Abstract
Background: An exploratory endpoint of the IRIS trial was measurement of BCR-ABL transcripts over time and its correlation with long-term outcomes. BCR-ABL measured by polymerase chain reaction (PCR) was required per protocol only after achievement of a complete cytogenetic response (CCyR). However, preplanned substudies occurred at sites in Germany and Australia who conducted PCR measurements on pts at intervals from the start of treatment independent of cytogenetic response (CyR). Additionally, other IRIS investigators contributed non-protocol specified molecular assessments. This first entire PCR dataset from IRIS assesses the prognostic value of molecular response (MR) at specific time points.
Methods: 553 pts were enrolled onto the IM arm of IRIS; of these, 476 pts with at least one PCR measurement form the basis for this analysis. A major molecular response (MMR) is defined as the ratio of BCR-ABL/control gene (BAC) of ≤0.1%. Analyses were conducted at 6, 12 and 18 mo relating BAC percent reduction to event free survival (EFS), where events were defined as death during study treatment, loss of complete hematologic response, loss of Major CyR (MCyR), progression to accelerated phase (AP) or blast crisis (BC), or an increasing white blood cell count to > 20 × 109/L.
Results: Among pts receiving first line IM for CML-CP, MMR was observed in 13% of samples available for study at 3 mo, 33% at 6 mo, 50% at 12 mo, 65% at 18 mo, 75% at 48 mo, 85% at 60 mo, and 86% at 72 mo. The degree of molecular response in pts who achieved CCyR is described in Table 1. This exploratory analysis demonstrates close correlation between CCyR and BAC ≤1% at 6 months and beyond.
Table 1. Correlation of CCyR with molecular response at 3, 6, 12 and 18 mo.
Time point Pts with CCyR and PCR samples available (n) CCyR and ≤0.1% BAC [MMR], n (%) CCyR and ≤1% BAC, n (%) 3 mo 51 17 (33%) 38 (75%) 6 mo 127 61 (48%) 114 (90%) 12 mo 177 110 (62%) 168 (95%) 18 mo 163 127 (78%) 154 (94%)
At 6 mo, half of the pts with BAC >10% who also had a cytogenetic assessment at the same time had at least a partial cytogenetic response (PCyR) with an EFS of 91% at 72 mo, and 64% of these pts achieved MMR later. The other half of the pts with >10% BAC who did not have a PCyR at 6 mo had an EFS of 43%, and 31% later achieved MMR. A separate landmark analysis by CyR status alone showed EFS rates at 72 mo of 92% for pts in CCyR, 86% for pts in PCyR, 60% for Minor/Minimal CyR and 49% for No CyR. At 12 mo, pts with BAC ≤ 1% had excellent long term outcomes (72 month EFS of >90%, >95% without progression to AP/BC). Those pts with BAC > 1–≤ 10% (n = 36) had a 67% EFS, and 44% later achieved an MMR. These molecular analyses compare similarly to cytogenetic analyses alone (Baccarani et al; ASH 2006), with 60 mo EFS of 93% for pts in CCyR, 78% for pts in PCyR and 61% for pts without PCyR At 18 mo, pts with MMR could be statistically distinguished from pts with BAC >0.1–≤ 1%; EFS was 98% versus 89%, p=0.0137 (with 6 events in each group). The rate without AP/BC at 72 mo was not significantly different (with only 2 events in the >0.1 – ≤ 1% group). Baccarani et al (ASH 2006) reported an EFS at 60 mo of 96% for pts in CCyR, 80% for pts in PcyR and 69% for pts without PCyR.
Table 2: Long-term outcomes (estimated rates at 72 mo) by MR levels at 6, 12 and 18 mo.
BCR-ABL categories ≤0.1% (MMR) >0.1 −≤1% >1 −≤10% >10% *P=.0137. None of the other comparisons between MMR and > 0.1–≤1% BAC were statistically significant. 6 mo landmark N=86 N=89 N=44 N=39 EFS rate at 72 mo 90% 94% 88% 55% Without AP/BC at 72 mo 96% 100% 95% 74% 12 mo landmark N=153 N=90 N=36 N=26 EFS rate at 72 mo 94% 93% 67% 46% Without AP/BC at 72 mo 100% 96% 83% 76% 18 mo landmark N=164 N=48 N=25 N=16 EFS rate at 72 mo 98%* 89%* 67% 47% Without AP/BC at 72 mo 100% 96% 83% 82%
Conclusion: In pts on first-line IM, MMR rates increase over time, and in pts who achieved an MMR at any time point progression is rare. Achievement of a CCyR correlated well with BAC of ≤1% from 6 mo onwards. Exploratory molecular analyses show pts with BAC >10% at 6 mo have EFS rates distinguishable by their cytogenetic status. At 12 mo, pts with a BAC > 1% or without CCyR, fare more poorly than those with BAC ≤ 1% or those in CCyR. At 18 mo pts with BAC ≤ 1% have excellent long term outcomes, with the best outcomes seen in those with BAC ≤ 0.1%. Molecular and cytogenetic evaluations are recommended until at least CCyR is achieved, with molecular assessments measured indefinitely thereafter.
INTEGRATED MANAGEMENT OF WEEDS IN A PERENNIAL CROP:THE EXAMPLE OF CRANBERRIES
