John M. Burke, MD

As I write this column, I am attending the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. As is always the case, there are more big stories of amazing progress in the field of hematology and oncology than I can possibly summarize in one short column. One of these, which I have written about before and will probably write about again, is the emergence of bispecific antibodies to redirect native T lymphocytes against malignant B lymphocytes. But in this column I’ll focus on a different and perhaps equally important story—namely, that measurement of circulating tumor DNA (ctDNA) can be used to predict outcomes and assess responses to treatment of various lymphomas.

Detection of microscopic amounts of measurable residual disease (MRD) is not entirely a new story in hematology. At this ASH meeting, we are now seeing firm evidence that MRD testing with novel technologies can be used in a variety of ways in lymphomas. First, higher baseline levels of ctDNA correlate with adverse outcomes in patients with both aggressive non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. Second, failure of MRD to become undetectable during and after therapy for aggressive NHL, mantle cell lymphoma, and Hodgkin lymphoma predicts a higher likelihood of recurrence. Third, when used at the end of treatment in aggressive lymphoma, a specific test used to measure ctDNA called PhasED-Seq was superior to PET/CT scans, the conventional method of assessing response to therapy in aggressive lymphomas, at predicting which patients would and would not relapse. 

One can imagine using MRD results during treatment to tailor therapy for individual patients. Can patients who achieve undetectable MRD during therapy have their therapy shortened or reduced? Should patients who do not achieve undetectable MRD during or after therapy have their therapy intensified? Can we omit scans in patients whose MRD tests become negative after therapy, thereby reducing cost and exposure to potentially harmful radiation? I would advise that we not jump to conclusions and think we know the answers to these questions without controlled clinical trials. For example, in a mantle cell lymphoma study, patients with undetectable MRD still benefited from maintenance rituximab (Rituxan) as opposed to stopping treatment. Not all MRD tests are created equal, so the characteristics of the tests will need to be considered when designing trials to act on MRD results.

Articles

John M. Burke, MD, highlights progress in the field of hematology and oncology presented at the 64th American Society of Hematology Annual Meeting and Exposition.

Circulating Tumor DNA Measurement in Lymphoma One of the Big Stories From ASH

Significant attention has been paid in recent years to the problem of physician burnout, a syndrome characterized by emotional exhaustion, depersonalization, and a reduced sense of professional accomplishment. The prevalence of burnout among physicians has reached 50%. Among oncologists, the prevalence is significant, perhaps because the long hours and challenging aspects of our work are balanced by its rewarding nature. Burnout has adverse consequences not only for doctors, but for their coworkers and patients as well. Factors that contribute to it include workplace ineffi ciencies, use of electronic medical records, area of specialization, payment model, and institutional and personal factors—and that was before COVID-19 added a host of new stressors.

Given that burnout has become more common and widely recognized, it is heartening to see that professional societies have taken note—and acted. The American Society of Clinical Oncology (ASCO) created a Well-Being Task Force that in 2021 released a “roadmap” to enhance oncology clinician well-being and the sustainability of oncology practices. The 2022 ASCO Annual Meeting offered a session entitled “Burnout and Mental Health in Oncology Providers: You Are Not Alone,” which I would recommend to anyone interested in the topic.

And attempts to address the problem are not limited to ASCO. I am now planning my week at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. It’s easy to feel overwhelmed during such a gathering—from educational sessions to oral and poster presentations, from investigator meetings about ongoing trials to the get-togethers that take place at every single coffee break and the advisory meetings that start at 6 or end at 11.

As I review the ASH agenda, I see with appreciation that the society has created ways for attendees to decompress. The Wellness Studio offers sessions entitled “Yoga,” “Money Issues Are Burning You Out,” “Fix the Way You Sit,” “A Simple Way to More Resilience,” “Financial Order of Operations,” and many others.

Clearly, ASH has recognized that the conference can be busy and stressful, and it has hired professionals to help clinicians cope and reduce burnout in the long run.

I am reminded of the advice a colleague gave me during predawn rounds early in my professional life: “Remember, your career is a marathon, not a sprint.” Those words mean more than ever to me as I enter the second half of my career. The recent death of my mother also serves to remind me that my days are numbered. It’s important for us to work hard, learn as much as we can, advance our field, and improve outcomes for patients. But we cannot forget to take care of ourselves.

According to John M. Burke, MD, significant attention has been paid in recent years to the problem of physician burnout and as oncologists continue to care for patients, it important to also care for themselves.

