Cover Story

Reimbursement remains ‘difficult issue’ in CAR T-cell therapy rollout

Before the FDA approval of two chimeric antigen receptor T-cell therapies, children and young adults with B-cell acute lymphoblastic leukemia and adults with relapsed or refractory diffuse large B-cell lymphoma were considered incurable.

Chimeric antigen receptor (CAR) T-cell therapy has restored hope for those patients, but at a significant cost to the health care system.

The ELIANA trial showed 76% of children with B-cell ALL who received tisagenlecleucel suspension (Kymriah, Novartis) achieved 1-year OS. In ZUMA-1, 52% of adults with relapsed or refractory DLBCL who received axicabtagene ciloleucel (Yescarta; Kite, Gilead) achieved 18-month OS.

Those durable responses earned CAR T-cell therapy recognition as ASCO’s “Advance of the Year.”

“As a true believer, I absolutely think we’ve just gotten started,” Stephan A. Grupp, MD, PhD, chief of cellular therapy and transplant section and director of cancer immunotherapy at Children’s Hospital of Philadelphia, told HemOnc Today. “If we can see it work in acute myeloid leukemia or even solid tumors, then my optimism about this being paradigm shifting is warranted.”

However, at $475,000 for a single infusion of tisagenlecleucel and $373,000 for axicabtagene ciloleucel, billing and reimbursement impediments could limit recipients to select populations from small pockets of the United States.

“There are medical centers across the country who are not opening their CAR T programs until they get assurances that Medicare is going to pay,” Sergio A. Giralt, MD, chief of adult bone marrow transplant service and Melvin Berlin family chair in multiple myeloma at Memorial Sloan Kettering Cancer Center, and a HemOnc Today Editorial Board Member, said in an interview. “Memorial Sloan Kettering decided to take the risk, but we have been advised that if the financial risk becomes too great, the institution would need to reassess its commitment to the program. They cannot jeopardize the financial health of the rest of the institution for a product like this.”

Most CAR T-cell recipients will average an estimated 14 days in the hospital following infusion, according to Sergio A. Giralt, MD.
Most CAR T-cell recipients will average an estimated 14 days in the hospital following infusion, according to Sergio A. Giralt, MD. “If that’s the case, I need four new beds for that many days in a hospital that is 100% at capacity,” he said.

Source: © 2018 Juliana Thomas for Memorial Sloan Kettering Cancer Center.

HemOnc Today spoke with CAR T-cell program directors, hematologists, pharmaceutical representatives, and economic and regulatory experts about CAR T-cell therapy coding and reimbursement issues; criteria for hospital accreditation; challenges associated with toxicities; and future indications likely to gain FDA approval.

‘A very difficult issue’

Medical centers have been slow to offer the groundbreaking therapy.

“You’re dealing with the most desperate situation — a child with relapsed/refractory ALL — and only 50% of states have a CAR T-cell therapy unit,” Samuel M. Silver, MD, PhD, MACP, assistant dean for research and professor of internal medicine at University of Michigan Medical School, as well as a HemOnc Today Editorial Board Member, said in an interview. “Multiple hospitals that don’t have units are starting to see children who have no options. It’s really become a very difficult issue.”

At the time of reporting, 33 centers had received risk evaluation and mitigation strategy certification by Novartis for the delivery of tisagenlecleucel, and 26 facilities were fully operational. Kite, a Gilead subsidiary, had approved 28 centers to deliver axicabtagene ciloleucel.

According to John F. Milligan, PhD, president, CEO and director of Gilead Sciences, Inc., the pharmaceutical company is actively working on training and certifying additional centers. He anticipated that, by the middle of this year, there would be enough centers certified to treat 80% of the estimated 7,500 patients eligible for T-cell infusion in the United States.

“If you go to a lot of the big centers, there are a lot of people who may be eligible for Yescarta but are in areas of the country where it’s impractical or unlikely a center would be set up, and so they would have to travel,” Milligan said during a conference call.

Gilead’s manufacturing facility has the capacity to produce about 4,000 treatments per year at full operation, according to spokesman Nathan Kaiser.

Novartis reported that around 600 patients will be eligible each year for tisagenlecleucel. Pascal Touchon, senior vice president and global head of oncology strategy and business development at Novartis, declined to disclose the manufacturing capacity of tisagenlecleucel but stated “Novartis has made significant investments and continues to invest in support of the anticipated demand to meet the needs of patients.”

Financial toxicities

Pricing and pathways for reimbursement have posed challenges to many medical centers and insurers.

Touchon told HemOnc Today that Novartis set the price for tisagenlecleucel at $475,000 based on its scientific innovation, as well as its medical, patient and societal value and overall impact to the health care system.

Quantitative assessments indicated a cost-effective price of $600,000 to $750,000, Touchon said, which is in line with the expected total cost associated with allogeneic hematopoietic stem cell transplant, which can range between $500,000 and $800,000 in the first year.

“Long-term costs associated with Kymriah’s one-time treatment are expected to be minimal,” Touchon stated, adding that a first-generation CAR T-cell therapy requires significant investments that translate into “unprecedented” costs per patient covered by the manufacturer during the clinical trial process.

Novartis also is implementing an outcomes-based approach that will allow for payment only when pediatric and young adult patients with ALL respond after 1 month.

“In other words, there is no charge for patients treated at centers that have opted into the outcomes-based approach who don’t respond in this timeframe,” Touchon said. “We are working through the specific details with stakeholders to put this new pricing model in place.”

