Session: 618. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: High-risk T-ALL and Prognostic Biomarkers
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Biological therapies, adult, Clinical Research, Diseases, real-world evidence, Therapies, Lymphoid Malignancies, Technology and Procedures, Study Population, Human, Minimal Residual Disease , Transplantation, molecular testing
The prognostic utility of measurable residual disease (MRD) in adult acute lymphoblastic leukemia (ALL) has been defined at a sensitivity of 10-4. Measurement of MRD by ultra-sensitive next-generation sequencing (NGS) of Ig and/or TCR rearrangements has a sensitivity of 10-6 and is increasingly used across the United States to evaluate treatment response. However, the clinical utility of very low level NGS-based MRD (<10-4) is unknown. In this large multicenter cohort of adult ALL patients who underwent allogeneic hematopoietic cell transplant (HCT), we evaluated the prognostic value of ultra-sensitive NGS-based MRD.
Adults (18+) with ALL who underwent HCT at Stanford University or Oregon Health and Science University (OHSU) between January 2014 and April 2021 with planned MRD monitoring using the NGS-based clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) were included. Pre-HCT MRD (MRDpre) and post-HCT MRD (MRDpost) were followed for up to one-year post-HCT. MRD was evaluated as residual clonal cells per million nucleated cells and was defined as undetectable (0), low (<10-4), high (≥10-4 to ≤10-3) and very high (>10-3). Patients were followed for leukemia relapse for up to two years. Competing-risks analyses were used to model the hazard of relapse according to MRDpre and MRDpost levels. A univariate analysis using a Fine-Gray subdistribution hazard competing risk regression model was used to estimate the effect of MRDpre level on the cumulative incidence of relapse. A Cox regression model with time-varying covariates was fit to evaluate the association between MRDpre and MRDpost levels with relapse.
158 ALL patients who underwent HCT (Stanford n = 116, OHSU n = 42) had a trackable clonoSEQ clone. The median age was 43 years (range 18-77); 136 patients (86%) had B-ALL, 22 (14%) had T-ALL, and 131 (83%) underwent myeloablative HCT. Of the 122 patients with MRDpre assessment, MRDpre was undetectable, low, high, and very high in 82 (67%), 24 (20%), 11 (9%), and 5 (4%), respectively. Of the 111 patients with both MRDpre and at least one MRDpost assessments, 38 had at least one positive MRDpost result.
The cumulative incidence of relapse differed significantly according to level of MRDpre (Figure 1), including among patients with low MRDpre of <10-4 where post-HCT relapse risk was strikingly higher than in patients with undetectable MRDpre (HR 3.56, 95% CI 1.39-9.15, p = 0.01). A very strong association with post-HCT relapse was also seen in patients with detectable MRDpost at any level (including <10-4), even after controlling for MRDpre (HR 4.41, 95% CI 2.90-6.70, p < 0.0001).
Finally, we found that patients entering HCT with undetectable MRDpre who remained undetectable through the first year of MRDpost monitoring had <10% likelihood of relapse in the second post-HCT year (Figure 2). In contrast, patients entering HCT with detectable MRDpre had an ongoing risk of continued detectable of MRDpost without a clear plateau of relapse risk post-HCT.
In this analysis across two large transplant centers, we found that detection of MRD by ultra-sensitive NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT. Detectable MRDpre even at a low level of <10-4 increases the risk of post-HCT relapse. The presence of MRDpost at any level following HCT also substantially increases the risk of relapse. Finally, we found that patients with undetectable MRDpre who continue to have undetectable MRDpost through the first year of monitoring have excellent post-HCT outcomes.
Disclosures: Shiraz: Kite, a Gilead company: Research Funding. Leonard: Pfeizer: Consultancy; AbbVie: Research Funding; Adaptive: Consultancy; Amgen: Research Funding; KiTE: Consultancy; Takeda: Consultancy. Muffly: Kite: Consultancy, Research Funding; Jasper: Research Funding; BMS: Research Funding; Astellas: Consultancy, Research Funding; Adaptive: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Consultancy; Medexus: Consultancy; CTI Biopharma: Consultancy.
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