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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. - PowerPoint PPT Presentation
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DR
Discontinuation of second generation tyrosine kinase inhibitors
CML and MPDs UK national meetingNewcastle, March 1st, 2013
Dr Delphine ReaService des Maladies du Sang
Hôpital Saint-LouisParis, France
Fi-LMC (France Intergroupe-Leucémies Myéloïdes Chroniques)
DR
Current goals of TKI therapy
CP-CML atDiagnosis
M3 M6 M12 M18
CHR, Minor CyR
PCyRCCyR
MMR Stable or improving MMR
> M18
PFS EFS
Time on TKI therapy
Leuk
emic
bur
den
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: 6041-6051Björkholm et al. JCO 2011: 2514-2420Gambacorti-Passerini et al. JNCI 2011; 103: 553-561
« Induction » phase « Lifelong maintenance »
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 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: 319-3252Copland et al. Blood 2006; 107: 4532-45393Jorgensen et al. Blood 2007; 109: 4016-40194Konig et al. Blood 2008; 111: 2329-23385Corbin et al. JCI 2011; 121: 396-4066Hamilton et al. Blood 2012; 119: 1501-1510
DR
Median BCR-ABL (IS) transcript levels over 84 months in the IRIS trial
Hughes et al. Blood 2010; 116: 3758-3765
0.003% 0.004%
DR
STIM: Stopping imatinib is feasible
Mahon et al. Blood (ASH) 2011; 118: Abstract 603
Sur
viva
l with
out m
olec
ular
rela
pse 1.0
0
0.90.80.70.60.50.40.30.20.10.0
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
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 50 000 copies of the ABL control geneMolecular relapse: defined by 2 positive RQ-PCR results over 1 month showing a significant risein BCR-ABL transcripts; triggers imatinib resumption.
CP-CMLImatinib ≥ 3 yearsUndetectable BCR-ABL ≥ 2 years
DR
Factors potentially associated with outcome
Study Factors
French prospective STIM study1
Sokal risk groupImatinib treatment duration
Australian prospective CML8 study2
Sokal risk groupIFN treatment duration prior to imatinib therapy
Japanese survey3 Imatinib treatment durationDuration of undetectable BCR-ABL transcriptsImatinib dose intensityPrior exposure to IFN
Korean retrospective study4 Sokal risk groupTime to undetectable BCR-ABL transcriptsImatinib treatment duration
1Mahon et al. Blood (ASH) 2011; 118: Abstract 603 2Ross et al. Haematologica 2012; abstract 0189.
3Takahashi et al. Haematologica 2012; 97: 903-9064Yhim et al. Leukemia Research 2012; 36: 689-693
DR
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: 2251-22595Kantarjian et al. N Engl J Med 2010; 362: 2260-22706Rea et al. Leukemia 2009; 23: 1158-11597Ross et al. Haematologica 2011; 96: 1720-1722
1O’Hare et al. Cancer Res 2005; 65: 4500-45052Shah et al. J Clin Oncol 2008; 26; 3204-32123Kantarjian et al. Blood 2007; 110: 3540-3546
DR
STOP 2G-TKI: study design
• Primary endpoint: survival without loss of MMR• Molecular relapse: loss of MMR• Loss of MMR triggered treatment resumption
M12 M60D1
STOP2G-TKI
UndetectableBCR-ABL*≥ 24 months
*Molecular monitoring performed in local laboratories filling international standardization requirements.*20 000 copies of ABL at least.
