Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies

Abstract

The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10^-4 and 70 with MRD≥5×10^-4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis.

Figure 1.

EsPhALL treatment schema and MRD results. EsPhALL treatment schema with minimal residual disease (MRD) sampling time points (time point, panel A). Sample size at different follow-up time points, by IG/TR (panel B) and BCR/ABL1 (panel C). MRD load at different follow-up time points, by IG/TR (panel D) and BCR/ABL1 (panel E): MRD negative (white), low positive (<5×10⁻⁴, gray) and highly positive (≥5×10⁻⁴, black). BM: bone marrow; HSCT: hematopoietic stem cells transplantation; IG/TR: immunoglobulin/T-cell receptor; G-CSF: granulocyte-colony stimulating factor.

Figure 2.

Event-free survival and cumulative incidence of relapse according to IG/TR MRD levels. Event-free survival (EFS; panels A, C, E and G) and cumulative incidence of relapse (CIR; panels B, D, F and H) according to IG/TR MRD levels at time points 1 through 4 (TP1-TP4). At TP1, there were seven good-risk and two poor-risk (panel B) negative patients with no relapses. At TP2, among the 14 new negative patients, nine were good-risk (1 relapse) and five were poor-risk (1 relapse). CUM: cumulative; EsPhALL: European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia; SE: standard error.

Figure 3.

Event-free survival and cumulative incidence of relapse according to BCR/ABL1 MRD levels. Event-free survival (EFS; panels A, C) and cumulative incidence of relapse (CIR; panels B, D) according to BCR/ABL1 MRD levels at time points 1 (TP1) and 2 (TP2). The patient who was negative at TP1 and relapsed is not represented at TP2 because their MRD at this time point was not available. At TP2 only three patients were ‘new negative’. CUM: cumulative; EsPhALL: European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia; SE: standard error.

Figure 4.

Overall concordance of IG/TR vs. BCR/ABL1 MRD. Scatterplot of IG/TR- and BCR/ABL1-based minimal residual disease (MRD) sample values on the logarithmic scale. Positive samples with MRD below the quantitative range (‘positive, not quantifiable’ – POS, NQ) were conventionally represented with 10⁻⁶; MRD negative samples are labeled with NEG. The black diagonal line represents the exact agreement; the area within the green lines includes concordant samples with acceptable agreement, defined as less than 1 log difference between the two measurements. Red boxes include discrepant cases, while green boxes include cases with either ‘POS,NQ’ or ‘NEG’ results via at least one of the two methods, for which assessment of concordance was based on sensitivity. n=number of samples; numbers of patients are indicated in parenthesis. Panel A includes all samples for all patients, while panels B–D and C–E show only samples at TP1 and TP2, respectively. Panel D and E show the comparison of MRD measurements by IG/TR and BCR/ABL1 according to Bland-Altman, with the continuous line representing zero difference, and the dashed line representing the estimated mean difference ±2 SD. Among ten IG/TR negative and BCR/ABL1 positive patients (who were concordant according to the definition above), seven carried the p190 fusion protein, one carried the p210 fusion protein and two did not have this information available. The fusion protein detected in nine IG/TR POS<QR and BCR/ABL1 positive patients (who were concordant according to the definition above) was p190 in eight patients, and not known in the remaining patient. IG/TR: immunoglobulin/T-cell receptor.

Figure 5.

MRD in discordant cases. MRD pattern from TP1 through TP4 (or TP5 if available) of four patients with persistently discordant results by IG/TR (dashed lines) and BCR/ABL1 (continuous lines). Patients identified with ID 184, ID 111 and ID 44 carried the p190 variant protein; for patient ID 25, this information was not available.