AUTHORS
Sinan Cetin, MD, Meagan Matuska, MD2, Alexandra Harris, MD3, Madelyn Burkart, MD4, Michael Wang5, Matthew P Connor, MD6, George Morcos7, Dan Lichtenstein, MD8, Emily Curran, MD9, Emily Dworkin, PharmD10, Shira Dinner, MD11, Kristen O'Dwyer, MD12, William Blum, MD13, Lourdes Mendez, MD14, Geoffrey L. Uy, MD15, Selina Luger, MD, FRCPC16, Jonathan Allen Webster, MD17, Matthew Joseph Wieduwilt, MD, PhD18, Wendy Stock, MD19, Anand Ashwin Patel, MD20
AFFILIATIONS
1 University of Chicago, Chicago, Illinois, United States
2 University of Chicago, Chicago, Illinois, United States
3 University of Chicago, Chicago, Illinois, United States
4 Wake Forest University, Winston-Salem, North Carolina, United States
5 John Hopkins University, Baltimore, Maryland, United States
6 University of Pennsylvania, Philadelphia, Pennsylvania, United States
7 Washington University in St. Louis, St. Louis, Missouri, United States
8 University of Cincinnati, Cincinnati, Ohio, United States
9 University of Cincinnati, Cincinnati, Ohio, United States
10 University of Chicago, Chicago, Illinois, United States
11 Northwestern University, Chicago, Illinois, United States
12 University of Rochester, Rochester, New York, United States
13 Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
14 Yale School of Medicine, New Haven, Connecticut, United States
15 Washington University in St. Louis, St. Louis, Missouri, United States
16 University of Pennsylvania, Philadelphia, Pennsylvania, United States
17 John Hopkins University, Baltimore, Maryland, United States
18 Wake Forest University, Winston-Salem, North Carolina, United States
19 University of Chicago, Chicago, Illinois, United States
20 University of Chicago, Chicago, Illinois, United States
ABSTRACT
Background:
InO, a CD22-directed antibody-drug conjugate, has demonstrated efficacy in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Several single-arm trials have also reported encouraging efficacy and survival with InO-based regimens in older adults with newly diagnosed Philadelphia-chromosome negative (Ph-) B-ALL. These results have led to increasing use of InO in frontline treatment strategies, particularly in patients (pts) considered unfit for pediatric-inspired regimens. However, real-world data characterizing the use of frontline InO-based approaches, particularly InO monotherapy, are limited. Therefore, we conducted a real-world analysis to evaluate the outcomes of adults with Ph- B-ALL that received frontline InO-based therapy.
Methods:
We performed a multicenter retrospective analysis of adults with newly diagnosed Ph- ALL who received a frontline InO-containing regimen outside of a clinical trial. Response was assessed per standard ALL criteria; overall response rate (ORR) was defined as complete remission (CR) plus CR with incomplete hematologic recovery (CRi). Kaplan-Meier method with log-rank test was used for survival analysis. Fisher’s exact test and Mann-Whitney U test were used for group comparisons.
Results:
A total of 64 eligible pts (n=44 InO monotherapy (InO-M), n=20 InO combination (InO-C)) were identified. Within the InO-C cohort, 17 received mini-CVD and 3 received Hyper-CVAD. The median age was 69.5 years (range 28-86); 58% were male, and 36% had ECOG performance status 2-4. When comparing pts treated with InO-M compared to InO-C therapy, those that received InO-M had a similar median age (70.0 vs 68.5 years, p=0.280) and a similar rate of ECOG performance status 2-4 (31.8% vs 45.0%, p=0.401). Therapy-related B-ALL was documented in 17/44 InO-M pts (38.6%) and 8/20 InO-C pts (40.0%). TP53 mutation was identified in 18/43 evaluable InO-M pts (41.9%) and 6/19 InO-C pts (31.6%). KMT2A rearrangement was present in 3/43 evaluable InO-M pts (7.0%) and 0 InO-C pts. Ph-like ALL was identified in 8/43 InO-M pts (18.6%) and 0 InO-C pts.
The ORR for the entire cohort was 84.4% (95% CI 73.6-91.3%); CR rate was 70.3% and CRi rate 14%. The InO-C group demonstrated superior ORR (100% vs 77.3%; p=0.024) and CR rate (95.0% vs 59.1%; p=0.003) compared to InO-M. Among 54 pts achieving CR/CRi, measurable residual disease (MRD) was assessed by flow cytometry (sensitivity 10-4) in 40 pts, with 75.0% achieving negativity. MRD by next-generation sequencing (NGS) (sensitivity 10-6) was performed in 27 of 54 pts that achieved CR/CRi, with 18 achieving negativity (66.7%).
Grade 3+ treatment-related adverse events occurred in 1 of 44 InO-M pt (2.3%) and 10 of 20 InO-C pts (50%). Among the 10 InO-C pts with Grade 3+ adverse events, 3 had liver function abnormalities and 6 patient infectious/cytopenia-related complications. Two pts developed veno-occlusive disease (VOD), one in each group.
Within our 64 pt cohort, 46 pts received blinatumomab (blina) during their treatment course. Forty pts received blina as maintenance/consolidation in CR1 after InO-based therapy, 3 pts received blina for relapsed disease, and 3 pts received blina for maintenance/consolidation in CR1 and were re-treated with blina for relapsed disease. Of the 18 pts who did not receive blina, 14 received InO-M and 4 received InO-C frontline therapy. Seven pts (10.9%) underwent allogeneic stem cell transplantation in first remission; 5 received InO-M and 2 received InO-C therapy. At a median follow-up of 2.4 years, median OS was not reached (95% CI 1.9 years-NR); 1-year and 2-year OS rates were 77.9% and 64.6%, respectively. Median OS was significantly longer in the InO-C arm versus InO-M (NR vs 2.8 years; log-rank p=0.014).
Conclusions:
This multicenter real-world analysis of frontline InO-based therapy demonstrated high response rates (ORR 84.4%), durable OS (2-year OS 64.6%), and a low rate of VOD (3%) in adults with Ph- B-ALL. Notably, 38% of pts harbored a TP53 mutation. InO-C regimens were associated with improved response rates and OS; of note pts treated with InO-M had a higher rate of adverse-risk features and a lower rate of blina use. These findings support utilization of frontline InO-based strategies in this population. We aim to continue expansion of this analysis cohort and to perform multivariate analysis to identify independent factors impacting OS and identifying who may benefit most from InO-M compared to InO-C.
DISCLOSURES
Sinan Cetin, MD: No relevant conflicts of interest to declare.