Mary Caffrey

When a physician makes the call that chimeric antigen receptor (CAR) T-cell therapy offers the best chance for survival in patients with relapsed large B-cell lymphoma (LBCL), there isn’t time to spare. But data gathered over the past 2 years by a team from Cardinal Health Specialty Solutions revealed that community oncology practices can encounter roadblocks when trying to navigate payer approvals for CAR T-cell therapy. These barriers can lead to time running out before patients can receive the therapy—and the situation isn’t improving, even though the first CAR T-cell treatments were approved more than 3 years ago.

With a new, less toxic CAR T-cell therapy now approved

and more in the pipeline—including treatments for multiple myeloma—the findings raise concerns that disconnects among payers, providers, and patients are stalling, and could continue to stall, timely implementation of this lifesaving treatment. Data from hematologists/oncologists were gathered a year apart, first in February 2019 and then between November 2019 and February 2020. The initial survey covered 59 physicians, who were all in some type of community practice; the second included 168. Each time, almost one-third of patients who were referred for CAR T-cell therapy ultimately were unable to receive it. “High cost and toxicity continue to be potential deterrents to CAR-T consideration and appear to be increasing in significance,” the authors concluded.

™ (EBO) spoke with lead author Ajeet Gajra, MD, MBBS, FACP, vice president at Cardinal Health, about identifying and removing the barriers for offering CAR T-cell therapy at the community practice level. The interview is edited for clarity.

It’s normal to have challenges with payers when a new therapy is approved. However, your findings show that the percentages of patients who were unable to receive CAR T-cell therapy after referral were about the same nearly a year apart, with the second survey coming more than 2 years after approval. What accounts for this?

These are complex therapies—they are essentially living cells derived from a particular individual, then engineered to be used as therapy for that individual. Obviously, the therapies are challenging in terms of logistics, and there’s also the cost factor. The issues are twofold. The first rests with the providers: They need to be very clear in terms of who they’re referring for CAR T therapy. The labels are very explicit: [the patient needs to have had] 2 prior therapies and progression, and [must meet requirements] also in terms of medical comorbidities. This is not just something that you can try [on a whim], because CAR T therapy needs planning and it requires following each step of a detailed process.

The second issue, as we all know, is the complex prior authorization process with payers. For some of these patients, it can be daunting for the managing team to collect all the information needed in a timely fashion to satisfy a payer’s requirements. [To start,] the payer needs the records of the diagnostic biopsy, the history of therapies and regimens received thus far, [whether] they’ve had bone marrow transplant.

If care has been fragmented—especially if the patient was treated at another facility or, say, a tertiary center where they went for care or a transplant—all that information has to be populated. That is a potential barrier, which leads to delays. Diffuse LBCL is not a disease that you can temporize with simple measures. If it’s recurring a third time, these patients tend to be quite ill. A delay of a week or two sometimes can force the hand of the provider to take an alternative route, because they feel, “My patient is deteriorating, I still don’t have the authorization, so what am I to do?” And they have to craft an alternative plan. So, we may be capturing some of those issues when it comes to the patient, provider, and payer factors leading to delays.

As you noted, the payer delays can lead to the to the patient not receiving the therapy at all. Do providers need more support to navigate the process, whether from a professional organization or from the manufacturers themselves?

Absolutely. I feel strongly that additional support would be valuable. We found that most providers thought that they were quite well versed with the science behind CAR T. Many of them, though, may not actually be aware of the [full] complexity of the process involved in getting a patient on to CAR T and then managing them afterward. I feel it still starts with education—you don’t want to refer the wrong patients, because ultimately, they’re going to go through the rigmarole and not end up getting the treatment. That’s another piece we captured, where patients were being referred to CAR T centers, but ultimately not getting the treatment.

Second is support, support, support. We [generated] these results [at a time when] only 2 CAR T products [were available]. We now have 3 CAR T-cell products approved, with 1 for mantle cell lymphoma. CAR T therapies [must] be administered at designated CAR T centers, but about 1 in 6 providers didn’t have a CAR T center in their geographic vicinity, which is a barrier. Also, there’s a question of whether there can be reciprocity. Must each center be approved for every therapy that they’re going to administer? Manufacturers can help with that piece. Patient support and access services sponsored by pharma companies can help with streamlining the prior authorization process, to expedite how quickly patients can check all the boxes—get all the i’s dotted and the t’s crossed so that they can at least be evaluated sooner. Hopefully, patients can be approved by the payer sooner, when appropriate, to move to the next step.

We talked about toxicity as being among the big challenges with CAR T-cell therapy; that’s been the case from the time it was approved. Is this a bigger challenge at the community level, in terms of the patient in this setting being more concerned about the looming threat of [cytokine release syndrome] CRS? Is it more the provider who has the concern? Or is it a combination?

 It’s a great question. I certainly agree that the specter of toxicity is still [quite] strong, and that community practices have a lower threshold or a greater concern for toxicity than the academic centers. This has come out loud and clear at [live meetings] when we engage with providers. [The audiences] often include a mix—largely community oncologists, but with some academic representatives as well.

