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Kymriah approval generates questions about cost, access, long-term impact of CAR T-cell therapy
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The recent FDA approval of tisagenlecleucel T-suspension for the treatment of children and young adults with refractory B-cell precursor acute lymphoblastic leukemia marks the first-ever chimeric antigen receptor (CAR) T-cell therapy approval in the United States.
In addition to introducing a new class of cellular therapies into the cancer treatment landscape, the agent also stands to change the outcomes for patients with this disease who have relapsed and are refractory to standard treatments, according to Patrick Brown, MD, director of the pediatric leukemia program and associate professor of oncology and pediatrics at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
“There is fairly well-established standard therapy that includes chemotherapy, primarily, for newly diagnosed ALL,” Brown told HemOnc Today. “For the first relapse of ALL, there are also relatively standard therapies that can be effective in achieving remission. Bone marrow transplant is part of standard therapy for certain patients. What we have not had, up until recently, is effective therapy for patients who are completely refractory to chemotherapy or who experience a second relapse.”
The approval of tisagenlecleucel T-suspsension (Kymriah, Novartis) was based on results of the open-label, single-arm, phase 2 ELIANA trial. HemOnc Today spoke with Brown and Bijal D. Shah, MD, a medical oncologist in the malignant oncology program at Moffitt Cancer Center, about the approval of tisagenlecleucel, the potential for a practice-changing shift in the treatment of refractory B-cell precursor ALL and the barriers that may affect access to this therapy, as well as strategies for addressing these concerns. – by Julia Ernst, MS
What is the significance of this development?
Brown: Currently, there is no good standard of care for leukemia that has failed to respond to other therapies. This agent is a new treatment option that works by completely different mechanisms than our standard chemotherapy approaches.
The number of immunotherapy treatments that are commercially available has just exploded, between checkpoint inhibitors and the antibody-based therapies like blinatumomab and inotuzumab, and now we have CAR-T cell therapy. This is the most exciting time I’ve experienced in the field of leukemia and even maybe cancer in general.
Shah: In terms of cellular immunotherapy, there is no question that this sets a new precedent. No other cellular immunotherapy exists.
Fifty-two patients – or 83% – treated with tisagenlecleucel achieved complete remission or complete remission with incomplete blood count, but I prefer to focus on the relapse-free survival, which was about 60% at one year. I think that’s a better measure of what this therapy can do. When we look at patients with relapsed leuekemia treated with standard therapies, the 1-year relapse free rate was between 10% and 20% – 20% for children and closer to 5% to 10% for adults. That was the long-term benefit that we had come to expect. This therapy has pushed that to 60%. That is enormous.
What concerns does the medical community have about this new class of agents?
Shah: There are a lot of factors we now have to account for. When we think about CAR-T cell therapy, the biggest issue we’re going to be concerned with is infection. We spend a lot of time discussing the percentage of patients who develop cytokine release syndrome, as well as neurotoxicity, but these issues are short-lived. They last a week or two and then people get better. There are also concerns about cerebral edema and some other events, but they’re rare – extremely rare.
The actual mortality associated with CAR-T cell therapy is on par with what we see with an autologous stem cell transplant. Depending on which trial you’re looking at in the leukemia space, it’s between 2% and 5%.
I think the real question is what we’ll see in the long-term with this therapy. Fundamentally, what we’re doing with tisagenlecleucel is eliminating B cells. What do we envision in terms of infections for patients treated with this agent?
Emily Whitehead, the first pediatric patient to be treated with CAR-T cell therapy, has become the poster child for this type of treatment. She receives monthly intravenous immunoglobulin infusions to support her immune system. Now, she’s not being hospitalized for recurrent infections, but it is something we have to keep in mind: If we’re really successful, and the CAR-T cell therapy does what we expect it to, there may be the risk that, in patients who achieve long-lasting remission, we will have to support their immune systems. But that isn’t a huge sacrifice for patients, as intravenous immunoglobulin is fairly safe.
