Diffuse large B-cell lymphoma (DLBCL) is an aggressive and common form of cancer that impacts thousands of individuals globally. In recent years, the treatment landscape of DLBCL has shifted rapidly due to evolutions in molecular profiling, immunotherapy, and response-adapted monitoring. At the 67th American Society of Hematology Annual Meeting and Exposition, which takes place December 6 through 9 in Orlando, Florida, experts discussed how emerging modalities and novel research insights are powering the next frontier of DLBCL care.1
Presenters at the session, titled “Now Is the Time to Improve Outcomes in Diffuse Large B-Cell Lymphoma,” included Sarah Rutherford, MD, an associate professor of clinical medicine in the division of hematology/oncology at Weill Cornell Medicine; Jennifer Crombie, MD, a senior physician at Dana Farber Cancer Institute; and Franck Morschhauser, PhD, Centre Hospitalier Universitaire de Lille, Lille, France. Together, the presenters outlined a series of innovations that are helping to inform personalized treatment strategies, in addition to expected challenges as these methods are utilized.1
Early Response Assessment Could Lead to Treatment Modification, Improved Outcomes in DLBCL
Improving outcomes in patients with DLBCL begins with earlier response assessments that can be analyzed to determine therapy modifications, according to Jennifer Crombie. Her presentation detailed opportunities for improving prognosis and early detection, including using interim positron emission tomography (iPET) scans and measuring circulating tumor DNA (ctDNA) to detect minimal residual disease (MRD). Crombie explains why utilizing ctDNA could be particularly effective at identifying patients who may benefit from a treatment alteration.1
After frontline chemotherapy, often consisting of treatment with rituximab (Rituxan; Roche), cyclophosphamide (Cytoxan; Bristol Myers Squibb), doxorubicin (Adriamycin; Pfizer), vincristine (vincristine sulfane injection; Pfizer), and prednisone (R-CHOP) or polatuzumab (Polivy; Genentech) with the R-CHOP regimen, many patients will achieve significant improvements in their disease. For patients who do not exhibit a complete response following cycles of therapy, a PET scan—at the end of treatment—or an iPET scan—in the middle of treatment—determines the state of the cancer and impact of treatment.1
Crombie described numerous challenges regarding the use of PET scans that could hamper efforts to assess the patient’s cancer. These include imperfections in end-of-treatment PET that, despite predicting progression-free survival (PFS) and overall survival (OS) after first-line (1L) treatment, could miss patients who relapse.1
“There is a high false-positive rate,” Crombie explained. “It makes you worry about potentially changing the therapy of someone who may be driving benefit [from their current regimen.”1
Moreover, investigators of response-adapted trials have attempted to derive a clinical benefit with intensive chemotherapy using iPET with little results. In a 10-year follow-up of the PETAL trial (NCT00554164), for example, although iPET predicted outcomes in aggressive lymphoma, iPET-based treatment alterations did not improve outcomes.2-4
Crombie highlights molecular testing using ctDNA assessments as a more productive avenue, asking the crowd, “Can we do better?” She outlined a series of next-generation sequencing assays for MRD, including clonoSEQ (Adaptive Biotechnologies Corporation), CAPP-Seq (Roche), and PhasED-Seq (Foresight Diagnostics). Recent studies demonstrate improved personalized cancer profiling and heightened sensitivity with these novel diagnostic assays, especially in Roschewski et al, who demonstrated that PhasED-Seq can be prognostic at both interim and end-of-therapy assessments.1,5,6
Barriers remain erected against the use of interim MRD in clinical practice, including workflow and turnaround time considerations, along with a lack of commercial availability of diagnostic assays. However, Crombie envisions a future where frontline induction—whether it be chemotherapy or a novel agent—could be followed by iPET and interim ctDNA assessment, with results that can guide future treatment plans. These interim assessments could play a complementary role in future DLBCL treatment.1
“We’re not there yet, but this is, I think, an attractive potential strategy to consider for the future,” Crombie explained. “And I hope clinical trials start to answer these types of questions, as to whether or not we can use MRD and PET scans in this fashion.”1
Optimizing Treatment Sequencing in Second and Third Lines
Novel modalities of response assessments in the form of ctDNA MRD could transform how DLBCL is treated. But how do health care professionals determine exactly which treatments to utilize in each patient in relapsed or refractory disease, especially given the myriad novel therapies and regimens now available? Franck Morschhauser explained how this consideration finds itself at the forefront of a shifting field, which is transitioning from defining patients after the 1L based on their transplant eligibility to defining them on their eligibility for chimeric antigen receptor (CAR) T-cell therapy.1
CAR T-cell therapies have transformed the paradigm of second-line treatment in DLBCL. In phase 2 trials such as ALYCANTE (NCT04531046) and PILOT (NCT03483103), agents like axicabtagene ciloleucel (axi-cel, Yescarta; Gilead Sciences) and lisacabtagene maraleucel (liso-cel, Breyanzi; Bristol Myers Squibb) have demonstrated strong PFS rates within 1 year. CAR T-cell therapy carries numerous advantages compared with autologous stem cell transplantation, including not requiring a response from a prior line of therapy and not necessitating a referral to a specialty setting. Still, Morschhauser cautions providers that “eligibility for CAR T-cell therapy is a dynamic process,” noting that older adults and patients with comorbidities face a higher risk of neurotoxicities.1,7-10
While new CAR T-cell therapies are becoming standard of care options, bispecific antibodies (BsAbs) and combination agents with antibody-drug conjugates are pushing treatment capabilities even further. Investigators have tested regimens such as glofitamab (Columvi; Genentech) plus gemcitabine and oxaliplatin, mosunetuzumab (Lunsumio; Genentech) plus polatuzumab vedotin, and polatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin. The sheer number of combinations provides countless new ways to better treat patients with DLBCL in the relapsed or refractory setting, Morschhauser explained.1,11-13
Still, Morschhauser noted that data on the impacts of prior BsAb exposure on CAR T-cell outcomes remains limited; he told the audience that “we should be very cautious…before making a decision to shift the sequence in the other direction.” Given the unanswered questions that remain in the field, Morschhauser gave his preference in the second line setting towards CAR T-cell therapy. However, in the third line—following the failure of CAR T-cell therapy—Morschhauser discussed the merits of treatment with BsAbs. Research led by Topp et al previously demonstrated the effectiveness of monotherapy with the BsAb odronextamab in patients with disease progression after CAR T-cell therapy.1,14
“Patients experiencing disease progression after CAR T and bispecifics still have [significant] unmet need, and we should focus our research on those patients,” Morschhauser concluded.1