Patients are concerned, but for the most part, with appropriate counseling, they’re willing to receive therapy because they realize they are running out of options. I would also highlight that as the field evolves, remarkable improvements have been made in the management of toxicity, so a lot of it can be mitigated and managed early. The thresholds have improved in terms of identifying CRS as well as neurotoxicity; [the latter] can be quite scary and devastating.

The scientific literature shows that management of toxicity has definitely improved, especially now with real-world use of CAR Ts being reported. Patients, for the most part, are quite eager to receive what many of them probably perceive as lifesaving and/or significantly life-prolonging therapy. But [it’s a different challenge] for community physicians, especially those who aren’t attached to a large tertiary care hospital. They don’t have immediate access to critical care—to an intensive care unit
(ICU)—and if your patient’s health is declining [due to CAR T toxicity], they are going to [need to] land in the ICU. A lot of work [has been done] on the disparities in rural settings and smaller communities, and I think there’s definitely more apprehension with therapies like CAR T in the smaller, more remote practices.

In data that you presented at the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition, the emergence of the cost factor as a barrier is very apparent in the second round of data collection. What accounts for this? 

 We learned from our initial work that cost was a major concern in the minds of the treating oncologists. Thus, we decided to reassess as a follow-up: We had a larger sample size than in [the first survey], and it was more than 2 years since the approval of the initial therapies. However, [our results] showed that in addition to intake and toxicity concerns, cost remained a major barrier, or major concern, in the minds of the providers [due to gaps between the treatment list price and reimbursement rates, especially from Medicare]. That gap has perhaps never been completely bridged….[As far as] we know, the [list price] is about $373,000 for treatment. Certainly, attempts have been made with NTAP, the New Technology Add-on Payment [in Medicare], to reduce that burden; [the goal is to not rely on the hospitals] where the majority of CAR-T is being administered just to supplant the funding for the facilities. [Still,] it cannot be denied that it is still a very high-cost therapy.

Some of this cost sensitivity may arise from the fact that providers are looking at longer-term outcomes. If providers are [committing] to a complex process and an expensive therapy, then do the outcomes bear that out? Especially if there are a lot of early failures of therapy, then this perhaps is a barrier. I don’t have evidence for this, but it has been brought up by providers as a possible barrier during discussions at live meetings on the subject. In my mind, if a greater confidence [develops] in being able to safely administer these therapies in the clinic vs in the hospital, there will be greater interest in these therapies. Otherwise, it’s really the hospital that’s bearing the cost. If you do it as an outpatient infusion, though, then it becomes a proposition for the practice, given that it’s a very expensive infusion….The community practice planning on outpatient administration has to assess the risk of the patient getting sick and getting admitted for toxicity. As we learn more, though, community oncologists will become more confident about preventing toxicity and ensuring that they can safely administer these treatments on an outpatient basis. That’s where the future is, and I think that will really help CAR T-cell therapies take off.

You mentioned the gap in Medicare funding. How does this compare with reimbursement for patients with commercial coverage?

We don’t have an answer for this question yet. We haven’t teased that out. That’s just the honest truth—it wasn’t part of what we’ve surveyed thus far. This question will be more suited for CAR T centers performing the actual infusions.

Fair enough. I’d like to ask about coronavirus disease (COVID-19). It would seem that during the pandemic, there would be an interest in not keeping patients in the hospital any longer than necessary. COVID-19 emerged since you gathered your information, but I’m wondering what it’s been like since then—has the pandemic made it more favorable to administer CAR T-cell therapy in the community setting?

Absolutely. We’re actually redoing the survey as we speak. We hope to get a decent sample size of current practices; we wanted to redo it in the context of having 3 products now approved. And, hopefully, we’ll see more CAR T therapies coming down the pike in 2021; some data looked really good coming out of ASH 2020. There seems to be anecdotally a lot of interest, especially among larger practices that are geographically close to a hospital setting, in taking on outpatient infusion of CAR T-cell therapies. We certainly got that [impression] during our discussion the last time, [last] spring, so we’re trying to see if that change has actually transpired.

[COVID-19 is a driver for outpatient care and for almost everything else], including CAR T. [Please note] that the label of one of the initial 2 products indicated that it should be given in the hospital, while that was not the case for the other product. The labeling, or the implications of the label, also impacts practice. As we see new products emerge, if there’s no direction that they should be given in a hospital, I think that will encourage the use of these therapies in the outpatient setting. But the COVID-19 pandemic, as we all know, has been a driver to push care away from the hospital and into the clinic.

We’ve covered a lot of ground. Would you like to add anything that we didn’t cover?

First of all, even though now it’s been 3-plus years since the original approval, there is still room for educating and keeping the community provider especially engaged. It’s not every day or every other day that a community provider will have the opportunity and will have the appropriate patient for a CAR T-cell therapy. It’s not like, say, hormone-positive breast cancer, which they [commonly] see. So, I think, as more and more indications become amenable to CAR-T therapy, that ongoing engagement with be essential, [whether it stems] from the manufacturers, from organizations, or from [health care media]—whatever avenue there is.

Second is the prior authorization process. Streamlining that process for the appropriate patient is so critical, and anything that can be done to simplify and facilitate that, both from the payer perspective and the manufacturer side, would really help drive this therapy further.