One thing the medical community has proposed is a second allogeneic transplant in patients receiving this treatment. This would replace patients’ B cells, giving them a functional immune system. As this technology advances, moving up in lines of therapy, I think we’re going to be performing fewer transplants. I think we’ll have the power to ask the question: Does a stem cell transplant even help?
However, with both treatments – an additional stem cell transplant and intravenous immunoglobulin – we have to think about additional costs for our patients.
How will the cost of this agent affect patients’ ability to obtain treatment?
Shah: I think it’s important to contextualize the cost of tisagenlecleucel as it relates to other therapies. The straightforward cost of blinatumomab (Blincyto, Amgen), which is a continuous, 28-day IV infusion, is approximately $100,000 a month, but that doesn’t include any of the administration costs; patients are also required to come back to the treatment center every 2 days with that agent. They recently developed a 7-day treatment cycle, so that will hopefully minimize some of the travel that is required, but for that first cycle – and monitoring for some of the same events like cytokine release syndrome, neurologic toxicities and infections that can occur with blinatumomab – it’s still going to require a lot of follow-up. From a socioeconomic standpoint, that means a lot of traveling to, and staying at, an academic center, and that will be cumbersome.
Inotuzumab ozogamicin (Besponsa; Wyeth Pharmaceuticals, Pfizer) is a weekly therapy, but we’re talking about weekly therapy with a high propensity for causing low blood counts. In particular, the risk for neutropenic fever is quite high, at around 25%. This treatment will also lead to low blood counts and the need for transfusions – and it has a similar price tag of around $112,000 per cycle, with the expectation of delivering a minimum of two cycles. When we talk about the cost of tisagenlecleucel in the context of these other therapies, this $475,000 price tag sounds crazy – and it is – but it is not that much more dramatically priced than the other agents that are in this same space.
ALL has a tendency, at least in my experience in Florida, to affect Hispanic individuals, and some of these individuals may not be U.S. citizens. There are companies that have been willing to provide free medication regardless of citizenship status; that will absolutely be necessary with the high cost of tisagenlecleucel. I’m also trying to imagine what international referrals might look like for patients from the Middle East or South America with refractory leukemia – what are we going to require of these patients before we can proceed with CAR-T cell therapy?
The real question is the degree to which insurance and Medicaid will cover the cost. Luckily, because of the age parameters for this agent, affected patients can remain on their parents’ insurance as they proceed through treatment. But there’s no question that tisagenlecleucel will add cost.
Brown: Considerations related to socioeconomic status and access to therapy are always important when discussing a new therapy. This agent is $475,000, which is very expensive. There are some medications that must be taken continuously, where cost is expressed on a per-month basis, and these costs can be enormous over time. Tisagenlecleucel is a one-time treatment – and a one-time cost. That doesn’t make it any less expensive, but I want to contextualize the cost.
To further put this in perspective, the cost of tisagenlecleucel is very similar to, if not a little bit less than, most estimates for what a bone marrow transplant costs, which is a fairly standard treatment for this subtype of leukemia as well as others. Whether this therapy can potentially replace bone marrow transplant as a curative treatment is an unanswered question, but I think it’s reasonable to consider tisagenlecleucel, at this point, to be comparable to a bone marrow transplant in terms of cost.
Importantly, Novartis has put a patient assistance program in place to help the under-insured, the uninsured and patients and families of lower socioeconomic status gain access to this therapy.
Is there anything unique about the patient assistance program for this therapy?
Brown: It’s very similar to existing patient assistance programs that Novartis and other companies have put in place for expensive medications, but it’s novel in that it includes travel and lodging costs, as this therapy will require patients to relocate for a period of time. Many patients will be coming from relatively far away to access this treatment, because it will only be available in a limited number of centers, and the program will help defray the cost of travel.
Disclosures: Brown reports serving as a consultant for Novartis. Shah reports serving on advisory boards for Adaptive Biotechnologies, Jazz Pharmaceuticals, Pfizer and Shire.