John M. Burke, MD

After seeing all the amazing presentations at the American Society of Oncology (ASCO) Annual Meeting, I cannot help but reflect on how far our field has come over the course of my 20-year career.

In 2000, I moved from San Francisco, California, to New York, New York, to begin my fellowship at Memorial Sloan Kettering Cancer Center. My first rotation was on the inpatient myeloma, lymphoma, and autologous stem cell transplant service, where I encountered patients with myeloma and painful bone lesions causing fractures and spinal cord compressions. We treated patients with myeloma with chemotherapy and autologous stem cell transplant. Thalidomide (Thalomid) was starting to make a splash by showing strong efficacy in myeloma trials, and bortezomib (Velcade) emerged during those years, as well.

Nevertheless, the state of the art was exemplified by an article in the 

 in 2003, describing the results of an Intergroupe Francophone du Myélome (IFM) trial. Myeloma patients were treated with vincristine, doxorubicin, and dexamethasone induction followed by single or double autologous stem cell transplant. The median event-free survival was 2 years and the median overall survival was 4 years, which seem grim by modern standards.

Fast forward about 20 years to the Plenary Session of the 2022 ASCO Annual Meeting, at which we saw the results of modern therapy in the DETERMINATION trial (NCT01208662). Patients treated with the modern standard regimen of lenalidomide (Revlimid), bortezomib, and dexamethasone followed by autologous stem cell transplant achieved a median progression-free survival of 5.5 years. In the IFM trial 20 years ago, approximately 50% of patients were alive at 4 years. In DETERMINATION, 85% of patients were alive at 4 years. We’ve come a long way.

DETERMINATION represents only an infinitesimal fraction of the degree of innovation demonstrated at the ASCO meeting: an antibody-drug conjugate besting conventional chemotherapy in patients with low expression of the HER2 target in breast cancer; a KRAS inhibitor demonstrating marked activity in KRAS-mutated non–small cell lung cancer; a bispecific antibody redirecting T cells to suppress diffuse large B-cell lymphoma; an antibody-drug conjugate added to chemotherapy, extending survival in Hodgkin lymphoma compared with the decades-old standard-of-care regimen; and a checkpoint inhibitor rendering mismatch repair–deficient rectal cancer completely helpless.

After a meeting like this, one cannot help but be reinvigorated to continue advancing cancer care and feel optimistic about the future of oncology. We have a lot of progress to celebrate—and a lot more to accomplish.

Articles

After a meeting like the 2022 ASCO Annual Meeting, one cannot help but be reinvigorated to continue advancing cancer care and feel optimistic about the future of oncology, says John M. Burke, MD.

Innovative Therapies, Care Equity Highlight 2022 ASCO Annual Meeting

In this month's 10-year anniversary issue of 

™ (TTO), we feature an article on the evolution of immunotherapy approaches in oncology over the past decade. It is amazing to think about how much immunotherapy has changed the practice of oncology. 

I have a somewhat fuzzy memory of a lecture I attended more than 20 years ago as a first-year oncology fellow at Memorial Sloan Kettering Cancer Center in New York, New York. If I am not mistaken, I think the lecturer was the emerging star Jedd D. Wolchok, MD, PhD, and the topic was melanoma. Dr Wolchok showed old photographs of patients whose melanoma had spontaneously regressed. Simultaneously with the regression of their melanomas, some of these patients developed vitiligo, suggesting that, in these rare and lucky individuals, their immune systems had figured out a way to attack melanocytes. These observations had convinced many scientists that finding ways to direct the immune system to attack cancer cells could help overcome the limitations of conventional chemotherapy, which seemed to have reached its potential as a therapeutic modality for cancer. I remember in the early 2000s being somewhat pessimistic about the potential of such efforts, given that attempts to harness the immune system to treat cancer had been largely unsuccessful and chemotherapy and targeted therapies were the mainstays of cancer treatment. 

Fast forward 20 years and we now have seen tumor-directed monoclonal antibodies, antibody-drug conjugates, cancer vaccines, checkpoint inhibitors, oncolytic viruses, and chimeric antigen receptor (CAR)–modified cellular therapies change how we treat both solid tumors and hematologic malignancies. And of course, the field of immunotherapy for cancer is showing no signs of slowing down. Bispecific antibodies to redirect T cells toward malignant target cells are demonstrating potent activity in hematological malignancies and will likely be in the clinic soon. Inhibition of novel targets such as LAG3 and TIGIT is emerging as a way of making immunotherapy work better. Natural killer cells are undergoing evaluation as cellular therapy. Allogeneic CARs are being explored for their potential to deliver therapeutic cells. 

For me, the take-home message of the cancer immunotherapy story is that basic and clinical investigators working together have created novel effective treatments that have moved the field of oncology way beyond what I was able to foresee as an oncology fellow 20 years ago. The dramatic progress in our field has been the result of collaborative efforts, with countless individuals each playing a small role to push the field forward, leading to better outcomes for patients with cancer.

In this month's 10-year anniversary issue of Targeted Therapies in
Oncology™, we feature an article on the evolution of immunotherapy
approaches in oncology over the past decade.

Collaborative Efforts Push the Boundaries of Immunotherapy

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.

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.

Videos

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