Oxford Style Debate on STOPPING Treatment. This house believes that there are good reasons NOT to stop CML treatment. It should be done within clinical trials, OR only in expert centers where frequent, best quality PCR is available IN FAVOUR of the motion Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy
Oxford Style Debate on STOPPING Treatment. This house believes that there are good reasons NOT to stop CML treatment. It should be done within clinical trials, OR only in expert centers where frequent, best quality PCR is available IN FAVOUR of the motion Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy
Postulate 95% of all the newly diagnosed CML patients are currently NOT interested in treatment discontinuation
then Only 5-7% of all the newly diagnosed CML patients are currently potentially interested in treatment discontinuation This house believes that there are good reasons NOT to stop CML treatment. It should be done within clinical trials, OR only in expert centers where frequent, best quality PCR is available
Deep Molecular Responses 100% (IRIS baseline) 10% 1% 0.1% (IRIS MMR) 0.01% 0.0032% 0.001% Deep molecular responses: Categories MR4: 4 log reduction; detectable disease 0.01% IS or undetectable with 10000 ABL1 transcripts MR4.5: 4.5 log reduction; detectable disease 0.0032% IS or undetectable with 32.000 ABL1 transcripts) MR5: 5 log reduction; detectable disease 0.001% IS or undetectable with 100000 ABL1 transcripts) log reduction = reduction from IRIS baseline, not individual pre treatment levels Cross et al. Leukemia 2015; 29: 999-1003. Cross et al. Ann Hematol 2015; 94 Suppl 2: S219-S225. Baccarani et al. Blood 2013; 1242: 872-884. Cross et al. Leukemia 2012; 26: 2172-2175.
Durability of deep molecular responses: ENESTnd Nilotinib 300mg BID N=282 Nilotinib 400mg BID N=281 Patients with MR4.5 at anytime, n(%) 56.4% 56.2% 33.9% Estimated durability of responses,% MR4.5 sustained for 1 year 81.5% 84.3% 84.4% MR4.5 sustained for 2 years 73.1% 77.8% 76.9% MR4.5 sustained for 3 years 66.3% 76.7% 70.6% Imatinib 400mg QD N=283 Hypothesis: TKI cessation Attempt if 2 years of MR4.5 Hypothesis: ~ 50% TFR success rate (loss of MMR as relapse definition) 41% 43.7% 26% 20.5% 21.6% 13% Hochhaus et al. ASH Annual Meeting 2015. Abstract 2781.
So The current BEST estimation possible is that roughly 20% of all CML patients can be expected to be at least in MMR after at least 12 months from discontinuation. BUT
Kaplan-Meier estimates of CMR after discontinuation of imatinib in 100 patients with CML according to factor By SOKAL score Around 50% of newly diagnosed CML patients are NON LOW RISK Among the 11 patients with high sokal risk score 9 relapsed
Durability of deep molecular responses: ENESTnd Nilotinib 300mg BID N=282 Nilotinib 400mg BID N=281 Patients with MR4.5 at anytime, n(%) 56.4% 56.2% 33.9% Estimated durability of responses,% MR4.5 sustained for 1 year 81.5% 84.3% 84.4% MR4.5 sustained for 2 years 73.1% 77.8% 76.9% MR4.5 sustained for 3 years 66.3% 76.7% 70.6% Imatinib 400mg QD N=283 Hypothesis: TKI cessation attempt if 2 years of MR4.5 Hypothesis: ~ 50% success rate in Treatment-Free Remission (loss of MMR as relapse definition) 41% 43.7% 26% 10.5% 20.5% 6.5% 13% Hochhaus et al. ASH Annual Meeting 2015. Abstract 2781.
Imatinib-free remission: Long-term follow-up Early relapses Molecular relapse-free survival Late relapses Very late relapses: not yet described, cannot be excluded 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Months since imatinib discontinuation Etienne et al. Blood (ASH) 2015; abstract 345.
