CAR-T may move more patients with CLL ‘toward a potential cure’
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Novel targeted therapies have become standard treatment for chronic lymphocytic leukemia due to their ability to delay progression of this slow-growing malignancy.
Nevertheless, CLL remains incurable. Even though some patients do not need immediate treatment upon diagnosis, those who do require therapy often continue it for the rest of their lives.
Early research into the use of chimeric antigen receptor T-cell therapy for CLL suggests that may not always need to be the case.
For example, the phase 2 TRANSCEND CLL 004 study assessed lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) — a CD19-directed CAR-T commonly called liso-cel — for adults with relapsed or refractory CLL after two or three lines of prior therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
Patients who received liso-cel appeared three times as likely as historical controls to achieve complete response, results presented at this year’s ASCO Annual Meeting and published in The Lancet showed.
The findings are “extremely promising,” according to study investigator Tanya Siddiqi, MD, associate professor in the division of lymphoma at City of Hope and member of Healio | Cell Therapy Next’s Peer Perspective Board.
One patient remained in ongoing response at last follow-up more than 5 years after a single infusion, Siddiqi said.
“I have treated many of these patients and I’ve seen the clinical benefits of CAR-T in real time,” Siddiqi told Healio. “CLL is not typically a curable condition, but we are trying to get more patients moving toward a potential cure using CAR T cells, especially in patients who have already gone through our best available therapies. Five treatment-free years is a huge clinical benefit for someone who was receiving continuous treatment before CAR-T.”
Healio spoke with cell therapy specialists about why CAR T-cell therapy may be an appealing treatment option for CLL, what early studies have shown in terms of efficacy and safety, and how the modality ultimately may fit into the treatment paradigm.
CAR-T for chronic disease
CAR-T has been successful using the same target antigen — CD19 — and a few basic constructs to treat multiple diseases.
Use of CAR-T for treatment of adults with CLL comes with a different set of expectations about what is possible due to the nature of the disease and the fact it typically affects older adults.
Investigators at University of Pennsylvania began using CAR-T to treat CLL more than a decade ago when tisagenlecleucel (Kymriah, Novartis) was in investigational stages.
Toxicities such as severe cytokine release syndrome and neurotoxicity tend to prevent the evaluation of CAR-T among older patients in clinical trials due to comorbidities. However, the real-world experience has shown CAR-T can be given safely to older individuals, according to David L. Porter, MD, director of cell therapy and transplantation at Penn’s Abramson Cancer Center and member of Healio | Cell Therapy Next’s Peer Perspective Board.
“CAR T cells have routinely been given to patients well into their 60s and 70s, and even early 80s,” Porter told Healio. “There’s not an absolute upper age limit for giving CAR T cells, although sicker, more frail patients may not be appropriate candidates because of the [adverse] effects.”
The most important criterion is “good physiologic reserve,” which allows a patient to adapt to CAR-T’s effects on the body, Porter said.
CAR-T is becoming safer as clinicians become more familiar with managing toxicities, Porter added.
A single CAR-T infusion — which has demonstrated potential as a one-time curative therapy in B-cell lymphomas and B-cell acute lymphoblastic leukemia — may have a role in the management of a chronic disease like CLL.
“If you compare a one-time therapy to long-term treatment with a very expensive regimen, then you might find a one-time therapy to be more cost-effective over time,” Porter said. “Even though they’re expensive upfront, CAR T cells still may be an attractive option — both medically and from a resource utilization standpoint — for those with CLL.”
CD19-directed CAR-T also has demonstrated clinical benefit for individuals with CLL who develop Richter’s transformation, according to Deborah M. Stephens, DO, associate professor and director of the CLL and Richter’s program at Lineberger Comprehensive Cancer Center at University of North Carolina at Chapel Hill.
Some of these patients have experienced complete remission with CAR-T — either alone or as a bridge to hematopoietic stem cell transplant — and many have “an opportunity for long-term remission,” Stephens told Healio.
In CLL, CAR-T may provide the most value to patients with advanced disease that progressed after targeted therapies, Stephens said.
She expressed concern about CAR-T’s durability among patients with CLL and the safety of this modality for an older treatment population. However, these patients lack effective treatment options, and trial results thus far suggest CAR-T can provide clinical benefit for some.
“In CLL ... the area of biggest need [is patients] who have become resistant or refractory to currently available BTK inhibitors and BCL2 inhibitors,” she said. “Those patients really have the shortest survival.”
Addressing those most in need
Results of the TRANSCEND CLL 004 trial showed patients with CLL who have the greatest need are the ones who derived the most benefit from CAR-T.
The study included 117 adults (median age, 65 years; range, 49-82; 68% men; 85% white) with relapsed disease who previously received a BTK inhibitor and were refractory to treatment with the BCL-2 inhibitor venetoclax (Venclexta; AbbVie, Genentech).
