Verso un interruzione dei farmaci nella leucemia mieloide cronica Giuseppe Saglio
Rational to try to discontinue therapy Quality of life Long-term side effects of therapy still unknown Cost
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
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
After discontinuation, some patients may show fluctuation in MRD CML patient in CP 31 years old Low risk Sokal score Rousselot P, personal data.
RousselotPet al. JCO 2014
(i) (ii) (iii) (iv) (v) (vi) Goh et al. Leukemia &Lymphoma 2011
Goh et al. Leukemia &Lymphoma 2011
Pagani IS et al. Oncoscience 2014
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: 1029-1035 2 Mahon et al. Blood (ASH) 2011; 118: Abstract 603 3 Ross et al. Leukemia 2010; 24: 1719-1724 4 Ross et al. Haematologica 2012; abstract 0189 5 Rousselot et al. Blood (ASH) 2011; 118: abstract 3781 6 Takahashi et al. Haematologica 2012; 97: 903-906 7 Yhim et al. Leukemia Research 2012; 36: 689-693 *50 000 copies at least of ABL at study entry **RT-PCR sensitivity of at least 4.5log ***RT-PCR sensitivity of at least 4 logs
Australian CML8 experience (Twister) Imatinib discontinuation 43% Ross M et al, Haematologica 2012; 97:[abstract 0189].
Prerequisites for TKI discontinuation
Prerequisites for discontinuation Mahon FX, et al. Blood 2011;118:abstract 603.
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; 97:903-06.
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 603 2 Ross et al. Haematologica2012; abstract 0189. 3 Takahashi et al. Haematologica2012; 97: 903-906 4 Yhim et al. Leukemia Research 2012; 36: 689-693
Deep molecular response according to BCR- ABL transcripts level at 3 months Branford et al. Blood 2013 121:3818-3824; Prepublished online March 20, 2013
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; 11:1029-1035.
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 % 100 80 60 40 20 Kaplan-Meier estimates of MMR after a second discontinuation of imatinib in patients with CML 0 0 10 20 30 40 50 60 0 6m 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; 120:1959-60.
Can we improve the discontinuation rate? Can we identify those patients who are Can we identify those patients who are candidate for discontinuation attemps?
Early molecular response predicts: PFS & OS The achievementof deeper molecularresponses
Probability of CMR % 70 60 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 50 40 30 20 10 0 0 12 24 36 48 60 Months after commencing imatinib Branford et al. Blood. 2008:112. Abstract 2113. P<0.0002 P<0.01 37% 69% 93% 47% P<0.001 No MMR by 18mo 0%
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 76.2-85.8) % of patients with MR 4.5 55.9% (95%CI 49.3-62.5) 31.5% (95%CI 20.1-42.8) 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
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, % 100 90 80 70 60 50 40 30 20 10 0 BCR-ABL Level 1% > 1% to 10% > 10% Pts 144 89 24 MR 4.5 by 4 Years a 58% P =.0001 28% P =.0135 4% MR 4.5 by 5 Years a 70% P =.0046 52% 8% P =.0001 0 1 2 3 4 5 6 Time Since Randomization, Calendar Years Patients With MR 4.5, % 100 90 80 70 60 50 40 30 20 10 0 BCR-ABL Level 1% > 1% to 10% > 10% Pts 43 133 88 MR 4.5 by 4 Years a 65% P <.0001 24% 5% MR 4.5 by 5 Years a 67% 34% P =.0001 P =.0016 P = 15%.0001 0 1 2 3 4 5 6 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
Cumulative Incidence of MR 4.5 Patients With 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) 6% to 10% By 1 Year a 11%, P <.0001 7%, P <.0001 1% By 4 Years a 40%, P <.0001 37%, P =.0002 14% to 17% 23% By 5 Years a 54%, P <.0001 52%, P <.0001 21% to 23% 0 1 2 3 4 5 6 31% Time Since Randomization, Calendar Years MR 4.5, molecular response 4.5-logs (BCR-ABL IS 0.0032%). a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. 25
Puo la sospensione della terapia diventare comune pratica clinica?
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 16-121); 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: 30-90 mesi).
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.
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).
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% 05/05/2014 100,5 63,2 tempo da rq-pcr a ultimo follow-up (mesi) 19/11/2012 0% 0% 0 off treatment 05/05/2014 17,7 2 19/02/2007 0% 27/10/2005 8,54% 7 off treatment 0% 04/11/2013 97,7 81,7 22/10/2007 0% 12,20% 10 off treatment 04/11/2013 73,5 02/02/2009 0,022% 82,92% 68 off treatment 04/11/2013 57,9 06/11/2012 0% 1,22% 1 CML VAX 04/11/2013 12,1 3 21/10/2010 0% 10/05/2004 2,439% 2 off treatment 0% 14/01/2013 105,7 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% 05/05/2014 105,9 64,0 28/03/2013 0% 14,63% 12 off treatment 05/05/2014 13,4 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 / 0,0 10 31/07/2013 0% / 30,49% 25 Imatinib 0,0006% 03/03/2014 / 7,2 11 17/02/2014 0% / 3,66% 3 Imatinib 0,0013% 16/05/2014 / 2,9 12 31/07/2013 0% / 4,88% 4 Dasatinib 0,0007% 09/04/2014 / 8,4 13 24/02/2014 0% / 7,32% 6 Imatinib 0% 14/04/2014 / 1,6 14 24/02/2014 0% / 1,22% 1 Imatinib 0% 09/04/2014 / 1,5
Our next goal for CML therapy? Treatment discontinuation!
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-214662) Wnt/beta catenin inhibitors IL-1 receptor accessory protein Old known drug Low cost Powerful Investigational drugs Long term side effects unknown
Grazie per l attenzione!