Kaiser noted that adults with relapsed or refractory DLBCL faced an unmet need before the approval of axicabtagene ciloleucel and that Gilead set its pricing based on clinical trials that showed a 70% response rate and nearly a 50% complete response rate.

“Yescarta provides a more than sevenfold improvement over the existing standard of care,” Kaiser said. “We conducted extensive market research with commercial and government payers, as well as targeted cancer centers, to arrive at its list price.”

These prices are based on the premise that the products are delivered as one-time infusions.

However, there is considerable debate in the field over whether patients who receive CAR T-cell therapy may later require HSCT or a second CAR T-cell infusion.

In pediatric and adolescent ALL, between 50% and 60% of CAR T-cell recipients remain in long-term remission after a single infusion “and that gets us to the provocative question of a cure,” Grupp said.

“However, if you believe you need coverage for 6 months — and I do — maybe one more dose at 3 months is appropriate,” Grupp added. “The reality is that when they make these T cells, 80% of the time they make a second bag, so you could do that second infusion for free.”

With increased competition, the pricing for CAR T-cell therapy is expected to decrease.

“How much and when, I don’t know,” Silver said, “but it will happen.”

In the meantime, medical centers and insurers remain unsure over reimbursement procedures, and that uncertainty has kept some centers from performing infusions.

“It’s taken centers a while to understand the math on the Medicare side,” Stephanie Farnia, MPH, director of health policy and strategic relations at American Society for Blood and Marrow Transplantation (ASBMT), said during a symposium sponsored by the Leukemia & Lymphoma Society. “They are potentially looking at substantial losses. It makes people nervous.

“Some centers from the outset decided to establish CAR T programs and said they’d figure out the money later,” she added. “There is now heavy advocacy by the programs going back to CMS and saying this is not sustainable. Centers have shared that they are treating those patients who urgently need it right now, but they can’t guarantee that will continue unless the payment system is fixed.”

Medicare and Medicaid

CMS relies on a fixed coding system to calculate payment. According to ASBMT, about 55% of CAR T-cell therapy for pediatric ALL is paid for by commercial insurance companies, usually a parent’s employer insurance. Medicaid pays for about 40%, and Medicare or other pays for 5%.

In adult DLBCL, 50% of CAR T-cell therapy is covered by Medicare, 40% by commercial/employer insurance, 8% by Medicaid and 2% by other.

“Providers are actually the first payers because they take that upfront cost of purchasing the product at its price point, bringing it inhouse to give to patients and then seek reimbursement later,” Farnia said. “The risk shifts to them.”

FDA approval does not automatically take a product out of the experimental investigational category. An increasing number of plans will only pay for drugs or procedures if they are outlined in certain care pathways, Farnia said.

Oct. 20 marked the deadline to submit an application for fiscal year 2019 for new technology add-on payments, which means reimbursement coding for the approved CAR T-cell products will not be available until at least 2019.

“For the Medicare beneficiary, that winds up being a huge issue for payment,” Silver said.

Samuel M. Silver, MD, PhD, MACP
Samuel M. Silver

In the absence of a formatted billing formula, Farnia said hospitals create purchase orders for CAR T-cell therapy after a patient’s T cells have been extracted and sent to the manufacturer, but before those cells are manufactured and returned for infusion.

“The hospital is really committing at that point to pay for the product, even though it has not received the dollars back from the payer yet,” Farnia said.

Billing and coding

Once a CAR T-cell infusion is completed, the hospital billing team collects medical notations, translates them into codes and files a claim. The payer then takes a “hard look at every item” on that claim, checks to make sure all criteria are met, and makes a payment decision, Farnia said.

Complicating those payment decisions is the absence of comprehensive coding for therapy delivery, which carries a dramatically higher profit margin for providers if administered as an outpatient procedure.

“The manufacturers have a monopoly on pricing power and how a company is reimbursed plays into the pricing decision as much as the product’s value,” Anna Kaltenboeck, program director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering, told HemOnc Today. “If your expectation is that it will be an outpatient drug, it is priced so that the provider administering it will get a markup of 6% from CMS on top of the cost of the drug.

“From that perspective, it’s attractive financially to the provider,” Kaltenboeck added. “Still, if you look at the inpatient reimbursement procedures in place, we often see diagnosis-related groups using bundled payments, where payment encompasses all treatment at a flat rate, in which case the pressure is on the provider to push down on the cost of therapy.”

The cost of CAR T cells could decrease if they are used as inpatient bundled payments more often, Kaltenboeck said.

“If it remains where the system makes money off the higher prices, it’s less likely,” she said.

If a recipient is hospitalized within 72 hours of infusion, the procedure is considered inpatient and payment is bundled, Silver said. Hospitals designate unusually expensive therapies as outlier cases, increasing the inpatient prospective payment system to protect the hospital from large financial losses.

“For Medicare, currently the only way to mitigate losses is by the use of outlier payment,” Silver said. “Essentially, you would have to mark up the drug 400% — from roughly $400,000 to $1.6 million — to have an outlier payment system that ensures you don’t lose too much money. That’s under the assumption these patients are not going to go to the ICU or have major toxicities, which can be up to 50% of patients.”

Some private insurance companies have agreed to the bundled payment methodology, in which acquisition costs are bundled into a hospital stay on a cost-plus basis.

