Survival Following Post–HCT Relapse in ALL Improves With Targeted Immunotherapies

Survival rates of adult patients with acute lymphoblastic leukemia (ALL) who experience relapse following hematopoietic cell transplantation (HCT) has considerably improved within the past few years, possibly due to the increased use of immunotherapy agents, according to data from a single-institution analysis presented during the 2020 ASH Annual Meeting and Exposition.¹

Results showed that survival had nearly doubled in patients who had relapsed following transplant between 2014-2019 versus those who relapsed between 2008-2013. The median overall survival (OS) for patients in the earlier cohort was 7.99 months versus 15.75 months those in the more recent cohort (P = 5e-04).

To understand these improvements, investigators examined therapies that were used to treat patients following relapse and found that the frequency of those who did not receive any therapy for relapse decreased in the more recent cohort compared with the earlier cohort, at 10% versus 18%, respectively. While the use of chemotherapy had also decreased, going from 70% to 38%, respectively, the use of novel therapies has increased exponentially, growing from 3% to 40%, respectively. The use of TKIs proved to be fairly consistent, being used in 8% of patients in both cohorts.

“We show that the OS of patients with ALL relapsing after transplant has significantly improved since 2014,” Juliana Craig, lead clinical research coordinator of Cell Therapy at Stanford University School of Medicine, said in a presentation of the data during the meeting. “This is likely influenced by the use of targeted immunotherapies to treat post-transplant relapse, which has also increased dramatically since 2014.”

Historically, adult patients with ALL who have relapsed following allogeneic HCT have experienced poor survival outcomes, as was demonstrated in the MRC UKALL12/ECOG 2993 study that reported a long-term survival rate of 9% in this patient population (2P = 1.0).²

The armamentarium of effective salvage approaches for patients with relapsed/refractory ALL has expanded with the availability of numerous targeted immunotherapy agents. For the analysis presented during the meeting, investigators set out to evaluate survival in adults with ALL who relapsed following HCT based on 2 time period cohorts: those who relapsed between 2008-2013 and those who relapsed between 2014-2019. The secondary goal of the analysis was to evaluate the salvage therapies used to treat patients following transplant relapse between the 2 cohorts. Investigators hypothesized that the expanded treatment arsenal equipped with several efficacious immunotherapy agents has led to superior survival in this population.

The retrospective analysis focused on adults who received their first allogenic HCT between 2008 and 2019 at Stanford University and subsequently relapsed. Patients were stratified based on the time period in which their relapse occurred. The Kaplan Meier method was utilized to determine OS, with log-rank tested significance between the time periods. The follow-up time for the earlier time period was shortened to 5.4 years in order to match the maximum follow-up time of the more recent time period.

A total of 285 adult patients with ALL who received transplants between 2008 and 2019 were included in the analysis. Among these patients, 119 transplants occurred during the earlier time period versus 166 transplants in the more recent time period. In total, 39 patients relapsed following HCT between 2008 and 2013 and 42 relapsed between 2014 and 2019. The median time to relapse was 7.72 months (95% CI, 3.88-14.0), with no significant differences noted between the 2 time periods.

Patients within the 2008-2013 cohort were primary male (62%) with a median age of 46 (range, 19-67). In this cohort, 36% of patients had Philadelphia (Ph; BCR/ABL-positive) chromosome–positive ALL, 8% had KMT2a/mixed-lineage leukemia (MLL) rearranged, 36% had normal disease, and 20% had other disease. At the time of transplant, 51% of these patients had a disease status CR1, 23% were CR2-positive, and 26% had active disease (P = .008). Also, within this cohort, 61% received donated cells from a matched sibling, 8% had a haploidentical donor, 18% had an unrelated donor (URD) 10/10, and 13% had an URD 9/10. No patients received donor cells from URD double cord.

In the 2014-2019 cohort, 52% of patients were male with a median age of 47 years (range, 19-70). Among these patients, 33% had Ph-positive (BCR/ABL-positive) disease, 7% had KMT2a/MLL rearrangements, 45% had normal disease, and 14% had other disease. Within this group, 62% had a disease status of CR1 at the time of transplant, 36% had CR2-positive disease, and 2% had active disease at the time of transplant. Donors for this group consisted of a matched sibling (38%), haploidentical (10%), URD 10/10 (29%), URD 9/10 (14%), and URD double cord (10%).

The most commonly used novel therapies administered in the recent era included blinatumomab (Blincyto; 64%), inotuzumab (Besponsa; 41%), and CAR T-cell therapy (36%).

“Eight patients received at least 2 of these novel therapies after relapse,” Craig said. “Donor leukocyte Infusion was used infrequently in both time periods and only 2 patients in the entire cohort received a secondary allogenic transplant.”

The analysis was not without limitations, according to Craig. Baseline patient transplant differences between the time periods analyzed may have contributed to the final outcome. “For example, more patients had active disease in the earlier cohort, while there more cord blood transplants were done in the later cohort,” Craig said.

Additionally, more sensitive minimal residual disease monitoring done in the later cohort could have helped to detect patient relapses earlier. This study also lacked the power to determine outcomes based on the specific novel therapy administered following relapse. Thus, investigators cannot conclude which novel drug yielded the best results.

“Although these data represent an improvement relative to historical outcomes, post-transplant relapse remains an area of ongoing need in adult ALL,” said Craig.

References

1. Craig J, Iglesias M, Cunanan K, et al. Survival following post-HCT relapse in adult acute lymphoblastic leukemia has improved in the era of novel immunotherapies: a single institution analysis. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 495. https://bit.ly/39OcmXy
2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944-950. doi:10.1182/blood-2006-05-018192