Third, perhaps manufacturers can help identifying the pain points at the CAR T centers. These are typically large academic or tertiary-care cancer centers. We’ve encountered concerns from community oncologists, including that the patient was referred for CAR T, but was ultimately treated with a transplant; that a finite percentage of patients never ended up getting CAR T at the CAR T center; and that communication wasn’t adequate in terms of what the community provider should do when the patient returns after CAR T-cell therapy.

[In short,] we’ve heard that the intake of the CAR T was so slow. Here, you have a patient for whom you’ve moved heaven and earth for prior approval authorization, and you referred them, but then they couldn’t get in or it took too long. So, I think that’s another area where we can shave some time off in terms of getting the patient in line for CAR-T. Another potential barrier to CD-19–directed CAR T therapies in LBCL is the recent approval of tafasitamab (Monjuvi), a CD-19–directed monoclonal antibody, which is easy to give in the office and technically targets the same antigen. What is not known clearly is whether prior exposure to tafasitamab leads to impaired response with CAR T-cell therapy and vice versa.

One other thing that we learned—and I think the community physicians are learning this as well—is that patients are likely to need bridging therapy while they are awaiting CAR T-cell therapy. In the early days, they were sort of taken aback: “Oh, what am I supposed to do now? You’re not going to have your product for another 6 to 8 weeks?” But now they’re learning that yes, something else is needed to hold the disease—ie, bridging therapy—while awaiting the CAR T product, so it’s really a multipronged approach. And I feel the manufacturer, CAR T center, provider, and the patient, and then the payer, are in it together, and little tweaks can streamline the process [to work] somewhat better than it does now.

1. Gajra A, Jeune-Smith Y, Kish J, Yeh T-C, Hime S, Feinberg B. Perceptions of community hematologists/oncologists on barriers to chimeric antigen receptor T-cell therapy for the treatment of diffuse large B-cell lymphoma. Immunotherapy. 2020;12(10):725-732. doi:10.2217/imt-2020-0118
2. Gajra A, Hime S, Smith Y, Feinberg BA. Adoption of approved CAR-T therapies among US community hematologists/oncologists. Blood. 2020;136(suppl 1):34-35. doi:10.1182/blood-2020-141990
3. FDA approves new treatment for adults with relapsed or refractory large B-cell lymphoma. News release. FDA; February 5, 2021. Accessed February 5, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-relapsed-or-refractorylarge-
b-cell-lymphoma

Articles

Ajeet Gajra, MD, MBBS, FACP, talks about identifying and removing the barriers for offering CAR T-cell therapy at the community practice level.

Delays With Payers Mean Some Patients Miss Window for CAR T-Cell Therapy, Findings Show

More than 3 years have passed since FDA approved the first chimeric antigen receptor (CAR) T-cell therapy to treat patients whose B-cell lymphoma had not responded to other treatments. Since 2017, researchers have learned more about controlling side effects and which patients make good candidates for therapy, but one question remains: why does this process work for some patients but not others?

question we struggle with,” said Stephen J. Schuster, MD, who on Friday offered an overview of developments in CAR T-cell therapy during the National Comprehensive Cancer Network’s Virtual Annual Meeting.

Schuster, director of the Lymphoma Program at the Abramson Cancer Center, University of Pennsylvania, was the principal investigator for the trial that led to the approval of tisagenlecleucel, or tisa-cel (Kymriah). He has also led trials involving bispecific antibodies, and said he’s given them to patients when CAR T-cell therapy failed.

Since July, 2 more CAR T-cell treatments have been approved: they are brexucabtagene autoleucel (Tecartus), a new treatment for mantle cell lymphoma, and lisocabtagene maraleucel, or liso-cel (Breyanzi), which is also approved for refractory B-cell lymphoma but uses a manufacturing process that promises less toxicity that previously approved CAR T-cell therapies.

Schuster discussed differences among the 3 approved anti-CD19 therapies, tisa-cel, liso-cel, and axicabtagene ciloleucel, or axi-cel (Yescarta), and also discussed the path ahead, which will involve deciding which patients will benefit from CAR T-cell therapy, how early to give it, and how to combine it with other drugs for the best result.

“We’re going to be combining CAR T cells with other therapies, and moving it up earlier in therapy for patients,” Schuster said. “I think it's going to change the landscape.”

Added choices and recent advances reflected in the 

 of the NCCN guidelines for lymphoma include:

In follicular lymphoma, there are now distinctions between second-line and subsequent treatments and third-line and subsequent treatments for the elderly or infirm.

Liso-cel was added in 5 different places as a category 2A recommendation: in follicular lymphoma, marginal zone lymphoma, DLBCL, and for forms of high-grade B-cell lymphoma.

Schuster highlighted the approval in mantle cell lymphoma, saying in this condition, “recurrence was the norm.” Schuster cited 2020 data published by Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, showing the 61% complete response rate at 12 months when a BTK inhibitor is used a bridge therapy, which Schuster said was “clearly better than any of the other agents approved for relapsed/refractory mantle cell lymphoma.”