“But you can’t charge Medicare 400% markup and then charge Blue Cross Blue Shield 108% as a line item,” Silver said. “A hospital can assume it will get reimbursed from an insurer’s acquisition costs plus 8% as part of a bundle, and that will make them whole.”

Touchon stated that hospitals independently seek reimbursement for products, services and procedures related to patient care and Novartis has made “significant progress” involving reimbursement with commercial insurers and Medicaid, noting CMS approved a Q-code for tisagenlecleucel on Jan. 1.

“In addition, Kymriah will be provided free of charge for eligible uninsured or underinsured patients,” Touchon said.

Addressing neurologic toxicities

Updated results from ELIANA showed 77% of patients experienced cytokine release syndrome (CRS), 21% of which was grade 3 and 25% grade 4. In ZUMA-1, 43% of patients experienced grade 3 or higher CRS (12%) or other neurologic toxicities (31%).

“Anything that we could use to try to lessen the side effects of CAR T would be important to us,” Milligan said. “We’re actively looking at technologies to lower CRS and perhaps neurotoxicity.”

Neurologists at Memorial Sloan Kettering provided Montreal Cognitive Assessment training to HSCT providers so that they could identify early signs of neurocognitive dysfunction and successfully complete a certification exam from Novartis and Gilead.

“They all had to know that a fever in a patient who had outpatient CAR T therapy required antibiotics within 35 minutes,” Giralt said.

CRS typically occurs within 3 to 4 days after infusion and is manifested as a fever in the 104-degree range. Patients can also develop low blood pressure, breathing difficulties, renal insufficiency and bleeding.

“What’s been a worry in the field over the last couple years is cerebral edema, which has been fatal in some patients,” Grupp said. “But, we have not seen that in ALL.”

Tocilizumab (Actemra, Genentech) — FDA approved for CRS based on a retrospective analysis of pooled outcome data — is frequently used but has no ICD-10 code for CRS, Farnia said.

“When entirely new services are created, codes often need to be created along with them,” Farnia said. “There is not a diagnosis code for CRS, only diagnosis codes for its underlying pieces. These nuances make it an interesting puzzle.”

The timeline for establishing new codes differs by type, but could be 1 to 2 years for a CRS diagnosis code, according to Farnia.

“In the meantime, there will be a hodgepodge of codes coming through the system,” she said.

Even with tocilizumab, almost all recipients with more than 40% of blast disease in their bone marrow will spend at least a week in intensive care, Grupp said.

That has raised debate over whether CAR T-cell therapy should be bundled as an inpatient procedure instead of its current outpatient indication.

“Those who receive the Novartis product very often are back in the hospital that day because of CRS risk,” Silver said. “The sicker patients with lymphoma and pediatric ALL are already in the hospital anyway, and infusion happens as an extension of their previous hospital admission.

“Having the appropriate facilities for outpatient therapy and getting patients into the hospital quickly is a huge investment by institutions” he added. “Do we have enough ICU beds to take care of these patients? That’s another question hospitals are asking.”

Following an outpatient CAR T-cell infusion, Memorial Sloan Kettering requires patients stay with a caregiver within a short drive of the hospital for 30 days. Patients are seen daily for 14 days at 20 patient residences within three blocks of the center, followed by three times a week for 2 weeks.

“We want to be overcautious so that everything is in place,” Giralt said. “We’re being overzealous. After day 30, we need to make sure our handoff to the referring physician is excellent. Up to now, we’re not seeing late side effects, but we need to monitor disease and make sure we are advised if there are late side effects.”

Giralt estimates most CAR T-cell recipients will average 14 days in the hospital following infusion.

“If that’s the case, I need four new beds for that many days in a hospital that is 100% at capacity,” he said.

Building a garage for CAR T

For a medical center to receive Novartis or Gilead accreditation, it must first be accredited by the Foundation for the Accreditation of Cellular Therapy, perform allogeneic HSCT, and have experience with T-cell therapies and leukemia. Only centers trained and certified by Novartis and Gilead are permitted to collect cells for manufacturing.

“Comprehensive training for treatment centers covers the standards for collection, cryopreservation and transport of cells, as well as the prescribing information and patient and safety management for the respective clinical teams,” Touchon said. “There also are dedicated account managers, field-based medical directors and field medical liaisons who provide ongoing support and education.”

Before opening its center in January, Memorial Sloan Kettering conducted clinical trials on both approved CAR T-cell products. In preparation for those trials, Novartis and Gilead provided educational seminars for physicians and nurses in the bone marrow transplant center, as well as for ED and outpatient clinic personnel.

Once Memorial Sloan Kettering received Novartis and Gilead accreditation, Giralt said it took 1 year and more than 400 hours of strategic planning to “build the garage” for CAR T-cell therapy.

“There’s a dramatic difference between developing an investigational product and bringing that product to commercial use where the volume of patients is significantly higher,” Giralt said.

Giralt estimated his unit will infuse 150 patients with CAR T cells this year.

The first aspect of training centered around the wording and presentation of information sheets for potential patients and referring physicians.

“Once a product becomes commercially available, the public believes they only have to get their insurance company to pay for it,” Giralt said. “They expect to get that product and it’s our obligation to be able to message appropriately who is and is not eligible.”

Memorial Sloan Kettering spent a significant amount of time creating scripts and workflows so when patients called requesting the therapy, those calls escalated immediately to the nurse coordinator, who worked with triage services to ensure ineligible patients would be referred to other protocols.

