Brian T. Hill, MD, PhD, director of the Lymphoid Malignancies Program and staff physician at Taussig Cancer Institute, as well as an assistant professor of hematology and oncology at the Cleveland Clinic, discusses ​the safety profiles of BTK inhibitors in mantle cell lymphoma (MCL).

​Currently, the BTK inhibitors zanubrutinib (Brukinsa), acalabrutinib (Calquence), and ibrutinib (Imbruvica) ​are approved for the treatment of patients with MCL ​who have received at least 1 prior therapy.

BTK inhibitor​s can elicit bleeding and bruising as a class-specific adverse effect (AE), says Hill. Moreover, a patient may experience gastrointestinal toxicities, such as diarrhea, ​with BTK inhibitors; however, these ​AEs tend to be self-limiting, Hill says. ​More specifically, arthralgia is commonly reported in patients who receive ibrutinib; atrial fibrillation is also reported in about 5% to 10% of patients ​on ibrutinib.

However, less cases of atrial fibrillation ​are reported in patients who receive acalabrutinib orzanubrutinib. In addition, mild ​to severe headaches can be observed with acalabrutinib. Notably, the AEs ​uniquely associated with zanubrutinib are less established; however, further evaluation of the agent may lend additional insight ​into its specific safety profile in the future, Hill concludes.

Videos

Brian T. Hill, MD, PhD, discusses ​the safety profiles of BTK inhibitors in mantle cell lymphoma. 

Dr. Hill on the Safety Profiles of BTK Inhibitors in MCL

 R2-GDP-GOTEL is a phase 2 clinical trial that combined lenalidomide with a very well-known regimen for salvage chemotherapy, R-GDP, which consists of rituximab, cisplatin, dexamethasone, and gemcitabine. The patients were to receive lenalidomide from day 1 to day 14, in addition to the standard dose of R-GDP [rituximab, cisplatin, dexamethasone, and gemcitabine], up to 6 cycles. Patients who completed the regimen and had at least a PR [partial response] or complete remission [CR], they went on to receive lenalidomide as maintenance. They enrolled 79 patients, 78 patients were evaluated for efficacy and toxicity. The overall response rate was 59%, with a CR rate of 32%. The adverse events were mainly related to the chemotherapy, like thrombocytopenia and neutropenia, patients had rashes, also febrile neutropenia of course, reported in about 14% of patients. Further biomarker analysis showed that there was no difference in responses according to the cell of origin, and also the regimen was active in primary refractory lymphoma. Unfortunately, there were 4 toxic deaths in the study. That’s important to know when we add a new agent into our salvage regimen.

The conclusion is that this is an active regimen, it’s a phase 2. The question is whether this is better than the standard GDP [gemcitabine, dexamethasone, cisplatin]. The reported efficacy of gemcitabine, dexamethasone, cisplatin, the overall response rate is about 45%, with CR rates in the range of 13% to 15%. Keep in mind that the earlier studies didn’t include a PET [positron emission tomography] scan as mandatory to assess for CR rates, so we don’t really know the true CR rates in the earlier studies. That’s just to keep in consideration. Also, I would say that long-term follow-up is needed to see whether that matches the long-term efficacy of this regimen in these patients. Until we know whether we need to add lenalidomide to the gemcitabine, dexamethasone, cisplatin regimen in real life, I think it’s early to say. There were some toxicities and 4 deaths in a relatively small study. I think we should be careful. Whether we need to add it, I think the decision has to be made based on a larger study, or a phase 3 randomized study.

The Smart Start study is a single-center, phase 2 clinical trial that was presented by Jason Westin, MD, and colleagues from The University of Texas MD Anderson Cancer Center. It’s a trial that consisted of 2 phases. There was a lead-in phase of rituximab, lenalidomide, and ibrutinib for 2 cycles, followed by the combination plus chemotherapy. Whether it was R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin], it was physician discretion to decide which regimen the patient would go on. The overall response rate was 86%, with a CR rate of 36%, which is expected for lenalidomide and ibrutinib. There is not a high CR rate. But once the patients completed the chemotherapy part, up to 6 cycles, the overall response rate was 100%, with a CR rate of 95%. The 1-year PFS [progression-free survival]—the study has a short follow-up—was 95%.

The adverse events were expected as related to the chemotherapy agents used. There were some toxicities that we typically don’t see in patients who receive chemotherapy, like Aspergillosis. There was a patient who had CNS [central nervous system] Aspergillosis, and 1 patient who died of Aspergillosis, probably systemic Aspergillosis. That underscores the fact that adding another agent into a chemotherapy regimen could be complicated. There are descriptions of fungal infections with ibrutinib, especially in combination with steroids and cytotoxic agents, so that’s something physicians have to keep in mind.

The other interesting thing about this study is the time to initial treatment, that was about 24 days. The reason I’m pointing this out is it’s a little unusual for patients to wait 3 weeks or almost 4 weeks to start therapy, especially with an aggressive lymphoma. That tells us about a possible selection bias. You’re probably selecting the best patients, the more stable patients to do these therapies, whereas the sickest patients, the patient who was in the hospital with aggressive disease, probably is not eligible for this trial.

Overall, I think the combination showed activity in DLBCL [diffuse large B-cell lymphoma], it’s promising activity. Whether that will implicate a change in the standard of care, I think it’s early. We need to sort out this question in a randomized clinical trial, phase 3. Finally, we have to consider the cost, because you’re adding lenalidomide and ibrutinib, and that can easily be a costly therapy over 6 months. I think it’s a study that showed very interesting activity. Tolerability was acceptable. Some of the infections that we typically don’t see with the standard chemotherapy, such as Aspergillosis or fungal infections, were shown in this study, so that’s something we have to keep in mind when we decide whether to do this treatment. I wonder whether patients need to complete 6 cycles of chemotherapy. That’s something that needs to be studied. Probably fewer cycles of chemotherapy would be more convenient and may not impact efficacy. I believe there will be a follow-up study with fewer cycles of therapy to see whether that will be feasible.

Novel Therapies: R2-GDP-GOTEL and Smart Start 

The POLARGO study, as it’s called, is a large, global phase 3 trial that compares a standard chemotherapy regimen, R-GemOx, which is rituximab, gemcitabine, oxaliplatin. And the comparator arm is rituximab, gemcitabine, oxaliplatin with polatuzumab vedotin, which is an antibody-drug conjugate now approved for diffuse large B-cell lymphoma.

The purpose of this study is to demonstrate or test whether the introduction of this antibody-drug conjugate improves the outcome of patients with diffuse large B-cell lymphoma treated with rituximab, gemcitabine, oxaliplatin in the relapsed/refractory setting. This trial is ongoing, but I think there’s a fair amount of optimism that we may see a positive result here, which would improve or expand the number of treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma.

