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Minimal Residual Disease Detection in Childhood Precursor–B-Cell Acute Lymphoblastic Leukemia: Relation to Other Risk Factors

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Minimal Residual Disease Detection in Childhood Precursor–B-Cell Acute Lymphoblastic Leukemia: Relation to Other Risk Factors Leukemia (2003) 17, 1566–1572 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Minimal residual disease detection in childhood precursor–B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children’s Oncology Group study MJ Borowitz1, DJ Pullen2, JJ Shuster3,4, D Viswanatha5, K Montgomery6, CL Willman5 and B Camitta7 1Johns Hopkins Medical Institutions, USA; 2University of Mississippi, USA; 3University of Florida, Gainesville FL, USA; 4Children’s Oncology Group, Arcadia, CA, USA; 5University of New Mexico, USA; 6Genzyme Genetics, Santa Fe, NM; and 7Milwaukee Childrens Hospital, USA Minimal residual disease (MRD) can be detected in the marrows prognostic significance at several time points. MRD levels at the of children undergoing chemotherapy either by flow cytometry end of induction are highly prognostic. Since intensification of or polymerase chain reaction. In this study, we used four-color therapy after successful induction can improve the outcome of flow cytometry to detect MRD in 1016 children undergoing 33 therapy on Children’s Oncology Group therapeutic protocols many patients with adverse prognostic features, it is possible for precursor–B-cell ALL. Compliance was excellent, with that a similar approach might benefit patients with MRD. For follow-up samples received at the end of induction on nearly these reasons, we have chosen to focus our MRD studies on 95% of cases; sensitivity of detection at this time point was at end-of-induction therapy. least 1/10,000 in more than 90% of cases. Overall, 28.6% of Although MRD and other measures of early response to patients had detectable MRD at the end of induction. Patients 34–36 with M3 marrows at day 8 were much more likely to be MRD therapy are important to prognosis, many other clinical and positive (MRD+) than those with M2 or M1 marrows. Different biological factors also affect outcome. Chromosome number genetically defined groups of patients varied in their prevalence and certain translocations also identify patients with good or of MRD. Specifically, almost all patients with BCR-ABL had high poor prognoses.37–41 Most studies of MRD have not had enough levels of end-of-induction MRD. Only 8.4% of patients with TEL- patients to determine the relation between the presence of AML1 were MRD+40.01% compared with 20.3% of patients with residual leukemia and these other factors. Moreover, although trisomies of chromosomes 4 and 10. Our results show that MRD MRD has been shown to be an independent prognostic factor in correlates with conventional measures of slow early response. 1,9,14,30 However, the high frequency of MRD positivity in favorable multivariate analysis, the precise relation between trisomy patients suggests that the clinical significance of MRD morphologic assessment of slow early response and MRD has positivity at the end of induction may not be the same in all been studied incompletely. In this report, we describe the patient groups. relation between the end-of-induction MRD as detected by Leukemia (2003) 17, 1566–1572. doi:10.1038/sj.leu.2403001 multiparameter flow cytometry and other known prognostic Keywords: acute lymphoblastic leukemia; minimal residual disease; flow cytometry factors, in a series of more than 1000 children with precursor-B- cell ALL. We find that there is a significant correlation between end-of-induction MRD and day 8 morphologic assessment of marrow response. In addition, we find significant differences among MRD rates in genetically defined groups of patients, Introduction which suggest that the clinical significance of MRD at the end of induction may not be the same in all patient subgroups. Minimal residual disease (MRD) can be detected in many patients, who undergo therapy for acute lymphoblastic leukemia (ALL). 1–16 MRD may be detected at a sensitivity of at least 10À4 Materials and methods either by molecular means, generally based on polymerase chain reaction (PCR) amplification of rearranged immunoglo- bulin (Ig) or T-cell receptor genes13,14,16–20 or by multiparameter Patient samples flow cytometry.1,2,8–10,15,21–26 The latter approach is based on The children in this study were enrolled on one of three ongoing the fact that leukemic cells express aberrant phenotypic treatment studies for childhood precursor-B ALL from April 2000 combinations of antigens that are not present on normal bone 9,22,27–29 to January 2002. Enrollment was based on patients’ NCI risk marrow cells. Both methods are generally recognized groups and the presence of specific molecular abnormalities, as as useful, although they have different advantages and shown in Table 1. All patients were enrolled on the POG 9900 disadvantages. When optimally performed, molecular studies classification study, which required shipment of blood and bone are more sensitive, and