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Discontinuation of second generation tyrosine kinase inhibitors

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

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Discontinuation of second generation tyrosine kinase inhibitors

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

  2. Current goals of TKI therapy « Induction » phase « Lifelong maintenance » CP-CML at Diagnosis Near-normal life expectancy PFS EFS CHR, Minor CyR PCyR CCyR MMR Leukemic burden Stable or improving MMR > M18 M3 M6 M12 M18 Treatment change upon lack or loss of an optimal response, progression or unacceptable side effects Time on TKI therapy Baccaraniet al. JCO 2009; 27: 6041-6051 Björkholm et al. JCO 2011: 2514-2420 Gambacorti-Passerini et al. JNCI 2011; 103: 553-561

  3. 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 vitro1-4 • CD34+CD38- BCR-ABL+ cells escape from TKI-induced cell death is independent from BCR-ABL in vitro5 • CD34+CD38- BCR-ABL+ residual cells in optimal responders to imatinib survive independently from BCR-ABL and possess in vivo repopulating capacities in mice6 1Graham et al. Blood 2002; 99: 319-325 2Copland et al. Blood 2006; 107: 4532-4539 3Jorgensen et al. Blood 2007; 109: 4016-4019 4Konig et al. Blood 2008; 111: 2329-2338 5Corbin et al. JCI 2011; 121: 396-406 6Hamilton et al. Blood 2012; 119: 1501-1510

  4. Median BCR-ABL (IS) transcript levels over 84 months in the IRIS trial 0.003% 0.004% Hughes et al. Blood 2010; 116: 3758-3765

  5. STIM: Stopping imatinib is feasible CP-CML Imatinib≥3 years Undetectable BCR-ABL≥2 years 1.0 Survival without molecular relapse: 39% (95% CI: 29-48) at 24 and 36 months 0.9 0.8 0.7 0.6 Survival without molecular relapse 0.5 0.4 0.3 0.2 Molecular relapses: n=61 0.1 Median follow-up: 34 months (9-50) 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Months since discontinuation of imatinib Undetectable BCR-ABL: at least 50 000 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. Mahon et al. Blood (ASH) 2011; 118: Abstract 603

  6. Factors potentially associated with outcome 1Mahon et al. Blood (ASH) 2011; 118: Abstract 603 2Ross et al. Haematologica 2012; abstract 0189. 3Takahashi et al. Haematologica 2012; 97: 903-906 4Yhim et al. Leukemia Research 2012; 36: 689-693

  7. Rationale for 2G-TKI discontinuation • Dasatinib and nilotinib display increased potency in vitro against BCR-ABL compared with imatinib1 • Dasatinib and nilotinib are efficient salvage therapies in patients with intolerance or resistance to imatinib2,3 • Frontline dasatinib and nilotinib induce higher rates of deep molecular responses than imatinib4,5 • Case reports on dasatinib cessation in 4 patients with imatinib-resistant CML with very low or undetectable BCR-ABL transcripts6,7 4Saglio et al. N Engl J Med 2010; 362: 2251-2259 5Kantarjian et al. N Engl J Med 2010; 362: 2260-2270 6Rea et al. Leukemia 2009; 23: 1158-1159 7Ross et al. Haematologica 2011; 96: 1720-1722 1O’Hare et al. Cancer Res 2005; 65: 4500-4505 2Shah et al. J ClinOncol 2008; 26; 3204-3212 3Kantarjian et al. Blood 2007; 110: 3540-3546

  8. STOP 2G-TKI: study design Primary endpoint: survival without loss of MMR Molecular relapse: loss of MMR Loss of MMR triggered treatment resumption CP-CML TKI therapy ≥ 3 years 2G-TKI frontline or after imatinib intolerance or resistance D1 M12 M24 M36 M48 M60 Undetectable BCR-ABL* ≥ 24 months STOP 2G-TKI Year 1 Year 2 Year 3-5 RQ-PCR monthly RQ-PCR Every 2-3 months RQ-PCR Every 3-6 months *Molecular monitoring performed in local laboratories filling international standardization requirements. *20 000 copies of ABL at least.

  9. Baseline characteristics *ELN 2006 definition Rea et al. Blood (ASH) 2012; 120: Abstract 916

  10. 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 100 Month 12: 61.1% (95% CI: 45.6-76.6) 80 60 Survival without MMR loss % 40 20 0 0 6 12 18 24 30 36 42 KM analysis Months since 2G-TKI discontinuation Rea et al. Blood (ASH) 2012; 120: Abstract 916

  11. STOP 2G-TKI Outcome after MMR loss • Median BCR-ABL transcript level at MMR loss: • 0.35% IS (0.12-1.95) • 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) Rea et al. Blood (ASH) 2012; 120: Abstract 916

  12. STOP 2G-TKI Responsiveness to 2G-TKI upon therapy resumption: patient case STOP DASATINIB 10 DASATINIB RESUMPTION 1 MMR 0.1 BCR-ABL/ABL % IS 0.01 MR4.5 0.001 0.0001 0 6 12 18 24 30 36 42 48 54 60 66 Detectable BCR-ABL Months since dasatinib-induced undetectable BCR-ABL transcripts Undetectable BCR-ABL with at least 32000 copies of ABL Dr D Rea, Hôpital Saint-Louis, Paris

  13. STOP 2G-TKI Factors associated with outcome KM analysis, two-tailed logrank test Rea et al. Blood (ASH) 2012; 120: Abstract 916

  14. STOP 2G-TKI BCR-ABL transcripts in patients remaining in MMR

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

  16. 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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