I think you’re referring to the LYSA trial presented at ASCO [the American Society of Clinical Oncology annual meeting], which was atezolizumab, a checkpoint inhibitor, with obinutuzumab and venetoclax in relapsed/refractory large cell lymphoma. This was a small number of patients.

I think 80%-plus of patients had at least 2 lines of therapy, and two-thirds of them were refractory to the last regimen. I don’t remember the exact number of patients, but the trial was reported with an overall metabolic response at the end of treatment of 24%, and an 18% complete metabolic response. It’s early for the follow-up, but this is again one of these combinations, a biological agent plus immunotherapy. That might bring an opportunity to the unmet need of patients who are not eligible for high-dose therapy, transplant, or potentially CAR [chimeric antigen receptor] T-cell therapy. It’s another example of the impact of immunotherapy as well.

I would like to summarize and say that this is a very exciting time in the field of medicine, particularly in lymphoma where we have been, for decades, doing R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], which remained as the standard of care default. But we definitely should be aware that this is not sufficient in a high-risk IPI [International Prognostic Index] patient, double hit, double expresser, and non-GC [germinal center] subtype, and other high-grade lymphoma that I alluded to previously. And I think that these patients should be recommended for clinical trials and probably more intensive therapy and maybe cell therapy consolidation, like the ZUMA-6 trial looking at CAR [chimeric antigen receptor] T-cell therapy as consolidation in patients who have double-hit lymphoma, high-grade lymphomas.

It is really not altered, but probably underestimated. But the future is the biological classification of lymphoma and trying to improve this curve that we see, to identify truly the high grade. And to do this, we need to have a baseline signature that is usable in routine and actionable. I think cell-free DNA, or circulating tumor DNA, is likely to be more usable and used in the future. As I mentioned, immunotherapy is more and more part of the induction or pre-phase consolidation. And again, given all the opportunities that I just mentioned tonight, it reflects on the fact that it is really important to encourage physicians to go to clinical trials, to participate. The reason being is that when you look, the impression is that large cell lymphoma now is a clinical result, the outcome is so great. But when you look at real-world data in high-risk patients, the outcome particularly in a high-risk patient is still very poor. So I would encourage physicians to look at clinical trials in this population as well. Thank you.

Novel Treatment Combinations for R/R DLBCL

We still have unmet needs for patients with diffuse large B-cell lymphoma. As I mentioned, for older patients in their 80s and above, even standard therapy with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] is very difficult to receive. And in those cases after failure of less intense regimens, such as mini R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], or bendamustine, or others, there is a significant unmet need for patients to be treated with targeted agents. Tafasitamab with lenalidomide is likely to be an option for those patients in the future, as well as selinexor, and polatuzumab vedotin, which is approved in combination with bendamustine/rituximab.

 I think overall in cancer, immunotherapy will continue to expand dramatically. I think more and more we’re going to try to combine small molecules, biological agents as sort of an induction with or without immunotherapy, and immunotherapy afterward as a consolidation. That’s 1 model. But there’s also lymphoma—more and more we see that we can, as I mentioned for example, the R-squared, ibrutinib window-type trials in the patients who are particularly non-GC [germinal center] subtype and frail patients can respond really well to this and have a shortened version of chemotherapy. And then there are ongoing trials looking at checkpoint inhibitors in combination with chemotherapy. BiTE [bispecific T-cell engager], as I mentioned, combination with trastuzumab, in combination with chemotherapy. More and more we’re going to integrate that.

And the third piece that is important is the role of immunotherapy as an immuno-consolidation post-induction. We know that cell-free DNA might help us with the depth of response in those patients. But we know that the patient’s immune status post-chemotherapy—although we don’t have a great way to quantify it, but based on the ratio data from the Mayo Clinic, for example, the ratio of lymphocytes to monocytes, across the board in a number of diseases and many subtypes of lymphoma—shows that it has a dramatic impact on the outcome. We don’t exactly know yet how to tackle this, but that’s an opportunity as a consolidation eventually. Definitely the question is more novel therapy, more immunotherapy, either in addition or to replace chemotherapy.

 With the new therapies coming to the clinic, how does cost affect your patients’ access to treatment? I’m sure that cost and access impact a patient’s and oncologist’s decision and, hence, care for therapies, especially for an aggressive disease like diffuse large B-cell lymphoma. Not only the cost of the drug itself, but also the cost of the logistics, such as in CAR [chimeric antigen receptor] T-cell therapy. There is a lot of cost implicated in treating the adverse effects, admission to the hospital, admission to the ICU [intensive care unit], the use of a caregiver, the caregiver has to be off work, the patients cannot drive for 2 months. There is cost in relation to that.

When you talk about the combination of tafasitamab and lenalidomide, I would think that it will be a top price for tafasitamab. But then you have to add the cost of lenalidomide, and whether insurance can cover part of the cost of lenalidomide, there may be a copay for patients. That should be considered in terms of the cost. Tafasitamab is a treatment that is given indefinitely. Patients get treatment for as long as they respond or for as long as they tolerate the medication. So that’s a cost because patients have to keep coming to an infusion center, they have to maintain a line. If they have complications related to the line, like infections or thrombosis, that adds to the cost because we have to treat those conditions. It’s important to consider those.

In the case of selinexor, which is a single oral agent, it will have definitely a top price. It doesn’t have the cost of hospitalization, it doesn’t have the cost of having an IV [intravenous] line. It’s an indefinite treatment, so if there is a patient who had a response, those patients have to remain on the drug for a long time. As far as I remember, in the trial some patients went on treatment for up to 3 years. That should be a consideration in regard to the cost. However, there are other costs that should be considered for selinexor. It’s a novel agent, has specific adverse effects that need to be taken care of, such as diarrhea, nausea, adding the medications to treat the nausea, adding the medications to treat the diarrhea. There are issues with cytopenias as well as thrombocytopenia. There are recommendations in the trial about using growth factors, they also have costs. So it is important to keep in mind when we use the novel therapies available, the other costs that are outside of the specific medications.

Relapsed/Refractory DLBCL: Unmet Needs

There is a potential for tafasitamab in combination with lenalidomide to significantly impact the treatment landscape for diffuse large B-cell lymphoma [DLBCL] in the relapsed/refractory setting.

As I mentioned, the standard approach really should still be CAR [chimeric antigen receptor] T-cell therapy for patients who are young and fit enough to receive this therapy. But for patients who relapse after CAR T cell, or who are unable to make it to an authorized treatment center for CAR T, or are of significantly advanced age or with poor performance status, in those cases more traditional pharmacologic therapies are likely to be needed. And they will probably cycle through on an ongoing basis as the patients will likely eventually lose their response to these agents.

