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Effect of the Philadelphia Chromosome on Minimal Residual Disease In Leukemia (1997) 11, 1497–1500 1997 Stockton Press All rights reserved 0887-6924/97$12.00 Effect of the Philadelphia chromosome on minimal residual disease in acute lymphoblastic leukemia MJ Brisco1, PJ Sykes1, G Dolman1, S-H Neoh1, E Hughes1, L-M Peng2, G Tauro3, H Ekert3, I Toogood4, K Bradstock5 and AA Morley1 1Department of Haematology, Flinders Medical Centre, Bedford Park, South Australia; 2Department of Laboratory Medicine, School of Medicine, West China University of Medical Sciences, Chengdu, People’s Republic of China; 3Department of Haematology, Royal Childrens Hospital, Parkville, Victoria; 4Department of Haematology/Oncology, Womens and Childrens Hospital, North Adelaide, South Australia; and 5Department of Haematology, Westmead Hospital, Westmead, NSW, Australia The Philadelphia translocation is associated with a poor prog- number of leukemic cells remaining at the end of induction nosis in adults and children with acute lymphoblastic leukemia, provides a good approximation of the degree of drug resist- even though the majority of patients achieve remission. To test ance in vivo. the hypothesis that the translocation leads to drug resistance 6–10 in vivo, we studied 61 children and 20 adults with acute lym- Since the initial reports, a number of groups have phoblastic leukemia and used the level of minimal residual dis- developed sensitive methods to quantify minimal residual dis- ease at the end of induction as the measure of drug resistance ease (MRD) by use of the polymerase chain reaction (PCR). in vivo. In children the presence of the translocation was asso- Our own approach has been to use the rearranged immuno- ciated with a significant increase in residual disease, indicating globulin heavy chain gene as a molecular marker for the higher drug resistance in vivo; five of seven Philadelphia-posi- tive children but only five of 54 Philadelphia-negative children leukemic clone; to sequence the gene; to synthesise patient- had a minimal residual disease level .1023, a level which is specific PCR primers, which enable detection of the marker associated with a high risk of relapse in childhood acute lym- gene (and hence the leukemic cells); and to quantify leukemic phoblastic leukemia of standard risk. By contrast, in adults, cells by using limiting dilution analysis and Poisson stat- residual disease and hence drug resistance was already higher istics.11,12 In this paper, we have applied this approach to a than in children, and the presence of the Philadelphia translo- series of children and adults with ALL, in order to determine cation in seven patients had no obvious additional effect. We conclude that the Philadelphia chromosome may increase directly whether the Philadelphia translocation is associated resistance to drugs in vivo in children, but not detectably in with increased levels of residual disease at the end of induc- adults. tion, implying increased drug resistance in vivo. Keywords: minimal residual neoplasm; Philadelphia chromosome; acute lymphoblastic leukemia; drug resistance; polymerase chain reaction Materials and methods Patients Introduction Patients were eligible for this study if: (1) they had B lineage It is well known that the presence of the Philadelphia translo- ALL; (2) their leukemia could be quantified by the techniques cation (t(9;22)(q34;q11)) markedly worsens the prognosis of described below; (3) they achieved morphological remission children and adults with acute lymphoblastic leukemia after induction treatment, and (4) there was enough material 1,2 (ALL). Philadelphia-positive (Ph+ve) patients achieve available for study. Patients were excluded if their cytogenetic remission less frequently or take longer to do so, and, even if testing was unsuccessful, or revealed a translocation other they achieve remission, most will relapse. The most obvious than the t(9;22): 23 otherwise eligible patients had no cyto- explanation is that the 9;22 translocation directly increases genetic information available, mainly due to technical prob- drug resistance even in patients who achieve remission. There lems; another 13 patients were not studied because they had is some evidence supporting this, as in several in vitro studies a translocation other than t(9;22) associated with higher on chronic myelogenous leukemia the presence of the bcr-abl relapse risk, eg t(1;19), t(4;11) or t(8;14). The 20 adult patients fusion gene prevented apoptosis following drug exposure.3–5 had been treated between 1984 and 1994 with the 7801-A However, other explanations of the poor outcome in Ph+ve protocol which involved a 5-week induction therapy of vincri- ALL are possible. For example, the 9;22 translocation might stine, prednisolone, daunorubicin, cytosine