John M. Burke, MD

Last years, a 70-year-old woman presented to her (and my) local hos- pital with a seizure. An MRI of the brain demonstrated a 2.4-cm mass in the left temporal lobe. A lumbar puncture demonstrated lymphocytes and an elevated protein, and flow cytometry on the cerebrospinal fluid detected malignant B cells. A craniotomy was performed, and biopsy of the brain tumor, read by an expert pathologist at an academic institution, indi- cated lymphomatoid granulomatosis, grade 1—not a diagnosis I personally am accustomed to seeing on a brain biopsy, to say the least.

This work-up took quite some time, and then I had to muddle around, trying to figure out how to manage the extremely rare situation of lymphomatoid granulomatosis of the brain.

My patient and I decided to initiate rituximab (Rituxan). However, at the family’s urging, I sought a second opinion on the pathology. Several weeks later, the second expert pathologist, who happened to be at a different aca- demic institution, informed me that this was not lymphomatoid granuloma- tosis but was, instead, a CD5-expressing diffuse large B-cell lymphoma. So after having given this patient 3 doses of weekly rituximab, I changed her treatment to rituximab, methotrexate, vincristine, and procarbazine. One year later, she remains in a complete remission.

Wouldn’t it be great if we could reliably diagnose central nervous system lym- phoma without an invasive brain biopsy? One potential solution to this problem, and perhaps to many others we face in our field, is discussed in the Precision Medicine in Oncology column in this issue: “Exploring Prognostic Testing in Hematologic Malignancies” (page 67).

Novel testing modalities are already changing the practice of hematology and oncology and will likely do so even more in the future. One example that has affected clinical practice is testing for measurable residual disease, or MRD. In acute lymphoblastic leukemia, the results of MRD testing after multiagent chemotherapy are now used to select patients for treatment with the bispecific T-cell engager blinatumomab (Blincyto).

Improving our diagnostic and prognostic testing capabilities is certainly one of the most important and exciting ways to improve how we care for patients with cancer. I would predict that 10 to 20 years from now, how we diagnose cancer, how we choose therapies, how we adjust treatments during therapy, and how we monitor for relapse will be quite different from what we do today...at least I hope so, for the patient’s sake.

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Improving our diagnostic and prognostic testing capabilities is one of the most important and exciting ways to improve how we care for patients with cancer, according to John M. Burke, MD.

Novel Testing Modalities Are Poised to Improve Diagnosis and Prognosis

There has been welcome news recently in the field of treatments for COVID-19. Amid the surge of the omicron variant, the FDA issued an emergency use authorization for the orally administered antiviral combination of nirmatrelvir/ritonavir (Paxlovid), which, when initiated within 5 days of symptom onset, reduced the rate of hospitalization or death by 88%. Similarly, a 3-day course of intravenously administered remdesivir (Veklury) was shown to reduce the rate of hospitalization or death in outpatients by 87% compared with placebo.

One would hope that the utilization of these new tools, plus the vaccines that were previously developed and made available, would markedly reduce the death toll that SARS-CoV-2 has infl icted upon the world and, disproportionately, our patients with malignancies and suppressed immune systems. Perhaps such a reduction in the death toll will occur soon.

Early in the pandemic, I could count exactly how many patients I had lost to COVID-19. After the first 8 to 9 months of the pandemic, that number was about 15 patients. I could even name each one of them for a while. After that, I began to lose count. My best guess is that the number is somewhere between 40 and 50. I can no longer list every patient by memory. This past month alone, I lost 3 more patients to COVID-19. In fact, I suspect that I’ve lost many more patients to COVID-19 in the past 2 years than I have to cancer itself.

We need to get these new treatments out to our patients quickly. The rollout and availability of these treatments have been spotty. For example, although tixagevimab/cilgavimab was given emergency use authorization on December 8, 2021, I first got access to it on February 1, 2022. In talking to colleagues around the country, some of them have had access to it, whereas others have not. Obtaining nirmatrelvir/ritonavir has not been simple either. Where I practice in Colorado, it has been made available only through hospital pharmacies but not through commercial pharmacies. Some of these hospital pharmacies have run out of the medication quickly, and guidance for physicians on how to obtain it has been lacking. And where better to give 3 daily doses of intravenous remdesivir than the oncology clinic, where infusions are given all day every day? At this point, my patients have been able to access remdesivir only in the inpatient setting, not in the outpatient setting, where it probably works best. Making these effective treatments more readily available in local pharmacies and infusion centers will go a long way toward reducing the frequency, severity, and death toll of COVID-19—a goal that has been a long time coming.

