Detection of Minimal Residual Leukemia Predicts the Outcome of Patients with Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy
Authors: Ravandi Farhad , Thomas Deborah A. , O'Brien Susan , Garris Rebecca , Faderl Stefan , Shan Jianqin , Borthakur Gautam , Burger Jan A. , Ferrajoli Alessandra , Kebriaei Partow , Champlin Richard , Estrov Zeev , Wang Sa A. , Jorgensen Jeffrey L. , Luthra Rajyalakshmi , Cortes Jorge E. , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 1453

Background:
Combination of the hyperCVAD regimen and imatinib or dasatinib has produced long-term leukemia free responses in patients (pts) with Philadelphia (Ph) chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) even without an allogeneic stem cell transplant. Identifying high risk pts can allow for a better selection of pts to undergo a transplant procedure in first complete remission (CR).

Methods:
From April 2001 to March 2011, 122 pts with newly diagnosed Ph+ ALL were treated on sequential frontline regimens of hyperCVAD + imatinib (n= 54) and hyperCVAD + dasatinib (n= 68). Among these, 101 pts achieved complete response (CR) with one induction course and had at least one minimal residual disease (MRD) assessment; 25 pts underwent an allogeneic stem cell transplant in first remission and were excluded from this analysis. MRD monitoring by multi-parameter flow cytometry (MFC) was performed using 4 or 6 color combinations of antibodies to lymphoblast and myeloid antigens (e.g., CD10, CD13, CD15, CD19, CD20, CD22, CD25, CD33, CD34, CD38, CD58, CD66c, and CD81), with a sensitivity of 0.01%. RQ-PCR for BCR-ABL was performed using TaqMan primer/probes for the e1a2, e13a2 (b2a2), and e14a2 (b3a2) BCR-ABL transcripts in a single tube with normalization to total ABL transcripts. All values were standardized to the international scale.

Result:
The median age for the cohort was 54 years (range, 21 – 84 years). Cytogenetics were Ph alone (n=13; 17%) and Ph with another abnormality (n=50; 66%). The other 13 pts (17%) were positive for the BCR-ABL fusion gene. There was no difference in survival by achievement of a major molecular response (MMR, BCR-ABL/ABL < 0.1%) at CR (p=.22). However, pts achieving a MMR, at 3, 6, 9, and 12 months had a significantly better survival than those not achieving MMR at these time points (p=.02, p=.04, and p=.05, and p=.01, respectively). Similarly, achievement of a negative MFC at CR did not predict for improved survival (p=.2). At 3 and12 months (insufficient data at 6 and 9 months), achieving a negative MRD status by MFC was associated with a significantly improved survival (p=.04 and p=.001). Figures represent data for landmark analysis at 3 months.

Conclusion:
MRD monitoring by PCR and MFC can identify pts who may benefit from intensification of treatment with an allogeneic stem cell transplant in first CR.

Disclosures:
Ravandi: Novartis: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Off Label Use: First line treatment of Philadelphia-chromosome positive ALL with dasatinib. Burger:Cellgene: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genzyme: Consultancy; Calistoga: Research Funding; Noxxon: Consultancy, Research Funding. Cortes:Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.