The full efficacy analysis population included 87 patients. Investigators also performed a separate efficacy analysis in a subgroup of 49 patients with BTK inhibitor progression and venetoclax failure.
Results showed 18% (95% CI, 11-28) of all patients achieved complete remission (CR) or CR with incomplete bone marrow recovery CRi.
Researchers also reported an 18% (95% CI, 9-32) CR/CRi rate for the subset of patients with BTK inhibitor progression/venetoclax failure.
The study met its primary endpoint, showing significant improvement in CR/CRi with liso-cel compared with historical controls.
Siddiqi called the results “highly statistically significant” for the subgroup previously treated with BTK inhibitors and venetoclax.
Additional results from this subgroup showed median PFS of 11.9 months (95% CI, 5.7-26.2) and median OS of 30.3 months (95% CI, 11.2 to not reached).
Safety analysis of the entire study population showed most participants (85%) experienced CRS, with 9% having grade 3 symptoms. Researchers reported no grade 4 or grade 5 cases. Nearly half (45%) of study participants developed neurotoxicity, including 18% with grade 3 symptoms and one patient with grade 4 symptoms.
Overall, liso-cel is safe, Siddiqi said. However, trial data showed higher rates of CRS and neurotoxicity among those who received liso-cel for CLL than lymphoma.
“Because CLL is a leukemic-phase disease, there are more reactions occurring within the bloodstream because of the cancer cells in the blood,” Siddiqi said.
Five treatment-related deaths occurred during TRANSCEND CLL 004. Investigators considered four of them unrelated to liso-cel. They attributed one death — due to macrophage activation syndrome-hemophagocytic lymphohistiocytosis — to the study drug.
Stephens — also an investigator on the trial — said she is encouraged to see overall response rates with liso-cel greater than 50% in a population of patients with highly refractory CLL.
CR rates among patients with CLL tend to be lower because of scattered lymph nodes that are slightly larger than International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria of less than 1.5 cm in diameter, she added.
“When we do more specific evaluation with minimal residual disease testing by flow cytometry or by sequencing, we see a deeper rate of remission in approximately 60% to 70% of these patients who have undetectable minimal residual disease following their CAR-T,” she said.
Sustaining remission is just as important as achieving it. Patients who achieve initial complete response to liso-cel are likely to have a more durable response, Stephens said.
“We’ve seen median responses of 3 years or more,” she said. “However, there is a subset of patients who never clear their detectable disease, and those patients usually have short-lived responses.”
‘Dramatic activity’
Researchers at Fred Hutchinson Cancer Center have investigated CAR-T’s potential in CLL for more than a decade, starting with the construct that eventually became licensed as liso-cel.
“We treated a large number of patients with CLL and have first-hand experience that CAR T cells against CD19 can have dramatic activity,” David G. Maloney, MD, PhD, medical director for cellular immunotherapy for the Bezos Family Immunotherapy Clinic at Fred Hutch, told Healio.
Many patients with CLL treated with liso-cel have experienced “very deep remissions, including undetectable minimal residual disease remissions,” said Maloney, also a professor of medicine in the division of oncology at University of Washington and co-investigator on TRANSCEND CLL 004.
Some have been in remission for at least 7 years.
“I definitely think CAR-T can have a major impact on this disease,” Maloney said.
Maloney agreed CAR-T’s initial role will be treating adults with CLL who are double refractory to BTK and BCL2 inhibitors.
“These are our best two classes of agents right now,” he said. “If I had someone who had failed a BTK inhibitor and was now starting on venetoclax, then I would be looking to see if there was a way to get them CAR T cells, because that’s a very high-risk situation — especially if the patient has high-risk genetics.”
Patients with double-refractory CLL and high-risk genetics have few treatment options and often experience poor outcomes.
“It is intriguing to think that CAR-T could replace any consideration of transplant, such as an allogeneic transplant,” Maloney said. “I think people would definitely prefer CAR T cells before even considering a transplant, and — in my experience — I have no doubt they can induce very deep molecular remissions and potentially cure patients.”
Providing value beyond a cure
CAR-T may be appropriate after currently available targeted therapies. However, questions remain about the viability of CAR-T — and liso-cel in particular — for CLL given response rates and durability are less robust than those observed with CAR-T in other aggressive blood cancers.
In those settings, the complexity and costs of CAR-T administration are offset by long-term improvements in disease and quality-of-life outcomes.
The question becomes whether clinicians and patients may need to accept less robust returns on their CAR-T investment in CLL — and whether it may prove to functionally treat the condition but never cure it.