RQ-PCRmonthly
RQ-PCREvery
3-6 months
CP-CMLTKI therapy ≥ 3 years2G-TKI frontline orafter imatinib intoleranceor resistance
Year 1 Year 2 Year 3-5
RQ-PCREvery
2-3 months
M24 M36 M48
DR
Baseline characteristicsData, as of November 30, 2012 Patients with a min. follow-up of 6 months
(median 17: 7-38), n=39
Median age 58 years (34-81)
Gender Male n= 15 (38.5%), Female n=24 (61.5%)
CML phase at diagnosisSokal 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 onlyImatinib + dasatinib or nilotinibImatinib + dasatinib and nilotinib
2 (5%)31 (79%)6 (16%)
Reason for 2G-TKIUpfrontIntolerance to imatinibSuboptimal response/resistance to imatinib*
2 (5%)27 (69%)10 (26%)
TKI discontinuationDasatinib / nilotinib 20 (51%) / 19 (49%)
Median time since diagnosisMedian time since first TKIMedian time since 2G-TKIMedian 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
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
0
20
40
60
80
100
0 6 12 18 24 30 36 42
Sur
viva
l with
out M
MR
loss
%
Months since 2G-TKI discontinuation
Month 12: 61.1% (95% CI: 45.6-76.6)
KM analysisRea et al. Blood (ASH) 2012; 120: Abstract 916
DR
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)
STOP 2G-TKI
Rea et al. Blood (ASH) 2012; 120: Abstract 916
DR
Responsiveness to 2G-TKI upon therapy resumption: patient case
Months since dasatinib-inducedundetectable BCR-ABL transcripts
BC
R-A
BL/
AB
L %
IS
Detectable BCR-ABL
Undetectable BCR-ABLwith at least 32000 copies of ABL
DASATINIBRESUMPTION
STOP 2G-TKI
Dr D Rea, Hôpital Saint-Louis, Paris
0 6 12 18 24 30 36 42 48 54 60 660.0001
0.001
0.01
0.1
1
10STOP DASATINIB
MMR
MR4.5
DR
Factors associated with outcome
Factors Estimated survival without MMR loss at 12 months (%, 95% CI) p value
Age: ≤ 58 years vs > 58 68.7 % (44.8-89.7) vs 52.6 % (30.2-75) 0.219
Gender: Female vs male 61.3 % (41.3-81.3) vs 66.7 % (42.8-90.5) 0.901
Sokal risk group: Low vs others 66.7 % (46.5-86.8) vs 52.1 % (29.4-74.8) 0.31
Prior IFN exposure: no vs yes 56.8 % (37.4-76.2) vs 69.2 % (44.1-94.3) 0.581
Reason for 2G-TKI:Frontline/imatinib intoleranceSuboptimal response/resistance to imatinib
68.2 % (51-85.5)40 % (9.6-70.4)
0.0188
Type of 2G-TKI: Dasatinib vs nilotinib 60 % (38.5-81.5) vs 62.7 % (40.8-84.7) 0.599
Time since diagnosis: ≤ 84 months vs > 84 months 63.6 % (41.8-85.4) vs 57.9 % (35.7-80.1) 0.599
Time since first TKI: ≤ 78 months vs > 78 months 63.6 % (41.8-85.4) vs 57.9 % (35.7-80.1) 0.599
2G-TKI duration: ≤ 37 months vs > 37 months 62.2 % (42.7-81.7) vs 66.7 % (42.8-90.5) 0.949
UMRD duration: ≤ 27 months vs > 27 months 70 % (49.9-90.1) vs 52.1 % (-74.8) 0.310
STOP 2G-TKI
KM analysis, two-tailed logrank testRea et al. Blood (ASH) 2012; 120: Abstract 916
DR
BCR-ABL transcripts in patients remaining in MMR
Patients in MMR without therapy(median follow-up 17 months: 7-37) n=23
Always undetectable 7/23 (30.4%)
Occasionally detectable on 1 test 8/23 (34.8%)
Occasionally detectable on ≥ 2 consecutive tests 8/23 (34.8%)
STOP 2G-TKI
DR
Different outcomes of persistent LSC
Self renewal
Survival
TKI + BCR-ABL+LSC
Mat Pre
Pro
CML disease relapse
STOPTKI
STOPTKI
MatMat
Mat
Pre
PrePro
Ph+ LSC-driven hematopoiesis
Inhibited Ph+ LSC-driven hematopoiesis No
CML diseaserelapse
Deep and sustainedMolecular response
Why ?
CML-relatedfactors?
Therapy-relatedfactors?
Host-relatedfactors?
DR
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.