Out-of-spec CAR-T appears safe, effective for younger patients with ALL
Click Here to Manage Email Alerts
B-cell acute lymphoblastic leukemia is the most common type of cancer among children.
It also is a contemporary treatment success story, with American Cancer Society data showing a 5-year survival rate of 90%.
Although B-cell ALL is highly curable, a sizable percentage of younger patients do not respond to standard therapies. Outcomes in this group had been unfavorable prior to the development of tisagenlecleucel (Kymriah, Novartis), the first commercially available chimeric antigen receptor T-cell therapy.
Most patients who begin the CAR-T process eventually receive the therapy. However, the complexity of manufacturing coupled with the use of a patient’s own often heavily pretreated cells means a small proportion of final CAR-T products will be unable to meet the FDA’s cell viability specifications for commercial use, according to Jenna Rossoff, MD, instructor of pediatrics in the division of hematology, oncology and stem cell transplantation at Northwestern University Feinberg School of Medicine and attending physician at Ann & Robert H. Lurie Children's Hospital of Chicago.
“It’s not the majority of the patients, but certainly it’s not an infrequent problem,” Rossoff told Healio.
When CAR-T does not meet the FDA’s manufacturing specifications, clinicians must consider whether a patient has time for a second round of apheresis — the method of T-cell collection by which the therapy is produced.
Otherwise, prescribing physicians and their patients can apply to the FDA for a single-use investigational new drug application or request that the manufacturer release the out-of-spec product via its managed access program (MAP).
Rossoff coauthored a research letter in Blood with colleagues from the Pediatric Real World CAR Consortium, which includes 15 member institutions that perform CAR-T for pediatric patients and collects granular data on patients and outcomes.
Despite the increased commercial use of tisagenlecleucel for younger patients with B-cell ALL, many questions remain regarding its clinical use, Rossoff said. Among them: What should physicians consider when a patient’s final CAR-T product does not meet commercial specifications?
“What do you do for a patient whose only option for a cure is tisagenlecleucel but for whom their manufactured product is not to spec?” Rossoff said.
The situation often leaves physicians unsure whether they should still administer CAR-T or consider another — likely ineffective — treatment option, she added.
“This is definitely something that clinicians should be aware of for kids who are not able to undergo a second apheresis, because it’s hard to know what to do in this situation,” Rossoff said. “We wanted to see if out-of-spec CAR-T is safe to give, whether these patients have more toxicities, and if the efficacy is similar.”
Overlapping outcomes
Rossoff and colleagues used the Pediatric Real World CAR Consortium database to conduct a retrospective study of younger patients with relapsed or refractory B-cell ALL who underwent apheresis for commercial tisagenlecleucel at one of its member institutions.
Researchers aimed to compare the safety and efficacy of out-of-spec CAR-T given to patients via a single-use IND or MAP with standard-of-care products that meet commercial use specifications.
Complete response rate at day 28 after CAR-T infusion served as the study’s primary outcome measurement. OS and EFS at 6 months and 12 months after infusion served as secondary outcomes. Investigators also evaluated safety, including rates of cytokine release syndrome, neurotoxicity and infections.
The FDA requires cell viability of 80% or greater to meet its specifications for use of commercial CAR-T products, whereas the pivotal ELIANA clinical trial that led to FDA approval of tisagenlecleucel required a cell viability of at least 70%.
All 24 patients (mean age, 6 years; range, 0-22; 66.7% male; 41.7% non-Hispanic white) who received out-of-spec CAR-T in Rossoff and colleagues’ analysis had a cell viability of at least 70%.
Researchers reported no statistically significant differences in efficacy or safety outcomes between patients who received standard or out-of-spec tisagenlecleucel.
Results showed a complete response rate of 85% among those who received standard tisagenlecleucel vs. 83% among those who received out-of-spec CAR-T.
The data for out-of-spec CAR-T compared favorably to the 81% 3-month complete response rate observed in the ELIANA trial.
Safety measures trended more favorably toward those who received out-of-spec CAR-T, but investigators reported no statistically significant differences between groups for any outcomes evaluated.
