World Lymphoma Awareness Day: Novel Therapies Are Paving the Way to Better Patient Outcomes

This World Lymphoma Awareness Day, it’s important to remember that while the disease is increasingly more common, multiple novel therapies are available to better combat this disease.

According to the National Institute of Health Surveillance, Epidemiology, and End Results (SEER) program, the estimated number of new cases of non-Hodgkin lymphoma alone will account for 4.1% of all new cancer cases.¹ Further, they estimate that 3.3% of all cancer deaths will be due to non-Hodgkin lymphoma cases, a total of approximately 20,180 deaths. However, because of novel therapies and approaches to treatment, the 5-year relative survival rate from data SEER collected from 2013-2019 is 74.3%.

In an interview with Targeted Oncology^TM, Yuliya P.L. Linhares, MD, chief of lymphoma services at Miami Cancer Institute Baptist Health South Florida, discussed how novel therapies are changing the landscape for patients with different kinds of lymphoma and what physicians should consider when integrating these treatments into their practice. Moreover, she addressed the remaining challenges in the field but pointed to the hope of prolonging the patient’s life presented by new understandings of this disease.

Yuliya P.L. Linhares, MD

Targeted OncologyTM: How has the field for the treatment of patients with lymphoma changed in the past couple years?

LINHARES: I'm extremely excited to specialize in lymphoma now because I don't think there has been a revolution in the treatment of patients with other kinds of cancers like there has been for the treatment of patients with lymphoma. We have new therapies approved almost every couple of months. Most importantly, the novel therapies that are coming out are not the classical cytotoxic therapies, which are the treatments that traditionally scare our patients because of their adverse events [AEs], such as hair loss, severe nausea, and vomiting.

The majority of novel drugs are targeted therapies, and targeted therapy drugs kill cancer cells via attacking them through specific antigens on tumor cells or via breaking specific biochemical pathways inside of the cancer cells, and therefore, specifically attacking lymphoma cells rather than also attacking other cells in the patient's body. Of course, there are some off-target effects where some normal cells can still be affected, especially cells of the immune system, as they are the origins of lymphoma. Otherwise, the [safety] profile of targeted drugs is usually more agreeable with the patients. Most importantly, with the novel treatments, a big percentage of patients with lymphoma can maintain their quality of life while on treatment.

What excites you about these novel therapies for patients with lymphoma?

Some of the novel therapies that are coming out include antibody-drug conjugates [ADCs] where the antibody is loaded with a chemo-molecule and the antibody takes this chemotherapy molecule specifically to lymphoma tumor cells.

Other exciting drugs that have been recently approved for the treatment of [patients with] relapsed/refractory diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma are bispecific T-cell engagers [BiTEs]. These drugs are basically 2-headed antibodies that approximate our own immune system T-cells to tumor cells, enabling our own immune system cells to kill the lymphoma cells. Of course, everybody knows about chimeric antigen receptor T-cells, or CAR T-cells, and now we have more CAR T-cell products available in use. We are working on improving the AE profile and avoiding treatment resistance. CAR T-cell therapies are now in research trials where we are looking at allogeneic off-the-shelf T-cells that are modified to specifically attack and eliminate lymphoma cells.

Another [development] that is happening now is that, finally, the companies that are producing these drugs are starting to [work] together, meaning that we're getting trials with the combinations of these novel therapies where you combine, for example, ADC and BiTE, or where you combine a small molecule inhibitor with CAR T-cells. Now, we're finally getting more powerful non-cytotoxic drug combinations for patients.

How has the understanding of treating patients with relapsed/refractory disease change in this space?

What's very important is that we now have more effective treatments for patients with relapsed/refractory lymphomas. For example, in the past, patients with early relapse of DLBCL had a dismal prognosis with survival limited to months, and now they have a chance for long-term survival and possibly a cure.2 We have novel therapies that we can sequence to potentially give these patients years of time. Now we can treat some patients with aggressive lymphomas almost as if they have a chronic disease, which is a new concept.

I encourage oncologists to think of aggressive lymphomas as chronic disease in certain patient populations, because we can sequence therapies with low toxicities for years to help our patients stay alive with an excellent quality of life. Additionally, with the advent of these low-toxicity targeted therapies, we can treat older patients with more success. Previously, older patients would have trouble if they had relapsed/refractory disease because they wouldn't be able to tolerate repeated cytotoxic chemotherapy regimens and would not be transplant candidates. Now, we can sequence therapies that are targeted, for example, starting with ADCs, then using BiTEs, and potentially even CAR T-cells, so our older patients are able to gain this valuable quality of life and more years to share with their families.

What challenges remain in this space?

Despite all the progress, unfortunately, there're still challenges and I'm sure that all my colleagues have had a patient with lymphoma where the pace of disease is so high that they were unable to keep up. The tumor growth can be exponential and seem to be unstoppable, with multiple therapies failing. A lot of times, these are tumors that have a mutation in the p53 gene. The p53 gene is “the guardian of the genome.” It makes cells with damaged or mutated DNA suicide, a process known as programmed cell death or apoptosis. Cancer cells tend to have multiple DNA mutations, and many chemotherapy drugs work via damaging DNA.

Mutation in the p53 gene enables lymphoma cells to grow without committing apoptosis, which then contributes to chemotherapy resistance, and p53-mutant disease is still a huge problem for patients with mantle cell lymphoma [MCL] and DLBCL. Additionally, in DLBCL, we have disease with double- and triple-hit biology where we have translocations of the BCL2 and MYC genes, which basically make the cells immortal and very metabolically active. So, this is still an area of need, but we're excited to be bringing CAR T-cells into the earlier line of treatments, potentially the first line of treatment, for these hard-to-treat DLBCL cases.

What advice would you give community oncologists treating these patients?

I would contemplate using targeted therapies in patients who are demonstrating chemotherapy resistance in the earlier lines since we have so many higher efficacy and lower toxicity regimens now. Switching gears to targeted therapies usually helps patients to preserve their quality of life and to bridge them to definitive treatments such as CAR T-cell therapy. For example, I have a wonderful 86-year-old patient who came to me with stage IV DLBCL in tumor lysis. She also had coronary artery disease and chronic kidney disease, and she told me that she didn't want chemotherapy because she didn't want to lose her quality of life.

We treated this patient with only 1 cycle of classical chemotherapy, which she didn't tolerate well due to nausea and fatigue. We were subsequently able to switch to polatuzumab vedotin [Polivy] and rituximab [Rituxan] with rapid achievement of complete remission, which lasted for about a year. Subsequently, we used tafasitamab-cxix [Monjuvi] with lenalidomide [Revlimid], again inducing complete remission, which lasted slightly over a year.

When her disease progressed, we went back to rituximab and polatuzumab and the patient went into complete remission after only 1 cycle of this treatment. She subsequently completed a full 6 cycles [of treatment] virtually without any AEs. I celebrated her 88th birthday with her and her family, and now she's 89. She loves spending time with her children and her 2 puppies. In the modern times, even when it might seem there are no good treatment options, we may have novel therapies or exciting clinical trials available.

^References

^{1. Cancer Stat Facts: Non-Hodgkin Lymphoma. NIH SEER Program. 2023. Accessed September 11, 2023. https://seer.cancer.gov/statfacts/html/nhl.html}

^{2. Survival rates and factors that affect prognosis (outlook) for non-hodgkin lymphoma. American Cancer Society. March 2, 2023. Accessed September 11, 2023. https://www.cancer.org/cancer/types/non-hodgkin-lymphoma/detection-diagnosis-staging/factors-prognosis.html}