Cellular Therapies in Lymphoma Bring Hope, but Optimizing Their Use Remains a Challenge

Recent decades have seen marked improvements in hematological cancer outcomes, with novel therapeutics and sequencing strategies emerging at increasing frequency. While these developments have given hope to patients and clinicians, who now have a sizable armamentarium of therapies available and in the pipeline, questions around how best to utilize and improve upon these agents persist.

Cellular therapies that leverage the immune system to attack cancer, such as chimeric antigen receptor (CAR) T-cell therapies, have made waves in the blood cancer treatment landscape in the past few years. Several have been FDA approved for a range of hematological malignancies, and some patients remain in remission years after CAR T infusion, suggesting curative potential with this revolutionary class of therapies.

CAR T cell therapy rendering | Image credit: AIGen - stock.adobe.com

“CAR T-cell therapy and the introduction of CAR T-cell therapy has significantly changed the way we are treating patients with relapsed and refractory aggressive B-cell lymphomas. And we can consider that it is a curative strategy—at least, for a proportion of them,” Anna Maria Sureda Balari, MD, PhD, of the Institut Català d'Oncologia-L'Hospitalet in Barcelona, Spain, explained during a presentation at the 2023 American Society of Hematology Annual Meeting and Exposition. “Unfortunately, the long-term follow-up of patients included in phase 1/2 prospective clinical trials indicate that a significant proportion of these patients will ultimately relapse from the underlying disease.”

While many in the research and clinical communities expected the relapse rate to decrease as CAR T-cell therapy moved into second-line treatment strategies, Sureda noted that data coming out of the ZUMA-7 and TRANSFORM trials of second-line axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, suggest more than half of patients will relapse after CAR T-cell therapy.^1,2

Improving Prognostication for Patients Treated With CAR T Cells

Identifying predictive and prognostic factors for CAR T outcomes is of substantial clinical importance because clinicians cannot properly counsel patients and families without knowing which patients are most likely to do well after CAR T-cell therapy. This knowledge gap also makes it difficult for clinicians to determine the best ways to use the various CAR T-cell therapies in the current treatment landscape.

Pre-infusion prognostic factors related to patient characteristics, the cancer itself, and CAR T-cell treatment all come into play, Sureda said, first highlighting the fact that age is not necessarily a contraindication for CAR T-cell therapy. This notion is supported by recent research published in Blood showing older patients experienced no differences in terms of overall survival (OS) compared with younger patients, although patients older than 75 years did experience lower event-free survival.³

ECOG performance status, however, is a clear prognostic factor, with current literature showing significantly worse OS and progression-free survival (PFS) outcomes among patients with ECOG performance of 2 or higher, Sureda said. Severe comorbidities are also poor prognostic factors for long-term outcomes, with OS and PFS outcomes worse in those with severe comorbidities compared with patients without severe comorbidities.

Disease-related prognostic factors include genetic profile, with certain mutations conferring lower rates of complete remission (CR) or a higher possibility of CAR T resistance. Disease burden and aggressiveness also serve as prognostic indicators, Sureda said, noting that high lactate dehydrogenase (LDH) before apheresis and before lymphodepletion has been associated with poor prognosis in terms of OS and PFS,⁴ and that LDH is easy to measure. Metabolic tumor volume (MTV) has also been associated with CAR T outcomes, with low MTV associated with better PFS and OS.⁵ Inflammatory markers may also impact long-term CAR T-cell therapy outcomes, with several studies outlining inflammatory parameters associated with outcomes, Sureda said.

Later in the presentation, session chair Manali K. Kamdar, MD, MBBS, of the University of Colorado, Denver, echoed the sentiment that age and other characteristics alone do not necessarily indicate ineligibility for CAR T.

