Sequential monitoring of minimal residual disease in acute lymphoblastic leukemia: 7-year experience in a pediatric hematology/oncology unit

Abstract

We evaluated minimal residual disease (MRD) in 91 children with acute lymphoblastic leukemia (ALL) by PCR amplification of clonal rearrangements, immunoglobulin (IgH; VDJ rearrangement, CDR3 region) and T-cell receptor (TCRdelta). Sequential monitoring of MRD was performed at different time points during and after chemotherapy and was correlated to patient outcome. In total, 792 bone marrow samples were assessed for MRD at the end of induction, and during and after treatment completion. MRD positivity at the end of induction was detected in 12% of patients and was associated with high incidence of relapse, 54.55% (p = 0.0002), at 5 years. On the other hand, 88% of patients were MRD-negative at the end of induction and the relapse rate at 5 years was very low, 5%. The frequency of MRD decreased to 16% in the first 6 months of chemotherapy; however, the incidence of relapse in MRD-positive patients remained high, 42.8%. After treatment completion (24-36 months from diagnosis), 32% patients were MRD-positive and the relapse rate was 36.5% (p = 0.0009). Our results indicated that monitoring of MRD constituted an essential prognostic marker, and detection of MRD particularly at the end of induction and after treatment completion was strongly predictive for patient outcome.

Detection of minimal residual disease in pediatric acute lymphoblastic leukemia

“…Such studies have focused on newly diagnosed patients (5)(6)(7)(8)(82)(83)(84)(85)(86)(87)(88)(89), patients with first relapse leukemia (9,(90)(91)(92), and patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) (93-96). They unanimously showed that MRD is a powerful predictor of outcome, leading to the adoption of MRD as a critical risk-assignment criteria (12,52).…”

Duplication of Philadelphia chromosome and trisomy of chromosome 21 in a pediatric patient with acute lymphoblastic leukemia

“…The rate of clearance of leukemic cells from the bone marrow during the early phases of therapy is an independent prognostic factor in ALL. Patients who respond slowly have high risk of relapse, and patients who fail to achieve complete remission within 4-6 weeks of the induction treatment have a particularly dismal prognosis [1,5]. The poor prognosis of patients with Philadelphia positive ALL is partly due to relatively slow rate of reduction of the leukemic clone by chemotherapy.…”

“…These alterations lead to the formation of a sequence that represents the hypervariable region, known as the third complementary determining region (CDR3) of the rearranged heavy chain gene. The coding sequence of CDR3 is a fingerprint-like sequence and is used as a molecular marker for the estimation of the level of MRD [1]. The rate of clearance of leukemic cells from the bone marrow during the early phases of therapy is an independent prognostic factor in ALL.…”

“…More specifically, immunoglobulin heavy chain gene rearrangements (V H D H J H region) analyzed by polymerase chain reaction (PCR) have been widely exploited for the detection of minimal residual disease (MRD). The evaluation of MRD has proven an independent risk factor [1,2]. Additional molecular parameters including point mutations of the D835/I836 in the activation loop (AL) domain of the second tyrosine kinase domain of the fms-related tyrosine kinase 3 (FLT3) gene and NRAS (neuroblastoma cell line) point mutations may play a direct role in the pathogenesis of the disease [3].…”

Treatment of Pediatric Acute Lymphoblastic Leukemia and Recent Advances

“…and Campana, 2000). Recent studies indicated that monitoring of MRD constituted an essential prognostic marker, and that detection of MRD, particularly at the end of induction and after treatment www.intechopen.com completion, was significantly predictive for patient outcome (Katsibardi et al, 2010;Stow et al, 2010).…”