In the case of tafasitamab, this is an anti-CD19 monoclonal antibody, which was studied in a phase 2 trial in combination with lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma. And what was reported and recently published was that a high proportion of patients, somewhere in the 40% to 50% range, achieved reasonably long-term remission with an impressive overall response rate of this combination.

With the anticipated approval of tafasitamab, in combination with lenalidomide for diffuse large B-cell lymphoma, I think we’re going to have more in our armamentarium and more options for patients with this disease.

The Re-MIND study was presented at the ASCO [American Society of Clinical Oncology] annual meeting. It’s an interesting study looking at lenalidomide as a single agent in the relapsed large cell lymphoma and to use it as real-world evidence to compare with the L-MIND trial, which was tafasitamab plus lenalidomide, where I mentioned the results were very impressive. This was to try to compare the outcome of this population with a combination versus a single agent. I think this was an important work because the awareness of the importance of real-world data is increasing rapidly. And these real-world data can confirm the clinical benefits of a new trial but also give you, if we can see a control group, although this was not completely matched as a control group, to suggest that the combination was really beneficial, with the anti-CD19 in addition to lenalidomide.

Emerging Treatments for Relapsed/Refractory DLBCL

The FDA approval for selinexor is anticipated this summer, and it is likely to be approved for relapsed or refractory diffuse large B-cell lymphoma [DLBCL].

The treatment landscape for diffuse large B-cell lymphoma is changing now that we have CAR [chimeric antigen receptor] T-cell therapy. It’s important to know that although a proportion of patients with CAR T cells may be cured, as I mentioned previously, with this therapy, 60% or more of the patients will not enter durable remission and will relapse.

For those patients, there are limited treatment options. Polatuzumab vedotin is a treatment option for those patients in combination with bendamustine and rituximab, which is approved in this setting. It’s anticipated that selinexor will also be approved in this setting.

This is an oral agent that can be used as a single agent in third-line therapy, as I mentioned, it was just approved. But I think the real benefit will be when we start to combine this with other agents, and hopefully have better disease control.

In my opinion, what I look at more is efficacy, how efficacious is a drug or a regimen. For patients with DLBCL, what I typically do is ask them what are their goals, if their goals are to cure the disease, or to maintain the disease in some type of remission, but no cure. If they want to achieve a cure and they’re healthy enough to do it and they don’t have a lot of significant comorbidities, I offer what is the standard of care, which is CAR T-cell therapy. That’s the main thing. I would say with all the CAR T-cell drugs available, essentially, the majority of patients could get CAR T-cell therapy. Age is not a limitation. Our oldest patient was 84 years old, he was in good shape, he was able to get treatment and he’s in remission. I think that’s a reason we have to offer what is the best care and best option, which is a curative option.

If the patient prefers not to undergo CAR T-cell therapy, not only because of the adverse effects, but also because of the logistics—traveling, leaving home, staying in a different place—that’s definitely a factor in deciding whether to pursue CAR T-cell therapy. In those cases in which CAR T cell is not possible for all those reasons, the patient is too weak, too sick, or logistic reasons, then oral agents such as selinexor play a role. Also other agents can be given closer to home, like monoclonal antibodies such as tafasitamab or polatuzumab. Those are viable options in the community.

When you have all these options, you have to choose the option that is more efficacious, but at the same time, less toxic. As I mentioned before, the monoclonal antibodies are used commonly by community oncologists, so they’re familiar with it. I wouldn’t see a problem in using tafasitamab orpolatuzumab. So there are options for those patients and they know how to use them. Selinexor is a novel agent, so you have to try to learn how to manage the adverse effects. Also the activity is modest. I don’t deny there is activity, but it’s not probably the greatest clinical activity, if you compare it to tafasitamab with lenalidomide, or polatuzumab/bendamustine/rituximab.

Finally, the other aspect is the maintenance of an IV [intravenous] line. So far, selinexor is the only oral agent approved for diffuse large B-cell lymphoma in the relapsed/refractory setting as a single agent. That’s definitely convenient because patients just take 1 pill. But again, it’s probably the less important factor in my opinion.

One of the things that has come up recently, one of the concerns, is that we’re experiencing the global pandemic of COVID-19 [coronavirus disease 2019]. This has led to some concern about intensive treatment regimens that are highly immunosuppressive, including autologous stem-cell transplantation, and potentially CAR T-cell therapy.

In my mind, the risks and benefits of using immunosuppressive therapy have to be weighed against the risk of infections, including COVID-19. But for a treatment for a disease such as relapsed diffuse large B-cell lymphoma, I think the benefits of the therapies that we discussed, including transplant and CAR T, still outweigh those risks.

There may be patients who are presented with the option of continuing to receive IV therapy as opposed to an oral agent like selinexor that can be taken at home. And it’s possible that an oral agent may be safer because of less exposure to the patient, but it also has to be taken into account that some of these agents can cause neutropenia and even if they’re oral, and that can predispose patients to infection.

SADAL Trial Regimen FDA Approval

The mechanism of action for selinexor, which is a novel targeted agent, is that the medication works as a selective inhibitor of nuclear export. Nuclear exporters are proteins that cycle transcription factors and other regulatory proteins between the nucleus and the cytoplasm of the cell.

By inhibiting this nuclear export protein, selinexor leads to accumulation of various protein regulators that leads to reduction, cell proliferation, and apoptosis of the target cell. We know that certain malignant cells, including diffuse large B-cell lymphoma [DLBCL], are sensitive to this agent, and recent data have shown that it’s clinically active in this disease.

Selinexor is an exportin XPO1 that is an inhibitor. XPO1 is overexpressed in lymphoma and correlates with a poor outcome. This oral selective nuclear transport inhibitor has shown activity in a preclinical setting and was tested in aggressive lymphoma, in large cell lymphoma, in the third-line setting. It was testing a number of lymphomas in the SADAL study, including large B-cell lymphoma. These patients have really no options. This was a heavily pretreated population of 120-plus patients. And the response rate was 36% and 15% CR [complete response]. This was something that was very interesting because we had some patients who were not very high-risk large cell lymphoma but multiple failures and who had very durable response.

It was a single agent. This is really interesting, and it was approved last month in June. Based on that, the next step is to try to build up this activity and the mechanism that would make a lot of sense combined with other agents. It is being looked at in a very interesting trial that is looking at the number of different arms, combining selinexor with chemotherapy, biological agents, and checkpoint inhibitors to see how we can build a new regimen for patients who are not eligible for CAR T [chimeric antigen receptor T-cell therapy] or transplant or fail after CAR T cells.

