‘Exciting’ research spotlights CAR-T’s evolving role in blood cancer treatment
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Only a decade ago, many in oncology considered chimeric antigen receptor T-cell therapy too fringe for real-world use.
The volume of practice-changing CAR T-cell therapy abstracts presented at ASH Annual Meeting and Exposition in December, however, illustrate the modality’s critical role in the blood cancer treatment armamentarium, according to Ryan D. Cassaday, MD, associate professor at University of Washington and Fred Hutchinson Cancer Center and member of the Healio | Cell Therapy Next Peer Perspective Board.
“In the early days, a single oral abstract session would report these data from the centers at the vanguard of this technology,” he told Healio. “Now, when you attend an international conference like ASH, there are entire categories devoted to adoptive cellular therapy, with multiple oral sessions and countless posters. The data we see at these meetings have gone from borderline-science fiction to truly practice-changing.”
Oral abstracts highlighted new constructs, how prior therapy may influence cell therapy’s effectiveness and the potential benefit of moving CAR-T earlier into the treatment paradigm.
“The breadth of data on CAR-T presented at ASH this year was as vast as any other discipline or therapy available,” Cassaday said.
Healio provides the following overview of significant CAR-T studies presented at ASH, with perspectives from key opinion leaders in the field who offer insights into the potential implications of the findings.
Impact of prior chemotherapy
Patients with non-Hodgkin lymphoma appeared significantly less likely to respond to CAR T-cell therapy if they previously received the chemotherapy drug bendamustine, retrospective study results showed.
The findings suggest a possible lymphotoxic effect on CAR T-cell production. However, researchers did not observe significant differences in safety or durability between bendamustine-naive patients and those with prior exposure, suggesting that any toxic effect on CAR T cells could be limited.
The final composition of each commercially approved CAR-T product varies based on the fitness of a patient’s lymphocytes, according to Gloria Iacoboni, MD, hematologist at Vall d’Hebron University Hospital in Barcelona, Spain. Prior research suggested a negative impact of bendamustine — a nitrogen mustard-derived alkylating agent — on CAR T-cell production due to potential lymphotoxic effects, she added.
“Consensus documents suggest avoiding use of bendamustine in CAR-T candidates,” Iacoboni said during a presentation. “However, there [are] scarce data regarding the impact of previous bendamustine exposure on T-cell kinetics and outcomes [of] patients treated with CD19-targeted CAR T cells.”
Iacoboni and colleagues conducted a multicenter retrospective study to determine the effects of bendamustine exposure on patients who received commercial CAR T cells for relapsed or refractory large B-cell lymphoma.
The analysis included 370 patients (median age, 62 years; interquartile range [IQR], 52-69; 60% men) who received either axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) — commonly called axi-cel — or tisagenlecleucel (Kymriah, Novartis) at one of seven centers in Europe.
The investigators reported a higher overall response rate (72% vs. 57%; P = .018) and higher complete response rate (51% vs. 41%) among bendamustine-naive patients than those with exposure prior to CAR-T apheresis. Multivariate analysis showed prior bendamustine exposure had a significant impact on overall response (OR = 2.13; 95% CI, 1.18-3.85).
Safety results showed no significant differences in cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS) based on previous bendamustine exposure. Researchers reported comparable rates of CRS (86% vs. 84%) and ICANS (38% vs. 34%) among bendamustine-naive patients vs. those previously exposed to the agent.
Iacoboni and colleagues reported significantly higher ORR based on timing of last bendamustine dose, with ORRs of 46% among those exposed within 9 months of CAR-T apheresis and 71% among those exposed more than 9 months before apheresis.
Multivariate analysis showed a significant association between bendamustine exposure in the 9 months before CAR-T apheresis and lower ORR (OR = 2.78; 95% CI, 0.9-9.1). Researchers also noted significantly shorter median PFS among those with bendamustine exposure in the 9 months prior to CAR-T apheresis and those who received the drug more than 9 months prior (1.45 months vs. not reached; HR = 2.95; 95% CI, 1.54-5.67).