Amid the surge of the omicron variant, the FDA issued an emergency use authorization for the orally administered antiviral combination, which can reduce the rate hospitalization or death by 87% compared with no treatment.

Barriers to Access for COVID-19 Treatments Put Patients With Cancer at Risk

As the new co-Editor in Chief of Targeted Therapies in Oncology™ (TTO), I am excited and honored to be working alongside Dr Robert Ferris and the entire team at TTO. My clinical practice focuses on hematological malignancies, and what better issue for me to start on than one focusing on the 2021 American Society of Hematology (ASH) Annual Meeting. In recent years at the ASH conference, diffuse large B-cell lymphoma (DLBCL) has taken a back seat to other hematological malignancies.

This year at ASH was different. Two major developments have the potential to revolutionize the management of DLBCL in more than 2 decades. The first development was the POLARIX trial (NCT03274492). In the trial, patients with previously untreated DLBCL were randomly assigned to either R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, or the anti-CD79b antibody-drug conjugate polatuzumab vedotin (Polivy) plus R-CHP (pola-R-CHP). Pola-R-CHP improved progression-free survival and reduced the need for additional antilymphoma therapy; however, the complete response rate and overall survival were not affected. 

The second major development was the investigation of chimeric antigen receptor (CAR) T-cell therapy in the management of first relapse of DLBCL. Three studies compared CAR T-cell therapies with conventional high-dose chemotherapy and autologous stem-cell transplantation in patients whose DLBCL had relapsed within 12 months of their initial therapy. In the ZUMA-7 trial (NCT03391466), axicabtagene ciloleucel (axi-cel; Yescarta) improved event-free survival (EFS) and response rates. In the TRANSFORM trial (NCT03575351), lisocabtagene maraleucel (liso-cel; Breyanzi) improved EFS, progression-free survival, and the complete response rate. Paradoxically, however, in the BELINDA trial (NCT03570892), tisagenlecleucel (tisa-cel; Kymriah) did not improve EFS or the response rate compared with standard therapy.

Taken together, these results have the potential to change the management of DLBCL. Whether the standard of frontline R-CHOP followed by high-dose chemotherapy and autologous stem-cell transplantation for first relapse will change in practice may depend on regulatory approvals of these products, reviews by panels of experts writing guidelines and pathways, the ability to manufacture products and deliver them to appropriate patients in a timely fashion, and the ability of society to pay for the costs of these novel agents.

Clinical trial findings presented during the ASH annual meeting have the potential to change the management of diffuse large B-cell lymphoma, according to John M. Burke, MD.

ADC, CAR T-Cell Therapy Push DLBCL Into Spotlight at ASH Conference

We’ve covered most of the clinically important stuff. We have some questions about the lymphodepletion and promising up-front therapies. We already discussed what’s most clinically important. We talked about the sequencing. Let’s move on to the future options in terms of what you’re excited about. I already hinted about what I’m excited about, and you’ve educated a lot about some trials that are going to be reporting out, especially for front line. Anything that excites you for large cell lymphoma in the coming months to years?

As you mentioned, the bispecific antibodies are probably first on most everyone’s minds. We saw 4 or 5 of them reported out at ASH [American Society of Hematology Annual Meeting] last year and some more follow-up from the summer meeting, so it will be exciting to hear more at ASH this year. That’s probably No. 1. High up there, as you mentioned, are some of the off-the-shelf cellular therapy products: T-cell and even NK [natural killer]–cell therapies. I hope it’s as easy as just seeing great efficacy of those things and then making cellular therapy more available to more people. That would solve a lot of problems, especially with some of the reduced toxicity problems that are being seen. It seems that’s a potential therapy that could be delivered more widely than CAR [chimeric antigen receptor] T. The biggest problem with CAR T is that it’s hard to get. It’s hard to get patients there and hard to get patients that treatment. There are a number of other novel therapies out there. One that’s crossed my radar screen is targeting the CD47-SIRPα interaction. There are antibodies being developed at both of those targets showing some potential for promise, particularly in combination. We’ll see how that turns out. How about you? Anything else high on your radar?

Yeah, CD47 is interesting in many malignancies as a different type of immunotherapy using phagocytosis. Thanks for bringing that up. I’m excited to see how that pans out in terms of will that be another tool in our toolbox. You and I mentioned previously bispecifics. There’s 1 that’s also a subcutaneous and that seems to be pretty manageable. I’m comfortable doing bispecifics even in the ALL [acute lymphocytic leukemia] setting, even not being a transplant center. That’s really promising as a salvage therapy and also in combination with front line. They’re both going to have some potential improvements on our standards and be fairly accessible in the community.

