Allogeneic Hematopoietic Stem Cell Transplantation Following CAR T Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Rafaeli Natalie , Marin David , Ledesma Celina , Jain Nitin , Tewari Priti , Khouri Issa F. , Olson Amanda L. , Alatrash Gheath , Short Nicholas J. , Jabbour Elias , Rezvani Katy , Alousi Amin M. , Popat Uday , Champlin Richard E. , Shpall Elizabeth J. , Kebriaei Partow 
Published: December 2024

In patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), CAR-T cells have shown very high complete remission (CR) rates with two therapies approved in this setting, tisagenlecleucel and brexucabtagene autoleucel with overall response rates of 81% and 71%, respectively (1,2). Despite being a highly efficacious therapy, relapse is still an issue among a subset of patients (3). Park, et al. evaluated 17 among 53 patients who received consolidative HSCT with no significant difference in event free survival (EFS) or OS compared to the non-transplanted group (3). Other retrospective studies have evaluated the effect of consolidative HSCT following CAR T therapy; however, most of these studies have smaller patient sizes and discordant findings (1,4-10). Due to conflicting findings, the role of transplant in this setting remains unclear.
A total of 30 patients with R/R ALL with prior CAR T therapy followed by HSCT at MDACC from January 2014 through December 2023 were identified. Patients who had received prior HSCT or previous CAR-T therapies were included. HSCT consolidation was defined as no relapse or intervening therapy between CAR-T and transplant therapy.
The median age was 24 years, nine pts (30%) were BCR::ABL1-like (Ph like) and 13 (43.4%) pts had additional high-risk features. MRD by multiparameter flow cytometry, or PCR in Ph positive patients, was detected in 9 patients (30%) prior to HSCT. The patients were a heavily pretreated population with 9 (30%) patients with a prior HSCT and the median number of prior lines of therapy being 4; 17 patients (57%) were in CR 3 or more advanced remission at time of HSCT. Fifteen patients (50%) received HSCT as consolidation following CAR-T therapy. The median time between CAR-T therapy to HSCT was 5.5 months for all patients, and 3.4 months in the consolidative transplant group.
The 12-month OS, PFS and TRM rates for the entire cohort was 51.1%, 35.0% and 29.3%, respectively. Using multivariate analysis, a significant difference in OS was found for patients who were in CR ≤2 as opposed to ≥3 (HR-4.787, CI 1.159-19.775, p=0.031) at time of transplant, in patients who had received fewer lines of chemotherapy (≤3 vs. ≥4) (HR-7.021, CI 1.720-28.659, p=0.007) and in the older patient population (age ≥25 vs. &lt;25) (HR-0.123, CI-0.028-0.538, p=0.005). Using univariate analysis, patients who had received ≥4 lines of chemotherapy had significantly worse OS and PFS (12-month OS 70.1 vs. 35.2, p=0.02; 12-month PFS 48.2 vs. 23.4, p=0.041). There was a difference in 12-month OS, PFS and TRM rates in patients in CR≤2 compared to ≥3 (741. Vs. 33.6, p=0.024; 59.3 vs. 17.6, p=0.011, 100 vs. 52.5, p=0.004). There was no difference found in OS in patients who were MRD positive, although there was a worse 12-month PFS and 12-month relapse (42.5 vs. 0, p=0.024; 37.6 vs. 100, p=0.003). HSCT as use of consolidation showed a trend in 12-month OS (33.3 vs. 72 mos., p=0.055). A shorter duration between CAR-T to HSCT compared by &lt;4 months or ≥4 months showed a trend towards significance in 12-month OS (77.1 vs. 40 mos., p=0.071).
There was a significant increase in OS in patients who were in an earlier remission status (CR≤2), patients who had received fewer lines of treatment (≤3) and patients who were older (ages &gt;25). Increased TRM is likely due to being a very heavily treated pediatric population. The use of HSCT as consolidation had a trend towards significance in OS as did shorter duration (&lt;4 months) between the CAR T and HSCT. Although the PFS and relapse rates were improved with MRD negativity prior to HSCT, likely due to the small patient cohort, no significant improvement in OS was found. For the patients who received HSCT as consolidation vs. those who did not, the TRM was 21% vs. 39.8%, respectively, p=0.355. The relapse rate was 44.1% vs. 53.6%, respectively, p=0.517.
Our data shows that CAR T therapy with HSCT used earlier in the patient's treatment course is associated with improved survival, with trend for improved survival in patients who received consolidative HSCT following CAR T and a trend towards decreased TRM and lower relapse rates with consolidative HSCT. Standard approach regarding sequencing of therapies still remains with a critical knowledge gap. Further larger trials are needed to determine if consolidation with transplant can ultimately cure patients who remain MRD positive after CAR T therapy, and to identify patient subsets who may benefit from HSCT following CAR T therapy.