Early Response Dynamics Including Minimal Residual Disease (MRD) and Adherence to Risk/MRD-Oriented Therapy Are Major Outcome Determinants in Adult Ph-Negative Acute Lymphoblastic Leukemia (ALL).
Authors: Bassan Renato , Spinelli Orietta , Oldani Elena , Tosi Manuela , Peruta Barbara , Borlenghi Erika , Pogliani Enrico Maria , Bona Eros Di , Cassibba Vincenzo , Scattolin Anna Maria , Romani Claudio , Ciceri Fabio , Cortelezzi Agostino , Gianfaldoni Giacomo , Mattei Daniele , Audisio Ernesta , Intermesoli Tamara , Rambaldi Alessandro 
Published: October 2019

Abstract
Abstract 2573

Introduction
In adult Ph- ALL two major risk groups are generally identified on account of patient age, presentation white blood cell (WBC) count, disease immunophenotype and genetics/cytogenetics, with 5-year overall and disease-free survival (OS, DFS) rates of approximately 50% in standard-risk (SR) and 30% in high-risk (HR) patients, respectively. Although the difference is significant, this classification reflects a static risk assessment and does not recognize increasingly important factors such as individual response dynamics (complete remission [CR] vs induction failure or early relapse; MRD course) and risk-oriented treatment decisions with or without stem-cell transplantation (SCT).

Aim
To evaluate dynamic risk factors in association with adherence to risk-oriented therapy as major determinants of outcome.

Patients and Methods
OS and DFS rates were reanalyzed according to MRD-related risk definitions and risk-oriented treatment steps in a prospective clinical trial (Bassan et al, Blood 2009;113:4153). Different risk and treatment subsets were identified according to (i) achievement of CR vs early failure due to induction death, early relapse or toxicity precluding the application of MRD/risk-oriented therapy according to trial design, and (ii) adherence to planned MRD/risk-oriented chemotherapy or SCT vs non-adherence unrelated to early failure. Outcome results were compared with those obtained using traditional SR and HR definitions.

Results
Three-hundred and four patients with Ph- ALL were treated (age range 16–68 years, median 35 years; male 57%), of whom 258 (85%) entered CR and 18 and 28 proved refractory or died early, respectively. Among CR patients, 78 did not complete early consolidation and MRD study (50 relapse, 9 toxicity and 19 very HR to early SCT), while 144 did it and were allocated to MRD-oriented therapy and 36 without a sensitive probe for MRD analysis were allocated according to clinical risk class. Six-year OS and DFS were 44% (n=138) and 43% (n=122) in SR vs 28% (n=166) and 28% (n=136) in HR, respectively (P=0.0009). Instead, OS and DFS results according to early treatment response, completion of MRD study for risk re-stratification and adherence to MRD/risk-oriented therapy identified several distinct prognostic categories, in which survival, largely unrelated to age and clinical risk class, ranged from 0% at 2.8 mos. (early deaths) to 73% at 6–10 years (MRD-negative), as detailed in the table and figure.

Conclusion
In this study, long-term survival rates were about 50% in SR patients (MRD unknown), 70% in MRD-negative ones receiving chemotherapy, and 40%–50% in all those proceeding to allogeneic SCT because very HR, HR MRD unknown or MRD-positive. Therefore, using a risk/MRD-oriented strategy, the adherence to protocol design concurs to identify the patient subsets with the highest probability of cure.

Disclosures:
No relevant conflicts of interest to declare.