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DR Discontinuation of second generation tyrosine kinase inhibitors CML and MPDs UK national meeting Newcastle, March 1 st, 2013 Dr Delphine Rea Service.

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Presentation on theme: "DR Discontinuation of second generation tyrosine kinase inhibitors CML and MPDs UK national meeting Newcastle, March 1 st, 2013 Dr Delphine Rea Service."— Presentation transcript:

1 DR Discontinuation of second generation tyrosine kinase inhibitors CML and MPDs UK national meeting Newcastle, March 1 st, 2013 Dr Delphine Rea Service des Maladies du Sang Hôpital Saint-Louis Paris, France Fi-LMC (France Intergroupe-Leucémies Myéloïdes Chroniques)

2 DR Current goals of TKI therapy CP-CML at Diagnosis M3M6M12M18 CHR, Minor CyR PCyR CCyR MMR Stable or improving MMR > M18 PFSEFS Time on TKI therapy Leukemic burden Treatment change upon lack or loss of an optimal response, progression or unacceptable side effects Near-normal life expectancy Baccarani et al. JCO 2009; 27: Björkholm et al. JCO 2011: Gambacorti-Passerini et al. JNCI 2011; 103: « Induction » phase « Lifelong maintenance »

3 DR Evidence that TKIs may not be curative Primitive CD34 + CD38 - BCR-ABL + cells are insensitive to imatinib-, dasatinib-, nilotinib- and bosutinib-induced cell death in vitro 1-4 CD34 + CD38 - BCR-ABL + cells escape from TKI-induced cell death is independent from BCR-ABL in vitro 5 CD34 + CD38 - BCR-ABL + residual cells in optimal responders to imatinib survive independently from BCR- ABL and possess in vivo repopulating capacities in mice 6 1 Graham et al. Blood 2002; 99: Copland et al. Blood 2006; 107: Jorgensen et al. Blood 2007; 109: Konig et al. Blood 2008; 111: Corbin et al. JCI 2011; 121: Hamilton et al. Blood 2012; 119:

4 DR Median BCR-ABL (IS) transcript levels over 84 months in the IRIS trial Hughes et al. Blood 2010; 116: % 0.004%

5 DR STIM: Stopping imatinib is feasible Mahon et al. Blood (ASH) 2011; 118: Abstract 603 Survival without molecular relapse Months since discontinuation of imatinib Median follow-up: 34 months (9-50) Molecular relapses: n=61 Survival without molecular relapse: 39% (95% CI: 29-48) at 24 and 36 months Undetectable BCR-ABL: at least copies of the ABL control gene Molecular relapse: defined by 2 positive RQ-PCR results over 1 month showing a significant rise in BCR-ABL transcripts; triggers imatinib resumption. CP-CML Imatinib ≥ 3 years Undetectable BCR-ABL ≥ 2 years

6 DR Factors potentially associated with outcome StudyFactors French prospective STIM study 1 Sokal risk group Imatinib treatment duration Australian prospective CML8 study 2 Sokal risk group IFN treatment duration prior to imatinib therapy Japanese survey 3 Imatinib treatment duration Duration of undetectable BCR-ABL transcripts Imatinib dose intensity Prior exposure to IFN Korean retrospective study 4 Sokal risk group Time to undetectable BCR-ABL transcripts Imatinib treatment duration 1 Mahon et al. Blood (ASH) 2011; 118: Abstract Ross et al. Haematologica 2012; abstract Takahashi et al. Haematologica 2012; 97: Yhim et al. Leukemia Research 2012; 36:

7 DR Rationale for 2G-TKI discontinuation Dasatinib and nilotinib display increased potency in vitro against BCR-ABL compared with imatinib 1 Dasatinib and nilotinib are efficient salvage therapies in patients with intolerance or resistance to imatinib 2,3 Frontline dasatinib and nilotinib induce higher rates of deep molecular responses than imatinib 4,5 Case reports on dasatinib cessation in 4 patients with imatinib-resistant CML with very low or undetectable BCR- ABL transcripts 6,7 4 Saglio et al. N Engl J Med 2010; 362: Kantarjian et al. N Engl J Med 2010; 362: Rea et al. Leukemia 2009; 23: Ross et al. Haematologica 2011; 96: O’Hare et al. Cancer Res 2005; 65: Shah et al. J Clin Oncol 2008; 26; Kantarjian et al. Blood 2007; 110:

8 DR STOP 2G-TKI: study design Primary endpoint: survival without loss of MMR Molecular relapse: loss of MMR Loss of MMR triggered treatment resumption M12M60D1 STOP 2G-TKI Undetectable BCR-ABL* ≥ 24 months *Molecular monitoring performed in local laboratories filling international standardization requirements. * copies of ABL at least. RQ-PCR monthly RQ-PCR Every 3-6 months CP-CML TKI therapy ≥ 3 years 2G-TKI frontline or after imatinib intolerance or resistance Year 1Year 2Year 3-5 RQ-PCR Every 2-3 months M24M36M48