Moderator Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, asked whether there was more news to come in chronic lymphocytic leukemia (CLL). Referring to 

 in December at the American Society of Hematology meeting, Schuster said “hopefully soon” results will be presented that show what liso-cel achieved is transformed follicular lymphoma “is true [in] at least 1 of the other 2 products I was discussing.”

While enthusiastic about CAR T-cell treatments, Schuster took note of newly approved third-line options that were quickly added to the NCCN guidelines: 

 (Monjuvi), or polatuzumab‐bendamustine‐rituximab (Polivy).

CAR T-cell therapy has saved the lives of patients who had been extremely ill, but it still fails in about two-third of patients who receive it, for reasons that are not fully understood. This is of great concern to payers, given the initial prices of $373,000 to $475,000.

Along with fellow Penn researchers Elise A. Chong, MD, and Marco Ruella, MD, Schuster 

 that progression-free survival at 5 years was 31% in patients with diffuse large B-cell lymphoma (DLBCL) and 43% in patients with follicular lymphoma; 60% of patients were in remission at 5 years. They wrote, “Of the patients who had a relapse, only one had no expression of the CD19 target antigen.”

The customized approach of CAR T-cell therapy—in which a patient’s T-cells are harvested and engineered to attack cancer before being reinfused into the body—brings with it pluses and minuses; a key downside is the time it takes to manufacture individual treatments for each patient. But a big plus is that CAR T-cell therapy now has more than 5 years of long-term data behind it, Schuster said. Despite the cost, both Schuster said payers have largely come on board with the early CAR T-cell therapies, at least at academic medical centers where the reimbursement process has been fine-tuned.

Success in CAR T-cell therapy will come from gaining more understanding of key steps in the treatment process: patient selection, apheresis and cell manufacturing, selection of bridge therapy, and management of toxicities.

There’s room for advancement in the role of bridging therapy, which Schuster called “the art of oncology,” with the arrival of new third-line agents and advances it other drug classes used as bridge therapy. Deciding the order of when to use immune checkpoint inhibitors, bispecific antibodies—whether it’s before, during, or after CAR T-cell administration—will open new possibilities.

“We’re talking about the two-thirds of patients that aren't responding to the CAR Ts, and maybe getting a third of them to respond to a bispecific [antibody] so I'm optimistic that bispecifics are going to have a role here,” he said. “We're looking at that in a more systematic fashion.”

Penn Medicine's Stephen Schuster, MD, offers an overview of an eventful year in CAR T-cell therapy at the NCCN Virtual Annual Meeting.

Looking at Long-term Results, New Opportunities With CAR T-Cell Therapies 

After delays that proved costly to investors, FDA 

 lisocabtagene maraleucel (liso-cel), the chimeric antigen receptor (CAR) T-cell therapy from Juno Therapeutics/Bristol Myers Squibb, that promises to offer the life-saving potential of the first generation of gene therapy with fewer toxic effects.

To be sold as Breyanzi, liso-cel was approved for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have not responded to at 2 other treatments. The CAR T-cell therapy is not indicated for patients with primary central nervous system lymphoma.

“Today’s approval represents another milestone in the rapidly progressing field of gene therapy by providing an additional treatment option for adults with certain types of cancer affecting the blood, bone marrow, and lymph nodes,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in statement. “Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens.”

Liso-cel’s original target date for approval was mid-August of 2020, which then moved November 16, 2020. But that date came and went with no word from FDA—only reports that regulators had not visited a manufacturing facility where the CARs would be made. When the inspection finally occurred in early December, regulators found issues and BMS said it responded quickly. But no word came from FDA, and investors who held $6.4 billion in 

 that were tied to BMS’ purchase of Celgene saw their payment evaporate when the calendar year ended without the approval.

DLBCL is newly diagnosed in about 25,000 people a year and represents the most common type of non-Hodgkin lymphoma in adults. When DLBCL is aggressive and does not respond to treatment, patients may quickly find themselves with few options.

Like the first 2 approved CAR T-cell therapies, treatment with liso-cel involves a process in which a patients own T-cells are collected and then modified to include a new gene that allows the T-cells to hunt down and kill the cancer cells. The customized T-cells are then infused back into the patient. In a trial of 250 patients with refractory or relapsed LBCL, the complete remission rate after treatment was 54%.

, Tanya Siddiqi, MD, of City of Hope, explained that liso-cel involves a different manufacturing process that has led to reduced toxicity in clinical trials. The process results in precise, equal numbers of CAR cells that are CD4+ and CD8+, while other treatments can have varying ratios of CD4+ and CD8+ cells. “The thought is, the researchers and the drug manufacturer feel that this helps to have an expectation of what expansion you will have of these cells in the body,” Siddiqi said.

As a result, patients in clinical trials experienced less toxicity from cytokine release syndrome (CRS), which occurs as the T-cells mount their charge against the lymphoma, and fewer effects from hyperinflammation or neurotoxicity.

“We've just seen fewer severe adverse events so much so that at some [cancer] centers across the country, we’ve been able to give liso-cel CAR T-cells to patients in the clinic or outpatient setting rather than having to admit them to the hospital, depending on the patient's situation,” Siddiqi said.