What are your pearls for the community hematologist-oncologists who may see diffuse large B-cell lymphoma [DLBCL]? That’s our final question.

The pearl is that we have long-term disease control and a lot more therapies that work for a significant duration of time in the second- and third-line settings. That’s my mantra. It’s no longer life and death, and it’s possible to live with decent quality of life with relapsed diffuse large B-cell lymphoma. That’s where I find a lot of hope. I see a lot of geriatrics, so it’s been fun to have this new role to palliate.

I can’t say it any better than that. The other thing I’ll add is that, all of a sudden, we have all these new agents. That’s a fairly uncommon scenario for us oncologists to be facing relapsed DLBCL. We have more treatment options now than you can possibly use as a community doctor. It’s hard to be an expert on all these and to get experience with all these. Nobody can use a ton of tafasitamab, a ton of loncastuximab, and a ton of selinexor and polatuzumab. Going back to a point you made earlier about contacting your local or regional expert in the field and finding somebody you can trust and work with to help manage these patients is important to make sure your patients are getting the right treatment.

Thank you so much. They chose both of us for a reason. We’re community doctors who happen to see a lot of lymphomas, and not depriving the opportunity for cure and working with your cellular therapy programs is quite important. This has been extremely informative for me. I hope our audience agrees. Dr. Burke, you’ve been such a wonderful discussant. Thank you so much to the audience for watching this 

™presentation of “CD19 as a Target in the Treatment of Diffuse Large B-cell Lymphoma.”We hope you found this to be useful, as I did, and we thank you for inviting us for this opportunity.

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The future of combined treatment approaches with anti-CD19 therapies for diffuse large B-cell lymphoma.

Next Steps Using Anti-CD19 Therapies in DLBCL

These are chimeric antigen receptor [CAR] T cells, and the most common of the 3. They’re all CD19, which is the important point. That’s why we raised these questions about sequencing with other targeted anti-CD19 therapies and the unknown questions. Yes, we have some data emerging about people going on to receive CD19 CAR T post-loncastuximab in the LOTIS registrational trial. They reported out a subset of those outcomes and then looked at tafasitamab before and after tafasitamab CAR T. From the toxicity scales to mitigation.

The 2 of us are not consenting our patients, but they’re coming back to us for guidance. They have this scary discussion, and they want us to tell them what to do. So we do need to know a little about the risks of the procedures. I’ve had probably a dozen or 2 that were on a lot of the trials, and BCMA [B-cell maturation antigen] and CAR T for myeloma. The neurotoxicity can be long-standing: long-standing cytopenias, long-standing B-cell depletion.

I talked to David Porter, who’s 1 of my mentors, from the University of Pennsylvania. Using CD19 for CLL [chronic lymphocytic leukemia], we’ve been doing initial studies at the University of Pennsylvania. Those patients are now over 10 years out, but a lot of them are still requiring IVIG [intravenous immune globulin]. There’s a cost to that potential cure. In my 75 year-olds who are very skittish, I say, “The stakes are high, but the outcome can be long-term remission and cure.” I do heavily push the youngsters, for sure. But those geriatric patients get in this category who are not fit enough for autotransplant but may be fit enough for CAR T. That’s a gray zone.

From a clinical perspective, let’s talk about that group. When they come back to you, are you enthusiastic about pushing them toward that, or do you say we have some other alternatives?

You’re talking about the group, post? Which group again?

The group of patients who relapse who are not fit enough for autotransplant but are considered fit enough for cellular therapy. That’s where I struggle the most on pushing people toward cellular therapy when we have some very effective alternatives that we never had before.

Those are borderline and not that healthy. It’s tough. I’ve heard people who do a lot of CAR T-cell therapy treatment say almost no one is not a candidate for CAR T-cell therapy. I’ve heard different perspectives. Not being a CAR T-cell treater, I’m not the 1 who usually makes that decision. You made a really good point earlier. Community doctors have got to be able to talk to patients. You haven’t even sent them off yet and you find out they have a relapse. You’ve got to be able to tell them about some of the risks and benefits of CAR T-cell therapy and help them make a decision about the right thing to do. It is important to know a bit about cytokine release syndrome, and neurological toxicities. Talk your patients through a bit about how it works, just as you do about transplant, and share that with them. Then help them make a decision: is that consult something they want to do? As you said, it’s important to give as many patients as possible that option because it’s potentially curative therapy where previously we had no such thing, right? Third-line DLBCL, especially post-transplant, was a death sentence. Nowadays that’s not necessarily the case.

Suggestions to hematologist-oncologists when talking to patients with relapsed/refractory diffuse large B-cell lymphoma about the potential benefits of CAR T-cell therapy and toxicities.