Oncology Societies Recognize and Address Burnout During Conferences

In December 2014, the FDA first granted accelerated approval to blinatumomab (Blincyto), a bispecific antibody simultaneously targeting CD19 on malignant B lymphocytes and CD3 on nonmalignant T lymphocytes, for patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

 Subsequently, additional data emerged demonstrating the value of blinatumomab not only in patients with relapsed ALL but also in those with detectable minimal residual disease.

Blinatumomab has the distinction of being the first bispecific antibody approved to treat cancer. Administration of blinatumomab is cumbersome; due to its short half-life, it requires continuous intravenous (IV) infusion. Because of the risk of cytokine release syndrome (CRS), patients receiving blinatumomab require admission to the hospital for monitoring during the early weeks.

In recent years, innovative scientists have been developing novel bispecific antibodies with different targets, such as CD20, B-cell maturation antigen (BCMA), and GPRC5D, making them potentially effective in a wider array of diseases like lymphoma and multiple myeloma. They have longer half-lives, thereby eliminating the need for continuous IV infusions, and they are being developed for IV and subcutaneous administration.

We are starting to see fruits of this labor. Recently, the CD20×CD3 bispecific antibody mosunetuzumab (Lunsumio) received conditional approval in Europe for patients with relapsed follicular lymphoma based on an overall response rate of 80% and complete response rate of 60% in a phase I/II trial (NCT02500407).

 On August 24, 2022, the BCMA×CD3 bispecific antibody teclistamab received conditional approval in Europe for patients with multiple myeloma who have received at least 3 prior therapies.

 In these patients teclistamab produced an overall response rate of 63%, including a 59% rate of very good partial response or better, and a median progression-free survival of 11 months. According to news reports, both mosunetuzumab and teclistamab are being reviewed by the FDA.

The incorporation of bispecific antibodies into the treatment arsenal for hematological malignancies is not going to end soon. Additional studies have demonstrated significant benefit of these products in different diseases and scenarios. The CD20×CD3 bispecifics glofitamab and epcoritamab have significant activity in diffuse large B-cell lymphoma.

 The GPRC5D×CD3 bispecific talquetamab has activity in multiple myeloma and has been granted a breakthrough designation by the FDA.

 With the efficacy rates we are seeing in heavily pretreated patients, I would predict that these drugs will find their way into earlier lines of therapy.

There is going to be a learning curve for all of us to be able to deliver these bispecifics to patients safely and efficiently. Bispecific antibodies cause CRS, characterized by fevers and sometimes hypotension, hypoxia, and organ dysfunction. CRS tends to occur within the first month of therapy. Although physicians who administer a lot of blinatumomab or CAR T-cell therapy are very experienced in managing CRS, the rest of us are not. We need to work with our clinical teams—nurses, pharmacists, advance practice providers, social workers, administration—in and out of the hospital to prepare the team to manage CRS and other toxicities.

After years of seeing promising results of bispecifics in clinical trials, the light at the end of the tunnel seems to be near. These products are going to be a big win for patients.

1. Przepiorka D, Ko CW, Deisseroth A, et al. FDA approval: blinatumomab. 

. 2015;21(18):4035-4039. doi:10.1158/1078-0432.CCR-15-0612

2. European Commission approves Roche’s first-in-class bispecific antibody Lunsumio for people with relapsed or refractory follicular lymphoma. News release. Roche. June 8, 2022. Accessed June 8, 2022. https://bit.ly/3H7bwDT

3. Janssen marks first approval worldwide for TECVAYLI (teclistamab) with EC authorisation of first-in-class bispecific antibody for the treatment of patients with multiple myeloma. News release. Johnson & Johnson. August 24, 2022. Accessed August 24, 2022. https://bit.ly/3wsRYFP

4. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and≥2 prior therapies: pivotal phase II expansion results. 

. 2022;40(suppl 16):7500. doi:10.1200/JCO.2022.40.16_suppl.7500

5. Clausen MR, Offner F, Belada D, et al. Subcutaneous epcoritamab+R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma: phase 1/2 update. Abstract presented at: European Hematology Association 2022 Congress; June 9-17, 2022; Vienna, Austria. Abstract P1214. Accessed July 8, 2022.

6. van de Donk NWCJ, Bahlis N, Mateos MV, et al. Novel combination immunotherapy for the treatment of relapsed/refractory multiple myeloma: updated phase 1b results for talquetamab (a GPRC5D×CD3 bispecific antibody) in combination with daratumumab. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Accessed July 8, 2022.

Additional data emerged demonstrating the value of blinatumomab not only in patients with relapsed acute lymphoblastic leukemia but also in those with detectable minimal residual disease.

Bispecifics Show Promise Against Hematologic Malignancies

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.

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.