Verso un interruzione dei farmaci nella leucemia mieloide cronica

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1 Verso un interruzione dei farmaci nella leucemia mieloide cronica Giuseppe Saglio

2 Rational to try to discontinue therapy Quality of life Long-term side effects of therapy still unknown Cost

3 Terms and definitions Therapy cessation Therapy discontinuation Treatment Free Remission similar definitions Recurrence, molecular relapse (the disease does not come back, but Bcr-Abl becomes again detectable or increases above a certain limit) Restart treatment

4 French STIM (Stop Imatinib) experience Imatinib discontinuation The overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI 29-48). 39% Molecular relapse occurred in 61 pts with 58 relapses occurring during the first 7 months 3 late relapses at month 19, 20 and 22, respectively Mahon FX, et al. Blood 2011;118:abstract 603

5 After discontinuation, some patients may show fluctuation in MRD CML patient in CP 31 years old Low risk Sokal score Rousselot P, personal data.

6 RousselotPet al. JCO 2014

7 (i) (ii) (iii) (iv) (v) (vi) Goh et al. Leukemia &Lymphoma 2011

8 Goh et al. Leukemia &Lymphoma 2011

9 Pagani IS et al. Oncoscience 2014

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11 Imatinib discontinuation Summary of imatinib-discontinuation studies STIM 1,2, n=100 CP-CML, imatinib 400mg/d frontline or post IFN-α for a least 36 months Undetectable BCR-ABL for at least 24 months confirmed at study entry* CML8 3,4, n=40 CP-CML, imatinib frontline or post IFN-α for at least 36 months Undetectable BCR-ABL on continuing imatinib for at least 2 years** A-STIM, n=34 5 CP-CML, imatinib frontline or post IFN-α MR4.5 or CMR4.5 for at least 24 months Japanese survey 6, n=43 Imatinib stopped for at least 6 months due to any cause except progression, transplantation or death Undetectable BCR-ABL on continuing imatinib for at least 12 months*** Korean retrospective study 7, n=14 Undetectable BCR-ABL on continuing imatinib for at least 12 months*** 1 Mahon et al. Lancet Oncol. 2010; 11: Mahon et al. Blood (ASH) 2011; 118: Abstract Ross et al. Leukemia 2010; 24: Ross et al. Haematologica 2012; abstract Rousselot et al. Blood (ASH) 2011; 118: abstract Takahashi et al. Haematologica 2012; 97: Yhim et al. Leukemia Research 2012; 36: * copies at least of ABL at study entry **RT-PCR sensitivity of at least 4.5log ***RT-PCR sensitivity of at least 4 logs

12 Australian CML8 experience (Twister) Imatinib discontinuation 43% Ross M et al, Haematologica 2012; 97:[abstract 0189].

13 Prerequisites for TKI discontinuation

14 Prerequisites for discontinuation Mahon FX, et al. Blood 2011;118:abstract 603.

15 Prerequisites for TKI discontinuation Stableand verylowamountof residual disease. MR 4 (4logs), MR 4.5 (4.5 logs) minimum For howlong? 1/2 years? 78% vs. 15%, P =.0002 by Log-rank test Takahashi N et al., Haematologica, 2012; 97:

16 Factors associated with outcome after imatinib cessation Study Significant factors STIM study 1 CML8 study 2 Japanese survey 3 Korean retrospective study 4 Sokal risk group Imatinib treatment duration Sokal risk group Prior exposure to IFN Imatinib treatment duration Duration of undetectable BCR-ABL transcripts Imatinib dose intensity Prior exposure to IFN Sokal risk group Time to undetectable BCR-ABL transcripts Imatinib treatment duration 1 Mahon et al. Blood (ASH) 2011; 118: Abstract Ross et al. Haematologica2012; abstract Takahashi et al. Haematologica2012; 97: Yhim et al. Leukemia Research 2012; 36:

17 Deep molecular response according to BCR- ABL transcripts level at 3 months Branford et al. Blood : ; Prepublished online March 20, 2013