R/R DLBCL: Educating Patients About CAR T Cells

We talked about loncastuximab and LOTIS data, LOTIS-1. There’s 1 more thing that’s out there to be aware of. LOTIS-8 is being tested in newly diagnosed patients, but I haven’t reviewed that yet. Be on the lookout for that to be reported. Of course, when I introduce myself, I always say I’m a recovering stem cell transplanter, and neither 1 of us is an actual cellular therapy prescriber. We’re referring physicians for cellular therapy. With that in mind, take our insights with a grain of salt. We represent—I wouldn’t say community, because Dr. Burke is amazing and impressive. I love this discussion learning. You know the data so well, but we’re not the ones managing toxicities, grading the ICANS [immune effector cell-associated neurotoxicity syndrome] score for neurotoxicity, cytokine release, and stuff like that. We come to this discussion from a prescriber’s perspective.

That being said, the other big area for all of us is where does CAR [chimeric antigen receptor] T-cell therapy fit in? We’ve talked about it a little in the beginning in our fit vs unfit. I will just say that if somebody is eligible for a curative therapy, they need to be referred and considered for that therapy. Loncastuximab, tafasitamab-lenalidomide, polatuzumab, and all these other new things are not curative therapies. Looking at all the major products, we have the ZUMA trial, JULIET, and TRANSCEND NHL 001, which is the liso-cel [lisocabtagene maraleucel]—I call it the Kite, the Novartis, and the Juno. These are the 3 options. If you look at big picture from a prescriber standpoint, of those patients, maybe 40% to 50% can be cured from CAR T in this setting, and it’s currently for third line. My general perspective is that anybody who can be considered for that should not be deprived of potentially curative therapy. What do you think, John?

Liso-cel, tisa-cel [tisagenlecleucel], and axi-cel [axicabtagene ciloleucel]. You made an important point earlier that very few patients who are eligible for CAR T-cell therapy receive it. It was in 1 of the ASH [American Society of Hematology] journals within the last year. Since CAR T was approved for DLBCL [diffuse large B-cell lymphoma], about 2000 patients have been treated with it. Within the last year I saw that in writing, so that’s not many if you think about how many relapsed large cell lymphomas have happened in the United States over the last 2 years since CAR T became available. It’s important, as you say, to think about it, to offer that to patients as a potentially curative option, and to make every effort you can to get your patients to it.

There’s a reason that not that many patients have gotten it or many reasons, including all the barriers—the insurance hurdles, the cost, the potential toxicities might scare some patients away, the need to travel to selected centers, the lack of wide availability, many potential barriers to it. That does open the door for some of these newer therapies that, as you say, may not be curative. I’m a little cautious on saying that because chemotherapy alone can be curative. If you go back and look at the old PARMA trial, there’s a tail on that curve even in the chemotherapy arm. Tafasitamab-lenalidomide sure has pretty good PFS going out at 3 or 4 years. Even polatuzumab-bendamustine-rituximab has a percentage of patients who haven’t relapsed after getting that treatment. CAR T-cell therapy does appear to be the leader in terms of potential for cure in relapsed DLBCL.

I don’t think either 1 of us wants to look in depth at axi-cel, tisa-cel, and liso-cel. We all seen those trials out there for a while. The new kid on the block is the liso-cel, and that FDA approval was almost 2 years after the other 2. That may be interesting in terms of outpatient because they have a lot more data there. Steve Schuster, 1 of my mentors from fellowship, did try to compare tisa-cel and liso-cel. There was no real measure; it was not prospective. Looking at the data, there was no significant difference in outcomes between those 2 products. More data are needed in terms of comparing these head-to-head.

I’m excited about the allogeneic ones as well, maybe having an off-the-shelf version that decreases the processing time. That may be more accessible to people in the community or who aren’t able to travel. My dream is to not need FACT [Foundation for the Accreditation of Cellular Therapy] certification to do that because my background is as a transplanter. It would be good for remote areas if that could be a product in the future. The [University of Texas] MD Anderson [Cancer Center] data looking at those NK [natural killer] allogeneic products look really exciting.

We have these 3 available, and the hope is that No. 1, in my opinion, we can move up to second line for those wham-bam-thank-you-ma’am, chemotherapy-refractory patients who you know aren’t going to be cured with an autotransplant, and then getting people fast enough and bridging them to CAR T. You don’t disagree, John, that if somebody is potentially a candidate, they should try to get it if possible.

Recommendations to increase the uptake of CAR T-cell therapies into clinical practice when managing patients with relapsed/refractory diffuse large B-cell lymphoma.