arabinoside, and increase genetic instability and drug resistance could be a asparaginase. The clinical features of most have been consequence of one or more secondary mutations. Alterna- described.13 The Philadelphia-negative adult patients (10 tively the 9;22 translocation might lead to a poor outcome by male, three female) had at diagnosis a median white cell mechanisms entirely unrelated to drug resistance. count 13 × 109/l (range 3–57 × 109/l) and median age of 21 In vivo drug resistance can be inferred from the rate of (range 15–38). Clinical data for Philadelphia-positive adults decline of leukemic cell number during treatment. However, are shown in Table 1. Three patients, including two with the since the number of leukemic cells in the body at diagnosis t(9;22), had white cell counts above 50 × 109/l (Table 1). The probably varies between patients by no more than one order 61 child patients were treated between 1985 and 1994 on of magnitude, whereas the number of leukemic cells at the Australian and New Zealand Children’s Cancer Group Studies end of induction varies by many orders of magnitude, the V (1985–92) and VI (1993–6), which involved the same 5- week induction therapy of vincristine, prednisolone, dauno- rubicin and asparaginase. The Philadelphia-negative child Correspondence: AA Morley, Department of Haematology, Flinders patients (28 male, 26 female) had at diagnosis a median white Medical Centre, Bedford Park, South Australia 5042 cell count of 10 × 109/l (range 1–252 × 109/l) and a median Received 27 January 1997; accepted 7 May 1997 age of 3 years 9 months (range 1 year 2 months to 15 years 11 Drug resistance in Ph1ve ALL MJ Brisco et al 1498 Table 1 Clinical characteristics of patients with the Philadelphia Statistics translocation Comparisons between groups were made using the Mann– No. Sex Age WCC MRD Whitney U test, one-tailed unless otherwise indicated. (years) ×109/l at end of induction Adults 1 F 74 25 5.2 × 10−2 Results 2 M 20 23 4.1 × 10−2 3 M 17 102 1.6 × 10−2 MRD was detected and quantified in 46 patients, at levels 4 M 33 10 4.9 × 10−3 from .10−1 to ,10−6 (Figure 1, closed circles). For children, − 5 M 42 86 4.3 × 10 4 the MRD levels at the end of induction were significantly 6 F 19 2.8 6.6 × 10−6 + 2 × −6 higher in Ph ve patients than in Ph ve patients (medians 3 7 M 27 9.8 ,3.3 × 10 − − 10 2 vs 8 × 10 5; P = 0.0008). For adults, the MRD levels at the end of induction in Ph+ve patients were not significantly Children −2 × −2 higher than in Ph−ve patients (medians 1.0 × 10 vs 4.2 × 8 M 8 7.7 6.7 10 − 9 F 2 181 3.9 × 10−2 10 3; P = 0.18; one-tailed). 10 F 14 2.3 3.2 × 10−2 11 M 5 73 2.1 × 10−2 12 M 15 186 8.4 × 10−3 13 M 3 17 ,3.0 × 10−4 14 M 9 4 ,1.4 × 10−4 months). Clinical data for Philadelphia-positive children are shown in Table 1. Twelve patients, including three with the t(9;22), had white cell counts above 50 × 109/l. This work was approved by the Flinders Medical Centre Committee on Clinical Investigation. Tissue samples Bone marrow was aspirated at diagnosis and at the end of induction treatment, and was usually available as fixed, stained bone marrow smears, although unfixed smears or frozen marrow were sometimes used. Quantification of minimal residual disease This was performed as previously described.11–14 Briefly, DNA was extracted by phenol-chloroform extraction. The rearranged immunoglobulin heavy chain gene, which acts as a marker for the leukemic clone, was amplified from the bone marrow at diagnosis, and sequenced. PCR primers were designed to the complementary determining region (CDR)3 and occasionally CDR2 regions and tested for specificity and sensitivity by ensuring that large amounts of amplified product of the correct size were obtained from one or a few molecules of the target DNA, and by demonstrating that no signal was obtained from 1 mg DNA from peripheral blood obtained from a healthy volunteer. Quantification was performed by using limiting dilution analysis. For leukemic genomes we used a nested PCR either with consensus primers or occasionally with one patient-specific primer and one consensus primer in the first round, followed by one or two patient-specific primers in the second round. For total amplifiable genomes we used primers for the N-ras gene in a one-round PCR. MRD levels were expressed as the proportion of nucleated cells which belong to the leukemic clone. Sequences of the rearranged immunoglobulin heavy chain Figure 1 Levels of minimal residual disease in bone marrow aspir- genes and details of the primers used for quantification can ates at the end of induction treatment in acute lymphoblastic leuke- be obtained from Genbank, and a list of accession numbers mia. (I) MRD detected in marrow; (o) MRD not detected; upper limit can be obtained from the authors.
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