“It's important to note that transplant eligibility is not the same as CAR T eligibility. Octogenarians and nonagenarians were included in clinical studies evaluating CAR T-cell therapy, so we think that the recommendation would be to refer potential patients who fit this label to an academic center or a multidisciplinary clinic for functional optimization prior to CAR T-cell therapy,” Kamdar said. “These at-risk patients, based on several real-world studies that have been done, would be patients over the age of 70, an ECOG performance status of 2 or over, multiple comorbidities, poor nutrition, sarcopenia, or baseline cognitive impairment,” among others.

The effects of prior lines of therapy also come into play as novel therapies emerge, and Sureda noted research showing that treatment with bendamustine prior to CAR T was linked with poorer outcomes.6 This suggests a need for exploration of sequencing and the impact of treatment with drugs available prior to novel therapies.

Another hot topic in CAR T has been the impact—or lack thereof—of bridging therapy on long-term CAR T outcomes. At the moment, it is difficult to come to a consensus with available data, Sureda said, and the same goes for whether different CAR T-cell therapy constructs significantly impact outcomes.

Tumor microenvironment rendering | Image credit: HN Works - stock.adobe.com

In the post-infusion setting, potential disease-related prognostic factors include response times based on PET-CT, which Sureda said is the current gold standard, and circulating tumor DNA (ctDNA) measurement. In the future, combining PET-CT with non-invasive ctDNA assessments will likely prove useful for post-infusion determination of which patients will experience CR and which may be candidates for consolidation therapy, she noted.

Sureda also highlighted prognostic factors at relapse, emphasizing that patients who do relapse tend to have very poor outcomes and represent an unmet medical need for effective treatments. So far, emerging research suggests bulky disease at apheresis, a lack of CAR T response, older age, and elevated LDH at treatment are associated with poorer outcomes.⁷

“Currently, we don't have a personalized risk score system for our patients being treated with CAR T. But if I have to think about the potential ideal candidate to be treated with CAR T, I would think of a patient that has a good performance status, a patient that has low tumor burden—with that, I mean normal LDH levels, eventually low MTV or total MTV—and eventually, patients that respond to bridging therapy strategies.”

Current Options for Managing Aggressive Lymphomas After CAR T-Cell Therapy

“In the modern era, we're clearly excited about the number of therapies that are entering into the treatment landscape,” Loretta J. Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas, said during her portion of the presentation. With these treatments, outcomes such as OS have improved in recent years, but less than half of patients who relapse after CAR T-cell therapy are typically alive at the 5-year mark, she noted.

Nastoupil ran through the current treatment paradigm for relapse or refractory (R/R) large B-cell lymphoma (LBCL). For fit patients with LBCL who have relapsed within 12 months, axi-cel or liso-cel should be considerations, and Nastoupil typically bases her decision between the 2 on patient age and fitness. For younger or fitter patients, she leans toward axi-cel; for older, less fit patients, liso-cel may be preferred.

In young, fit patients relapsing beyond 12 months, she noted, salvage-based chemotherapy and autologous stem-cell transplant (ASCT) should still be considerations, which leaves CAR T as a third-line option. In older, frailer patients, more in-depth discussions around alternatives or liso-cel may be warranted. The realm of targeted therapies is an emerging area where more options are becoming available.

Nastoupil looked at several studies pointing to potential new options, noting that patients in these studies are heavily pretreated and that these studies carry limitations, but also that clinicians must work with what is available. She listed polatuzumab vedotin plus bendamustine and rituximab; tafasitamab plus lenalidomide; and loncastuximab tesirine as potential options that have shown reasonable efficacy in trials and may be considerations depending on the patient.^8-10

As far as readily available and practical approaches, Nastoupil is most enthusiastic about bispecific antibodies, which she described as an intriguing class of drugs for relapsed B-cell lymphomas. In this vein, epcoritamab and glofitamab, which are CD20 antibodies that also engage CD3, are already available in the United States for DLBCL and DLBCL or LBCL arising from follicular lymphoma, respectively. For patients progressing on CD19-targeted therapies, CD20 antibodies target a different antigen and are off-the-shelf therapies that typically have manageable toxicities. Another CD20xCD3 bispecific antibody, odronextamab, is not yet FDA approved but has shown promising results,¹¹ Nastoupil said.