Selinexor is a novel agent that has been recently approved for relapsed/refractory diffuse large B-cell lymphoma, after at least 2 lines of therapy. In the trial, about 17% of patients discontinued the drug because of side effects, mainly related to GI [gastrointestinal] toxicity, nausea and diarrhea, and also hematology toxicity, specifically neutropenia and thrombocytopenia. This trial, when it was studied in non-Hodgkin lymphoma, actually utilized a higher dose of selinexor. In the SADAL study, they actually used a lower dose of selinexor but also showed the adverse effects I just mentioned. Part of it included the use of olanzapine during the treatment, especially given the day before, following 5 days after the treatment. Also, they include the use of appetite stimulants and growth factor support to prevent the hematology toxicity. They reported that the adverse effects were manageable in those patients, but they still show a significant rate of GI toxicity specifically.

As I mentioned, in the SADAL study, selinexor in relapsed/refractory DLBCL, they administered the drug at 60 mg on days 1 and 3 every week until disease progression or development of intolerance. All patients were required to receive ondansetron, which is a common antiemetic medication for cancer patients. After patient discussion, they also received olanzapine to prevent nausea. In the non-Hodgkin lymphoma study, which was probably 3 years ago, they included all histologies, including DLBCL. They tested the selinexor at 3 mg/m2, all the way to 80 mg/m2, which was the highest dose. They actually break down in those levels, and essentially there was no significant difference in response rates, even with the lowest dose. They showed an overall response rate of 31%, but that was across all histologies. Based on that data, I don’t think those modifications could have affected the efficacy of the drug. I believe that actually was a good move from the investigators—to use a lower dose, a less toxic drug—because it seems that the toxicity was dose related.

Selinexor has an advantage. The main advantage is it’s a single agent and an oral agent. These 2 factors actually help physicians treat patients. Because they don’t need an IV [intravenous] line, the patients don’t have to come every time to get the therapy. So it’s convenient. The schedule could be a challenge. Patients get selinexor on days 1 and 3 every week, so I’m not sure whether patients will be able to remember. It’s easy when you take a drug every day or once a week, but if it’s twice a week, you may forget. It’s important for the clinicians or the nurses to follow up with the patients when they receive this therapy.

Also, it’s important to know that this is a novel agent with a novel mechanism of action, so the toxicity profile is also novel. Physicians are familiar to use monoclonal antibodies like tafasitamab, so there may be more appeal to use that drug as opposed to selinexor because it’s still unknown, it’s new, and no one has used it, unless they did it for myeloma patients with selinexor.

There are other drugs that are not approved for DLBCL but that doctors are familiar with, like lenalidomide. Lenalidomide has activity in relapsed/refractory DLBCL. Physicians know how to use it because it has been in the market for a while for other conditions such as MDS, myelodysplastic syndrome; mantle cell lymphoma; or even multiple myeloma. Physicians are very familiar with it, and even if it’s not approved, I don’t see any issues with insurance approval or around the co-pays that we sometimes see with this drug.

When using selinexor, physicians have to make sure they know the efficacy and toxicity, so that patients are not surprised and they’re managed appropriately.

SADAL Trial Overview 

 The long-term treatment outcomes for patients treated with CAR T [chimeric antigen-receptor T-cell] therapy are very impressive in the sense that historically we knew that these patients really had very limited overall survival. What we can see in some of the long-term studies is that there are about 30% or 40% of patients who achieve durable remission after treatment with CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma.

This really represents a paradigm shift where previously most of the treatments would have been palliative or clinical trials of new drugs. This really has become the standard of care, and it suggests that patients can be cured with this approach.

Given the known adverse effects of CAR T-cell therapy, especially CRS [cytokine response syndrome] and neurotoxicity, there is always a concern of how our older-patient population will tolerate these therapies. The way I see it, it’s more than age. It’s a functional age that is driven by other factors, like physical health or impact of comorbidities.

This interesting study is based on the retrospective study of 77 patients. They include patients over the age of 70 years old, and what they did is they divided patients from 70 to 74 and 75 years and older. Patients received a standard of care CAR T-cell therapy, either tisagenlecleucel or axi-cel. One, the PFS [progression-free survival] was no different, the overall survival was worse in patients older than 75 years old, and more interestingly, it was what they analyzed actually. They did a multivariate analysis that showed the use of axi-cel and risk score, hematopoietic cell therapy comorbidity score that is used commonly in transplant patients. When the score was more than 2, it was associated with a worse PFS. In terms of toxicity, they found out that patients who developed grade 3/4 cytokine release syndrome was associated with higher CIRS [cumulative illness rating scale] score, which is a comorbidity-illness score that measures the comorbidity and the impact on the patients, and also the use of axi-cel was associated with CRS. In addition, the CRES, which is CAR T-cell-related encephalopathy syndrome, was also associated with older age and CRES score of more than 6.

What this tells us is this is a valuable study that is evaluating patients older than 75 years old and the toxicity associated with CAR T-cell therapy. In real life, we do see those adverse effects. We prefer to use the less toxic product that’s proven by this study. We feel the axi-cel, while it’s very effective treating lymphomas, is essentially more toxic than tisagenlecleucel or other similar CAR T cells. However, age by itself is not the only factor that we keep in account. We also take into account other factors, specifically comorbidities, that we call functional age.

CAR T-Cell Therapy Clinical Trials 

 I alluded to the limits and practical issues to get access to the CAR [chimeric antigen-receptor T] T-cell therapy. But what do we do to try to make it better? With this ASCO [American Society of Clinical Oncology] 2020 Annual Meeting data, there was a small experience on re-treatment. Can you re-treat those patients with CAR T? And the reasoning behind this is that there is some evidence that these T cells will not stick around long enough. There was some discussion that on the need or not to have precise CAR T-cells. We had about one-third of the long responders in the ZUMA-1 trial who did not have resistant, long-term precision CAR T cell.

With the recovery of the B cells and even immunoglobulin, after a year we can see the CAR T cells disappear. But there’s also the idea that we can re-treat those patients who relapse. This was a small number of patients who were from the axi-cel setting, and over half the patients achieved a response: 4 CR [complete response], 3 PR [partial response]. What was interesting is that some of these responses can be durable: close to 3 months, up to 225 days for the longest. There was a rate of CRS [cytokine release syndrome] at re-treatment, but it seems there was less neurotoxicity and maybe also less CAR T expansion. We don’t know exactly how to read this, but it’s feasible.

