Lymphoma Treatment Paradigm Refined Over Years, Expert Says on World Lymphoma Awareness Day

The treatment paradigm for lymphomas has undergone significant advancements over the recent years. Although there are more than 100 types of lymphomas, investigators have refined the treatment landscape, particularly for some of the most common lymphomas, which include Hodgkin lymphomas (HLs) and non-Hodgkin lymphomas (NHLs).

Although the landscape started with chemotherapy regimens, both immunotherapy and targeted therapy have made their way into the treatment landscape for lymphomas. In addition, significant advancements have been observed with chimeric antigen receptor (CAR) T-cell therapy across a variety of lymphomas. Most recently, a supplemental Biologics License Application for axicabtagene ciloleucel (axi-cel) was submitted for the treatment of patients with relapsed/refractory follicular or marginal zone lymphoma, which appeared promising in the phase 2 ZUMA-5 trial where the objective response rate by the independent radiologic review committee in the overall population was 93% (95% CI, 86%-97%).

Annually on September 15 we call attention to the complex set of diseases known as lymphomas with World Lymphoma Awareness Day.

In an interview with Targeted Oncology, Thomas M. Habermann, MD, hematologist and internist at the Mayo Clinic, reflects on the advancements he has observed in the treatment paradigm for lymphomas. He highlighted the prognosis and treatment options for some of the most common types of lymphomas and shared his thoughts on the Light It Red for Lymphoma initiative, for which the Plummer Building at the Mayo Clinic will be lit red for World Lymphoma Awareness Day.

TARGETED ONCOLOGY: Lymphoma is the most common type of blood cancer. Do you want to provide an overview of this landscape and what the prognosis is typically like for patients with lymphomas?

Habermann: There are over 106 types of lymphoma, which makes this a complex question, but epidemiologic observations put this into perspective. The understanding of the 2 most common NHLs and HLs provide insights into prognosis.

[Approximately] 32.5% of patients with NHL have diffuse large B-cell lymphoma (DLBCL), and 65% to 75% of patients are in long-term remission with immunochemotherapy—rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). If patients have not relapsed or been retreated at 24 months, then survival is similar to that of an age- and sex-matched population.²

Seventeen percent of patients have follicular lymphoma. At 10 years, 80% of patients are alive. The natural history of follicular lymphoma has recently been reported in patients from a French cohort and from the Molecular Epidemiology Research Program of Mayo Clinic.³ The 10-year survival rates were 80%. Fifty-six percent of the deaths were from lymphoma, and half of those were from transformation. We have previously reported that immunotherapy—rituximab—reduces the risk of transformation.⁴ The event-free survival data at 12 months and 24 months predict long-term survival.⁵

In HL, in a stage-based approach, 5% to 25% of patients relapse. The results of the North American trial, E2496, demonstrated that in patients treated with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) with advanced disease, the failure-free survival rate was 74% at 6.5 years and the overall survival rate was 88%.⁶ The ECHELON-1 trial that randomized ABVD to AVD + brentuximab vedotin (Adcetris). There was a 5% improvement in progression-free survival with this. New drugs have contributed to outcomes in patients including brentuximab vedotin with an overall response rate of 75% and nivolumab (Opdivo) with an overall response rate of 87% with similar results with pembrolizumab (Keytruda).

In Burkitt lymphoma, the 2-year overall survival rate was 84% with an event-free survival rate of 80% in 264 real-world patients. For patients in complete remission the 2-year risk of relapse was 6% but diminished to 0% to 6% for patients reaching 12 months of post-remission event-free survival if this was obtained, the life expectancy was similar to that of the general population. This information contributes to meaningful follow-up strategies.7

TARGETED ONCOLOGY: Could you highlight some of the recent advances in lymphomas?

Habermann: The outcome predictions have been refined. The biology of the disease has further defined disease subsets and will define future therapeutic interventions. In HL, drugs now target the surrounding T cells and not the malignant cell with the PD-1 and PD-L1 inhibitors such as nivolumab. An unspoken recent advance in lymphoma research have been examples of demonstrable international and national collaborations. We're all realizing you can't do this alone, and it's really been phenomenal. A lot of barriers have been broken down. There still are more barriers to break down as far as tissue being able to be utilized in different countries and so forth.

TARGETED ONCOLOGY: Where does CAR T-cell therapy fit into the treatment landscape, and how do you think it may continue to evolve in the coming years?

Habermann: CAR T-cell therapeutic interventions are contributing to the outcomes of patients with DLBCL in the relapsed/refractory setting including patients who have relapsed after transplant. There are now 3 approved. A new CAR, brexucabtagene autoleucel (Tecartus) has been approved in mantle cell lymphoma in 2020. The management of cytokine release syndrome/macrophage activation syndrome complications has improved and the strategies have actually been incorporated into the management of patients with coronavirus disease 2019 (COVID-19) with severe systemic illnesses. There are remarkable future opportunities to develop different CARs, and these trials are ongoing. This opens up an entire new era in the management of malignancies.

TARGETED ONCOLOGY: What are the unmet needs that still need to be addressed in the lymphoma treatment paradigm?

Habermann: “Unmet needs” is a very complex question. In 2019, I had the opportunity to be on the organizing committee for the Lymphoma Research Foundation on marginal zone lymphoma and adolescent and young adult lymphoma. We actually put together issues with 1-year and 5-year questions. I was the senior author on an international commission on toxicity in 2018. I have been involved in publications in clinical trials on 21 different drugs before FDA approval if approved, and 6 were [approved].