may require less material. However, marrow samples to reference laboratories at the University of flow cytometry is less expensive than molecular methods that New Mexico and the Johns Hopkins Medical Institutions. rely on sequencing to detect clone-specific markers, and is Patients with precursor-B-cell ALL, as confirmed by the Johns rapid, with test results available within a few hours of sample Hopkins laboratory, were categorized at the end of induction as receipt. low-, standard-, or high-risk based on modified age and white MRD detected using either method is an important prognostic 42 1,5–8,13,14,26,29–32 blood cell (WBC) criteria and molecular studies performed at factor in the outcome of children with ALL. the University of New Mexico, as described below. These MRD has been studied at multiple time points throughout patients were enrolled on consolidation/continuation treatment treatment. These studies show that although patients are noted protocols 9904, 9905, and 9906, respectively. All patients or to be positive less frequently as treatment progresses, MRD has their parents or guardians gave separate informed consent for the classification and treatment studies. Patients with precursor- Correspondence: MJ Borowitz, Children’s Oncology Group, 440 E. Huntington Dr. Suite 300, PO Box 60012, Arcadia, CA 91066-6012, B ALL enrolled on the classification study 9900 received USA; Fax: +1 626 445 4334 induction therapy of three drugs (vincrinstine, dexamethasone, Received 24 December 2002; accepted 26 March 2003 and L-asparaginase) or four drugs (vincristine, prednisone, Minimal residual disease in childhood ALL MJ Borowitz et al 1567 Table 1 Risk group classification for treatment assignment at day recovery with time in some but not all specimens. Thus, we 29 cannot rule out some level of false negatives among the older specimens. Risk group Definition (Treatment protocol #) Flow cytometry Low-risk group NCI standard risk for induction (POG 9904) (WBC o50 000/ml, Diagnostic samples: Each sample received in the Johns age 1.001–9.999 years) Hopkins reference laboratory that had been classified as No CNS-3* or testicular involvement No adverse translocations precursor–B-cell ALL was studied with a limited panel of (ie E2A-PBX1, BCR/ABL, MLL) antibodies in four-color flow cytometry to confirm the diagnosis, Has one of the following: to identify phenotypes associated with particular translocations, trisomies 4 and 10 by FISH as previously described,27 and to define an abnormal phenotype Tel-AML1 by PCR for purposes of monitoring. In nearly 90% of cases, the two-tube panel CD20ÀFITC/CD10ÀPE/CD45-perCP/CD19ÀAPC and Standard-risk group Not low risk (POG 9905) Not high risk CD34ÀFITC/CD9ÀPE/CD45ÀperCP/CD19ÀAPC was sufficient for this purpose, and defined several abnormal phenotypes High-risk group Does not have trisomies 4 and useful for monitoring for residual leukemia. In the remaining (POG 9906) 10 or Tel-AML1 cases, additional markers including CD38, CD15, CD13, 3 CD66b, CD22, or TdT were added to these combinations to Age (rounded down)/WBC ( Â 10 /ml) within pragmatic high definition, further define an informative phenotype for monitoring. All as follows: antibodies were obtained from Becton Dickinson (San Jose, CA, Age/WBC for day 28 high risk USA) except for CD10 (Dako, Carpenteria, CA, USA) and Age (years) CD66b, CD38, and TdT (Beckman-Coulter/Immunotech, Mia- mi, FL, USA). Cases in which the local institutional diagnosis Boy Girl WBC at diagnosis was not known were initially studied with a larger panel of antibodies to confirm lineage, and cases identified as precursor- 8 12 >80 B ALL were handled as described above. 9 13 >60 10 14 >40 Follow-up samples: Day 8 blood samples were processed 11 15 >20 by a modified stain-then-lyse procedure, usually using the single >12 >16 Any WBC Regardless of other factors if has four-color tube that best discriminated normal and abnormal MLL rearrangement cells. Since most cases had low cell numbers, a procedure was CNS-3a or testicular involvement developed using a buffy-coat-enriched specimen. Serum, buffy coat and the top of the red cell layer were obtained from a Patients >12 months of age with precursor–B-cell ALL [t(9;22) and pelleted cell preparation, and the material resuspended and hypodiploidy o45 chromosomes are not eligible for these studies] processed by our usual stain-then-lyse procedure. When the aCNSÀ3=CSF WBC X5/ml with blasts on cytospin. buffy-coat method was compared in 15 samples to a lyse-then- stain method using ammonium chloride, there was a high correlation (r ¼ 0.99 by linear regression analysis) in the percent of leukemic cells found, with a few samples showing superior recovery with the buffy-coat method. Day 29 marrow samples L-asparaginase, and daunomycin) based on their NCI risk almost always had sufficient cells to process using standard classification at diagnosis. Patients o1 year old, those with methods, but in about 2% of samples, only sufficient material T-cell ALL, Burkitt’s leukemia, Philadelphia chromosome- was available to run a single informative tube.
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