“The impact of bendamustine on CAR T-cell outcomes seems to be time-dependent,” Iacoboni said. “Patients with recent exposures — during the previous 9 months in our study — have worse outcomes after CAR T-cell therapy.”
Data from this study raise questions about the possible damage that can be done by therapies given prior to T cell collection for CAR-T manufacturing, according to David L. Porter, MD, director of cell therapy and transplantation at University of Pennsylvania’s Abramson Cancer Center and a member of the Healio | Cell Therapy Next Peer Perspective Board, and Nasheed Hossain, MD, assistant professor of medicine at Perelman School of Medicine at University of Pennsylvania and member of Abramson Cancer Center.
Major differences between the two study groups should be considered when analyzing the results, Porter and Hossain wrote in an exclusive analysis provided to Healio.
“The bendamustine group comprised older patients (median age, 66 years vs. 61 years), with poorer performance status and more lines of prior therapy,” they wrote. “It is possible a decision to use bendamustine instead of other agents may represent selection for sicker, more frail patients.”
Durability of response also appeared to be unaffected by previous exposure to bendamustine, Porter and Hossain wrote.
“The lack of statistically significant differences in median PFS and OS suggests that the initial differences in response rates are transient,” they wrote. “Thus, this important study highlights that recent (within 9 months) bendamustine exposure prior to apheresis may negatively affect outcomes, although this needs to be assessed in the context of patient-specific variables that may influence the observations.”
Bendamustine lymphodepletion ‘good alternative’ to fludarabine
The use of bendamustine as part of a preconditioning regimen resulted in significant CAR T-cell expansion among patients with relapsed or refractory non-Hodgkin lymphoma, results of an ongoing single center prospective study showed.
The approach also appeared safe, with low incidence of high-grade neutropenia.
The results are particularly welcome given the ongoing severe nationwide fludarabine shortage, according to Saurabh Dahiya, MD, FACP, associate professor of medicine and clinical director of cancer cell therapy at Stanford Medicine.
Fludarabine is used as part of the standard preconditioning regimen prior to CAR-T infusion for most commercial CAR-T products. Very little data exist regarding the efficacy of alternative regimens, Dahiya said.
“We found that bendamustine produced similar day-28 complete response rates compared with fludarabine and cyclophosphamide,” Dahiya told Healio. “In terms of safety, rates of CRS and ICANS were similar between patients treated historically with fludarabine and those [we treated] with bendamustine.”
Dahiya and colleagues prospectively analyzed 27 patients (median age, 63 years; IQR, 56-71; 52.6% men) who received bendamustine 90 mg/m2 as a lymphodepleting agent on day 3 and day 4 prior to axi-cel infusion for large B-cell lymphoma.
The investigators compared data on cell expansion, toxicity and treatment outcomes with a group of 57 historical controls who received the standard lymphodepletion regimen of fludarabine and cyclophosphamide prior to axi-cel infusion.
Results showed no significant differences in ORR or complete response rates at 1 month after axi-cel infusion between the bendamustine and fludarabine groups. Patients who received bendamustine prior to CAR-T had an ORR of 85.2% compared with 89.4% among those who received a fludarabine-based lymphodepletion regimen.
Researchers reported a 47.4% complete response rate for the bendamustine group compared with 59.3% for the fludarabine group.
Safety results also showed similar rates of overall and severe CRS or ICANS.
Although the results are early, Dahiya highlighted a potential benefit with bendamustine with regard to treatment-related toxicity. Only one patient in the bendamustine group required antibiotics for febrile neutropenia, compared with up to 60% of patients in the historical control group who received fludarabine-based preconditioning.
“More data are needed before we can consider using bendamustine as part of the standard of care for the [CAR-T] lymphodepletion regimen,” he said. “But, for now, bendamustine is a good alternative to fludarabine while ongoing shortages occur in the U.S.”