There is an interesting question being explored at some other trials: Can we do repeat infusion of CAR T? That’s 1 strategy. The other 1 is that can we improve by bringing the CAR T earlier. That’s the question about the timing of the CAR T if we do it earlier in the second line. There’s the ZUMA-7 trial that has completed, but the results are pending. This other study is with liso-cel and tisa-cel also at a second line with a crossover, so in second-line therapy, randomizing against salvation transplant.

There was an interesting study looking at liso-cel in patients who are not transplant eligible. It is an interesting study because liso-cel potentially has an initial toxicity profile, so it might be easier to do. It’s a slightly different product when the CD4 and CD8 subtype of T cells are prepared separately and infused separately. They get the same for the patient. What was impressive in that study was not a huge number of patients but that the overall response rate was 89% and the CR rate was 56% with very low toxicity, and 12 of 29 patients we have done as an outpatient. This is really important because that offer is potentially an option for these nontransplant-eligible patients. It’s for durability, but this is something to take into account.

As for the results and data on the dual CAR T anti-CD19 and -CD22 in combination with pembrolizumab, there’s a very interesting study called the ALEXANDER study. The rationale for this is there is a subset of patients in large cell lymphoma that become resistant to CAR T because they lose CD19 expression. It’s something we see more frequently in ALL [acute lymphoblastic leukemia] as a mechanism of resistance than in large cell lymphoma, but it still happens. And so we try the dual CAR T CD19,-CD22 with PEMBRO [pembrolizumab] to try to see if we can improve. Knowing that a checkpoint blockade is also 1 of the mechanisms of resistance, can we improve the responses seen? This is dose escalation, not a large number of patients. But the response rate was very high: 10 of the 11 CRs. A small number are ongoing. There was no grade 3 CRS and 1 grade 3 neurotoxicity. The recommended phase 2 is 150 to 450 million, and we did want PEMBRO [pembrolizumab] selected.

The last study at ASCO that is worth mentioning was the ALLO CAR T-cell off the shelf. That is a product called ALLO-501, a gene-editing-based technology to remove the T-cell receptor and CD52. This is also used as a dose escalation, presented by Dr Sattva Neelapu. It shows a response rate of 63% with half these patients in complete remission, and 75% of the patients who responded were still in response at the time of cutoff.

That’s also interesting because there was no GvHD [graft-vs-host disease], and there was allogeneic healthy T cell. There was no dose-limiting toxicity, 1 grade 3 CRS, and no neurotoxicity. That’s very appealing because it would be off-the-shelf, ready-to-go T-cells. Potentially that’s very important because 1 of the factors of failure of CAR T is the T-cell fitness. Patients who are heavily pretreated have a lot of immunosuppressive adverse effects with the active disease of ongoing lymphoma. These patients don’t have the best activity. If we have normal allogeneic normal T cells, that might address the problem.

The last aspect that is also important was from ASH [American Society of Hematology Annual Meeting], and this is the BiTE [bispecific T-cell engager] antibody because we know that patients still can fail quite a bit of CAR T cells, and it was an anti-CD20 bispecific antibody, a BiTE antibody, presented in a plenary session at ASH. It was very impressive because this was a response rate of 39%, 22% CR. But there were some responses, durable and a CR durable in continued remission, even in patients who had stopped therapy after 16 months of treatment. This is also being explored in the frontline setting in combination with chemotherapy, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–POLA [polatuzumab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. A number of initiatives are trying to address the new unmet need that we have in CAR T cells. Now we know how to manage more toxicity. Can we improve on efficacy and look at easier ways to use those CAR T cells?

CAR T-Cell Therapy Response Rates

 Chimeric androgen receptor T cells, or CAR T cells, are autologous T cells, T lymphocytes, that are derived from the patient. They have to be collected through a standard leukapheresis procedure at an authorized treatment center. Then the cell product in a self-contained isolated sterile container is shipped to a manufacturing center. Right now, in 2020, there are 2 FDA-approved therapies, axi-cel and tisa-cel. The 2 FDA-approved therapies are both directed against anti-CD19 on the target of B cells. And the chimeric antigen receptor is introduced into the patient’s own T cells through a viral transduction method, which is done, again, in an authorized treatment center in a manufacturing facility that works with an authorized treatment center. That viral transduction process takes a couple of weeks to take place, then those cells expand to sufficient numbers that can then be used to be delivered to the patient for therapeutic benefit.

In our center we have been involved quite a bit in CAR T cells with the NCI [National Cancer Institute] for 7, 8, 9 years ago now. When the patients who are candidates for this with the approved CAR T cells are in third-line setting, there are a number of ongoing trials that they are trying to look at if we can take advantage of this approach early on in the disease.

But what’s really important to summarize is that there are 3 different products among the most advanced axi-cel therapies from the ZUMA-1 data. Now that we have follow-up with this, the tisa-cel from JULIET and liso-cel from the JCAR017 trial TRANSCENDWORLD, they’re slightly different in terms of the signal CD28 for axi-cel and 4-1BB for tisa-cel and liso-cel. There’s a slight difference in the population of relapsed/refractory, the dosing process, the bridging therapy allowed on that. What is interesting is that the response rates went from 52% to 83% and the CR [complete response] rate from 40% to 58%. In a population that really has no option, this is quite considerable. And what is interesting in that setting is that there is some late delayed response. Up to 20%, 30% of patients can have a late response. Sometimes it can take up to a year, and that’s really important. Typically patients respond very rapidly, but it can take a while because it’s a live therapy. This is very important.

With our long-term follow-up, what is interesting also is that particularly in the ZUMA-1, where we have the longest follow-up, we’re at 27 months and close to 40% of the patients are doing really well and half the patients are alive. This is very impressive, and potentially a good fraction of these patients can be cured. One issue is the durability of the remission in this population, because the relapse is still definitely an issue, and the salvage after CAR T is very difficult. The patient who has CNS [central nervous system] involvement, for example, is also a significant issue.

There are some data—not a lot of data, particularly on tisa-cel—looking at patients who had known CNS disease, including disease with some durable responses. But overall, there’s not a lot of experience, and it could be a challenge, particularly toxicity from T cells. Toxicity from the CRS [cytokine release syndrome] and the neurotoxicity are very well known now. But we can manage this toxicity much better preemptively with tocilizumab and then with steroids. One of the questions that comes up is, what’s the best timing and the best combination that you can build on CAR T cell and how we overcome the resistance to CAR T? Those are the issues that I can see in CAR T.

How does CAR T-cell therapy affect patient outcomes and costs? We currently have 2 CAR T-cell products approved for relapsed/refractory diffuse large B-cell lymphoma, tisagenlecleucel and axicabtagene ciloleucel, but there has not been a comparison head-to-head. In clinical practice, there are some differences in terms of toxicity and efficacy. They both have the inherent risk of CRS and neurological events. There is probably more toxicity with axi-cel than tisagenlecleucel. But in general, both carry the same risk, so the patient has to be monitored closely in CAR T-cell therapy centers.