According to Leukemia & Lymphoma Society, eligible patients must:

  • have tumors positive for the CAR target (eg, CD19);
  • have an adequate number of T cells for collection, and the threshold for absolute lymphocyte count varies by protocol;
  • have adequate performance status and organ function;
  • not have an active, uncontrolled infection, including hepatitis B, hepatitis C or HIV; and
  • not have relevant comorbidities, such as certain cardiovascular, neurologic or immune disorders.

Further, changes in a patient’s health status in the 2 weeks between T-cell collection and infusion could prevent them from completing therapy, Giralt said.

“We may collect your cells, but it doesn’t commit us to giving them to you,” he said. “If we no longer thing you’re a good candidate for the product, we will not give them to you. Safety prevails. Patients and their families need to understand that.”

Looking ahead

In January, the FDA granted priority review to tisagenlecleucel for adults with relapsed or refractory DLBCL who are ineligible for or relapse after autologous HSCT.

“We are hoping for approval of tisagenlecleucel for non-Hodgkin lymphoma within the next few months,” David L. Porter, MD, Jodi Fisher Horowitz professor of leukemia care excellence and director of blood and marrow transplantation at Perelman School of Medicine at University of Pennsylvania, told HemOnc Today. “I would really like to see eventual approval for adult ALL next. The large multicenter trials haven’t been done, but there are so much preliminary data that it’s hard to envision these therapies won’t be tested and approved.”

Following adult ALL, focus should be on CLL and myeloma, Porter said.

“To me, there is no difference between CLL and non-Hodgkin lymphoma,” he said. “It’s solely a matter of resources to do larger clinical trials and show efficacy. Those are the low-hanging fruit. This provides therapy for an incredible unmet need when there is nothing else.”

Novartis is continuing studies of tisagenlecleucel in DLBCL, ALL and relapsed or refractory follicular lymphoma. Other CAR T-cell therapies in Novartis’s pipeline include targeting CD19 in CLL, anti-B-cell maturation antigen (BCMA) CAR T for multiple myeloma, anti-EGFRvIII CAR T for recurrent glioblastoma, and CAR-T-Meso for advanced ovarian cancer and mesothelioma, according to Touchon.

According to Norbert W. Bischofberger, PhD, executive vice president of research and development and chief scientific officer at Gilead, data from the randomized phase 3 ZUMA-7 study comparing axicabtagene ciloleucel to the standard-of-care second-line DLBCL treatment are expected in 2020.

Also, ZUMA-6 is a phase 1/phase 2 study of axicabtagene ciloleucel combined with anti-PD-L1 antibody atezolizumab (Tecentriq, Genentech) and KITE-585, a CAR T-cell therapy engineered to target BCMA in patients with relapsed or refractory multiple myeloma, is currently in phase 1 study.

“There are several areas where we want to try to figure out where we could be more effective,” Milligan said. “One is increasing the number of targets. We are looking at ways that we can perhaps move from autologous to allogeneic, or a ‘universal’ donor CAR T.”

Gilead is sponsoring additional clinical trials with axi-cel/KTE-C19 for indolent NHL, mantle cell lymphoma, and adult and pediatric ALL, according to Kaiser.

“In 2018, myeloma is going to be leading the way,” Giralt said. “There are going to be large national trials trying to position CAR T earlier in the course of disease, particularly CAR T vs. transplant. We believe CAR T actually would make a great consolidation therapy for transplants to reduce relapse. Whether companies are going to sponsor that space is uncertain.”

Ongoing research in manufactured regulatory T-cell “switches” might assist in controlling adverse events, according to Porter.

“There is a lot of research in generating either suicide switches or, even better, regulator switches that turn the T cells on and off, instead of killing them,” Porter said. “Instead of relying on drug therapy, we could rely on the biological ability to turn the T-cell up, and when people start getting sick, turn it down.

“It can be done in the laboratory relatively easily,” Porter added. “Whether it can be done in people remains to be seen.”

It may take years of research to determine if CAR T-cell therapy will make inroads in the treatment of solid tumors. Trials for ovarian cancer, mesothelioma, pancreatic cancer and glioblastoma should offer insight in the coming years.

“There first should be a fast track for research in those diseases,” Porter said. “There are still a lot of impediments that need to be overcome. I don’t see rapid approval for solid tumors, I see rapid research.” – by Chuck Gormley

Click here to read the POINTCOUNTER, “Should patients with ALL undergo HSCT after CAR T-cell therapy?”

References:

Maude SL, et al. N Engl J Med. 2018;doi:101056/NEJMoa1709866.

Neelapu SS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707447.

For more information:

Stephanie Farnia, MPH, can be reached at stephaniefarnia@asbmt.org.

Stephan A. Grupp, MD, PhD, can be reached at grupp@email.chop.edu.

Sergio A. Giralt, MD, can be reached at giralts@mskcc.org.

Nathan Kaiser can be reached at nathan.kaiser@gilead.com.

Anna Kaltenboeck can be reached at akaltenboeck@analysisgroup.com.

David L. Porter, MD, can be reached at david.porter@uphs.upenn.edu.

Samuel M. Silver, MD, PhD, MACP, can be reached at msilver@med.umich.edu.

Pascal Touchon can be reached at media.relations@novartis.com.

Disclosures: Grupp reports grant support and personal fees from Novartis; nonfinancial support from ArticulateScience, LLC. and personal fees from Jazz Pharmaceuticals and Adaptimmune. Porter reports intellectual property interests with Novartis. Farnia, Giralt, Kaltenboeck and Silver report no relevant financial disclosures.