18 TKI discontinuation: Are there risks? No eventsof relapsetoap or BC havebeenreported 10 No acquired drug-resistance: Sensitivity to imatinib is preserved % BCR-ABL/ABL 1 Start again 0,1 Stop 0,01 0,001 STIM: Among the 59 with recurrence, 49 achieved again CMR after imatinib rechallenge. A median time of 4 months (range 0 21) was necessary for CMR to recur. Mahon et al., Lancet Oncol. 2010; 11:

19 Can we try to stop several times? Second attempt of imatinib discontinuation in CP-CML patients with a second sustained undetectable molecular response S T O P R E L A P S E N=16 Achieved CMR with imatinib and maintained for a 1 year S T O P Survival without loss of MMR % Kaplan-Meier estimates of MMR after a second discontinuation of imatinib in patients with CML m 1y 2y Time since second imatinib discontinuation (months) It is possible to safely stop treatment several times in CML patients who are in sustained UMR but interruption strategies must be optimized before a new attempt at imatinib cessation. Legros L et al., Blood, 2012; 120:

20 Can we improve the discontinuation rate? Can we identify those patients who are Can we identify those patients who are candidate for discontinuation attemps?

21 Early molecular response predicts: PFS & OS The achievementof deeper molecularresponses

22 Probability of CMR % Probability of CMR by 60 months 181 de-novo patients 400/600 mg imatinib tested in Adelaide 100 MMR by 6 months 90 MMR >6 to 12 months 80 MMR >12 to 18 months Months after commencing imatinib Branford et al. Blood. 2008:112. Abstract P< P< % 69% 93% 47% P<0.001 No MMR by 18mo 0%

23 Pooled Landmark Analysis: Estimated Rates of MR 4.5 According to BCR-ABL IS at 3 Months a By 60 Months 81.0% (95%CI ) % of patients with MR % (95%CI ) 31.5% (95%CI ) Patients with BCR-ABL IS 1% at 3 months had the highest estimated rate of MR 4.5 by 5 years Data cutoff: September 30, 2013 a Among patients with evaluable baseline and 3-month assessments and without MR 4.5 by 3 months. 23

24 Proportion of Patients With MR 4.5 by BCR-ABL Levels at 3 Months Nilotinib 300 mg BID Imatinib 400 mg QD BCR-ABL IS 1%: 56% of pts BCR-ABL IS 1%: 16% of pts Patients With MR 4.5, % BCR-ABL Level 1% > 1% to 10% > 10% Pts MR 4.5 by 4 Years a 58% P = % P = % MR 4.5 by 5 Years a 70% P = % 8% P = Time Since Randomization, Calendar Years Patients With MR 4.5, % BCR-ABL Level 1% > 1% to 10% > 10% Pts MR 4.5 by 4 Years a 65% P < % 5% MR 4.5 by 5 Years a 67% 34% P =.0001 P =.0016 P = 15% Time Since Randomization, Calendar Years Patients with BCR-ABL 1% at 3 months have significantly higher rates of MR 4.5 by 5 years More patients achieve BCR-ABL 1% at 3 months on nilotinib 300 mg BID vs imatinib a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. 24

25 Cumulative Incidence of MR 4.5 Patients With MR 4.5, % Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 6% to 10% By 1 Year a 11%, P < %, P < % By 4 Years a 40%, P < %, P = % to 17% 23% By 5 Years a 54%, P < %, P < % to 23% % Time Since Randomization, Calendar Years MR 4.5, molecular response 4.5-logs (BCR-ABL IS %). a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. 25

26 Puo la sospensione della terapia diventare comune pratica clinica?

27 Risultati: pazienti off-therapy (1) 28su 272 pazienti analizzati hanno sospeso il trattamento con Imatinib Nessun paziente ha sospeso 2G-TKI Caratteristiche dei pazienti: Sesso: 46,4% F, 53,6% M; Rischio Sokal: 42,8% basso, 14,2% intermedio, 14,2% alto, 28,7% N.V. Età mediana alla diagnosi: 47 anni (range 18-78); Pregressa terapia con IFN: 59,8%; Durata mediana terapia con Imatinib: 69 mesi (range ); sesso M 46% F 54% Sokal score alto 14% intermedio 14% basso 43% n.v. 29% IFN si 60% no 40% Durata mediana risposta MR4: 38 mesi (range: mesi).