One of the challenges is some patients live far away from the centers, so they have to relocate into the cancer center, and that adds cost. They need a caregiver to stay off work for 1 or 2 months, and that’s another type of cost that families endure with the CAR T-cell therapy. I’m not talking about the cost of the treatment. CAR T-cell therapy is a very expensive treatment. There are also the management of the adverse effects, the use of tocilizumab on admission to the hospital, the use of an intensive care unit bed. Those factors increase the cost. For these reasons, cost and logistics, some patients may decide not to do CAR T-cell therapy, even though it’s a curative option.

CAR T Cell Therapy in Relapsed/Refractory DLBCL

 For patients who have relapsed or refractory diffuse large B-cell lymphoma [DLBCL], the standard of care remains second line, sometimes called salvage chemotherapy, usually with a platinum-based regimen such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin].

About half of patients who have relapsed or refractory DLBCL, who receive salvage or second-line platinum-based chemotherapy, will achieve a remission. Those patients are most appropriate to be referred on to consolidation, high-dose chemotherapy with autologous stem-cell transplant.

Of the patients who then go on to transplant, probably about 40% or in some series about half, will have a durable remission. But remember, only about half of the relapsed patients make it to transplant. So we’re talking about less than 1 of 4 patients with relapsed disease actually being cured with a standard salvage approach.

Second, for patients who receive second-line chemotherapy and fail to have an adequate response to let’s say a platinum-based regimen—such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide], R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin], or maybe rituximab with gemcitabine and oxaliplatin—it’s another regimen.

For those patients, the outcome has historically been extremely poor with very short overall survival measured in months. Over the past couple of years, since 2018, we’ve had FDA approval of anti-CD19 CAR [chimeric antigen receptor] T-cell therapy, which is the most appropriate treatment for patients who do not respond to second-line chemotherapy.

 Yes. Polatuzumab vedotin is an antibody-drug conjugate, humanized anti-CD79B monoclonal antibody, conjugated into MMAE(?). CD79B is a B-cell specific marker expressed on the surface of a number of lymphomas but particularly diffuse large cell lymphoma. As I mentioned, this was a treatment that was done in patients with relapsed/refractory, not candidates for transplant. In 40 patients per arm, the CR [complete response] rate was 40% versus 50%. It was a clear advantage in the duration of response, PFS [progression-free survival], and overall survival. This was relatively easy to tolerate. This is a population that is sometimes difficult because they have received several lines of therapy. But there is an ongoing phase 3 POLARIX trial that is trying to integrate this in a complex frontline setting to compare with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. This is really going to be an important aspect, particularly because these patients might not be candidates for doxorubicin. Who knows, in the future that might be an option for these patients.

As we mentioned before, there will be a significant percentage of patients who will not respond to standard chemotherapy such as R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and the standard of care for those patients is to receive chemotherapy followed by autologous transplant. However, this standard of care may not be applicable for all patients for many reasons, such as comorbidities, old age, access, or patients cannot get into a transplant center, for instance. The same applies for other regimens that are currently approved, like the CAR T-cell therapy, in which again the logistics, the cost, and the access will be a challenge for them.

In that regard, treatment options for ineligible patients for CAR T-cell therapy or transplant are needed. One of the agents that are approved, polatuzumab in combination with bendamustine and rituximab, is an interesting option for patients because it can be done in the community. Community doctors are familiar with the administration of BR [bendamustine, rituximab], and polatuzumab is a monoclonal antibody that has been approved for over 6 months already, and oncologists are familiar. It’s a time-limited therapy option, so patients don’t have to be on indefinite therapy, which is a convenience. But it’s not a curative option. That should be considered.

Other agents that are in the pipeline, like tafasitamab, is also an outpatient option. One of the disadvantages is that while it has good overall response rates, patients have to remain on treatment. So in theory, we cannot talk about cures with this regimen. Finally, selinexor, which is a recently approved regimen, is oral. The advantage is it’s not an IV [intravenous], you don’t need a line; however, some of the toxicity profile remains challenging because it’s a new agent and the doctor has to be familiarized with the agent. Also, its efficacy—in my opinion, it’s a modest efficacy, about 31% response rate, a little over 10% to 15% CR rates. That is the information that physicians need to know, that they can transmit to their patients in order to make a decision.

Relapsed/Refractory DLBCL Treatment Landscape

The question often comes up: What percentage of patients are refractory or relapse after standard frontline therapy? Depending on the risk category, this could be as high as 30% or 35% of patients who initially respond to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then relapse, or a primary refractory. Primary refractory disease is fairly rare, probably less than 5% of patients. But it does occur, and it typically results, or is manifest by, a positive PET [positron emission tomography] scan or a progressive disease during primary care for your R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. The more common scenario, which is going to occur in about up to a third of cases, is relapse after achieving a remission. Usually those relapses occur in the first year or 2 after completion of primary therapy.

For the patient with refractory/relapsed lymphoma, these patients can receive salvage chemotherapy and then high-dose therapy and transplant. The question is, is that who can qualify for this? Well, for the patients who are in first relapse and have chemotherapy-sensitive disease—the more chemotherapy sensitive, the better—reaching a PET-negative prior to high-dose therapy and transplant clearly has an impact. The issue here is that some of these patients are not great candidates for transplant high-dose therapy, but also some of these patients do not respond well to the second line. The primary refractory patients and the early relapse do very poorly in that setting. So this is not something that we actually recommend necessarily.

When you look at the overall in a patient in the R-chemotherapy [rituximab chemotherapy] era, the outcome of patient after high-dose therapy and autologous stem cell transplantation is still in the range of only 10% to 15% of the patients that you save. This is not the perfect option at this point, but thankfully we have other options we’ll talk about, including cell therapy.

The patients who are eligible for transplantation are really an unmet need. Similarly, so are the patients who fail after transplantation. There is some option now, so we’ll talk about CAR T [chimeric antigen receptor T cell] and cell therapy in a minute. But it may be easier to use. The polatuzumab data refer to BR [bendamustine, rituximab], which was very impressive and is approved. It was 40 patients per arm, but the CR [complete response], which was the primary end point, was 40% versus 15% and with a very significant difference in duration of response and survival. This is interesting. The R2 [lenalidomide, rituximab]–ibrutinib is something that we presented updated at ASH [American Society of Hematology Annual Meeting] in a non–GC [germinal center] subtype. It’s important because we go with age: Up to two-thirds of elderly patients, over 70 and above, can be ABC [activated B-cell] or non-GC subtype, so this is really 1 of the unmet needs we alluded to before.