Experimental therapy for T-cell malignancies
An investigational CAR-T induced a 78% complete response rate among patients with heavily pretreated T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma, phase 1/phase 2 study results showed.
Data revealed less robust survival outcomes for those with certain genomic alterations.
“Effective treatments are still lacking for refractory or relapsed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma,” Peihua “Peggy” Lu, MD, medical executive president of Lu Daopei Hospital and Beijing Lu Daopei Institute of Hematology, told Healio. “Once relapsed, the majority of patients only have a slim chance of long-term survival.”
Lu and colleagues sought to apply the success of CAR T-cell therapy for patients with B-cell ALL to those with T-cell disease.
The investigators chose CD7 — an antigen known to be highly expressed on T cells — as the target for their experimental therapy.
CD7 — expressed on both healthy and cancerous T cells — is susceptible to T-cell fratricide. This required Lu and colleagues to employ a novel approach that developed fratricide-resistant cells.
Investigators enrolled 65 patients to assess the efficacy and safety of NS7CAR for patients with relapsed or refractory CD7-positive T-cell malignancies.
The analysis included 60 patients (median age, 19 years; range, 2-47) with either T-cell ALL (n = 35) or T-cell lymphoblastic lymphoma (n = 25) who received a subsequent infusion of NS7CAR. Thirty-one patients (52%) had extramedullary disease.
All study participants received preconditioning chemotherapy prior to one-time infusion with NS7CAR at one of three dose levels, and 48 patients received bridging chemotherapy to control disease progression.
After median follow-up of 221.5 days (range, 23-621), 47 patients (78.3%) achieved complete response to therapy. The 28-day post-infusion evaluation showed 51 (94.4%) of 54 patients achieved minimal residual disease-negative status in bone marrow or peripheral blood.
Investigators reported an 81% ORR among 31 patients with extramedullary disease, including 18 patients (58%) who achieved complete response. Further analysis showed an 18-month OS rate of 72% for the entire study population, in addition to a 55% PFS rate at 18 months.
Most patients (88%) experienced low-grade CRS. Six patients (7%) developed grade 3 CRS, and one patient developed grade 4 CRS. Neurotoxicity appeared rare, with most patients (93%) reporting no symptoms.
The results suggest NS7CAR is “safe and highly effective” for patients with heavily pretreated CD7-positive T-cell malignancies, Lu said, particularly for patients with extramedullary disease and a history of previous allogeneic HSCT.
“However, patients with high-risk subtypes [and] complex cytogenetics tend to have poorer overall survival or progression-free survival,” she told Healio.
Despite this limitation, CD7 is an attractive target for T-cell malignancy treatments, Lu said, adding experimental cellular therapies like the one being evaluated by her group could offer an effective option for patients with relapsed or refractory disease.
The enthusiasm generated by these results cannot be understated, according to Cassaday and Noam Kopmar, MD, senior hematology-oncology fellow at University of Washington and Fred Hutchinson Cancer Center.
Despite therapeutic advances for treatment of B-cell ALL, options for patients with T-cell ALL remain limited. Nelarabine is the only FDA-approved therapy, and outcomes for these patients are “generally dismal,” Kopmar and Cassaday wrote in an exclusive analysis provided to Healio.
Kopmar and Cassaday exercised caution when interpreting the results and pointed to the 8% exclusion rate in the study by Lu and colleagues being substantially lower than other international CAR-T trials. They also cited the “enviable” 98% manufacturing success rate.
“Although the results are exciting, the data raise questions about the reproducibility of the approach,” Kopmar and Cassaday wrote. “These results — albeit preliminary — provide a glimpse of the future for patients with relapsed or refractory T-cell ALL. Longer follow-up will be needed to fully assess the durability of these responses and to assess for any long-term safety signals.”