“This means fewer days of inpatient hospitalization for these patients, so it may be less costly overall. I don’t think the efficacy is necessarily different—meaning that it seems to work as well as the other FDA-approved products already commercially available,” she said. “I think it might be a very good option for older patients, maybe patients who are bit more frail, or younger patients who just don't want to be admitted to the hospital—they just want to try to do it in the outpatient setting.

At a time when some hospitals are overwhelmed with patients due to coronavirus disease 2019 (COVID-19), the option to treat DLBCL in an outpatient setting could be a plus.

“As we see new products emerge, if there's no direction that they should be given in a hospital, I think that will encourage the use of these therapies in the outpatient setting. The COVID pandemic, as we all know, has been a driver to push care away from the hospital and into the clinic,” Ajeet Gajra, MD, FACP, vice president at Cardinal Health, told 

Patients who are treated with liso-cel are still at risk of severe adverse events, so the approval will come with a boxed warning for CRS, a risk evaluation and mitigation strategy, and a post-marketing study of long-term effects. Health care facilities offering liso-cel must receive a special certification. Other possible adverse events include hypersensitivity reactions, serious infections, low blood cell counts and a weakened immune system. Typically, adverse events with liso-cel occur within the first 7-14 days but some do occur later.

A CAR T-cell therapy that promises fewer side effects, and possibly lower hospital costs, wins approval after lengthy delays.


FDA Approves Less Toxic Liso-Cel in R/R Large B-Cell Lymphoma

Data gathered by Cardinal Health Specialty Solutions revealed roadblocks community oncology practices encounter when trying to navigate payer approvals for CAR T-cell therapy.

Delays Mean Some Miss Window for CAR T-Cell Therapy, Cardinal Health Data Show

A recent paper in Nature Cancer outlines a novel strategy for overcoming barriers to CAR T-cell therapy in glioblastoma by pretreating the vascular microenvironment.

Moving a Step Closer to Using CAR T-Cell Therapy in Solid Tumors

At the recent meeting of the American Society of Hematology, results from several studies involved the use of chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma. 

Deepu Madduri, MD, Discusses CARTITUDE-1 Data for Multiple Myeloma—and Clinical Trials During COVID-19

Karl Kilgore, PhD, a senior research scientist at Avalere Health, discusses Medicare data that offer insights on the overall costs of CAR T-cell therapy relative to transplants.

Real-World Data Offer Good News for CAR T-Cell Therapy

City of Hope's Dr. Tanya Siddiqi offers an update on a new chimeric antigen receptor (CAR) T-cell therapy awaiting approval from the FDA.

Tanya Siddiqi, MD, Discusses the Promise of Reduced Toxicity With Liso-Cel

Gaining Knowledge of CAR T-Cell Therapy, and CRS, Over Time

The vice president for Clinical Services at OneOncology describes challenges and opportunities for chimeric antigen receptor (CAR) T-cell therapy in the community practice setting.

OneOncology’s Duncan Allen, MHA, Discusses Bringing CAR T-cell Therapy to the Community Setting

From the Academic Center to Community Practice 

CAR-T Spotlight

CAR T-Cell Therapies Old and New: Cilta-Cel Wows in Multiple Myeloma; Axi-Cel Shows 44% OS at 4 Years in LBCL

Chimeric antigen receptor (CAR) T-cell therapy is no longer the new kid on the block at the 62nd American Society of Hematology (ASH) annual meeting, but results for this groundbreaking treatment still excite as the technology moves beyond acute lymphoblastic leukemia and different forms of lymphoma to multiple myeloma.

The virtual presentation December 5, 2020, featured phase 1b/2 results for ciltacabtagene autoleucel (cilta-cel), Janssen’s investigational B-cell maturation antigen (BCMA) CAR T-cell treatment for patients whose multiple myeloma has progressed after as many as 6 treatments.

Cilta-cel produced an overall response rate (ORR) of 97% and a stringent response rate of 67% with a median follow-up time of 12.4 months, according to data presented by Deepu Madduri, MD, of The Tisch Cancer Institute at Mount Sinai, New York, and the principal investigator of CARTITUDE-1.

Median duration of response and progression-free survival (PFS) were not reached.

Patients with multiple myeloma have a poor prognosis if their disease progresses after 3 treatments, Madduri said, with a typical overall survival (OS) of less than 6 months. But in CARTITUDE-1, cilta-cel has produced deep responses in these patients. “I think a one-time treatment to give these deep, durable responses is what we need for our myeloma patients. It’s one step closer to getting a cure.”

In an interview, Madduri cited no correlation between the number of prior treatments and patient response. “We had a median of 6 prior lines of therapy—it ranged anywhere from 3 to 18 prior lines of therapy.”

Results from the open-label study presented at ASH covered 97 patients; median age was 61 years and 58.8% were male. Data showed the following:

12-month PFS was 77% (95% CI, 66%-84%), and the 12-month OS rate was 89% (95% CI, 80%-94%).

Patients typically responded to cilta-cel within the first month, and manufacturing of the treatment was successful for all patients.

93% of patients achieved minimal residual disease, an important marker of response.

