SAN DIEGO — The field of CAR-T therapy took major steps forward this week at the American Society of Hematology's annual conference — but one big question still looms.

Near the sunny shores outside the San Diego Convention Center, a new wave of the cellular therapies showed positive impacts on hard-to-treat cancers like multiple myeloma. Fresh data on two already marketed CAR-T products, Novartis' Kymriah and Gilead Sciences' Yescarta, proved responses to therapy could be fairly long-lasting.

Hovering over those clinical victories, however, was a problem: How exactly will health systems pay for these powerful yet ultra-expensive therapies? The list price on Kymriah, for instance, sits at $373,000 for its diffuse large B cell lymphoma indication and $475,000 for its acute lymphoblastic leukemia indication.

Like many issues in cancer, the answer to that question is complicated and, to a large extent, not fully realized.

"None of us imagined we'd be ... reading through 1,000-page-long CMS documents and rules and proposals, but that's what life has come to at times," Joseph Alvarnas, vice president of government affairs at City of Hope in California, said at panel on CAR-T therapies, referring to biggest U.S. payer, the federal Centers for Medicare and Medicaid Services.

Alvarnas contends medicine is evolving faster than traditional payment systems, which were built around chronic illnesses that require long-term treatment. As such, hospitals are facing extra logistics and cost burdens.

It's a trend top regulators have noticed as well: "If we don't adapt the approach to reimbursement soon, we may foreclose therapeutic opportunities," Food and Drug Administration Commissioner Scott Gottlieb said in October during a discussion on cutting-edge therapies like CAR-T at the Milken Institute's annual Future of Health Summit.

To Gottlieb's point, CMS is currently conducting a National Coverage Analysis for CAR-T therapies that should wrap up by May. Earlier this year, the agency agreed to reimburse hospitals about $400,000 for Yescarta and $500,000 for Kymriah through Medicare Part B, which covers outpatient medical needs for people 65 years and older or who meet other specific criteria.

Though that's a step in the right direction, hospitals continue to grapple with inpatient care.

Inpatients by definition are those who stay in a hospital more than 24 hours — or more technically, at least two midnights. Unlike with outpatients, payers typically reimburse inpatients based on the bundle of treatment they received. Recently approved CMS rulings that took effect on Oct. 1 allow for hospitals to get around $225,000 in CAR-T reimbursement, but that still leaves them with a financial loss of roughly $200,000 per inpatient given the available treatments.

"The ability to manage a patient who requires inpatient hospitalization at the time of application of the drug is daunting," said Richard Maziarz, professor of medicine at Oregon Health & Science University and lead investigator of an updated analysis of JULIET, a trial that tested Kymriah in adults with diffuse large B cell lymphoma.

"It is doable, but it certainly will be more feasible if you have an agent that can be used effectively in the outpatient setting where you can be assured reimbursement," he added.

Medicare isn't the only headache either.

"Every single state has multiple Medicaid authorities, and you're dealing with every single one and you're inventing the wheel every time," said Stephan Grupp, lead investigator of ELIANA, a trial that tested Kymriah in children and young adults with lymphoblastic leukemia​.

Grupp, who also serves as director of the Cancer Immunotherapy Program​ at the Children's Hospital of Philadelphia, said that even with those challenges, coverage — either through Medicaid or commercial insurance — hasn't been a huge issue thus far at CHOP, where 30-some patients have received Kymriah since the therapy gained approval in Aug. 2017.

"We're getting paid for the product, regardless of the insurance," he said. "I think our hospital has not been presented with a choice of subsidizing the product, but I think they would be reluctant to do that. They would see that as a money-losing proposition. But it hasn't come up."

Maziarz has also found few commercial insurance barriers for adults needing CAR-T therapy.

Despite those successes, many view the reimbursement landscape as in need of additional overhaul.

ASH has expressed concerns the new CAR-T reimbursement rules from CMS don't do enough to cut costs for hospitals and academic medical centers, thereby putting patient access at risk.

Notably, the worries come at a time when hospitals are taking profit hits due to lower reimbursements. A report from Moody's determined not-for-profit and public hospitals operated at a net loss for a second straight year in fiscal year 2017. And a recent Morgan Stanley analysis of more than 6,000 U.S. hospital facilities found nearly 20% were at risk of closure or performing weakly, in part because of a lower operating efficiency index — a measure directly tied to government reimbursement.

As it relates to CAR-T, stakeholders see much work left to do.

"It's not a sustainable reimbursement system, and I think you'll find many of us ... have been trying to work with CMS to create a new language of reimbursement," Alvarnas​ said.

"The costs of the product acquisition coupled with the costs of care in managing toxicities like cytokine release or neurological toxicities are something that has not been seen before, and for CMS this is uncharted territory."