Remission by ’whatever means’: The role of CAR-T, HSCT for younger patients with ALL
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Clinicians who treat blood cancers often disagree whether chimeric antigen receptor T-cell therapies are a potential replacement for hematopoietic stem cell transplant.
Initial investigations into the use of CAR T cells led to divergent strategies. Some trials explored their use as a replacement for HSCT, whereas others evaluated them as a bridging strategy.
Regardless of approach, the objective is to get patients into “a clinical remission with whatever means” available, according to Daniel W. Lee, MD, director of pediatric stem cell transplant and immunotherapy in the department of pediatrics at University of Virginia Cancer Center and University of Virginia Children’s Hospital.
Despite outstanding initial responses observed with CD19 CAR T cells for younger patients with B-cell acute lymphoblastic leukemia, historical data show more than half of patients experience disease relapse within 4 to 5 years, Lee said. This prompted his group to explore whether HSCT after CAR T-cell therapy had a positive effect on treatment durability.
Although many clinicians — Lee included — view CAR T cells as a less toxic alternative to HSCT, the two therapies may prove more complementary. A study by Lee and colleagues, published in May in Journal of Clinical Oncology, suggested that CD19-directed CAR T-cell therapy before HSCT can lead to more durable remissions.
Lee said many clinicians who opt against HSCT after CD19 CAR T cells believe the CAR T cells will persist longer than conventional therapies, and that the additional cost and logistics of HSCT may be prohibitive for patients.
“Even [for] patients [in whom] CAR-T does persist for years, many of them will relapse with CD19-negative disease,” Lee told Healio. “If you don't consolidate them up front with a transplant — when you have the opportunity before they relapse — then you might have bought them only some time.”
Efficacy and safety
Lee and colleagues conducted a single-center, phase 1 dose-escalation study of an investigational CD19.28-zeta CAR T-cell therapy developed by the NCI. Additional patients from the dose-expansion portion study also were included in the analysis.
Patients received one of four lymphodepletion regimens, followed by CAR T cells at one of two dose levels. Median follow-up was 4.8 years.
The investigators reported outcomes of 50 younger patients (median age, 13.5 years; range, 4-30; 80% male) with relapsed or refractory B-cell ALL who received the investigational CD19 CAR T cells, some of whom underwent subsequent allogeneic HSCT.
Safety results showed 35 patients (70%) had cytokine release syndrome after CAR T-cell infusion, including nine patients (18%) who experienced grade 3 or 4 CRS.
Ten patients (20%) developed neurotoxicity, with four grade 3 cases.
Thirty-one patients (62%) achieved complete response to CAR T-cell therapy, with 28 patients (90%) achieving minimal residual disease (MRD)-negative status.
Twenty-one patients who achieved MRD-negative status after CAR T-cell therapy underwent subsequent allogeneic HSCT.
Median OS for patients who had HSCT after CAR T-cell therapy was 70.2 months (95% CI, 10.4-not estimable) compared with 10.5 months (95% CI, 6.3-29.2) for the entire study cohort.
Five-year EFS among patients who underwent allogeneic HSCT after CAR T-cell therapy was 61.9% (95% CI, 38.1-78.8) even when accounting for transplant-related mortality. In contrast, 100% of patients who responded to CAR-T but did not have a consolidative HSCT experienced disease relapse.
Overall, only 2 of 21 patients in the study who received CD19 CAR T cells followed by allogeneic HSCT experienced disease relapse.
The results show — at least for this CAR-T construct — younger patients who undergo allogeneic HSCT after complete response to CAR T-cell therapy can expect more durable remissions, Lee said.
“The patients who didn’t all relapsed and, frankly, they didn't live long,” he told Healio.
“If you compare those to historical controls, where a 2-year overall survival in that patient population should be less than 10%, about 70% of those patients who got into remission and had a subsequent transplant are still alive and disease free at an average follow-up of 5 years,” he added. “To me, this is the biggest take home point of [our] study.”
‘Superior outcomes’ for high-risk patients
Given the substantial increase in OS and EFS, the benefits of allogeneic HSCT after this CD19-directed CAR T-cell product are clear, according to Colleen Elizabeth Annesley, MD, attending physician at Seattle Children's Hospital and assistant professor in the department of pediatrics at University of Washington.
Annesley — who was not involved with the study — said these results should be read as specific to the CAR-T construct used in the study and may or may not be applicable to other CD19-directed CAR T cells, including commercially available products.
For example, the co-stimulatory domain used in the study CAR-T differs from that used in commercially available CAR-T products, which can affect the durability of response. There also are patient-specific considerations when determining whether someone should receive consolidative HSCT after CAR T-cell therapy, Annesley added.
“If someone had significant side effects with their first transplant, you might not recommend a second transplant,” she told Healio. “There may also be something intrinsic to their disease that would make you choose one way or the other.”
Ultimately, the way to determine the benefit of a consolidative HSCT after CD19 CAR T cells for B-cell ALL would be a randomized controlled trial, Annesley said.
“These are retrospective data, which always need to be interpreted with some caution,” she commented.
Despite the limitations, Annesley — a member of the National Comprehensive Cancer Network Pediatric Acute Lymphoblastic Leukemia Guidelines Panel — said the study by Lee and colleagues shows their CAR T-cell therapy is effective for getting patients into remission.
“And then patients who proceed to consolidated transplant in this study do quite well,” she told Healio. “So, in that sequence, this followed by transplant leads to superior outcomes for what would otherwise be a pretty high-risk population.”
Patients in this study clearly experienced better outcomes when receiving HSCT after achieving complete response with CAR T cells, Annesley said. Achieving a deep remission before HSCT is an important part of producing better outcomes, she added.
“It doesn't make sense for [patients] who do not achieve remission after CAR T cells to go on to consolidative transplant,” she said. “Patients have to respond — and respond well — to the CAR T-cell product first.”
Using allogeneic HSCT as consolidation therapy after CD19-directed CAR T cells is a promising strategy, but cost and availability will limit its use in the short term, Lee said.
“It's about access,” he said. “If they get access to CARS, then they should be able to move forward.
“It is important to plan with the referring clinician regarding the subsequent transplant and arrange for a donor before you infuse the CAR T cells,” Lee added. “If you do that, then you can give [patients] their best shot at responding and achieving good long-term outcomes as we demonstrated in our study.”
The optimal strategy would be differentiating upfront which patients are at higher risk for relapse after CD19 CAR T cells, Lee said. This way, higher-risk patients could go straight to consolidation therapy with HSCT and those at lower risk could avoid a potentially unnecessary procedure.
“But we’re not quite there yet,” Lee said.
References:
Lee DW, et al. Lancet. 2015;doi: 10.1016/S0140-6736(14)61403-3.
Shah NN, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02262.
For more information:
Colleen Elizabeth Annesley, MD, can be reached at Seattle Children’s Hospital, 4800 Sand Point Way NE, MB.8.501, Seattle, WA 98105; email: colleen.annesley@seattlechildrens.org.
Daniel W. Lee, MD, can be reached at University of Virginia Children’s Hospital, 1215 Lee St., Charlottesville, VA 22903; email: dwl4q@virginia.edu.
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