Before the FDA approval of two chimeric antigen receptor T-cell therapies, children and young adults with B-cell acute lymphoblastic leukemia and adults with relapsed or refractory diffuse large B-cell lymphoma were considered incurable.

Chimeric antigen receptor (CAR) T-cell therapy has restored hope for those patients, but at a significant cost to the health care system.

The ELIANA trial showed 76% of children with B-cell ALL who received tisagenlecleucel suspension (Kymriah, Novartis) achieved 1-year OS. In ZUMA-1, 52% of adults with relapsed or refractory DLBCL who received axicabtagene ciloleucel (Yescarta; Kite, Gilead) achieved 18-month OS.

Those durable responses earned CAR T-cell therapy recognition as ASCO’s “Advance of the Year.”

“As a true believer, I absolutely think we’ve just gotten started,” Stephan A. Grupp, MD, PhD, chief of cellular therapy and transplant section and director of cancer immunotherapy at Children’s Hospital of Philadelphia, told HemOnc Today. “If we can see it work in acute myeloid leukemia or even solid tumors, then my optimism about this being paradigm shifting is warranted.”

However, at $475,000 for a single infusion of tisagenlecleucel and $373,000 for axicabtagene ciloleucel, billing and reimbursement impediments could limit recipients to select populations from small pockets of the United States.

“There are medical centers across the country who are not opening their CAR T programs until they get assurances that Medicare is going to pay,” Sergio A. Giralt, MD, chief of adult bone marrow transplant service and Melvin Berlin family chair in multiple myeloma at Memorial Sloan Kettering Cancer Center, and a HemOnc Today Editorial Board Member, said in an interview. “Memorial Sloan Kettering decided to take the risk, but we have been advised that if the financial risk becomes too great, the institution would need to reassess its commitment to the program. They cannot jeopardize the financial health of the rest of the institution for a product like this.”

Most CAR T-cell recipients will average an estimated 14 days in the hospital following infusion, according to Sergio A. Giralt, MD.
Most CAR T-cell recipients will average an estimated 14 days in the hospital following infusion, according to Sergio A. Giralt, MD. “If that’s the case, I need four new beds for that many days in a hospital that is 100% at capacity,” he said.

Source: © 2018 Juliana Thomas for Memorial Sloan Kettering Cancer Center.

HemOnc Today spoke with CAR T-cell program directors, hematologists, pharmaceutical representatives, and economic and regulatory experts about CAR T-cell therapy coding and reimbursement issues; criteria for hospital accreditation; challenges associated with toxicities; and future indications likely to gain FDA approval.

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‘A very difficult issue’

Medical centers have been slow to offer the groundbreaking therapy.

“You’re dealing with the most desperate situation — a child with relapsed/refractory ALL — and only 50% of states have a CAR T-cell therapy unit,” Samuel M. Silver, MD, PhD, MACP, assistant dean for research and professor of internal medicine at University of Michigan Medical School, as well as a HemOnc Today Editorial Board Member, said in an interview. “Multiple hospitals that don’t have units are starting to see children who have no options. It’s really become a very difficult issue.”

At the time of reporting, 33 centers had received risk evaluation and mitigation strategy certification by Novartis for the delivery of tisagenlecleucel, and 26 facilities were fully operational. Kite, a Gilead subsidiary, had approved 28 centers to deliver axicabtagene ciloleucel.

According to John F. Milligan, PhD, president, CEO and director of Gilead Sciences, Inc., the pharmaceutical company is actively working on training and certifying additional centers. He anticipated that, by the middle of this year, there would be enough centers certified to treat 80% of the estimated 7,500 patients eligible for T-cell infusion in the United States.

“If you go to a lot of the big centers, there are a lot of people who may be eligible for Yescarta but are in areas of the country where it’s impractical or unlikely a center would be set up, and so they would have to travel,” Milligan said during a conference call.

Gilead’s manufacturing facility has the capacity to produce about 4,000 treatments per year at full operation, according to spokesman Nathan Kaiser.

Novartis reported that around 600 patients will be eligible each year for tisagenlecleucel. Pascal Touchon, senior vice president and global head of oncology strategy and business development at Novartis, declined to disclose the manufacturing capacity of tisagenlecleucel but stated “Novartis has made significant investments and continues to invest in support of the anticipated demand to meet the needs of patients.”

Financial toxicities

Pricing and pathways for reimbursement have posed challenges to many medical centers and insurers.

Touchon told HemOnc Today that Novartis set the price for tisagenlecleucel at $475,000 based on its scientific innovation, as well as its medical, patient and societal value and overall impact to the health care system.

Quantitative assessments indicated a cost-effective price of $600,000 to $750,000, Touchon said, which is in line with the expected total cost associated with allogeneic hematopoietic stem cell transplant, which can range between $500,000 and $800,000 in the first year.

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“Long-term costs associated with Kymriah’s one-time treatment are expected to be minimal,” Touchon stated, adding that a first-generation CAR T-cell therapy requires significant investments that translate into “unprecedented” costs per patient covered by the manufacturer during the clinical trial process.

Novartis also is implementing an outcomes-based approach that will allow for payment only when pediatric and young adult patients with ALL respond after 1 month.

“In other words, there is no charge for patients treated at centers that have opted into the outcomes-based approach who don’t respond in this timeframe,” Touchon said. “We are working through the specific details with stakeholders to put this new pricing model in place.”