28 Risultati: pazienti off-therapy (2) 28 pazienti hanno sospeso Imatinib 22 pazienti in CMR 6 pazienti non in CMR 18 pazienti mantengono la risposta Treatmentfree remission 10 pazienti hanno perso la MMR o l MR4 Ripresa della terapia Nuova remissione (MMR-MR4) 8pz in CMR 2 pz non in CMR 63% dei pazienti rimane in TFR dopo un follow-up mediano di 43,2 mesi; Nessuna morte correlata alla LMC, nessuna progressione alle fasi avanzate.

29 Risultati: pazienti off-therapy (3) treatment-free remission Il 10,3% della popolazione di pazienti analizzata ha sospeso Imatinib; IFN >12 mesi 86% IFN <12 mesi 53% p=0,038 I tassi di TFR sono stati significativamente maggiori nei pazienti con pregressa terapia con IFN >12 mesi; La treatment-free duration mediana è stata di 38 mesi (range7-104).

30 paziente data r Q-PCR RQ-PCR standard al momento della rq-pcr data discontinuazion e TKI pozzetti positivi % pozzetti positivi/82 trattamento al momento dell'analisi RQ-PCR all'ultimo follow-up data ultimo follow-up treatmentfree duration (mesi) 1 25/02/2009 0% 01/02/2006 0% 0 off treatment 0% 05/05/ ,5 63,2 tempo da rq-pcr a ultimo follow-up (mesi) 19/11/2012 0% 0% 0 off treatment 05/05/ ,7 2 19/02/2007 0% 27/10/2005 8,54% 7 off treatment 0% 04/11/ ,7 81,7 22/10/2007 0% 12,20% 10 off treatment 04/11/ ,5 02/02/2009 0,022% 82,92% 68 off treatment 04/11/ ,9 06/11/2012 0% 1,22% 1 CML VAX 04/11/ ,1 3 21/10/2010 0% 10/05/2004 2,439% 2 off treatment 0% 14/01/ ,7 27,2 14/01/2013 0% 0% 0 off treatment 14/01/2013 0,0 4 30/01/2009 0% 24/08/2005 0% 0 off treatment 0% 05/05/ ,9 64,0 28/03/2013 0% 14,63% 12 off treatment 05/05/ ,4 5 17/02/2014 0% / 0 0 Imatinib 0% 26/05/2014 / 3,3 6 10/12/2012 0% / 2,44% 2 Imatinib 0% 07/05/2014 / 17,1 7 14/10/2013 0% / 1,22% 1 Imatinib 0% 21/05/2014 / 7,3 8 29/07/2013 0% / 0% 0 Nilotinib 0% 02/04/2014 / 8,2 9 06/03/2014 0% / 0% 0 Nilotinib 0% 07/03/2014 / 0, /07/2013 0% / 30,49% 25 Imatinib 0,0006% 03/03/2014 / 7, /02/2014 0% / 3,66% 3 Imatinib 0,0013% 16/05/2014 / 2, /07/2013 0% / 4,88% 4 Dasatinib 0,0007% 09/04/2014 / 8, /02/2014 0% / 7,32% 6 Imatinib 0% 14/04/2014 / 1, /02/2014 0% / 1,22% 1 Imatinib 0% 09/04/2014 / 1,5

31 Our next goal for CML therapy? Treatment discontinuation!

32 In some cases TKIs alone, in other cases we need combination therapies with haematopoietic stem cell targeting agents IFN-alpha Vaccines/immunostimulatory agents Hh pathway antagonist/smo inhibitor HDAC inhibitor (e.g., panobinostat) PI3K +/- mtor inhibitors STAT5 pathway inhibitor PP2A activator (e.g., FTY720) FTI (e.g., BMS ) Wnt/beta catenin inhibitors IL-1 receptor accessory protein Old known drug Low cost Powerful Investigational drugs Long term side effects unknown

33 Grazie per l attenzione!