Monitoring treatment success and failure in CML Andreas
- Slides: 21
Monitoring treatment success and failure in CML. Andreas Hochhaus Universitätsklinikum Jena, Germany
Goals of CML therapy Leukemia cells >1012 CHR 1010 CCy. R 108 MMR 106 Undetectable range
The evidence obtained with the IRIS study is that the absolute and not the relative amount is important! Starting amount 3 rd month 6 th month 9 th month 12 th month CCy. R Minor Molecular Response Major Molecular Response
Definition of failure and suboptimal response Time Failure Subopt Resp Warnings Diagnosis - - High risk ACA in Ph+ cells 3 mos No CHR No Cg. R 6 mos < CHR No Cg. R < PCg. R 12 mos < PCg. R < CCg. R 18 mos < CCg. R < MMol. R Anytime ACA in Ph+ cells Loss of CHR Loss of CCg. R Mutation (IM-insensit. ) Loss of MMol. R Mutation (IM-sensit. ) Baccarani M, et al. JCO 2009. < MMol. R Any �BCR-ABL transcript level OCA in Ph- cells
IRIS-Study (imatinib): EFS: 18 -month landmark analysis 95% P =. 01 86% 62% 58% ≤ 0. 1% (n = 164) >0. 1 -1% (n = 47) >1 -10% (n = 25) >10% (n = 13) Hughes and Hochhaus et al, Blood. 2010; 116: 3758 -65.
Survival probability CML IV: OS according to molecular response by 12 months p=0. 0011 <0. 1% IS by 12 months, 0. 1%-1% IS by 12 months, >1% IS by 12 months, n=341, 5 -year OS: 97% n=240, 5 -year OS: 96% n=267, 5 -year OS: 88% Years after diagnosis Hehlmann et al. , J Clin Oncol 2011
Imatinib 800 mg vs. imtinib 400 mg +/- IFN Time to MMR by therapy n = 970 Hehlmann et al. , J Clin Oncol 2011
Probability of undetectable BCR-ABL Undetectable BCR-ABL % 100 90 MMR by 12 months 80 No MMR by 12 months 70 72% 60 50 P< 0. 0001 40 30 20 10 0 Pre 5% 1 2 3 Years on Imatinib Branford et al. , Clin Cancer Res 2007 4 5 6
Overall Survival (OS) BCR-ABLIS at 3 months ≤ 1% vs. 1 -10% vs. >10% ≤ 1% 1 -10% >10% BCR-ABLIS n 5 Y-OS ≤ 1% 218 97% 1 -10% 283 94% >10% 191 87% Hanfstein et al. , ASH 2011 p-value n. s. 0. 012
The International Scale (IS) for BCR-ABL LOCAL ASSAY International Scale 100% [IRIS baseline] 10% Conversion factor/ Reference samples 1% 0. 01% 0. 001% Cross NCP. Best Pract Res Clin Haematol 2009; 22: 355 -365. [IRIS MMR; 3 log reduction]
BCR-ABL levels in 58 labs pre and post conversion CV 1. 32 1. 30 1. 10 1. 02 0. 20 0. 24 0. 31 0. 41 1000 BCR-ABL 100 10 1 MMR 0. 1 0. 001 0. 0001 Level 2 Level 3 Level 4 reference results BCR-ABLL pre conversion Level 1 Level 2 Level 3 Level 4 BCR-ABLIS post conversion Müller et al. , Leukemia 2009
Monitoring: ELN Recommendations Diagnosis § § BM aspiration cytology (+biopsy) BM cytogenetics PB Multiplex PCR (Type of BCR-ABL transcript) (PB FISH) Follow up § § § BM cytogenetics 3 monthly until CCy. R q. RT-PCR 3 -6 monthly (interphase FISH to confirm CCy. R, if PCR is not available) Systematic monitoring is the best motivation for adherence. Baccarani et al. , J Clin Oncol. 2009
Definitions of Complete Molecular Response 100% [IRIS baseline] MR 4 (≥ 4 log reduction; ≤ 0. 01%IS) 10% 1% MR 4. 5 (≥ 4. 5 log reduction; ≤ 0. 0032%IS) 0. 1% [IRIS MMR] 0. 01% MR 5 (≥ 5 log reduction; ≤ 0. 001%IS) 0. 001% BCR-ABL undetectable log reduction = reduction from IRIS baseline, not individual pretreatment levels International Scale
Nilotinib: Cumulative Incidence of MR 4. 5* % With CMR 4. 5 40 n 282 281 283 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 30 By 3 Years 32%, P <. 0001 By 1 Year 11%, P <. 0001 28%, P =. 0003 20 Δ 13%-17% 15% 10 7%, P <. 0001 Δ 6%-10% 0 1% 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since Randomization * Equivalent to BCR-ABL transcript levels of ≤ 0. 0032% (IS). 14 Data cut-off: 27 Jul 2011.