Kaiser noted that adults with relapsed or refractory DLBCL faced an unmet need before the approval of axicabtagene ciloleucel and that Gilead set its pricing based on clinical trials that showed a 70% response rate and nearly a 50% complete response rate.

“Yescarta provides a more than sevenfold improvement over the existing standard of care,” Kaiser said. “We conducted extensive market research with commercial and government payers, as well as targeted cancer centers, to arrive at its list price.”

These prices are based on the premise that the products are delivered as one-time infusions.

However, there is considerable debate in the field over whether patients who receive CAR T-cell therapy may later require HSCT or a second CAR T-cell infusion.

In pediatric and adolescent ALL, between 50% and 60% of CAR T-cell recipients remain in long-term remission after a single infusion “and that gets us to the provocative question of a cure,” Grupp said.

“However, if you believe you need coverage for 6 months — and I do — maybe one more dose at 3 months is appropriate,” Grupp added. “The reality is that when they make these T cells, 80% of the time they make a second bag, so you could do that second infusion for free.”

With increased competition, the pricing for CAR T-cell therapy is expected to decrease.

“How much and when, I don’t know,” Silver said, “but it will happen.”

In the meantime, medical centers and insurers remain unsure over reimbursement procedures, and that uncertainty has kept some centers from performing infusions.

“It’s taken centers a while to understand the math on the Medicare side,” Stephanie Farnia, MPH, director of health policy and strategic relations at American Society for Blood and Marrow Transplantation (ASBMT), said during a symposium sponsored by the Leukemia & Lymphoma Society. “They are potentially looking at substantial losses. It makes people nervous.

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“Some centers from the outset decided to establish CAR T programs and said they’d figure out the money later,” she added. “There is now heavy advocacy by the programs going back to CMS and saying this is not sustainable. Centers have shared that they are treating those patients who urgently need it right now, but they can’t guarantee that will continue unless the payment system is fixed.”

Medicare and Medicaid

CMS relies on a fixed coding system to calculate payment. According to ASBMT, about 55% of CAR T-cell therapy for pediatric ALL is paid for by commercial insurance companies, usually a parent’s employer insurance. Medicaid pays for about 40%, and Medicare or other pays for 5%.

In adult DLBCL, 50% of CAR T-cell therapy is covered by Medicare, 40% by commercial/employer insurance, 8% by Medicaid and 2% by other.

“Providers are actually the first payers because they take that upfront cost of purchasing the product at its price point, bringing it inhouse to give to patients and then seek reimbursement later,” Farnia said. “The risk shifts to them.”

FDA approval does not automatically take a product out of the experimental investigational category. An increasing number of plans will only pay for drugs or procedures if they are outlined in certain care pathways, Farnia said.

Oct. 20 marked the deadline to submit an application for fiscal year 2019 for new technology add-on payments, which means reimbursement coding for the approved CAR T-cell products will not be available until at least 2019.

“For the Medicare beneficiary, that winds up being a huge issue for payment,” Silver said.

Samuel M. Silver, MD, PhD, MACP
Samuel M. Silver

In the absence of a formatted billing formula, Farnia said hospitals create purchase orders for CAR T-cell therapy after a patient’s T cells have been extracted and sent to the manufacturer, but before those cells are manufactured and returned for infusion.

“The hospital is really committing at that point to pay for the product, even though it has not received the dollars back from the payer yet,” Farnia said.

Billing and coding

Once a CAR T-cell infusion is completed, the hospital billing team collects medical notations, translates them into codes and files a claim. The payer then takes a “hard look at every item” on that claim, checks to make sure all criteria are met, and makes a payment decision, Farnia said.

Complicating those payment decisions is the absence of comprehensive coding for therapy delivery, which carries a dramatically higher profit margin for providers if administered as an outpatient procedure.

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“The manufacturers have a monopoly on pricing power and how a company is reimbursed plays into the pricing decision as much as the product’s value,” Anna Kaltenboeck, program director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering, told HemOnc Today. “If your expectation is that it will be an outpatient drug, it is priced so that the provider administering it will get a markup of 6% from CMS on top of the cost of the drug.

“From that perspective, it’s attractive financially to the provider,” Kaltenboeck added. “Still, if you look at the inpatient reimbursement procedures in place, we often see diagnosis-related groups using bundled payments, where payment encompasses all treatment at a flat rate, in which case the pressure is on the provider to push down on the cost of therapy.”

The cost of CAR T cells could decrease if they are used as inpatient bundled payments more often, Kaltenboeck said.

“If it remains where the system makes money off the higher prices, it’s less likely,” she said.

If a recipient is hospitalized within 72 hours of infusion, the procedure is considered inpatient and payment is bundled, Silver said. Hospitals designate unusually expensive therapies as outlier cases, increasing the inpatient prospective payment system to protect the hospital from large financial losses.

“For Medicare, currently the only way to mitigate losses is by the use of outlier payment,” Silver said. “Essentially, you would have to mark up the drug 400% — from roughly $400,000 to $1.6 million — to have an outlier payment system that ensures you don’t lose too much money. That’s under the assumption these patients are not going to go to the ICU or have major toxicities, which can be up to 50% of patients.”

Some private insurance companies have agreed to the bundled payment methodology, in which acquisition costs are bundled into a hospital stay on a cost-plus basis.

“But you can’t charge Medicare 400% markup and then charge Blue Cross Blue Shield 108% as a line item,” Silver said. “A hospital can assume it will get reimbursed from an insurer’s acquisition costs plus 8% as part of a bundle, and that will make them whole.”