“We wanted to provide more data to support physicians giving these out-of-spec products in the setting where a patient cannot undergo a second apheresis and they really don't have any other decent treatment options,” Rossoff told Healio. “The outcomes — both in terms of safety and efficacy — were fairly overlapping.”
Despite the small number of patients in the study, Rossoff said her group hoped to demonstrate noninferiority of out-of-spec CAR-T, “considering this is a product that has had such superb outcomes in an extremely refractory and heavily pretreated population.”
Clinical implications
The findings support earlier research that suggested noninferiority of out-of-spec CAR-T that met the 70% or greater viability standard used in the ELIANA trial.
Marcelo C. Pasquini, MD, and colleagues performed a real-world analysis of treatment outcomes among 33 patients who received out-of-spec CAR-T outside of clinical trials.
The results, published in Blood Advances, showed a higher initial complete response rate for patients who received products with less than 80% viability than those who received tisagenlecleucel with 80% or greater cell viability (94% vs. 84%).
The 80% cell viability threshold appears to be a bit conservative given available data on the use of out-of-spec CAR-T, according to Hiroto Inaba, MD, PhD, member in the oncology department at St. Jude Children’s Research Hospital and vice chair of the National Comprehensive Cancer Network Guidelines for Pediatric Acute Lymphoblastic Leukemia Panel.
This standard likely was set higher than that used in the academic clinical trial setting because of the novelty of CAR-T at the time of initial approval, Inaba said.
Rossoff and colleagues' analysis suggests 70% cell viability would be sufficient, Inaba said.
“The survival curves [between out-of-spec and standard groups] mostly overlap,” he said. “But, as always, these results need further confirmation, with higher patient numbers.”
Inaba said he would be comfortable using these products given the absence of safety concerns. He said he would be “especially comfortable” providing out-of-spec CAR-T to a patient if it is within the 70% to 80% cell viability range given current available data.
He agreed with Rossoff that out-of-spec CAR-T is not an issue for most patients, but that it still occurs in approximately 5% to 10% of cases of younger patients with heavily pretreated B-cell ALL.
“These are the patients who really need CAR T cells for a cure,” Inaba told Healio. “It’s very important when treating patients in this situation to know that the product you may use is still equivalent to those with greater than 80% cell viability.”
Physicians who face this decision should explain to patients that — even in the absence of extensive research — cell viability less than 80% can still provide benefits and may be their only option for a possible cure, Inaba said.
With further study planned, Rossoff said she hopes her group’s initial analysis will provide physicians who recommend CAR-T with enough evidence to feel confident about their decision to use products for younger patients that are sufficiently safe and effective but fall short of the FDA’s standards.
“I'm hoping that it will make clinicians who feel like they're in a bind more comfortable with giving an out-of-spec product,” she told Healio. “In the situation where a patient has almost no other curative options and an out-of-spec product — especially if it's not severely out of the acceptable range — I would hope physicians would feel secure in still infusing that product so their patient can hopefully gain benefit, especially because many of these patients don't have other options.”
References:
American Cancer Society. Childhood leukemia early detection, diagnosis, and types. www.cancer.org/content/dam/CRC/PDF/Public/8695.00.pdf. Revised Feb. 12, 2019. Accessed Jan. 24, 2022.
Maude SL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709866.
National Comprehensive Cancer Network. NCCN guidelines for pediatric acute lymphoblastic leukemia. www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Revised Oct. 1, 2021. Accessed Jan. 28, 2022.
Pasquini MC, et al. Blood Adv. 2020;doi:10.1182/bloodadvances.2020003092.
Rossoff J, et al. Blood. 2021;doi:10.1182/blood.2021012392.
For more information:
Hiroto Inaba, MD, PhD, can be reached at St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678; email: hiroto.inaba@stjude.org.
Jenna Rossoff, MD, can be reached at Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Ave., Chicago, IL 60611; email: jrossoff@luriechildrens.org.
Collapse
Click Here to Manage Email Alerts