An Unclear Path: What’s the Best Route After CAR-T Failure in B-Cell Lymphoma?

The majority of patients with aggressive B-cell lymphoma treated with chimeric antigen receptor (CAR) T-cell therapy will experience some disease response, but durable complete responses (CRs) only occur in a minority of patients.

“If you look at outcomes, we are potentially curing about one-third of patients [with CAR-T],” said Kami J. Maddocks, MD, Professor of Clinical Internal Medicine in the Division of Hematology at the Ohio State University Wexner Medical Center. “That leaves about two-thirds of patients who don’t respond to CAR T-cell therapy or [who] initially get a response but later progress.”

Outcomes in patients who progress or relapse after undergoing CAR T-cell therapy are poor. A recent analysis of the French registry DESCAR-T looked at outcomes from 550 patients with aggressive B-cell lymphomas who experienced progression or relapse after CAR T-cell therapy. Median progression-free survival (PFS) was 2.8 months, and median overall survival (OS) was 5.2 months. Patients who relapsed or progressed within 30 days had a median OS of 1.7 months.¹

These poor outcomes emphasize the need for dedicated treatment strategies in this patient population. Unfortunately, there are currently no real standards of care in place, Dr. Maddocks said.

Indeed, picking the best strategy and knowing how to sequence available therapies can be very challenging, noted Iris Isufi, MD, Associate Professor of Medicine at the Yale School of Medicine and Co-Director of the Adult CAR T-Cell Therapy Program at the Yale Cancer Center.

“The decision can really be crucial because that may be the only chance the patient gets,” Dr. Isufi said. “If they miss that chance, the majority die of disease progression.”

CAR T-Cell Treatment, Failure

There are currently several U.S. Food and Drug Administration (FDA)-approved CAR T-cell therapies for relapsed or refractory large B-cell lymphomas. Lisocabtagene maraleucel is approved after two or more lines of therapy for diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and certain follicular lymphomas (FLs). Tisagenlecleucel is approved for relapsed or refractory DLBCL. Axicabtagene ciloleucel is approved after two or more lines of therapy for DLBCL, primary mediastinal B-cell lymphoma, high-grade DLBCL after FL, and FL.

More recently, axicabtagene ciloleucel was also approved for large B-cell lymphoma refractory to first-line chemoimmunotherapy or disease that relapses within 12 months of first-line chemoimmunotherapy.²

Disease response and durability vary slightly across these different therapies and across disease subtypes, Dr. Isufi said, but approximately 35% to 40% of patients are long-term survivors.

“This is in comparison to the pre-CAR T cell era where probably fewer than 10% were long-term survivors and survived beyond six months,” Dr. Isufi said.

Certain factors seem to be associated with failure after CAR T-cell therapy, according to Dr. Isufi. A 2019 review paper broke these factors down into three categories: tumor-intrinsic factors, host factors, and inadequacies of CAR T cells.³

Several studies have shown that “about one-third of patients will have loss of CD19 expression at disease progression,” Dr. Maddocks said.^4,5

Host-related factors include presence of bulky disease, poor performance status, high inflammatory markers, and elevated lactase dehydrogenase. Resistance to CAR T-cell therapy may also be associated with tumor and systemic immune dysregulation.⁶

However, none of these factors are universal, Dr. Maddocks noted. “Patients with these characteristics are at high risk for not responding, but we have seen patients with low tumor burden going in who end up progressing,” she said.

The time of relapse can also be meaningful, Dr. Isufi said. The analysis of the DESCAR-T registry grouped patients into very early (day 0-30), early (day 31-90), and late (day 90) relapse categories. Less than 20% of patients who had very early relapse were alive at six months, and very early progression was associated with worse OS from time of relapse/progression on multivariable analysis.¹

Treatment Options

“There is no established first-line treatment after CAR T-cell therapy failure for aggressive B-cell lymphomas,” Dr. Isufi said. “The decision-making for these patients is very much physician-dependent and influenced by patient factors.”

Prior to undergoing CD19-targeting CAR T-cell therapy, most patients will not have received other CD19-directed therapies, according to Craig Sauter, MD, Director of the Blood and Marrow Transplant Program at the Cleveland Clinic.

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate approved for patients with DLBCL with two or more prior lines of therapy.⁷ Data from the LOTIS-2 trial showed an overall response rate (ORR) of 48.3%. A small study has shown that loncastuximab may be an option for patients who have relapsed after CAR T-cell therapy.⁸

Another CD19-directed option is the cytolytic antibody tafasitamab-cxix given in combination with lenalidomide. The FDA approved tafasitamab for patients with relapsed or refractory DLBCL who are not eligible for autologous hematopoietic stem cell transplant.⁹ Long-term data from the L-MIND study of tafasitamab showed an objective response rate of 57.5% among patients with one to three prior therapies, with a median duration of response of 43.9 months.¹⁰

“I would consider loncastuximab or tafasitamab and lenalidomide in patients who still have CD19-positivity after CAR-T failure,” Dr. Isufi said.

