Improving the Identification of High Risk Precursor B Acute Lymphoblastic Leukemia Patients with Earlier Quantification of Minimal Residual Disease

Abstract

The stratification of patients with acute lymphoblastic leukemia (ALL) into treatment risk groups based on quantification of minimal residual disease (MRD) after induction therapy is now well accepted but the relapse rate of about 20% in intermediate risk patients remains a challenge. The purpose of this study was to further improve stratification by MRD measurement at an earlier stage. MRD was measured in stored day 15 bone marrow samples for pediatric patients enrolled on ANZCHOG ALL8 using Real-time Quantitative PCR to detect immunoglobulin and T-cell receptor gene rearrangements with the same assays used at day 33 and day 79 in the original MRD stratification. MRD levels in bone marrow at day 15 and 33 were highly predictive of outcome in 223 precursor B-ALL patients (log rank Mantel-Cox tests both P<0.001) and identified patients with poor, intermediate and very good outcomes. The combined use of MRD at day 15 (≥1×10−2) and day 33 (≥5×1−5) identified a subgroup of medium risk precursor B-ALL patients as poor MRD responders with 5 year relapse-free survival of 55% compared to 84% for other medium risk patients (log rank Mantel-Cox test, P = 0.0005). Risk stratification of precursor B-ALL but not T-ALL could be improved by using MRD measurement at day 15 and day 33 instead of day 33 and day 79 in similar BFM-based protocols for children with this disease.

High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment

“…Susan L. Heatley, 1,2,3 Jeffrey Suttle, 5 Tamara Law, 4 Anthea Ng, 3,6 Walter Muskovic, 4 Murray D. Norris, 4 Tamas Revesz, 2,3,7 Michael Osborn, 3,7,8 Andrew S. Moore, 3,9,10 Ram Suppiah, 11 Chris Fraser, 3,9 Frank Alvaro, 3,12 Timothy P. Hughes, 1,2,13 Charles G. Mullighan,14 Glenn M. Marshall,3,4,6,8,15 Luciano Dalla Pozza, 3,6 David T. Yeung, 1,2,13 Rosemary Sutton 3,4,8,15 …”

A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B‐cell acute lymphoblastic leukaemia in children

“…The majority of relapses in the ANZCHOG ALL8 trial for newly diagnosed ALL in children occurred in the large medium risk group – a finding consistent with the results of related frontline trials with the same MRD stratification strategy ‐ AIEOP‐BFM ALL 2000 and DCOG ALL10 (Conter et al , ; Schrappe et al , ; Pieters et al , ). While risk assignment could be improved by changing MRD thresholds (Basso et al , ; Conter et al , ; Schrappe et al , ; Karsa et al , ), it was also apparent that other factors contribute to patient prognosis. In this paper, we focussed on clinical information that was already available or could be readily obtained by affordable, robust diagnostic tests, to detect common ALL microdeletions.…”

“…DNA was isolated from mononuclear cells purified from bone marrow aspirates at diagnosis, Day 33 and Day 79 and tested for MRD by Real‐time Quantitative PCR (qPCR) to detect rearrangements of immunoglobulin genes and T‐cell receptors (Flohr et al , ; Karsa et al , ; Sutton et al , ). MRD was measured by references to standards made by serial dilution of the patient's diagnostic DNA (1 × 10 −1 , 1 × 10 −2 , 1 × 10 −3 , 5 × 10 −4 , 1 × 10 −4 , 5 × 10 −5 and 1 × 10 −5 ), with data analysis according to EuroMRD guidelines for patient stratification (van der Velden et al , ).…”

“…In these iBFM MRD intervention trials: Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)‐BFM ALL 2000 (Conter et al , ), Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG) ALL8 (Marshall et al , ) and Dutch Childhood Oncology Group (DCOG) ALL‐10 (Pieters et al , ); only 11% of patients were classified as high risk and were successfully treated with more intensive chemotherapy and sometimes stem cell transplantation, increasing survival for this group from an estimated 30% to 76–82% at 5 years (Marshall et al , ; Pieters et al , ). The greatest number of relapses consequently occurred in the large medium risk group, which represented about 60% of patients in these trials (Karsa et al , ). The current AIEOP‐BFM ALL 2009 trial addressed this issue by incorporating Day 15 flow cytometry of bone marrow (Basso et al , ) and defining a slow early responder B‐precursor (BCP‐ALL) group based on high MRD load (>5 × 10 −4 ) at Day 33 and any MRD positivity at Day 79 for risk assessment (Conter et al , ), and the DCOG trial showed that MRD levels at the end of consolidation have additive predictive value (Pieters et al , ), but further improvements are needed.…”

Evaluation of rs62527607 [GT] single nucleotide polymorphism located in BAALC gene in children with acute leukemia using mismatch PCR-RFLP

“…After 2006, chemotherapy was carried out using the standard risk protocol for 55 patients, the ANZSTUDY intermediate risk protocol for 27 cases [17]and the LMB 89 protocol for 3 Burkitt type ALL cases [18]. The 3DFS rate was 70.6% (73.8 % for females and 67.6% for males), including 52% 3DFS for T-ALL and 75% 3DFS for the pre-B-ALL group (p=0.024) ( Table 1).…”