our goal should not only be prolonging patient survival but also providing our patients with a quality of life that is acceptable, so that they can enjoy the time that they have. So, in terms of CAR T-cell therapy, toxicities fall into two categories: acute toxicities or early toxicities, and late toxicities. Early toxicities include cytokine release syndrome (CRS), which is a result of cytokine release after administering CAR-T therapy. Fortunately, we've become really good at managing CRS with tocilizumab, steroids, or other novel agents that are currently being investigated in clinical trials, such as anakinra. And then, we have the other major acute side effect, which is neurotoxicity. That’s when these inflammatory markers cross the blood-brain barrier and go into the central nervous system. And we have learned to manage that toxicity with the administration of steroids as well. Then, we have late toxicities associated with CAR T-cell therapy, particularly cytopenia. So, for patients who receive CAR-T therapy, it might take them a while to recover their [blood] counts. Also, [there is] hypogammaglobulinemia, meaning lowering of the patient’s IgG, which can potentially increase the risk of infections. These are all really important factors, particularly when we are living in the era of a global pandemic.

In terms of novel agents, with [tafasitamab and lenalidomide] the major side effect is cytopenias; tafasitamab is a CD19 monoclonal antibody, and lenalidomide is immunomodulatory agent, which has been associated with cytopenia. So, I think the association of cytopenia with this combination becomes less as the patients go through the first year of treatment, because the second year is single-agent tafasitamab maintenance. But that being said, I give a lot of patients dose reductions of lenalidomide. We lower the dose to a level that they can tolerate it.

Also, lenalidomide is associated with a slightly increased risk of venous thromboembolism, or VTE. So, we always make sure that these patients are on some sort of anticoagulation, at least a low dose of aspirin. And we get them through the cytopenias with those reductions and sometimes with [treatment] delays. Giving a patient a treatment holiday is reasonable, especially if they're doing well and their disease is not raging anymore. With BR+pola, again, cytopenia is a major limitation. That's why we may have to reduce the dose or delay the dose to make sure that patients' bone marrow recovers, so that they can get further doses. And with loncastuximab, there are an increase in GG, is a side effect. Honestly, we don't know whether it has any clinical significance or not. For the majority of patients, other liver markers are totally fine.

Effusions are an issue, which we can manage with diuretics and steroids if necessary. And I always warn patients about photosensitivity, just so they know what to expect. So, the side effects are real, but with clear communication between physician and patient, by checking labs, by making sure that we listen to our patients and addressing what they're complaining about, we can get them through these treatments.

AJMC®: Chemoimmunotherapy followed by high-dose therapy with autologous stem cell rescue is the appropriate treatment for R/R DLBCL that is chemotherapy-sensitive at relapse, in patients who are candidates for transplant. What are some factors that would make a patient not a candidate for transplant?

Fakhri: That's a great question. So, one of the things that most centers look at is age. But we have gotten to a point that age is not a surrogate for aging. So, if we see a patient who's 80 years of age, we shouldn't automatically assume that they're not going to be a candidate for transplant. We should pause and think hard about it. There are some 80-year-old patients out there, with really good performance status and minimal comorbidities, who are very active at baseline. And for those people, age alone should not be a factor to deprive them from receiving potentially life-saving therapies. So, age is a factor where I pause, and I try to investigate and make sure that I don't have an age approach in my practice. The other thing is comorbidities. You know, to undergo autologous stem cell transplantation, you must have a good heart. And that's not negotiable. You must have good lungs—that’s not negotiable. So, we must make sure there are no major cardiovascular and pulmonary comorbidities. And if there are problems, some of those problems can be an absolute contraindication. And sometimes, if the level of severity is not too bad, we try to optimize patients before going into transplant. We try to work with cardiologists and pulmonologists if we have the luxury of time.

Unfortunately, a lot of times we do not because the disease is raging, and the patient needs to get an autologous transplant soon enough. But if you have the luxury of time, we try to work with our consultants to optimize the organ before going in for the transplant. And with the majority of other comorbidities, they're manageable. You know, we must make sure that we are on top of diabetes management to prevent long-term complications from hyperglycemia, which can get worse than with the use of steroids throughout the transplant or peri-transplant phase. For many autoimmune conditions, if they're well managed, they're not going to be a contraindication to receiving an autologous stem cell transplantation.

AJMC®: You contributed to the BRUIN study, evaluating pirtobrutinib in refractory B-cell malignancies. What was the objective of this study, and how was this study designed?

Fakhri: As you said, I was the [principal investigator] of this study. So, I'm biased. But honestly, I'm unapologetically biased because it has proved to be a great noncovalent [Bruton tyrosine kinase] inhibitor. Just a little background. So, BTK inhibitors made their way to the treatment of B-cell malignancies in 2013, with the approval of ibrutinib for mantle cell lymphoma, and then later to other B-cell malignancies. The covalent BTK inhibitor, they have 3 approved agents, ibrutinib, acalabrutinib, and zanubrutinib. They are great, but patients, a good number of patients, cannot tolerate these agents—either because of intolerance, side effects, or the patient develops a mutation such as 6481S mutation, or PLC gamma2 mutation—that prevents the drug from working because these are covalent BTK inhibitors. So, they require a very strict receptor shape, to be able to sit on the receptor and exert their function. And once there is a mutation in the receptor, they're not going to be able to do what they were supposed to be doing. And that's when noncovalent BTK inhibitors come into play, because they don't depend on that strict shape of the receptor. They bind, unbind, and rebind. They're more liberal in exerting their function.