Quantitative modeling of chronic myeloid leukemia: insights from radiobiology* Tomas Radivoyevitch et al, Blood PEP February 21, 2012;
SUBSEQUENT RELAPSE AMONG PATIENTS ALIVE AND IN REMISSION 5 YEARS POST-BMT 1.0 CUMULATIVE INCIDENCE 0.8 0.6 0.4 0.2 1: Sib + CP1 (N=1,482) 2: Sib + Not CP1 (N=239) 3: Other Donor + CP1 (N=407) 4: Other Donor + Not CP1 (N=106) 0.0 5 6 8 10 14 12 16 18 20 YEARS LTO03_21.ppt
Willingness
Oxford Style Debate on STOPPING Treatment. This house believes that there are good reasons NOT to stop CML treatment. It should be done within clinical trials, OR only in expert centers where frequent, best quality PCR is available IN FAVOUR of the motion Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy
Two minutes concluding remarks without slides
Oxford Style Debate on STOPPING Treatment. This house believes that there are good reasons NOT to stop CML treatment. It should be done within clinical trials, OR only in expert centers where frequent, best quality PCR is available IN FAVOUR of the motion Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy
Oxford Style Debate on STOPPING Treatment. This house believes that there are good reasons NOT to stop CML treatment. It should be done within clinical trials, OR only in expert centers where frequent, best quality PCR is available BACK-UP for 30 min Q&A IN FAVOUR of the motion Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy
History of imatinib discontinuation Case reports or series between 2004-2007: Patient request Adverse events Pregnancy STIM pilot series Pioneering stop trials: STIM and TWISTER Feasibility confirmed in further trials or observational studies: STIM 2, A-STIM, JALSG-STIM213, ISAV, KID, EUROSKI, HOVON 51 Mauro et al. Leuk Res 2004; 28S1: S71-S73. Cortes et al. Blood 2004; 10: 2204-2205. Ghanima et al. Eur J Haematol 2004; 72: 441-443. Merante et al. Haematologica 2005; 90: 979-981. Breccia et al. Leuk Res 2006; 30: 1577-1579. Rousselot et al. Blood 2007; 109: 58-60. Mahon et al. Lancet Oncol 2010; 11: 1029-1035. Ross et al. Leukemia 2010; 24: 1719-1724. Ross et al. Blood 2013; 122: 515-522. Takahashi et al. Haematologica 2012; 97: 903-906. Rousselot et al. JCO 2014; 32: 424-430. Mori et al. Am J Hematol 2015; 90: 910-914. Thielen et al. Eur J Cancer 2013; 49: 3242-3246.
Imatinib-free remission: STIM and TWISTER Stop after 3 years of imatinib and 2 years of CMR4.5 STIM TWISTER At 60 months 40% (95% CI: 30-49) Molecular relapse : detectable BCR ABL1 on 2 consecutive tests showing a significant increase or loss of MMR. Molecular relapse: any sample with loss of MMR or 2 consecutive positive samples at any value. Mahon et al. Lancet Oncol. 2010; 11: 1029-1035. Mahon et al. Blood 2013; 122: abstract 255. Ross et al. Blood 2013; 122: 515-522.
Imatinib-free remission: Despite Leukemic Stem Cell persistence Patients with longlasting UMRD: 3 off-ifn 2 off-ima 1 on DASA TWISTER Ross et al. Leukemia 2010; 24: 1719-1724. Chomel et al. Blood 2011; 118: 3657-3660.
Imatinib-free remission: Long-term follow-up Early relapses Molecular relapse-free survival Late relapses Very late relapses: not yet described, cannot be excluded 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 Months since imatinib discontinuation Etienne et al. Blood (ASH) 2015; abstract 345.
Imatinib-free remission: A-STIM, JALSG-STIM213 and KID A-STIM Imatinib 3 years CMR4.5 2 years, occasional BCR-ABL+ Relapse = loss of MMR JALSG-STIM213 Imatinib 3 years MR4.5 2 years Relapse = loss of MMR KID Imatinib 3 years CMR4.5 2 years Relapse = loss of MMR TFR at 36 months: 61% (95% CI: 51-73) Treatment Free Remission 1.0 0.8 0.6 0.4 0.2 0.0 TFR at 12 months: 69.1%(95% CI: 58-80) TFR at 12 months: 62.2% ±5.1% 0 5 10 15 20 Months Rousselot et al. JCO 2014; 32: 424-430. Lee et al. Haematologica. 2016 Feb 17. pii: haematol.2015.139899. [Epub ahead of print] Takahashi et al. Blood (ASH) 2015: abstract 4035.