Touchon stated that hospitals independently seek reimbursement for products, services and procedures related to patient care and Novartis has made “significant progress” involving reimbursement with commercial insurers and Medicaid, noting CMS approved a Q-code for tisagenlecleucel on Jan. 1.

“In addition, Kymriah will be provided free of charge for eligible uninsured or underinsured patients,” Touchon said.

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Addressing neurologic toxicities

Updated results from ELIANA showed 77% of patients experienced cytokine release syndrome (CRS), 21% of which was grade 3 and 25% grade 4. In ZUMA-1, 43% of patients experienced grade 3 or higher CRS (12%) or other neurologic toxicities (31%).

“Anything that we could use to try to lessen the side effects of CAR T would be important to us,” Milligan said. “We’re actively looking at technologies to lower CRS and perhaps neurotoxicity.”

Neurologists at Memorial Sloan Kettering provided Montreal Cognitive Assessment training to HSCT providers so that they could identify early signs of neurocognitive dysfunction and successfully complete a certification exam from Novartis and Gilead.

“They all had to know that a fever in a patient who had outpatient CAR T therapy required antibiotics within 35 minutes,” Giralt said.

CRS typically occurs within 3 to 4 days after infusion and is manifested as a fever in the 104-degree range. Patients can also develop low blood pressure, breathing difficulties, renal insufficiency and bleeding.

“What’s been a worry in the field over the last couple years is cerebral edema, which has been fatal in some patients,” Grupp said. “But, we have not seen that in ALL.”

Tocilizumab (Actemra, Genentech) — FDA approved for CRS based on a retrospective analysis of pooled outcome data — is frequently used but has no ICD-10 code for CRS, Farnia said.

“When entirely new services are created, codes often need to be created along with them,” Farnia said. “There is not a diagnosis code for CRS, only diagnosis codes for its underlying pieces. These nuances make it an interesting puzzle.”

The timeline for establishing new codes differs by type, but could be 1 to 2 years for a CRS diagnosis code, according to Farnia.

“In the meantime, there will be a hodgepodge of codes coming through the system,” she said.

Even with tocilizumab, almost all recipients with more than 40% of blast disease in their bone marrow will spend at least a week in intensive care, Grupp said.

That has raised debate over whether CAR T-cell therapy should be bundled as an inpatient procedure instead of its current outpatient indication.

“Those who receive the Novartis product very often are back in the hospital that day because of CRS risk,” Silver said. “The sicker patients with lymphoma and pediatric ALL are already in the hospital anyway, and infusion happens as an extension of their previous hospital admission.

“Having the appropriate facilities for outpatient therapy and getting patients into the hospital quickly is a huge investment by institutions” he added. “Do we have enough ICU beds to take care of these patients? That’s another question hospitals are asking.”

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Following an outpatient CAR T-cell infusion, Memorial Sloan Kettering requires patients stay with a caregiver within a short drive of the hospital for 30 days. Patients are seen daily for 14 days at 20 patient residences within three blocks of the center, followed by three times a week for 2 weeks.

“We want to be overcautious so that everything is in place,” Giralt said. “We’re being overzealous. After day 30, we need to make sure our handoff to the referring physician is excellent. Up to now, we’re not seeing late side effects, but we need to monitor disease and make sure we are advised if there are late side effects.”

Giralt estimates most CAR T-cell recipients will average 14 days in the hospital following infusion.

“If that’s the case, I need four new beds for that many days in a hospital that is 100% at capacity,” he said.

Building a garage for CAR T

For a medical center to receive Novartis or Gilead accreditation, it must first be accredited by the Foundation for the Accreditation of Cellular Therapy, perform allogeneic HSCT, and have experience with T-cell therapies and leukemia. Only centers trained and certified by Novartis and Gilead are permitted to collect cells for manufacturing.

“Comprehensive training for treatment centers covers the standards for collection, cryopreservation and transport of cells, as well as the prescribing information and patient and safety management for the respective clinical teams,” Touchon said. “There also are dedicated account managers, field-based medical directors and field medical liaisons who provide ongoing support and education.”

Before opening its center in January, Memorial Sloan Kettering conducted clinical trials on both approved CAR T-cell products. In preparation for those trials, Novartis and Gilead provided educational seminars for physicians and nurses in the bone marrow transplant center, as well as for ED and outpatient clinic personnel.

Once Memorial Sloan Kettering received Novartis and Gilead accreditation, Giralt said it took 1 year and more than 400 hours of strategic planning to “build the garage” for CAR T-cell therapy.

“There’s a dramatic difference between developing an investigational product and bringing that product to commercial use where the volume of patients is significantly higher,” Giralt said.

Giralt estimated his unit will infuse 150 patients with CAR T cells this year.

The first aspect of training centered around the wording and presentation of information sheets for potential patients and referring physicians.

“Once a product becomes commercially available, the public believes they only have to get their insurance company to pay for it,” Giralt said. “They expect to get that product and it’s our obligation to be able to message appropriately who is and is not eligible.”

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Memorial Sloan Kettering spent a significant amount of time creating scripts and workflows so when patients called requesting the therapy, those calls escalated immediately to the nurse coordinator, who worked with triage services to ensure ineligible patients would be referred to other protocols.