The BRUIN study is a phase 1/2 study, which means it evaluated dose escalation and dose expansion. And the major, primary endpoint of the study, was like any other phase 1 study—safety and efficacy. So, making sure that it's a safe drug, find the recommended dose for the phase 2 study, which happened to be 200 milligrams daily, once a day. And then, we determined whether this dose has activity among a different range of B-cell lymphomas. And the overall response rate in [chronic lymphocytic leukemia] patients was 70%. The patient population on this trial was heavily pretreated. So, we have a great noncovalent BTK inhibitor that hopefully, is going to receive approval very soon, in the relapsed refractory setting for patients who have been intolerant to other BTK inhibitors, or whose disease have progressed on other BTK inhibitors.

The good thing is these studies showed that the results are [consistent] regardless of 6481 mutations. So, whether patients had 6481 mutations or didn't have the mutation, they both responded to this drug. And the response was seen regardless of the prior lines of therapy. There were patients who in our language were penta-refractory, meaning they had failed CD20 monoclonal antibodies. They had failed chemoimmunotherapy, BTK inhibitors, BCL2 inhibitors, and P3 kinase inhibitors, and they still responded to pirtobrutinib. And the response was also [consistent] regardless of the reason for discontinuation of previous BTK inhibitor, whether it was intolerance or disease progression. So, this is a promising agent that is currently being investigated in other trials, including phase 3 trials.

AJMC®: Are Any other key clinical takeaways, you wanted to share from that study?

Fakhri: I think pirtobrutinib is an exciting agent. And the next trials are going to investigate pirtobrutinib versus ibrutinib, in the basically frontline and relapse refractory settings. And there're also studies going on combining pirtobrutinib with BCL-2 inhibitors, with the idea of time-limited therapy. So, not only from the BRUIN study, but I think the advances in the field in the past few years, have really revolutionized the field of B-cell lymphomas from diffused large B-cell lymphoma to indolent lymphomas, including CLL. So, it's never a good time to have lymphoma, but it's no better time to have lymphoma than now.

AJMC®: What are some important clinical patient characteristics to consider, when selecting various second-line therapies such as tyrosine kinase inhibitors?

Fakhri: So, in picking Bruton's tyrosine kinase inhibitor, again, we have the decision between covalent and noncovalent. [We have a consideration] if someone has a treatment-naive disease and has never been treated before. Currently, the only approved covalent BTK inhibitors that are ibrutinib, acalabrutinib, and zanubrutinib. Ibrutinib is associated with about 17% atrial fibrillation, which is quite high, especially if a drug is supposed to be continued potentially lifelong. The other major side effect associated with ibrutinib is the increased risk of hemorrhage—about 5%. Also, arthralgia and myalgia, which can be really debilitating if someone is supposed to be on a medicine lifelong. So, if someone has poorly controlled atrial fibrillation, or they've had any life-threatening bleed in the past like brain bleeds or any GI bleed, I definitely pause.

Fortunately, the new generation, the newer generation of covalent BTK inhibitors are better tolerated, and they're associated with a better side effect profile. So, acalabrutinib, the rate of AVB is still there 5%, but in general, it's better tolerated because it's more specific toward the BTK enzyme. The side effect associated with acalabrutinib is headaches, but fortunately, it's manageable. And it mostly happens in the first 2 cycles after we start patients on acalabrutinib. And then, the newest agent, zanubrutinib, is the best tolerated. The rate of atrial fibrillation is about 2%. The only drawback is, zanubrutinib in practice, has been associated with neutropenias. And I have to go to [granulocyte-colony stimulating factor], and basically support the patient's white blood cell count, to be able to remain on zanubrutinib. All 3 of them are equally effective, and a huge opportunity for patients with B-cell malignancies. But it's very important to know the exact side effects and patients' comorbidities and pick the right one for the right patient.

One last thing: in pirtobrutinib, I think the best testament to drug tolerability is the rate of discontinuation. So, among 600 patients who are on pirtobrutinib for different kinds of B-cell malignancies, only 6 patients had to come off because they couldn't tolerate, which is only 1%. And that's pretty impressive, for any agent.

AJMC®: Would you like to provide any additional thoughts on disease management considerations for DLBCL, that you find noteworthy to share with colleagues?

Fakhri: Definitely. For, our community partners, I recommend that they refer patients for CAR-T therapy as soon as possible, because it takes time. CAR-T therapy is not an off-the-shelf product. We have to collect the T-cells, and then send it to the companies for the manufacturing, process, which takes about 1 month. Often, these patients cannot wait that long. So, as soon as a patient does not respond to the first line of therapy, please refer them to an academic center, to be considered for CAR T-cell therapy. We always work with our community partners if bridging therapy is needed to just stabilize the patient as much as possible until the CAR-T product becomes available. We always talk to our community partners to administer the regimen mutually. And so, early referral in CAR-T therapy is key.

It’s also important, because now we have all these options like tafa-len, loncastuximab—or lonca for short—and BR plus polatuzumab. And even an agent that I use less frequently in clinic called selinexor, which is an XPO1 inhibitor. All these agents are available for patients with relapsed/refractory disease. But I think as academicians, we have a responsibility to come together and design randomized control trials, to compare them in a head-to-head fashion, to see how they're going to act in terms of survival and tolerability for our patients. Those are my messages: To our community partners—early referral for CAR-T therapy. And to my academic colleagues, we need randomized control trials, to compare these agents in a head-to-head fashion.