STOP imatinib STOP imatinib MMR 0.1 No treatment MMR 0.1 No treatment BCR-ABL1/ABL1 % IS 0.01 0.001 0.0001 0 6 12 18 24 30 36 42 48 Months since imatinib discontinuation BCR-ABL1/ABL1 % IS 0.01 0.001 0.0001 0 6 12 18 24 30 36 42 48 Months since imatinib discontinuation STIM: relapse TWISTER: relapse A-STIM: no relapse JALSG-STIM123: no relapse STIM: no relapse TWISTER: relapse A-STIM: no relapse JALSG-STIM123: no relapse Detectable BCR-ABL Undetectable BCR-ABL 32000 copies of ABL D. Rea personal data Patients enrolled in imatinib discontinuation studies
Safety of imatinib discontinuation: response to treatment resumption No case of imatinib resistance upon treatment resumption has been described in reported studies: MMR and deep molecular responses rapidly regained BCR-ABL/ABL % IS 10 1 0.1 0.01 0.001 STIM 2 patient Imatinib 0.0001 0 6 12 18 24 30 36 Months since imatinib discontinuation One case of acute lymphoblastic transformation in the A-STIM study, in a patient who had lost MMR after imatinib discontinuation but who had regained MMR after treatment reintroduction. Mahon et al. Lancet Oncol 2010; 11: 1029-1035. Ross et al. Blood 2013; 122: 515-522. Mahon et al. Blood (ASH 2013): abstract 654. Rousselot et al. JCO 2014; 32: 424-430. Mahon et al. Blood (ASH 2014); 124: abstract 151. Takahashi et al. Blood (ASH) 2015: abstract 4035. Mori et al. Am J Hematol 2015; 90: 910-914. Lee et al. Haematologica. 2016 Feb 17. [Epub ahead of print]
Depth of molecular response: Does it matter? Treatment-Free Remission 1.0 0.8 0.6 0.4 0.2 0.0 JALSG-STIM123 Imatinib 3 years, MR4.5 2 years Relapse = loss of MMR CMR4.5 (n=49) MR4.5 (n=19) The MR level (CMR4.5/MR4.5) at baseline of this study was the independent prognostic factor for TFR. Log-rand test p=0.025, Breslow p=0.024. Cox proportion hazard model; p=0.032, Exp(B) 2.475 (95% CI 1.081-5.663). Takahashi et al. Blood (ASH 2015): abstract 4035. 0 5 10 15 20 Months
Depth of molecular response: Does it matter? Deep molecular response level before TKI discontinuation and molecular relapse in EURO-SKI* Interim analysis 200 patients, median follow-up 12 months (1-27). Response level n=197 Relapse (n) Relapse (%) MR 4 74 37 49 MR 4.5 79 31 39 MR 5 44 17 39 *Discontinuation of imatinib, dasatinib or nilotinib after at least 3 years of treatment and 1 year in MR4. Loss of MMR defines molecular relapse and triggers treatment resumption. No significant difference but very preliminary results Mahon et al. Blood (ASH 2014); 124: abstract 151.
Treatment and response duration: Does it matter? Treatment and deep molecular response duration before TKI discontinuation in EURO-SKI Interim analysis 200 patients, median follow-up 12 months (1-27). Parameter n Relapses by 6 months (n) Relapses by 6 months (%) p TKI duration < 8y 114 54 47 0.0030 TKI duration > 8y 86 23 27 MR 4 duration < 5y 108 49 45 MR 4 duration > 5y 92 28 30 Median duration of TKI treatment: 8 years (3-13). Median duration of MR4: before TKI discontinuation: 5 years (1-12). No loss of MMR n = 123 / Loss of MMR n = 77. 0.0305 *Chi2 test Mahon et al. Blood (ASH 2014); 124: abstract 151.
Imatinib discontinuation studies Trial N Inclusion criteria Relapse definition TFR or RFS rate A-STIM 80 3 years of imatinib 2 years of CMR4.5 MMR loss 64% (95% CI: 54-75) at 12 and 24 months 61% (95% CI: 51-73) at 36 months JALSG- STIM213 68 3 years of imatinib 2 years of MR4.5 MMR loss 69.1% (95% CI: 58.1-80.1) at 12 months KID 90 (nontransplant subgroup) 3 years of imatinib 2 years of CMR4.5 MMR loss 62.2% ± 5.1 at 12 months and 58.5% ± 5.2 at 24 months ISAV 112 2 years of imatinib 18 months of CMR4 MMR loss 48.1% (95% CI: 38.4-58) at 36 months EURO- SKI 200 (interim analysis, at least 6 months of follow-up) 3 years of TKI 12 months of MR4 MMR loss 56% (95% CI: 49-63) at 12 months Mahon Rousselot et al. JCO 2014; 32: 424-430. Takahashi et al. Blood (ASH 2015): abstract 4035. Lee et al. Haematologica. 2016 Feb 17. pii: haematol.2015.139899. Mori et al. Am J Hematol 2015; 90: 910-914. Mahon et al. Blood (ASH 2014); 124: abstract 151.
