Impact of Minimal Residual Disease (MRD) on Prognosis in Children with Philadelphia Positive Acute Lymphoblastic Leukemia (ALL) Treated in the AIEOP-BFM ALL 2000 Study.
Authors: Biondi Andrea , Schrauder André , Valsecchi Maria Grazia , Bartram Claus R , Mann Georg , De Rossi Giulio , Möricke Anja , Parasole Rosanna , Harbott Jochen , Messina Chiara , Rizzari C. , Masera Giuseppe , Schrappe Martin 
Published: April 2020

Abstract
Introduction: The International “Berlin-Frankfurt-Münster” Study Group (I-BFM-SG) pioneered the evaluation of minimal residual disease (MRD) based on Immunoglobulin and T-cell Receptor gene rearrangements as PCR targets. The prospective AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica)-BFM ALL 2000 study is the largest in which standardized quantitative assessment of PCR-MRD at two time points (TP) was used for stratification in 127 centers.
Objective: To assess whether PCR-MRD levels discriminate outcome in patients with childhood Philadelphia positive (Ph+) ALL treated with intensive chemotherapy.
Material and Methods: Between 07–2000 and 07–2006, 79 Ph+ patients were enrolled in the AIEOP-BFM ALL 2000 study. They were eligible for the high risk (HR) treatment arm and treated with Induction (protocol IA + IB), poly-chemotherapy blocks, reinduction (by one or more Protocols II or III), followed by maintenance therapy. BM samples obtained at day 33 (Time Point 1, TP1) and 78 (TP2) of induction therapy were used for MRD analysis by patient specific PCR targets. At least one or two sensitive markers (≥ 1 × 10−4) could be determined in 62 (78.5%) and 54 (68.4%) patients, respectively. MRD-Standard Risk (SR) was defined by MRD-negative at both TP1 and TP2; MRD-HR by MRD ≥1×10−3 at TP2; MRD-Intermediate Risk (IR): all others. Median follow-up was 3 years; 5-year survival and event-free survival (EFS) (SE) estimates are given.
Results: Out of 79 registered patients, 3 (3.7%) died during Induction phase, 15 (19.2%) were Prednisone-poor responders (PPR), 12 (19.2%) were resistant to phase IA and 75 (94.9%) achieved CR. Forty-six patients (58.2%) underwent hematopoietic stem cell transplantation (HSCT). Overall, EFS and Survival (SE) were 44.3%(6.5) and 61.5%(6.2), respectively. Sixty-two patients were stratified by MRD (i.e. they were alive and valuable at day 78 and had at least one sensitive PCR marker). Eleven patients (17.7%) were at MRD-SR: 8 remained in CCR (4 after BMT), 1 died in CCR and 2 relapsed at 2.7 and 5.7 years from diagnosis; 28 (45.2%) were at MRD-IR: 18 remained in CCR (14 after BMT), 1 died in CCR and two for TRM after HSCT; 7 relapsed after 0.6 to 5.1 years; 23 (37.1%) were at MRD-HR and only 4 remained in CCR (all after BMT). The relapse rate was 18% in MRD-SR, 25% in MRD-IR and 61% in MRD-HR. Of note, within the Prednisone good-response subgroup (n=61), the evaluation of MRD identified those patients (MRD-HR, n=12 out of 51 PGR, MRD stratifiable) at very high risk of relapse (6/12: 50%).
Conclusions: PCR-MRD is a strong predictor for outcome in Ph+ ALL patients treated with BFM therapy. MRD response detected by PCR can tailor the selection of the best treatment (Imatinib or other tyrosine kinase inhibitors and chemotherapy with or without transplant). The prognosis in the subgroup of Ph+ALL as defined HR according to PCR-MRD detection is still very poor even after HSCT and accordingly new therapeutic strategies are needed.