According to Leukemia & Lymphoma Society, eligible patients must:

  • have tumors positive for the CAR target (eg, CD19);
  • have an adequate number of T cells for collection, and the threshold for absolute lymphocyte count varies by protocol;
  • have adequate performance status and organ function;
  • not have an active, uncontrolled infection, including hepatitis B, hepatitis C or HIV; and
  • not have relevant comorbidities, such as certain cardiovascular, neurologic or immune disorders.

Further, changes in a patient’s health status in the 2 weeks between T-cell collection and infusion could prevent them from completing therapy, Giralt said.

“We may collect your cells, but it doesn’t commit us to giving them to you,” he said. “If we no longer thing you’re a good candidate for the product, we will not give them to you. Safety prevails. Patients and their families need to understand that.”

Looking ahead

In January, the FDA granted priority review to tisagenlecleucel for adults with relapsed or refractory DLBCL who are ineligible for or relapse after autologous HSCT.

“We are hoping for approval of tisagenlecleucel for non-Hodgkin lymphoma within the next few months,” David L. Porter, MD, Jodi Fisher Horowitz professor of leukemia care excellence and director of blood and marrow transplantation at Perelman School of Medicine at University of Pennsylvania, told HemOnc Today. “I would really like to see eventual approval for adult ALL next. The large multicenter trials haven’t been done, but there are so much preliminary data that it’s hard to envision these therapies won’t be tested and approved.”

Following adult ALL, focus should be on CLL and myeloma, Porter said.

“To me, there is no difference between CLL and non-Hodgkin lymphoma,” he said. “It’s solely a matter of resources to do larger clinical trials and show efficacy. Those are the low-hanging fruit. This provides therapy for an incredible unmet need when there is nothing else.”

Novartis is continuing studies of tisagenlecleucel in DLBCL, ALL and relapsed or refractory follicular lymphoma. Other CAR T-cell therapies in Novartis’s pipeline include targeting CD19 in CLL, anti-B-cell maturation antigen (BCMA) CAR T for multiple myeloma, anti-EGFRvIII CAR T for recurrent glioblastoma, and CAR-T-Meso for advanced ovarian cancer and mesothelioma, according to Touchon.

According to Norbert W. Bischofberger, PhD, executive vice president of research and development and chief scientific officer at Gilead, data from the randomized phase 3 ZUMA-7 study comparing axicabtagene ciloleucel to the standard-of-care second-line DLBCL treatment are expected in 2020.

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Also, ZUMA-6 is a phase 1/phase 2 study of axicabtagene ciloleucel combined with anti-PD-L1 antibody atezolizumab (Tecentriq, Genentech) and KITE-585, a CAR T-cell therapy engineered to target BCMA in patients with relapsed or refractory multiple myeloma, is currently in phase 1 study.

“There are several areas where we want to try to figure out where we could be more effective,” Milligan said. “One is increasing the number of targets. We are looking at ways that we can perhaps move from autologous to allogeneic, or a ‘universal’ donor CAR T.”

Gilead is sponsoring additional clinical trials with axi-cel/KTE-C19 for indolent NHL, mantle cell lymphoma, and adult and pediatric ALL, according to Kaiser.

“In 2018, myeloma is going to be leading the way,” Giralt said. “There are going to be large national trials trying to position CAR T earlier in the course of disease, particularly CAR T vs. transplant. We believe CAR T actually would make a great consolidation therapy for transplants to reduce relapse. Whether companies are going to sponsor that space is uncertain.”

Ongoing research in manufactured regulatory T-cell “switches” might assist in controlling adverse events, according to Porter.

“There is a lot of research in generating either suicide switches or, even better, regulator switches that turn the T cells on and off, instead of killing them,” Porter said. “Instead of relying on drug therapy, we could rely on the biological ability to turn the T-cell up, and when people start getting sick, turn it down.

“It can be done in the laboratory relatively easily,” Porter added. “Whether it can be done in people remains to be seen.”

It may take years of research to determine if CAR T-cell therapy will make inroads in the treatment of solid tumors. Trials for ovarian cancer, mesothelioma, pancreatic cancer and glioblastoma should offer insight in the coming years.

“There first should be a fast track for research in those diseases,” Porter said. “There are still a lot of impediments that need to be overcome. I don’t see rapid approval for solid tumors, I see rapid research.” – by Chuck Gormley

Click here to read the POINTCOUNTER, “Should patients with ALL undergo HSCT after CAR T-cell therapy?”

References:

Maude SL, et al. N Engl J Med. 2018;doi:101056/NEJMoa1709866.

Neelapu SS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707447.

For more information:

Stephanie Farnia, MPH, can be reached at stephaniefarnia@asbmt.org.

Stephan A. Grupp, MD, PhD, can be reached at grupp@email.chop.edu.

Sergio A. Giralt, MD, can be reached at giralts@mskcc.org.

Nathan Kaiser can be reached at nathan.kaiser@gilead.com.

Anna Kaltenboeck can be reached at akaltenboeck@analysisgroup.com.

David L. Porter, MD, can be reached at david.porter@uphs.upenn.edu.

Samuel M. Silver, MD, PhD, MACP, can be reached at msilver@med.umich.edu.

Pascal Touchon can be reached at media.relations@novartis.com.

Disclosures: Grupp reports grant support and personal fees from Novartis; nonfinancial support from ArticulateScience, LLC. and personal fees from Jazz Pharmaceuticals and Adaptimmune. Porter reports intellectual property interests with Novartis. Farnia, Giralt, Kaltenboeck and Silver report no relevant financial disclosures.