DASISION: Cumulative incidence of BCR-ABLIS ≤ 0. 0032% (MR 4. 5) 100 Dasatinib 100 mg QD Imatinib 400 mg QD By 24 months 17% % 20 P=0. 002 10 8% 0 0 10 20 30 Months 40 Kantarjian et al. , ASCO 2011
BCR-ABL Mutations Glu 255 Lys/Val (IC 50 6. 7 μM): § Loss of H bonds to Tyr 257 & Lys 247 G A G = Glu G T G = Val Courtesy Paul Manley
Spectrum and frequency of BCR-ABL mutations Apperley Lancet Oncol. 2007; 8: 1018 -29.
Not all “mutations“ are related to resistance! Wild-type ABL alleles BCR-ABL allele 58758 G/A 58778 A/G 68708 T/G 74901 A/G T 240 T K 247 R F 311 V E 499 E Ernst et al. , Haematologica 2008
Nilotinib efficacy according to baseline BCR-ABL mutations in CML-CP (n=202) No Mutation Others* T 315 I F 359 C/V E 255 K/V Y 253 H IC 50 -based grouping 15% 3% 5% 4% 4% IC 50 ≤ 150 n. M M 244 V, L 248 V, G 250 E, Q 252 H, E 275 K, D 276 G, F 317 L, M 351 T, E 355 A, E 355 G, L 387 F, F 486 S IC 50 > 150 n. M Y 253 H, E 255 K/V, F 359 C/V 24% IC 50 ≤ 150 n. M IC 50 > 10, 000 n. M T 315 I * Mutations without available IC 50 data ASH 2008
Frequency of baseline BCR-ABL mutations by in vitro IC 50 to dasatinib Patients with resistance or suboptimal response to imatinib Unknown IC 50 to dasatinib (n=74) 38 different BCR-ABL mutations 9% No BCR-ABL mutation (n=421) 52% 31% IC 50 ≤ 3 n. M (n=248) M 244 V, G 250 E, Y 253 F/H/K, F 311 L, M 351 T, E 355 G, F 359 C/I/V, V 379 I, L 387 M, H 396 P/R <1% V 299 L (n=1) 1% Q 252 H (n=6) 2% F 317 L (n=13) 3% E 255 K/V (n=25) 2% T 315 I (n=20) IC 50 >200 n. M Müller et al. ASH 2008 IC 50 >3 n. M (n=42) 5%
Recommendations • BCR-ABL mutation analysis is recommended: At diagnosis: Only in AP/BC patients During 1 st-line imatinib therapy: In case of failure In case of an >5 -fold increase in BCR-ABL transcripts and loss of MMR In any other case of suboptimal response During 2 nd-line dasatinib or nilotinib therapy: In case of hematologic or cytogenetic failure • In all these cases, a positive result is an indication for therapeutic change Soverini et al. , Blood. 2011
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