9 DR Baseline characteristics Data, as of November 30, 2012 Patients with a min. follow-up of 6 months (median 17: 7-38), n=39 Median age58 years (34-81) GenderMale n= 15 (38.5%), Female n=24 (61.5%) CML phase at diagnosis Sokal risk group Low / Intermediate / High / Unknown CP 100% 21 (54%) / 9 (23%) / 6 (15%) / 3 (8%) Prior IFN (+/- AraC)12 (33%) Prior TKI Dasatinib or nilotinib only Imatinib + dasatinib or nilotinib Imatinib + dasatinib and nilotinib 2 (5%) 31 (79%) 6 (16%) Reason for 2G-TKI Upfront Intolerance to imatinib Suboptimal response/resistance to imatinib* 2 (5%) 27 (69%) 10 (26%) TKI discontinuation Dasatinib / nilotinib20 (51%) / 19 (49%) Median time since diagnosis Median time since first TKI Median time since 2G-TKI Median duration of undetectable BCR-ABL transcripts 84 months (31-218) 78 months (30-133) 37 months (19-72) 27 months (19-58) *ELN 2006 definition Rea et al. Blood (ASH) 2012; 120: Abstract 916

10 DR Survival without MMR loss Median follow-up was 17 months (7-38) –16/39 patients lost MMR –Median time to MMR loss was 3 months (1-25) STOP 2G-TKI Survival without MMR loss % Months since 2G-TKI discontinuation Month 12: 61.1% (95% CI: ) KM analysis Rea et al. Blood (ASH) 2012; 120: Abstract 916

11 DR Outcome after MMR loss Median BCR-ABL transcript level at MMR loss: –0.35% IS ( ) TKI therapy resumption in 15/16 patients –Median time between MMR loss and therapy resumption: 1 month (0-4) –Same 2G-TKI used prior to discontinuation in all patients but 1 No loss of CHR or progression to AP/BP With a median follow-up of 7 (1-35) months after therapy resumption: –MMR regained in14 patients, median time to MMR 2 (1-6) months –Undetectable BCR-ABL transcripts in 14 patients after a median time of 4 months (3-10) STOP 2G-TKI Rea et al. Blood (ASH) 2012; 120: Abstract 916

12 DR Responsiveness to 2G-TKI upon therapy resumption: patient case Months since dasatinib-induced undetectable BCR-ABL transcripts BCR-ABL/ABL % IS Detectable BCR-ABL Undetectable BCR-ABL with at least copies of ABL DASATINIB RESUMPTION STOP 2G-TKI Dr D Rea, Hôpital Saint-Louis, Paris STOP DASATINIB MMR MR4.5

13 DR Factors associated with outcome Factors Estimated survival without MMR loss at 12 months (%, 95% CI) p value Age: ≤ 58 years vs > % ( ) vs 52.6 % ( )0.219 Gender: Female vs male61.3 % ( ) vs 66.7 % ( )0.901 Sokal risk group: Low vs others66.7 % ( ) vs 52.1 % ( )0.31 Prior IFN exposure: no vs yes56.8 % ( ) vs 69.2 % ( )0.581 Reason for 2G-TKI: Frontline/imatinib intolerance Suboptimal response/resistance to imatinib 68.2 % ( ) 40 % ( ) Type of 2G-TKI: Dasatinib vs nilotinib60 % ( ) vs 62.7 % ( )0.599 Time since diagnosis: ≤ 84 months vs > 84 months63.6 % ( ) vs 57.9 % ( )0.599 Time since first TKI: ≤ 78 months vs > 78 months63.6 % ( ) vs 57.9 % ( ) G-TKI duration: ≤ 37 months vs > 37 months62.2 % ( ) vs 66.7 % ( )0.949 UMRD duration: ≤ 27 months vs > 27 months70 % ( ) vs 52.1 % (-74.8)0.310 STOP 2G-TKI KM analysis, two-tailed logrank test Rea et al. Blood (ASH) 2012; 120: Abstract 916

14 DR BCR-ABL transcripts in patients remaining in MMR Patients in MMR without therapy (median follow-up 17 months: 7-37) n=23 Always undetectable7/23 (30.4%) Occasionally detectable on 1 test8/23 (34.8%) Occasionally detectable on ≥ 2 consecutive tests8/23 (34.8%) STOP 2G-TKI

15 DR Different outcomes of persistent LSC Self renewal Survival TKI + BCR-ABL+ LSC Mat Pre Pro CML disease relapse STOP TKI STOP TKI Mat Pre Pro Ph+ LSC- driven hematopoiesis Inhibited Ph+ LSC- driven hematopoiesis No CML disease relapse Deep and sustained Molecular response Why ? CML-related factors? Therapy-related factors? Host-related factors?

16 DR

17 DR Conclusions Discontinuation of 2G-TKI in patients with deep and sustained molecular responses is possible without jeopardizing short-term outcome, under strict monitoring conditions. TKI discontinuation may not be a realistic goal for all patients but the increasing use of 2G-TKI may broaden access to treatment discontinuation attempts. Patients who successfully stop TKI may not be definitively cured, likely because of LSC persistence. Unknown long-term risk of relapse, acquired resistance and progression to AP/BP after TKI discontinuation. Targeting residual LSC with specific compounds may offer a chance for a definitive cure.


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