Earlier CAR-T effective for high-risk multiple myeloma
Idecabtagene valence (Abecma; Bristol Myers Squibb, 2seventy bio) induced initial complete remission among nearly half of patients with multiple myeloma who had early relapse after front-line therapy, results of a cohort analysis of the phase 2 KarMMa-2 trial showed.
Investigators reported a median duration of response of nearly 2 years among patients who had an initial complete response to idecabtagene vicleucel, also known as ide-cel.
“The expected survival for these patients is quite poor, with an approximate overall survival of 26 months,” Saad Z. Usmani, MD, MBA, FACP, chief of myeloma service at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, told Healio. “The fact that 85% of these patients are still alive at 2 years after receiving ide-cel is a very good thing.”
Ide-cel is an autologous, gene-edited B-cell maturation antigen-directed CAR-T.
The FDA approved the agent in 2021 for adults with relapsed or refractory multiple myeloma who received at least four previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody.
The multicenter, multiarmed KarMMa-2 study evaluated the efficacy and safety of ide-cel as earlier therapy for patients with relapsed or refractory and high-risk multiple myeloma.
Usmani and colleagues presented data on cohort 2a, which included patients whose disease progressed within 18 months of front-line treatment with hematopoietic stem cell transplant followed by a lenalidomide (Revlimid, Bristol Myers Squibb)-containing maintenance therapy.
Study participants underwent preconditioning lymphodepletion followed by a single infusion of ide-cel. The efficacy and safety analysis included 37 patients (mean age, 57 years; range, 36-77; 56.8% men; 78.4% white; 10.8% Black).
The study met its primary endpoint, with 45.9% (95% CI, 29.5-63.1) of participants achieving complete response to therapy.
Investigators reported an ORR of 83.8% (95% CI, 68-93.8), with a median response duration of 15.7 months among all responders. Those who achieved an initial complete response to therapy attained a median response duration greater than 23.5 months (95% CI, 10.2 to not estimable).
Median OS had not yet been reached. Investigators reported a 24-month OS rate of 84.7%.
Hematologic adverse events included neutropenia (94.6%), anemia (56.8%) and thrombocytopenia (51.4%). Twenty-two (59.5%) developed infections, with eight cases of grade 3 or grade 4 infection and two infection-related deaths (5.4%).
The majority (83.8%) of patients developed CRS, with one patient reporting grade 3/grade 4 symptoms.
FDA approval of ide-cel as an earlier therapy for multiple myeloma will require positive results from the ongoing randomized phase 3 KarMMa-3 trial, Usmani said.
The trial is designed to compare the CAR-T with standard regimens for patients with relapsed or refractory disease. Topline data published by the manufacturer showed ide-cel significantly extended PFS.
“On paper, there are many good options for patients who have an early relapse, but if ide-cel is given additional regulatory approval, it would allow us to give these patients a one-time treatment that would not require any additional maintenance therapy,” Usmani told Healio | Cell Therapy Next. “This is one of the major advantages of CAR T-cell therapies.”
Ashley Killen contributed to this report.
References:
- The following were presented at ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans:
- Bharadwaj S, et al. Abstract 4657.
- Iacoboni G, et al. Abstract 763.
- Usmani S, et al. Abstract 361.
- Zhang X, et al. Abstract 980.
For more information:
Ryan D. Cassaday, MD, can be reached at cassaday@seattlecca.org.
Saurabh Dahiya, MD, FACP, can be reached at sdahiya@stanford.edu.
Nasheed Hossain, MD, can be reached at nasheed.hossain@pennmedicine.upenn.edu.
Gloria Iacoboni, MD, can be reached at giacoboni@vhio.net.
Noam Kopmar, MD, can be reached at noamek@uw.edu.
Peihua “Peggy” Lu, MD, can be reached at peihua_lu@126.com.
David L. Porter, MD, can be reached at david.porter@pennmedicine.upenn.edu.
Saad Z. Usmani, MD, MBA, FACP, can be reached at usmanis@mskcc.org.
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