For these patients, R2 [lenalidomide, rituximab]–ibrutinib, during the chemotherapy-free part, we had a response rate of 60% and some very durable response. Patients were well over 3 years with the disease control with R2 [lenalidomide, rituximab]–ibrutinib, particularly in a non-GC diffuse large cell lymphoma. This is something to keep in mind. Finally, there are the L-MIND data, which is lenalidomide plus anti-CD19, tafasitamab, and the response rate in this situation was also very impressive and very durable. This is really potentially an option and that has been combined in a frontline setting in the context of BR/POLA [polatuzumab], or bendamustine-rituximab and POLA [polatuzumab], so we’re trying to integrate this novel therapy in the frontline setting.

In patients who are not candidates for transplant, this is really again an unmet need. Those are perfect candidates for clinical trials, and we’ll talk a little more about cell therapy in that setting. But in reality, the patients who are truly not eligible for autologous stem cell transplant because of frailty or comorbidities are not going to be necessarily great candidates for CAR T cell, at least at this point.

What’s a typical response and duration of response after R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]? This is a challenging question, and it all depends on where you get the data. If we talk about outcomes in real life, the R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] outcomes are worse, as opposed to clinical trials in which there is an inherent selection bias. We tend to select the healthier and less sick patients in trials, so they will probably tolerate better the treatment and they will complete the treatment, and also patients will have less aggressive disease.

In general, what I see in my general practice is about 60% to 70% of patients are cured with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]; the rest, 30% to 40% of patients will either relapse or remain refractory. In terms of long-term remission, probably the most important data that we have is on the GELA [Groupe d’Etude des Lymphomes de l’Adulte] study, the French study that compared R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] versus CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that showed that about 50% of patients were still alive at 10 years’ follow-up.

R/R DLBCL: Transplant Eligibility and R-CHOP

The treatment factors that affect newly diagnosed patients with newly diagnosed diffuse large B-cell lymphoma [DLBCL] include pretty standard clinical features, including age, functional status, and comorbidities. From the perspective of the disease, if the patient has double-hit lymphoma, that can also impact treatment selection.

For the majority of patients who have reasonable performance status, if they’re in their 60s or 70s and don’t have significant comorbidities, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still going to remain the standard in the current era outside clinical trials. If they have significant advanced age in their 80s or late 70s, comorbidities, or really poor performance status starting with less inventive regimens such as mini-R-CHOP [reduced-dose regimen of rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or just palliative treatment with steroids, Rituxan, and cyclophosphamide, or vincristine, like R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] is often used in that setting, that’s appropriate.

Again, for most fit patients who can receive R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that’s still the standard outside double-hit lymphoma. As we discussed, if a fit patient has double-hit lymphoma, that’s when a more intensive regimen is usually offered.

The stage of diffuse large B-cell lymphoma can impact treatment to a certain extent. Most patients are going to be advanced stage, with stage III or IV, depending on the extent or absence of extranodal disease. Again, for those patients, 6 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still standard therapy.

In the case of limited stage—so a true stage I—there are data from recent trials that show for low-risk early stage patients, it’s appropriate to offer either 3 or 4 cycles of systemic therapy with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], sometimes followed by radiation. Increasingly we’re seeing data that suggest that if you achieve a complete metabolic response, for instance, after 3 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], completing systemic therapy with 4 cycles and omitting radiation is still reasonable and achieves very good outcomes for early stage, stage I or II, DLBCL.

For germinal center or nongerminal center, which is said to be activated B-cell subtype, there have been a number of trials over the past decade that have attempted to improve the outcome of patients with higher-risk, nongerminal center, DLBCL, which usually has an activated B-cell phenotype. Investigators have attempted to introduce proteasome inhibitor bortezomib, lenalidomide, BTK [Bruton tyrosine kinase] inhibitors such as ibrutinib. To make a long story short, all these trials have not been positive.

Despite the significant biological rationale for introducing targeted agents for these subtypes of patients, particularly the ABC [activated B-cell] subtype, none of the studies has panned out. Some of this may be related to patient selection in terms of not getting the higher-risk patients on the studies. Another part of this is likely that the method of assigning subtypes has been too crude, and we really need to move to a more advanced molecular testing method to discriminate the subtypes and then assign targeted agent pathway inhibitors, targeted agents in those specific pathways for those specific subtype.

This is an important aspect. When you see patients having comorbidities and cardiac issues, neurological issues, etc, we know that this is a difficult situation. The definition is the geriatric assessment, but basically if it’s an older patient, more than 80 years old and with some comorbidities, you can use an attenuated form of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], which is the mini-CHOP [reduced-dose regimen of cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. That could be very helpful. If the patients have cardiac dysfunction, we can replace the doxorubicin with etoposide or gemcitabine, or liposomal doxorubicin. Sometimes bendamustine–Rituxan [rituximab] will be used, sometimes combinations with antibody-drug conjugates that are being looked at in the frontline setting. Hopefully other combinations will emerge as a possibility.

In patients who are older, it’s important to mention here—the patients that are older, frailer, a bit but not necessarily cardiac dysfunction—1 thing that works really well is to give them somewhat of a prephase with vincristine, rituximab, and steroids for 5 days. Then they come back a week later and then we can get them started on R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. These patients do really well.

There’s finally novel therapy, as I mentioned, that might offer an opportunity to replace chemotherapy in that setting. There are the R2 [lenalidomide, rituximab]–ibrutinib data from The University of Texas MD Anderson Cancer Center, from the SMART START trial from Jason Westin. That has shown very high response rates and CR [complete response] rates after an induction that is basically nonchemotherapy option: response rate of 80% and CR over 36%. These patients can receive an abbreviated course potentially of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] if they’re elderly. As I alluded to the polatuzumab, POLA, is used in the relapsed/refractory setting. We’ll talk a little later about this, but it is going to be integrated as well as bevacizumab is integrated in a frontline setting. We are building up by adding these types of therapy that might allow us to treat, even better, these patients who have comorbidities and issues that prevent them from using anthracycline.

Newly Diagnosed DLBCL: Treatment Decision Factors

We know large cell lymphoma is the most common lymphoma, about one-third of the cases. We know that over 50% of patients can be cured with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] chemotherapy, about 20% to 30% relapse and 10% to 15% suffer primary failures. The real challenge is that these failures occur in 80% of the cases—80% of these relapses occur in the first 18 months, and they usually are very challenging to administer salvage therapy, even with high-dose therapy and transplant. Therefore, this is very important to try to have markers that help us identify, prognosticate, and stratify patients.