Kamdar later reiterated the potential benefits of bispecifics, including their off-the-shelf availability, adding that, importantly, they can be administered in the community setting—not only at certified centers, which represents a limitation of CAR T-cell access.

A remaining question requiring real-world data is where ASCT fits into the era of bispecifics, Nastoupil said—should patients responding after CAR T-cell therapy receive consolidation, or should they be observed?

Overcoming Treatment Resistance and Finding the Path Forward

Another key question is why patients experience relapse after CAR T-cell therapy.

Mechanisms such as CD19 antigen loss, CD58 alteration, and disease-specific features such as TP53 mutations, DNA copy number alterations, or complex genomic features can drive resistance. The most challenging of these issues to address may be disease-specific features, Nastoupil said, noting that these traits are also seen in patients who are refractory to chemotherapy.

“As we learn more in terms of sequencing of therapy, and as we collect more samples, which I think is really critical, we may learn more lessons there,” Nastoupil said. Dual-targeting CARs or CARs targeting other antigens may hold some of the answers, but this remains to be seen. Another exploratory route Nastoupil’s and colleagues have experimented with in early studies is adding a checkpoint inhibitor such as pembrolizumab to regimens after CAR T cell failure. The potential of off-the-shelf CAR T cells is another area where research is ongoing.

Aside from the therapy options she outlined earlier in her talk, Nastoupil stressed the importance of getting patients whose disease progresses after CAR T-cell therapy into clinical trials when possible. This way, efforts to add options for these patients and improve outcomes can continue.

Another key shift in research has been an increased emphasis on patient-reported outcomes (PROs), Kamdar explained.

“Patient-reported outcomes is beginning to evolve as a really important marker to really assess our patients are feeling, and both [the TRANSFORM and ZUMA-7 studies] conducted robust PROs and health care quality of life analysis,” Kamdar said. “Both TRANSFORM and ZUMA-7 showed clinically meaningful improvement in the quality of life for patients randomized to CAR T-cell therapy compared to autologous transplant.” ^12,13

Kemdar closed with notes on sequencing therapies, concluding that CAR T is currently the preference ahead of bispecific antibodies in R/R LBCL after at least 2 lines of treatment based on higher response rates and longer follow-up data—unless access issues or manufacturing times make CAR T challenging. When CAR T is used in the second-line, bispecifics are the preferred third line, she noted.

Still, with both CAR T-cell therapies and bispecific antibodies still being investigated in earlier lines in ongoing trials, treatment choices are likely to evolve in the near future, she concluded.

References

1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

2. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730

3. Chihara D, Liao L, Tkacz J, et al. Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma. Blood. 2023;142(12):1047-1055. doi:10.1182/blood.2023020197

4. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38(27):3119-3128. doi:10.1200/JCO.19.02104

5. Dean EA, Mhaskar RS, Lu H, et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(14):3268-3276. doi:10.1182/bloodadvances.2020001900

6. Iacoboni G, Navarro V, Martín-López AÁ, et al. Recent bendamustine treatment before apheresis has a negative impact on outcomes in patients with large b-cell lymphoma receiving chimeric antigen receptor t-cell therapy. J Clin Oncol. Published online October 24, 2023. doi:10.1200/JCO.23.01097

7. Alarcon Tomas A, Fein JA, Fried S, et al. Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma. Leukemia. 2023;37(1):154-163. doi:10.1038/s41375-022-01739-2

8. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172

9. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

10. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

11. Kim WS, Kim TM, Cho SG, et al. Odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): results from a prespecified analysis of the pivotal phase II study ELM-2. 2022;140(suppl 1):1070-1071. doi:10.1182/blood-2022-158406

12. Abramson JS, Johnston PB, Kamdar M, et al. Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL. Blood Adv. 2022;6(23):5969-5979. doi:10.1182/bloodadvances.2022008106

13. Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022;140(21):2248-2260. doi:10.1182/blood.2022015478