To overcome these challenges, the only answer at the 30,000-foot level is research at all levels. Any lymphoma that is not cured in 100% of patients is an unmet need. In DLBCL, in 304 patients, there were 158 genetic driver alterations reported, and the individual patient with DLBCL has had a median of 17 genetic drivers. It is imperative that this be much better understood.

Significant unmet needs include access to clinical trials for patients at all socioeconomic levels. The costs of clinical trials and the infrastructure that is required in the present structure is almost prohibitive. Other significant unmet needs include patients who relapse after stem cell transplantation in DLBCL and HL, “financial toxicity” of new therapeutic interventions, primary refractory disease in the curable lymphomas is a very significant issue, and understanding the genomics and microenvironment

TARGETED ONCOLOGY: Would you also like to comment on the Light it Red for Lymphoma event and the importance of bringing more awareness to this disease?

Habermann: We’re going to light the Plummer Building at Mayo Clinic red again this year, so I’m cognizant of its tenth year this year. Lymphoma represents only 5% of malignant diseases. This disease has led the way in defining future directions in malignancy. Unfortunately, the successes have made this disease less of a priority for funding at a local, federal, and pharmaceutical perspective. The Light it Red for Lymphoma initiative genuinely enhances and brings out lymphoma awareness, as well as brings out the formal research. I’m biased because that’s what I do for a living, but I have come to be enamored with the whole concept. I think it’s a really neat thing, a neat idea.

TARGETED ONCOLOGY: What advice would you like to share with community oncologists that come across patients with lymphoma in their practice?

Habermann: There are a lot of good doctors and bright people, but lymphoma management strategies are complex and evolving at a remarkable pace. The biology is almost not possible to keep up with. The natural history of these diseases is being redefined clinically and biologically. It is important to introduce patients to education opportunities such as the Lymphoma Research Foundation, which is a remarkable education resource for patients and their families.

Lastly, participation in clinical studies is important to emphasize. Clinical trials are very expensive to activate at all sites. This is an issue in less common malignancies such as lymphomas. Clinical trials define changes in therapeutic approaches and biology.

It's also not just clinical trials, which are really so essential and so important. Epidemiologic studies have provided remarkable clinical insights and molecular biology associations and are critical to the further understanding of lymphoma. Peripheral blood and tissue samples will change the outcomes.

These are the things that are going to make the difference in the long run, and I think it's upon all of us to learn to work together as best we can, and better than we have. It's complicated, but I think that's what's going to move the field forward and help patients, especially those with more uncommon lymphomas.

TARGETED ONCOLOGY: Looking at blood cancers as a whole this month during National Blood Cancer Awareness Month, what would you say have been the most exciting advances? What message would you like to share with fellow colleagues making great strides in this space?

Habermann: The most exciting advances include the continued evolution of team science to further the field. Second, immunotherapy approaches continue to target the tumor, so we have engineered antibodies, antibody-drug conjugates (ADCs), bispecific antibodies, and CAR T cells; to target the host, so enhanced antibody-dependent cell cytotoxicity, removing check points in the immune system; and to target the tumor and the host.

New drugs have also been exciting, such as polatuzumab vedotin (Polivy), which is a CD79b-directed ADC that was FDA approved on June 10, 2019. There has been continued federal, foundational, and institutional support such as the Lymphoma Research Foundation, with programs to develop fellows and junior faculty that stay in the field.

Finally, the biology and genomic research is just exploding. In a study that we participated in, there were 159 driver genes and any given patient had 17 driver genes. There must be some different answers. The epidemiologic observations are also exciting as these can genuinely help patients.

The strides in lymphoma have been remarkable. I was born in 1953, the year that the second drug that was active in lymphoma came on the scene, methotrexate. In 1963, there was a second drug to come along, and then CHOP came around in 1975 and rituximab in 1997. We went from a chemotherapy era into the early 1990s then moved on to targeted therapy such as ADCs and other drugs. Now we’re into the tip of cellular approaches.

When you think about the perspective and where we've come from, it's really phenomenal, and I think the next 30 years are going to be fascinating. I think it’s incredibly unpredictable, about where we're going to be in and what we're going to be doing.

Lastly, we're all tied up in the COVID-19 pandemic, but this is only going to make us better at understanding inflammatory responses. There will likely be spin offs and other knowledge gleaned that then can help especially local proliferative disorders.

_References

_{1. Al-Hamadani M, Habermann TM, Cerhan JR, et al. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol. 2015; 90(9):790-795. doi:10.1002/ajh.24086}

_{2. Maurer MJ, Ghesquieres H, Jais JP, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol.2014;32(10):1066-1073. doi:10.1200/JCO.2013.51.5866}

_{3. Sarkozy C, Maurer MJ, Link BK, et al. Cause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts. J Clin Oncol. 2019;37(2):144-152. doi:10.1200/JCO.18.00400}

_{4. Link BK, Maurer MJ, Nowakowski GS, et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol. 2013;31(26):3272-3278. doi:10.1200/JCO.2012.48.3990}

_{5. Maurer MJ, Bachy E, Ghesquieres H, et al. Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol. 2016;91(11):1096-1101. doi:10.1002/ajh.24492}

_{6. Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684-691. doi:10.1200/JCO.2012.43.4803}

_{7. Jakobsen LH, Ellin F, Smeland KB, et al. Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy: an international study of 264 real-world patients. Br J Haematol. 2020;189(4):661-671. doi:10.1111/bjh.16425}