In the combined results, the most common hematologic adverse events (AEs) were neutropenia (96%), anemia (81%), thrombocytopenia (79%), leukopenia (62%), and lymphopenia (53%).

Cytokine release syndrome (CRS), a common AE of CAR T-cell treatment, was seen in 95% of patients and lasted for an average of 4 days (range, 1-97), with 99% of cases resolving within 14 days. Of CRS events, 95% (n = 87) were grade 1 or 2, 3% (n = 3) were grade 3, and 1 patient experienced a grade 4 event. The statement from Janssen reported 1 “grade 5” AE, or death from CRS; Madduri told the session that overall, 6 people have died due to AEs from treatment.

The median onset of CRS was 7 days after infusion, with 89% not seeing CRS until day 4. This could demonstrate the potential for cilta-cel to be given in an outpatient setting. Asked during the session to offer a possible reason why CRS starts later with cilta-cel than other CAR T-cell treatments, Madduri said, “We think this is probably related to cell expansion, because it expands a little bit later than some of the other therapies.”

Neurotoxicity was seen in 21% of patients, with 10% (n = 10) having neurotoxicity of grade 3 or higher, including 1 death. Immune effector cell–associated neurotoxicity syndrome was

seen in 16 patients and typically occurred alongside CRS. Other cognitive effects were seen in 12 patients; these generally occurred after CRS had resolved.

Madduri noted that clinicians have become more adept at managing toxicities. “We tend to give tocilizumab much earlier now, not necessarily waiting until grade 2 CRS—so I feel these patients are managed easily with the supportive care that we have,” she said.

The long-term promise of CAR T-cell therapy was seen in 4-year results for axicabtagene ciloleucel (axi-cel) in adult patients with refractory large B-cell lymphoma (LBCL). Sold as Yescarta (Kite Pharma/Gilead), axi-cel was the first CAR T-cell therapy approved for this indication and the second overall.

Kite Pharma announced long-term follow-up data for the ZUMA-1 trial; among 101 patients at least 4 years past a single infusion of axi-cel (median follow-up, 51.1 months), a Kaplan-Meier estimate of OS was 44%. The 101 patients who had refractory LBCL were among 111 patients enrolled in the original phase 2 ZUMA-1 trial. These patients had a median period of less than 2 months from leukapheresis to complete response. Also, no treatment-related secondary malignancies have been reported.

“With close to half of patients still alive after a single infusion of axicabtagene ciloleucel, we are transforming the way relapsed or refractory large B-cell lymphoma can be treated,” Frederick L. Locke, MD, said in a statement. Locke was the co-lead investigator of ZUMA-1 and is the vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “I continue to see these patients in the clinic, and this overall survival data confirms the durability of CAR T-cell therapy in a patient population that previously exhausted all viable treatment options,” he said.

Of note, the investigators reported results from 21 patients with blood samples at the 3-year mark; for 14 patients (67%), the CAR-marked cells were still detectable. Normal B cells were also found in 91% of evaluable patients, which investigators said suggests that the effects of treatment last beyond the persistence of functional CAR T cells.

Long-term results with axi-cel come as Kite Pharma/Gilead face possible competition from lisocabtagene maraleucel (liso-cel), an investigational therapy from Bristol Myers Squibb. Liso-cel would treat patients with diffuse LBCL, but it involves a different manufacturing process that could lessen the effects of CRS when the patients receive therapy. The FDA missed a target date for action due to delays inspecting a manufacturing facility, but approval is still possible before the end of 2020.

Results from the OUTREACH study presented December 5, 2020, also suggest that liso-cel can safely be administered in an outpatient setting,

 and an abstract for results scheduled to be presented Sunday suggests substantial savings when liso-cel is administered in the outpatient setting compared with the inpatient setting.

1. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 Study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper136307.html

2. Jacobson C, Locke FL, Ghobadi A, et al. Long-term survival and gradual recovery of B cells in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper134362.html

3. Godwin JE, Freytes CO, Maris M, et al. Outcomes of treatment with the chimeric antigen receptor (CAR) T cell therapy lisocabtagene maraleucel (liso-cel) in the nonuniversity setting: initial results from the Outreach study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. https://ash.confex.com/ash/2020/webprogram/Paper136640.html

4. Palomba ML, Jun MP, Garcia J, et al. Costs of postinfusion monitoring by site of care for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who received third-line or later treatment with lisocabtagene maraleucel (liso-cel) in the Transcend NHL 001 and Outreach trials. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 15, 2020. 

https://ash.confex.com/ash/2020/webprogram/Paper141415.html

Creating Personalized Immunotherapy in Large B-Cell Lymphoma

When the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel) works in large B-cell lymphoma (LBCL), the results can seem miraculous. But this expensive treatment does not work for about a quarter of patients who receive it, and researchers who presented results at the annual meeting of the American Society of Hematology (ASH) think they know why.

With CAR T-cell therapy, a patient’s T cells are removed and engineered in a manufacturing process to express a receptor that will target and kill cancer kills. These CAR T cells are then reinfused back into the patient, and it is typically clear within a month whether the treatment has worked.

