Non-Hodgkin lymphoma (NHL) is among the most common cancers in the United States. In 2020, an estimated 77,240 Americans will be diagnosed with the disease and about 20,000 people will die from it.1 Seventy-two percent of patients live for at least 5 years after diagnosis.2 However, the success of treatment varies widely across the many subtypes of NHL. Patients diagnosed with diffuse large B-cell lymphoma (DLBCL), the most common subtype, have a 5-year survival rate of 63% for all disease stages combined. By contrast, follicular lymphoma (FL) has a 5-year survival rate of 88% for all stages combined. Patients with mantle cell lymphoma, one of the more difficult-to-treat subtypes, have an average survival time of less than 5 years.3

But the treatment landscape is transforming across the entire spectrum of NHL. Novel immunotherapies and small molecule inhibitors are offering both previously treated and untreated patients entirely new options and new combinations. At the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program, researchers led by Jeremy Abramson, of Massachusetts General Hospital in Boston, provided a compelling overview of these new and upcoming treatments.4 Their overview, published in the ASCO Educational Book, offered a detailed and vital look at the present and future of NHL treatment.

CAR T-cell immunotherapy has been hailed as a major game-changer for some blood cancers.5 For aggressive B-cell lymphomas, such as DLBCL, anti-CD19 chimeric antigen receptor T cells (CAR-T) are a new option for patients who have relapsed following chemoimmunotherapy or autologous stem cell transplant (ASCT). For this patient group, which has a median overall survival of about 4 months, anti-CD19 CAR-T agents have elicited durable remissions in about 40% of patients.5-7 Clinical trial data has led to the approval of axicabtagene, ciloleucel, and tisagenlecleucel by both the US Food and Drug Administration and the European Medicine Agency. “CAR T-cells offer curative intent therapy to patients with relapsed DLBCL who are not eligible for stem cell transplant,” Dr Abramson told Cancer Therapy Advisor. “Previously these patients only had palliative options available.”

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Some clinicians envision CAR-T as a potential first-line therapy for patients with DLBCL who relapsed after first-line chemoimmunotherapy. These patients, noted Anton Hagenbeek, MD, PhD, professor of Hematology at Amsterdam University Medical Centers, who was not involved with the review paper, “represent one of the highest unmet needs in the treatment of lymphoma to date.” And Helen Heslop, MD, who directs the Center for Cell and Gene Therapy at Baylor College of Medicine in Houston, Texas, noted that trials for first-line CAR-T  therapy are already underway in acute lymphoblastic leukemia. Not everyone sees this potential. “First-line treatment in NHL is generally very effective and much less expensive than CAR T-cells,” explained Edward Copelan, MD, who chairs the Department of Hematologic Oncology and Blood Disorders at Carolinas Healthcare System in Charlotte, North Carolina, and who was not an author of the review. Though Dr Copelan emphasized that patients at extremely high risk of relapse following standard immunochemotherapy may respond well to CAR-T therapy.

Dr Abramson and co-authors highlighted a difficult conundrum with regard to DLBCL. Although the addition of rituximab to cyclophosphamide, doxorubicin, hydrochloride, and vincristine sulfate (CHOP) chemotherapy is curative for most patients, the number of patients who may be cured after relapse has declined. Thus improvements in second-line therapy are desperately needed. Several clinical trials are currently evaluating anti CD19 CAR-T for primary refractory or early relapsed aggressive B-cell lymphoma compared with traditional salvage therapy or ASCT. The same approach is being studied for relapsed DLBCL patients who are not transplant candidates.

Whether CAR-T therapy will find a place on the first line of care is another current question. The cost and logistics of CAR-T therapy make it unlikely that this approach will replace R-CHOP as the standard initial treatment, Dr Abramson and colleagues noted. “I do not think CAR T-cells will replace frontline chemotherapy,” Dr Abramson said. However, the authors note that for patients who do not respond well to initial treatment, such an approach may make sense — a possibility that is now being examined in the clinical trial setting. Dr Hagenbeek is more certain about the first-line role for CAR-T therapy, based on the “dismal prognosis” of DLBCL that is refractory to R-CHOP.

On the subject of CAR-T therapy as first-line therapy, the authors pay special attention to so-called double-hit lymphomas (DHLs), also known as double expressor lymphomas. According to a multicenter study published in 2017, R-CHOP is curative for more patients than conventional wisdom has held.9 Clinical trials are currently investigating the use of anti-CD19 CAR-T early for patients who consistently test positive for disease on PET scans during initial therapy, though Dr Abramson and colleagues call for caution with this approach because the prognostic value of PET/CT scans is controversial. Dr Hagenbeek is optimistic about the potential for CAR-T therapy to improve the prognosis for patients with double- and even triple-hit lymphomas, “if applied in the first complete, PET-negative metabolic remission.” Because these patients have a relatively small tumor load, this approach could, said Dr. Hagenbeek, “completely eradicate minimal residual disease.” It’s the double-hit patients who Dr Copelan sees as the likeliest candidates for first-line CAR T-cell treatment.