ATP-competitive TKIs in CML Imatinib Development Approval Off patent 2016 Dasatinib Development Approval Nilotinib Development Approval Bosutinib Development Approval Ponatinib Development Approval Year 2000 2005 2010 2015
New generation TKI discontinuation Few case reports from 2009: Patient request Adverse events (drug-related or not) Pregnancy Pioneering 1 st or 2 nd line dasatinib or nilotinib discontinuation STOP-2G TKI study. Dasatinib 2 nd line discontinuation: DADI trial. Company-sponsored studies ongoing: ENESTfreedom (1 st line nilotinib) ENESTstop / ENESTpath (2 nd line nilotinib) DASFREE (1 st or 2 nd line dasatinib) Rea et al. Leukemia 2009; 23: 1158-1206. Ross et al. Haematologica 2011; 96: 1720-1722. Aoki et al. Leukemia & Lymphoma 2012; 53: 1412-1414. Gado et al. Exp Hematol & Oncol 2012; 1: 17. Benjamini et al. Leukemia & Lymphoma 2014; 55: 2879-2886. Caocci et al. J Med Case Rep 2014; 8: 295. Rea et al Blood (ASH) 2014: abstract 811. Imagawa et al. Lancet Haematol 2015; 2: e528-e535.
Dasatinib or nilotinib-free remission: STOP 2G-TKI and DADI STOP 2G-TKI 1 st, 2 nd or 3 rd line dasatinib or nilotinib 3 years of TKI and 2 years of CMR4.5 N=52 Relapse = loss of MMR TFR at 12 months (overall): 59% (95% CI; 46-72) DADI 2 nd line dasatinib and MR4 consolidated for 1 year N=63 Relapse = loss of MR4 TFR at 12 months (overall): 48% (95% CI: 35-59) % Treatment-free survival in MMR 100 80 60 40 20 0 0 6 12 18 24 30 36 42 48 54 60 Months after 2G-TKI discontinuation Rea et al Blood (ASH) 2014: abstract 811. Imagawa et al. Lancet Haematol 2015; 2: e528-e535.
Dasatinib or nilotinib-free: STOP 2G-TKI and DADI STOP 2G-TKI N=52 Relapse = loss of MMR TFR at 12 months (overall): 59% (95% CI; 46-72) DADI N=63 Relapse = loss of MR4 TFR at 12 months (overall): 48% (95% CI: 35-59) % Treatment-free survival in MMR 100 80 60 40 20 0 p=0.048 First line or after imatinib intolerance After imatinib resistance or suboptimal response 0 6 12 18 24 30 36 42 48 54 60 Months after 2G-TKI discontinuation Rea et al Blood (ASH) 2014: abstract 811. Imagawa et al. Lancet Haematol 2015; 2: e528-e535.
ENESTnd: cumulative incidence of MR4.5 by 6 years Cumulative Incidence of MR 4.5, % 100 90 80 70 60 50 40 30 20 10 0 Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) By 1 Year 11%; P <.0001 a 7%; P <.0001 a Δ 6% to 10% 1% By 5 Years 54%; P <.0001 a 52%; P <.0001 a 31% 0 6 12 18 24 30 36 42 48 54 60 Δ 21% to 23% By 6 Years 56%; P <.0001 a 55%; P <.0001 a Δ 22% to 23% 33% 66 72 78 Months Since Randomization KM-estimated median times to first MR 4.5 were: Nilotinib 300 mg BID: 45.5 months (hazard ratio [HR] vs imatinib, 2.0387 [95% CI, 1.5807-2.6295]; nominal P <.0001) Nilotinib 400 mg BID: 49.8 months (HR vs imatinib, 1.7770 [95% CI,1.3780-2.2915]; nominal P <.0001) Imatinib 400 mg QD: 61.1 months a P values are nominal. Larson et al. Blood. 2014:[abstract 4541].
MR 4.5 by 5 Years a According to Sokal Risk Score 80 P =.0004 P =.0082 Patients With MR 4.5,% 70 60 50 40 30 20 P =.0148 53.4 36.5 61.2 P <.0001 60.4 31.7 50.0 P =.0105 P =.0041 44.9 23.1 42.3 10 0 n = 104 103 103 101 101 100 78 78 78 Low Risk Intermediate Risk High Risk Imatinib 400 mg QD Nilotinib 300 mg BID Nilotinib 400 mg BID (n = 283) (n = 282) (n = 281) a By cycle 60 (28 days per cycle). Saglio G, et al. Blood. 2013:[abstract 92].
ENESTcmr 4-Year Results Cumulative Incidence of MR 4.5 in Patients Without MR 4.5 at Baseline (excluding responses achieved after crossover): ENESTcmr Nilotinib Imatinib Patients With MR 4.5, % 70 60 50 40 30 20 10 0 n P =.0020 a 33 14 P =.0006 a 43 21 98 96 98 96 98 96 98 96 By 12 Months Δ 19% By 24 Months Δ 22% P =.0015 a 47 26 By 36 Months Δ 21% P =.0004 a 52 28 By 48 Months Δ 24% When only responses up to crossover were considered, 28% of patients in the imatinib arm without MR 4.5 at baseline achieved MR 4.5 by 48 months a P values are nominal and are provided for descriptive purposes only. Hughes et al. Haematologica 2015 (EHA); 100: abstract P229