Angela Weyand, MD
Treatment of lymphoma has come a long way since the 1600s when it was first described by Dr. Marcello Malpighi as “a disease of lymph nodes and spleen that was uniformly fatal.” Recent advances, ranging from chimeric antigen receptor T cells to antibody-drug conjugates with chemotherapy to targeted therapies, have changed the treatment landscape and improved the care of patients with lymphoma. But significant challenges remain.
The spectrum of disease in lymphoma is wide, ranging from indolent to aggressive, and treatments differ substantially. Significant advances have been made in our understanding of the molecular basis of aggressive lymphomas. As biologic drivers of disease are identified, they enable the identification of novel therapies. Historically, chromosomal translocations of the BCL6 and MYC genes have been shown to lead to perturbations in transcriptional programs. Additional transcription factors have increasingly been identified; these disturb transcriptional and epigenetic programs that regulate B-cell development and immune response. To hear about the latest and greatest in the treatment of aggressive lymphomas, tune in to the Education Program session “Aggressive Lymphomas: What Novel Approaches are Ready for Prime Time?” (Q&A available on demand). Dr. Michael Green reviews recent advances in our understanding of how somatic alterations modify the epigenome, with a focus on CREBBP and EZH2 mutations in follicular and diffuse large B-cell lymphomas, and discusses how this can be leveraged to pursue rational therapeutic strategies. Epigenetics has also been implicated in the development of resistant clones. Dr. Jennifer Amengual presents the epigenetic mechanisms that lead to acquired chemoresistance, including DNA methylation, histone methylation, disease severity in lymphoma, risk of relapse, and overall survival. These have been shown to correlate with methylation heterogeneity, with heterogeneity focused on promoter regions of BCL6, MYC, and EZH2. These epigenetic changes can be overcome with targeted therapies such as DNMT inhibition in the reversal of hypermethylation of SMAD1. There is significant intersection between epigenetics and immune surveillance, including DNA methylation and T-cell exhaustion limiting the efficacy of PD-1 blockade, loss of TET2, and deceased activity of PDL1 inhibitors in activation of CD3 and CD8 cells and EZH2 effects on CTLA4 and MHC II expression. Modulation of these epigenetic pathways in combination with other epigenetic targeting drugs, small molecules, chemotherapy, or checkpoint inhibitors circumnavigate resistance by rewiring these pathways.
Lastly, Dr. Kami Maddocks reviews emerging therapeutics in development for the treatment of relapsed and refractory non-Hodgkin lymphoma. CD19 is highly expressed on malignant B cells and is a target of chimeric antigen receptor t-cell (CAR-T) therapy, as well as the Fc-enhanced CD19 antibody tafasitamab. Tafasitamab as a single agent resulted in an overall response rate of 26 percent, but those who did respond had durable remissions. In combination with lenalidomide, tafasitamab has now been approved for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for transplantation. Antibody drug conjugates are discussed including loncastuximab (CD19), which has been shown to have activity in R/R DLBCL and is currently under U.S. Food and Drug Administration review, as well as polatuzumab (CD79B), which has been approved in combination with bendamustine and rituximab. There are currently two approved CD19 CAR-T therapies, with another pending approval, and given its efficacy there are ongoing studies of moving this option to earlier in treatment, including as first line in high-risk disease. Cellular therapies are limited by toxicity, logistics, and cost. Ongoing studies are continuing to attempt to increase efficacy and decrease toxicity. And in case you didn’t think there was any overlap between bleeding disorders and DLBCL, bispecific antibodies may be helpful for both. Mosunetuzumab and REGN1979, CD20/CD3 bispecific antibodies, have shown activity in R/R DLBCL and are well tolerated. Targeting B-cell receptor signaling has not been as effective in R/R disease, but using combination therapy (lenalidomide, ibrutinib, and rituximab) up front is being evaluated in the Smart Start study (#NCT02636322). Venetoclax, a BCL2 inhibitor, is being studied in combination with chemotherapy or chemotherapy and immunotherapy in different studies. One particular area of interest in the treatment of lymphoma is immune manipulation, as the antitumor immune response in lymphoma is typically compromised. The Education Program session “Understanding How to Manipulate the Immune System in Immunotherapy for Lymphoma” (Q&A available on demand) provides an overview of the optimal immune response, and covers the role of drugs to boost immune function, as well as the use of cellular therapy.
Despite improvements in survival of patients with aggressive lymphoma, challenges remain. The Education Program session “Challenging Situations for Patients with Aggressive Lymphomas” (available on demand) tackles these issues. Treatment of aggressive lymphoma typically requires aggressive treatment, which may be intolerable to older patients or those with significant comorbidities. Dr. Nancy Bartlett presents less intensive, yet still effective, treatments for aggressive B-cell lymphomas in patients older than 80 years, or those with multiple comorbidities. Dr. Bartlett reviews the use of fit assessment tools including the G8, the Charlson Comorbidity Index, and a simplified Children’s Global Assessment Scale score, to objectively categorize patients as fit, unfit and frail. Treatment-related mortality (TRM) most commonly occurs in older patients after cycle 1, which has led to the development of prephase treatment with steroids and vincristine. This change has led to a significant decrease in TRM, infection rates, and incidence of tumor lysis. The use of anthracyclines remains the standard of care, and dose intensity improves outcomes in all but the oldest and frailest.
The treatment of aggressive T-cell lymphomas is also discussed with Dr. Lauren Pinter-Brown addressing recent advances in frontline treatments and the utility of consolidative autologous hematopoietic stem cell transplantation. Using a case-based format, she covers treatment of a heterogenous group of uncommon lymphomas, highlighting the importance of accurate subtyping in prognostication, as well as selection of optimal treatments. Clinical-pathologic correlation is absolutely essential in accurate diagnosis and subtyping. . With the many recent advances in treatment of aggressive lymphomas comes increased uncertainty regarding individual patient prognosis. Dr. Oreofe Odejide, who chaired this session, presents approaches for the inclusion of palliative care in these challenging patients, including published tools to guide care conversations. As the treatment landscape continues to evolve, prognostication is becoming more and more complex. Triggers for inclusion of palliative care independent of prognostic certainty are likely to improve integration of palliative care into the treatment team. Patients with more indolent lymphomas present their own challenges; this is addressed in the Education Program session “Indolent Lymphomas: Answers to Smoldering Questions” (available on demand). Whatever your interest in lymphoma, #ASH20 has a session for you. And with recorded sessions, you can be sure to catch them all!
Dr. Weyand indicated no relevant conflicts of interest.