The skepticism is fair, Maloney said, but he believes CLL is curable for some adults. A number of patients treated with CAR-T have remained disease-free beyond 5 years, but in diseases like CLL, clinicians typically wait until 10 years before using the word “cure.”
“The proportion of people having durable complete remissions after 10 years is not yet known, but it’s less than 50% for sure,” Maloney said. “Whether CAR-T will be curative for CLL will depend on tumor burden and how much prior therapy the patient has had. Our goal is to find ways to make them work better, using healthier T cells that function better and cause less toxicity.”
Maloney favors earlier use of CAR-T for adults with CLL and said such a move would lead to more durable responses given the results seen thus far among highly pretreated individuals.
“The treatment landscape in CLL is changing so rapidly,” Maloney said. “Finding the right time to treat patients before they become refractory to everything is a moving target. As more new therapies are being developed, [they] don’t appear to lead to long-lasting molecular remissions. Therefore, CAR T cells will occupy a space in the treatment of CLL, even among all these novel agents.”
Some of the first patients with CLL to receive tisagenlecleucel remain in remission more than 13 years later, and many remain in remission more than a decade after infusion, Porter said.
“There is absolutely no doubt in my mind that there is a role for CAR T cells in CLL,” Porter said. “[They] can be dramatically effective for patients with far-advanced, relapsed and refractory CLL.”
One of the problems is that CAR-T often is not sufficiently effective for long enough in a sizable proportion of recipients, despite providing benefits to a majority of those treated.
“There has been a lot of work trying to make CAR T cells more effective in CLL,” Porter said. “There will be a real role for CAR T cells in managing CLL at various stages of the disease, and we will learn better how to do it most effectively.”
Stephens also mentioned the relatively low frequency of CR with CAR-T, as well as the inability to predict which patients will have a durable response. The ability to do that could support greater use in CLL, despite the older population and potential toxicities.
“There are some patients who we suspect may be cured, at least functionally, after 10 or more years of remission,” Stephens said. “But I think everyone’s a little bit hesitant to say that any patient with CLL is ever cured.”
Stephens said she has a tempered view of CAR-T’s future in CLL. Although liso-cel may become commercially available, its uptake likely will depend on researchers’ ability to develop less toxic and more durable next-generation agents that compete more favorably with current standard therapies, she said.
“If you’re asking a patient to go through a potentially very toxic therapy when there are other less toxic alternatives, then both the patient and the physician will likely want to choose something with less toxicity, assuming that the PFS rates are the same,”
Stephens said.
The rapidly evolving CLL pipeline includes BTK degraders and bispecific antibodies. However, none of the novel approaches to treat CLL are more likely to have curative potential than CAR T cells, Siddiqi said.
“Patients can go 3, 4 or 5 years without needing treatment again and can live a fully normal life during that period,” Siddiqi said. “I would want that type of treatment if I were a patient, so I do think there is value in that sense — even if it does not provide a cure.”
A look ahead
The cell therapy specialists with whom Healio spoke expressed hope that results of TRANSCEND CLL 004 may prompt the FDA to consider a CLL indication for liso-cel.
“The intent is to get an approval for CLL, and liso-cel is the only trial that is large enough to be used for registration at this time,” Maloney told Healio. “I don’t know what the agency will do, but there is clearly activity with the drug, with the potential for deep remissions in some patients with CLL.”
Porter expects a CAR-T product to be approved for CLL, pointing to liso-cel’s performance thus far and the agent’s ability to deliver dramatic results on the primary efficacy endpoint of TRANSCEND CLL 004.
The big question may not be ‘if’ but rather how soon.
“There are many potent new therapies for CLL, which is extremely encouraging,” Porter said. “Nevertheless, many of the available therapies have significant [adverse] effects, are tremendously expensive and require long-term therapy, all while far too many patients become resistant or refractory to these novel treatments,” Porter said. “Having the option for a very potent and effective one-time therapy is really important for these patients.”
Siddiqi also expressed confidence about commercial availability of CAR-T for adults with CLL. She said she is hopeful that the FDA will approve liso-cel in CLL at least for “the third-line-and-beyond setting” for those whose disease progressed after BTK inhibitor therapy and perhaps venetoclax.
The timeline for approval is less certain, with Siddiqi speculating it could happen by 2024.
“We are at the very beginning when it comes to the use of CAR-T for CLL,” she said. “I believe the results will only get better from this point on.”
References:
- Siddiqi T, et al. Abstract 7501. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Siddiqi T, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)01052-8.
For more information:
David G. Maloney, MD, PhD, can be reached at dmaloney@fredhutch.org.
David L. Porter, MD, can be reached at david.porter@uphs.upenn.edu.
Tanya Siddiqi, MD, can be reached at tsiddiqi@coh.org.
Deborah M. Stephens, DO, can be reached at deborah_stephens@med.unc.edu.
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