However, Dr. Sauter pointed to the presentation of “sobering” results from a real-world trial of the tafasitamab and lenalidomide combination at the 2022 American Society of Hematology Annual Meeting and Exposition that showed that clinical outcomes in terms of response and survival were lower than what was seen in the L-MIND clinical trial.¹¹ More than 90% of patients in this real-world study did not meet the criteria for the L-MIND study. However, the study did show that prior CAR-T or other CD19-directed therapy were not associated with worse outcomes.

“I suspect this combination regimen was difficult to give, potentially because of blood count issues and rapidly growing disease,” Dr. Sauter said.

Prolonged cytopenia is often an issue in patients after undergoing CAR T-cell therapy and may limit salvage treatment options.

For example, the CD79b-directed antibody-drug conjugate polatuzumab vedotin-piiq is approved in combination with bendamustine and rituximab in patients with DLBCL with two prior lines of therapy.¹² In the trial leading to regulatory approval, the objective response rate was 45%.

However, Dr. Isufi pointed out that it is challenging to give a triplet after CAR T-cell therapy failure due to increased risk for cytopenia.

“A majority of patients may only tolerate polatuzumab with rituximab,” Dr. Isufi said.

Despite the risk of cytopenia, Dr. Sauter added that in some patients who have aggressive disease, clinicians may prioritize the perceived speed of response gained with chemotherapy as opposed to more novel or “gentle” agents like lenalidomide or ibrutinib.

For patients who receive CAR T-cell therapy in the second line and progress, exposure to a platinum-containing salvage regimen may be the best option, Dr. Sauter said.

“Platinum-based salvage programs were generally developed for patients eligible to proceed to transplant,” he noted. “Whether or not these patients who get CAR-T in the second line should go on to a platinum agent and go to transplant is a wide-open question.”

Additional Options

Because T-cell exhaustion and an immunosuppressive tumor microenvironment can both be possible causes of CAR T-cell therapy failure, research has also explored the use of immune checkpoint inhibitors as a salvage therapy.

“The rationale for administering checkpoint inhibitors makes sense,” Dr. Sauter said. “There was early correlative experience that exhaustion markers are upregulated after infusion.”

“The thought was that you could reinvigorate the CAR T cells,” added Natalie Grover, MD, Clinical Director of the Cellular Therapy Program at the University of North Carolina Lineberger Comprehensive Cancer Center.

One small study of patients with B-cell lymphomas who were refractory or relapsed after CD19-directed CAR T-cell therapy treated them with pembrolizumab and showed a best ORR of 25%.¹³

“Initially, the data were promising, but it hasn’t seemed so more recently,” Dr. Grover said. “Some clinicians may go that route post-CAR T-cell therapy, but I generally haven’t been.”

Another option that could be used is selinexor, a first-in-class oral selective inhibitor of nuclear export compound, in combination with bortezomib and dexamethasone. The FDA approved this combination in June 2020 for patients with relapsed or refractory DLBCL who have had two or more prior lines of therapy.¹⁴ Results of the SADAL trial, which led to regulatory approval, showed an ORR of 29%, with a CR rate in 13% of patients.¹⁵

However, Drs. Grover and Sauter said they do not see this therapy used often in the post-CAR T-cell setting. More often it is used in patients who are not candidates for CAR T-cell therapy or as bridging therapy.

Dr. Grover said that for some patients experiencing local relapse, radiation may be a consideration.

“A lot of times patients who relapse post-CAR T-cell therapy will have a lot of cytopenia,” Dr. Grover said. “These patients are tired and deconditioned from other prior treatments. In specific cases, if the disease is amenable, I might try radiation to give the patient a break from those more intensive therapies.”

As with other treatment options, limited data exist for the use of radiation as a salvage strategy post-CAR T-cell therapy. One small study looked at 14 patients treated with salvage radiation to sites previously positron emission tomography-avid prior to CAR T-cell infusion. The median OS after radiation was 10 months. Six of 14 patients achieved 100% response, and three patients were bridged to allogeneic transplant.¹⁶

Finally, there may be some patients for whom palliative treatments are the best next step.

“In general, the prognosis is poor once a patient progresses after CAR T-cell therapy,” Dr. Grover said. “Some of these patients may have exhausted a lot of options prior to CAR-T. They may be CD19-negative, and already exposed to polatuzumab, be chemo-refractory, frail, or have really explosive disease. At that point, palliative options warrant a conversation.”

Future Hope

In addition to these approved options, clinicians are hopeful that T-cell-engaging bispecific antibodies may prove to be an effective option for patients who relapse after CAR T-cell therapy.