Researchers led by Robbie G. Majzner, MD, of Stanford University School of Medicine wanted to find out what went wrong when CAR T-cell therapy didn’t take hold.

 They analyzed genetic samples from 51 patients who received axi-cel and learned that 25% of patients had tumors that lacked a functioning version of the protein CD58. In all but 1 of these patients, the treatment did not produce lasting effects.

The researchers then confirmed their findings in a mouse model that lacked CD58; the team tested 3 different CAR T-cell therapies in the mice, but none worked.

Are patients whose tumors lack CD58 out of luck? Perhaps not. The research team determined that CD58 helped activate the biological mechanisms that allowed the CAR T-cell therapy to kill cancer. So, the investigators added a different protein, CD2, the T-cell ligand for CD58, to the job of the missing protein.

CD2, the researchers wrote in their abstract, “plays both an adhesive role and a costimulatory role in T cells.” In a series of experiments, they noted that blocking CD2 greatly reduced cytokine production after CAR stimulation, but this can be a sign that treatment is not working.

Conversely, by modifying CAR T cells with the additional protein, the researchers were able to show in experiments with mice that the treatment can work without CD58. This approach could be tested in clinical trials within the next 2 years.

The results would be of interest to payers, who have tried to create CAR T payment structures that reimburse drug makers only when the treatment works. However, the significant administrative costs for institutions must be absorbed somewhere, and this has created access issues for patients without commercial coverage.

“Achieving an uptick of 20% to 25% in the complete response rate would really bring cures to a large number of additional patients,” Majzner said.

 “Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy.”

1. Majzner RG, Frank MJ, Mount C, et al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual. Accessed December 12, 2020.

2. Genome editing and cellular therapies show promise for treating blood disorders, cancers. News release. American Society of Hematology. December 5, 2020. Accessed December 5, 2020. https://www.hematology.org/newsroom/press-releases/2020/genome-editing-and-cellular-therapies-show-promise-for-treating-blood-disorders-cancers

Exciting new and ongoing developments in chimeric antigen receptor (CAR) T-cell therapies were covered at the 62nd American Society of Hematology (ASH) annual meeting. 

ASH 2020: CAR T-Cell Therapy Updates

This year’s popular pieces in blood cancers and blood diseases appeared early in the year and offered glimpses into research that would bear greater fruit at the end of the year during the recent annual meeting of the American Society of Hematology. Here are the most read hematology articles on AJMC.com:

5. MRD: We’re Aware of It, Say Oncologists, but We Don’t Use it for Decisions. 

 from investigators at the University of Chicago Medical Center found that the concept of measurable, or minimal, residual disease (MRD) in multiple myeloma (MM) has reached clinicians but they had not yet incorporated it into decision-making. A total of 84 respondents completed the survey over a 2-month period, with 55% responding before FDA approved an NGS assay for MRD in MM. Whether the survey results still hold, the use of MRD has made its way into clinical research as an end point.

4. Once-Weekly KRd Shows Promise in Newly Diagnosed MM. 

 multiple myeloma (MM) often receive a twice-weekly triplet combination of carfilzomib (Krypolis), lenalidomide, and dexamethasone (KRd), but data published in October suggest that once-a-week dosing can be equally successful. The study reported an overall response rate of 97%, including those with a very good partial response (VGPR) or better among those who had a stem cell transplant and an ORR of 93.3% among those who did not have a stem cell transplant.

3. CAR T-Cell Therapies Show Promise for Multiple Myeloma, but Hurdles Remain.

 and challenges in bringing chimeric antigen receptor (CAR) T-cell therapy to the treatment of MM, which has already seen advances in the development of immunomodulatory drugs. But MM is still incurable, and 2020 saw significant leaps forward with solutions that involve targeting the B-cell maturation antigen (BCMA), which the authors note is highly expressed on the surface of malignant plasma cells, with restricted expression in normal tissues/cells except for a low-level expression in mature B-cells. Other possible targets include CD38, CD138, CD19, and immunoglobulin kappa light chain (Ig-Kappa). The greatest success has been in targeting BCMA, as other targets have yielded high response rates but not durable responses.

2.Janssen's Wildgust Breaks Down Bispecific Antibodies in Development for Non-Small Cell Lung Cancer and Multiple Myeloma. 

 with Janssen’s Mark Wildgust, PhD, vice president of Global Medical Affairs/Oncology, appeared in the special recap issue of 

™ from the American Society of Clinical Oncology (ASCO). During the meeting, Janssen presented results from the CHRYSALIS study on amivantimab, a bispecific antibody under development to treat non–small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma. Updated 

 for teclistamab were recently presented during ASH 2020.

Revolutionary Treatment for Sickle Cell Disease Shows Promise in Clinical Trial.

 on results from just 3 adult patients that had been presented at ASH 2019 offered a glimpse of what was to come: in this case, stem cells genetically engineered to produce healthy hemoglobin produced remarkable results in patients with sickle cell disease (SCD), a debilitating, incurable disease that results from painful sickle cell buildup, causing lack of oxygen. Dana-Farber Cancer Institute researchers targeted 

, which preclinical research showed could regulate the switch of fetal hemoglobin to adult hemoglobin. The concept of targeting this protein has taken flight and expanded; 

 took center stage at ASH 2020, focusing on the use of CRISPR technology to silence 

Gene-editing therapy in sickle cell disease and advances in multiple myeloma dominated hematology news in 2020.