I would say there are 3 types of factors, and they are the lymphoma factors: We know large cell lymphoma is a very heterogeneous entity and primarily large cell lymphoma, for example, is a separate subtype. But under the NOS [not otherwise specified] subtype of large cell lymphoma, there’s a different molecular subtype, the non–GC [germinal center]. But well beyond that, now we know that 7 factors are very important, unique BCL2, double expresser, double-hit lymphoma. Beyond the FISH [fluorescence in situ hybridization]—typically the definition is by FISH—there’s about 50% of these high-grade double-hit lymphoma that have a rare, poor prognosis with standard R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] that have the signature of a high-grade lymphoma but do not have the FISH by gene expression profiling. 

 next-generation sequencing is not done yet in routine. But we try to narrow down a molecular subtype.

Then there’s the tumor burden of the lymphoma, and the stage, the LDH [lactate dehydrogenase], bulky, and the baseline metabolic volume if you want to go by PET [positron emission tomography] scan. The second aspect that was developed is a prognostic model trying to put this in context, and we have revised IPI [ipilimumab] in the RQ era. We have the NCCN [National Comprehensive Cancer Center] IPI [ipilimumab] guidelines trying to use the same factors basically, the basic factors of the IPI [ipilimumab], but 25 is better, the age and the LDH and try to identify better smaller subset, particularly on the extreme, the very good-risk and the very high-risk patients.

There is something that is interesting called the PFS [progression-free survival] 24—no failure after 2 years; therefore the PFS 24 name. These patients do very well, similar to the control population that never have lymphoma. To identify these factors, there’s the IPI [ipilimumab] 24. There’s a calculator available online that also uses similar factors where it adds gender, bulky disease, and lymphocyte count at baseline. There’s another factor to take into account the diagnostical delay to start treatment versus immediate treatment, which obviously the patient started within 2 weeks. Those who start later usually have more symptoms.

That’s really important because these factors that are clinical factors are centrally based on the characteristics of each patient that have been very helpful, but not really to predict the long-term outcome or to predict the response to a therapy. There are some host factors that we heard about regarding gender. Comorbidities we’ll talk more in a minute, but there are a number of factors not yet used in practice: the class II MHC [major histocompatibility complex] expression; the beta-2 microglobulin, which is a class I molecule; microenvironment signature inflammation; cytokine; vitamin D. This is obviously growing, and those are more the host factor, and this again predicts for DFS [disease-free survival], PFS, and survival but not for the early failures, which is the real problem that I mentioned before.

Finally, the response to therapy is the PET scan. And the interim PET scan, although it is debated, when it’s a negative PET regardless of the stage, even in advanced stage, this is usually a very good outcome. Sometimes there’s nonspecific inflammation and residual gray zone like PET scan with low SUV [standardized update value], and what matters is the delta, the drop of the SUV. Typically in routine what we really look at is the patient who has a negative PET scan at the end of treatment. That was very predictive.

Here I just want to mention that when someone has a PET scan that is positive, it’s important to biopsy this patient. We need to know if it’s truly active disease because it has some hot spots. Finally I think there is another factor emerging, and that will take more role in the future on prognostic factor, the DNA, or cell-free DNA that is detectable in all patients at baseline, regardless of the stage. It reflects the tumor genetic makeup or signature profile if you want. Studies, not large studies but very impressive, show that patients who are PET negative and cell-free DNA negative after 3 cycles do remarkably well.

This is a number of factors. How do we use this in practice, so in a frontline setting, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] has remained the default, but it’s not sufficient for high-risk patient, double-hit, and double expresser, and non-GC lymphoma. But it’s important to understand that we can start to adjust with the treatment. In a non-GC subtype, so far the attempts to do R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] have not really panned out. Patients, about one-third of these non-GC double expresser, and we know that they do very poorly with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], so we try to give them something more intensive. Finally, in the high-grade lymphoma that I mentioned, these guys do very poorly with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and there’s definitely no standard therapy. We tend to use, if you’re a younger patient, the EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] regimen. That’s the impact, in a nutshell, of these prognostic factors in lymphoma.

The question is, what is the prognostic and predictive significance of DLBCL [diffuse large B-cell lymphoma] genetic signatures The management of DLBCL has evolved over the years. While next-generation sequencing has shown valuable information, there is an absence of a specific drug or medication that will target this specific gene signature. Its application in routine clinical practice remains elusive, in my opinion. However, it underscores the fact that there’s a need of developing trials using this genetic testing. One of the challenges I see using these tools, like next-generation sequencing, is the cost, the availability, and especially reproducibility, that it will be difficult for physicians who are not familiar with this testing to maintain their patients.

DLBCL Risk Assessment and Genetic Signatures

 We learned about diffuse large B-cell lymphoma over the past several years. It goes back to the recognition that really this is not a single disease entity but actually represents different types of lymphomas that collectively are referred to as diffuse large B-cell lymphoma. More specifically it’s been recognized that there is 1 type called germinal center subtype, and another ABC [activated B-cell] subtype, which have different biological features and different outcomes, with ABC subtype having the worst outcomes in germinal center subtype.

Over the past couple of years, we’ve done to identify that this is really an oversimplification of the subtyping, and with advanced molecular tests, next-generation sequencing, and high throughput genomic analysis, 2 separate groups of independently identified diffuse large B-cell lymphoma as really having a number of different subtypes. Germinal center is actually going to be divided into 2 different groups: worse and better outcomes. Similarly, ABC subtype can be divided into at least 2 or more subgroups, some of which have better outcomes than others.

From a practical perspective, I would say in 2020 to really approach diffuse large B-cell lymphoma the same way with the notable exception of double-hit lymphoma, is probably a germinal center–derived subtype of diffuse large B-cell lymphoma that tends to have a more aggressive course.

The question about initiating treatment before receiving the cytogenetic results is an important one. If you know that a patient has diffuse large B-cell lymphoma and they need immediate treatment, the standard of care still is R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and chemotherapy for frontline therapy outside of our clinical trial. If you don’t have the cytogenetic results to know that the patient takes double-hit lymphoma, it’s still reasonable if the patient has a clinical urgency to initiate treatment with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then potentially escalate a more intensive regimen such as dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] with subsequent cycles.

Turnaround time of getting these molecular tests back can be shorter or longer, depending on if the patient is being seen at a high-volume center or a community center. Many community centers send out the FISH [fluorescence in situ hybridization]test for the MEK, BCL2, and BCL6 translocations. And there may be a longer turnaround time. But again, I wouldn’t let that delay prevent me from initiating treatment if there’s a clinical urgency to start therapy. It’s perfectly fine to start with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then subsequently change after you have the results of those molecular tests.

Brian Hill, MD, PhD, Cleveland Clinic

Articles