Glofitamab, a CD20×CD3 bispecific monoclonal antibody, was evaluated in a phase II study of patients with relapsed or refractory DLBCL, about one-third of whom had received prior CAR T-cell therapy. The CR rate was 35% among the group with prior CAR-T.¹⁷

Epcoritamab, another bispecific antibody, was also evaluated in patients with relapsed or refractory DLBCL, approximately 39% of whom had received prior CAR T-cell therapy. The ORR among all patients was 69%. It was 54% among those with prior CAR-T, with 34% of patients achieving CR.¹⁸ Glofitamab and epcoritamab are both currently under priority review with the FDA.^19,20

“If I have a patient who is eligible for a trial of a bispecific antibody, I try to prioritize that option for these patients,” Dr. Maddocks said.

Dr. Grover agreed: “Once these get approved, they will be a potential first choice that I go to post-CAR-T relapse.”

More Research Needed

Dr. Sauter emphasized that there is often no clear choice for the best salvage treatment option in patients who are refractory to or have relapsed after CAR T-cell therapy. Retrospective studies attempting to identify superior approaches have had inconclusive results.

Two recent studies have indicated that responses may be better with novel therapies. One study summarizing outcomes of the first therapy given after CD19-directed CAR T-cell treatment failure showed that 74% of patients received some kind of subsequent anti-cancer treatment, most commonly polatuzumab-, standard chemotherapy-, or lenalidomide-based. No CRs were achieved with conventional chemotherapy. CR rates greater than 30% were seen with polatuzumab- or lenalidomide-based therapies. The presence of two or more risk factors—bulky disease, lack of CAR T-cell response, age greater than 65 years, or elevated lactate dehydrogenase—was associated with inferior survival.²¹

Results of a study out of Spain also indicated that salvage treatment with novel agents may be better than standard chemotherapy in regard to response rates, but survival differences were not addressed.²²

Another retrospective study assessing factors associated with response to salvage therapy confirmed better responses among patients who had initially responded to CAR T-cell therapy compared with non-responders. However, when comparing lenalidomide-based regimens, Bruton’s tyrosine kinase inhibitors, checkpoint inhibitors, chemoimmunotherapy, allogeneic transplantation, and other options, there was no significant difference in OS based on the type of salvage regimen used.²³

“It is a real conundrum,” Dr. Sauter said. “The need for prospective evaluation of interventions is a large unmet need.”

Even when bispecific antibodies are ultimately approved, how these drugs are sequenced in relation to CAR T-cell therapy will need to be evaluated.

Dr. Sauter also said that it is surprising that more research has not been done into whether a second infusion of CD19-targeted CAR T cells is a valid salvage approach.

One single-institution study looked at a second CD19 CAR T-cell infusion in B-cell malignancies, including leukemias, in patients who had evidence of persistent or relapsed disease 21 days or more after the first infusion. With the second infusion, complete remission was achieved in 19% of patients with non-Hodgkin lymphoma. Higher ORRs and longer PFS after the second infusion were associated with the addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion and an increase in the dose at the second infusion compared with the first infusion.²⁴

“When cellular therapies were developed for viral-mediated disease following allogeneic transplant in other settings, a lot of strategies looked at multiple infusions,” Dr. Sauter said. “In cancer, we often give therapies in cycles, so it is curious that there has not been more of an investigational pursuit.”

Dr. Sauter is currently involved in the Southwest Oncology Group’s 2114 trial, a phase II study that will evaluate whether the bispecific antibody mosunetuzumab-axgb and/or polatuzumab vedotin benefits patients who have received prior chemotherapy followed by CAR T-cell therapy.²⁵

“We are hoping to enroll at least 30 patients on each arm, so this will be a large study,” Dr. Sauter said. “The study is for patients [who] have stable disease or partial remission at day 30 after CAR to see if we can deepen response and improve PFS as a primary endpoint.”

Patients will be assigned to observation, mosunetuzumab, polatuzumab vedotin, or a combination of the two. At the time of publication, the trial was not yet recruiting.

Dr. Maddocks agreed that clinical trials are needed and can be an option for this patient population, but she added that the practicalities of enrolling these patients are complicated.

“These patients often have low blood counts, rapidly progressing disease, or have received a lot of prior therapies,” Dr. Maddocks said. “That often makes it difficult.”

In fact, a study looking at barriers to enrollment in clinical trials after post-CAR T-cell therapy disease progression found that approximately half of patients would be excluded from landmark clinical trials looking at salvage treatments, most commonly because of hematologic exclusion criteria.²⁶

As the field moves forward, more post-CAR T-cell therapy salvage regimen research may be done in patients who undergo CAR T-cell infusion as a second-line option.

Leah Lawrence is a freelance health writer and editor based in Delaware.

References

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