Rolling Submission Begins for BLA on Cilta-Cel in R/R Multiple Myeloma

Saturday’s virtual presentation featured phase 1b/2 results for ciltacabtagene autoleucel (cilta-cel), Janssen’s investigational B-cell maturation antigen (BCMA) CAR T-cell treatment for patients whose multiple myeloma has progressed after as many as 6 treatments.

® in an interview there was no correlation between the number of prior treatments and the patients’ response. “We had a median of 6 prior lines of therapy—it ranged anywhere from 3 to 18 prior lines of therapy.”

Results from the open-label study presented at ASH covered 97 patients, who were 58.8% male with median age of 61 years. Data showed the following:

Patients typically responded within the first month, and manufacturing of the treatment was successful for all patients.

93% of the patients achieved minimal residual disease, an important marker.

Cytokine release syndrome (CRS), a common AE of CAR T-cell treatment, was seen in 95% of the patients, lasting for 4 days (range, 1-97), with 99% of the cases resolving within 14 days. Of those with CRS, 95% (n = 87) were grade 1 or 2, 3% (n = 3) were grade 3, and 1 was grade 4. The statement from Janssen reported 1 "Grade 5" AE, or death from CRS; Madduri told the session that overall, 6 people have died due to AEs from treatment. 

The median onset of CRS was 7 days after infusion, with 89% not seeing CRS until day 4, which could show the potential for cilta-cel to be given in an outpatient setting.

Asked during the session to offer a possible reason why CRS starts later with cilta-cel, Madduri said, "We think this is probably related to cell expansion, because it expands a little bit later than some of the other therapies."  

Neurotoxicity was seen in 21% of the patients, with 10% (n = 10) have neurotoxicity of grade 3 or higher, including 1 death. Immune effector cell–associated neurotoxicity syndrome was seen in 16 patients and typically occurred alongside CRS. Other cognitive effects were seen in 12 patients that generally occurred after CRS had resolved.

Madduri said clinicians have become more adept at managing toxicities. “We tend to give tocilizumab much earlier now, not necessarily waiting until grade 2 CRS—so I feel these patients are managed easily with the supportive care that we have.”

The long-term promise of CAR T-cell therapy was seen in 4-year results for axicabtagene ciloleucel (axi-cel) in adult patients with refractory large B-cell lymphoma (LBCL). Sold as Yescarta (Kite Pharma/Gilead), this was the first CAR T-cell therapy approved for this indication and the second overall.

 announced long-term follow-up data for the ZUMA-1 trial; among 101 patients at least 4 years past a single infusion of axi-cel (median follow-up, 51.1 months), a Kaplan-Meier estimate of OS was 44%. The 101 patients who had refractory LBCL were among 111 patients enrolled in the original phase 2 ZUMA-1 trial. These patients had a median period of less than 2 months from leukapheresis to complete response. Also, no treatment-related secondary malignancies have been reported.

“With close to half of patients still alive after a single infusion of axicabtagene ciloleucel, we are transforming the way relapsed or refractory large B-cell lymphoma can be treated,” Frederick L. Locke, MD, said 

. Locke was the co-lead investigator of ZUMA-1 and is the vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “I continue to see these patients in the clinic, and this overall survival data confirms the durability of CAR T-cell therapy in a patient population that previously exhausted all viable treatment options.”

Of note, the investigators reported results from 21 patients with blood samples at the 3-year mark, and for 14 patients (67%), the CAR-marked cells were still detectable. Normal B cells were also found in 91% of evaluable patients, which investigators said suggest that the effects of treatment last beyond the persistence of functional CAR T cells.

Axi-cel’s long-term results come as Kite Pharma/Gilead face possible competition from lisocabtagene maraleucel (liso-cel), an investigational therapy from Bristol Myers Squibb. 

 would treat the patients with diffuse LBCL, but it involves a different manufacturing process that could lessen the effects of CRS when the patients receive the therapy. The FDA missed a target date for action due to delays inspecting a manufacturing facility, but approval is still possible before the end of 2020.

Results from the OUTREACH study presented Saturday also suggest liso-cel can safely be administered in an outpatient setting,

1. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 Study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 177. https://ash.confex.com/ash/2020/webprogram/Paper136307.html

2. Jacobson C, Locke FL, Ghobadi A, et al. Long-term survival and gradual recovery of B cells in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 1187. https://ash.confex.com/ash/2020/webprogram/Paper134362.html

3. Godwin JE, Freytes CO, Maris M, et al. Outcomes of treatment with the chimeric antigen receptor (CAR) T cell therapy lisocabtagene maraleucel (liso-cel) in the nonuniversity setting: initial results from the Outreach study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020. Abstract 1196. https://ash.confex.com/ash/2020/webprogram/Paper136640.html

Results were released for a leading chimeric antigen receptor (CAR) T-cell therapy candidate in multiple myeloma, along with long-term findings for an early treatment that may soon face competition.