Stopping TKI therapy in chronic myeloid leukemia

Delphine Rea, MD, PhDPôle Hématologie Oncologie Radiothérapie

INSERM UMR-1160Centre Hospitalo-Universitaire Saint-Louis

AP-HP, Paris

BHS meetingLa Hulpe, BelgiumFebruary 11, 2017

CML: state of the art in 2017

• Five ATP-competitive TKIs are currently approved for CML.

• Life expectancy of optimal responders to TKIs is close to that of the general population and increase in CML prevalence.

• Leukemic stem cells are resistant to TKI-induced cell death and are capable of restoring leukemia in mice and upon TKI discontinuation in most patients, explaining current recommendation of a lifelong therapy.

• However, clinical trial contradicted the notion that TKI may never be stopped and treatment-free remission may be achievable under certain conditions.

Gambacorti-Passerini et al. J Natl Cancer Inst. 2011;103(7):553-61.Huang et al. Cancer. 2012 Jun 15;118(12):3123-7.Hehlmann R. Blood. 2012;120(4):737-47.Bower et al. J Clin Oncol. 2016;34(24):2851-7.

Lauseker et al. J Cancer Res Clin Oncol. 2016;142(7):1441-7.Gunnarsson et al. Eur J Haematol. 2016;97(4):387-92.Pearson et al. Leuk Res. 2016;43:1-8. Cortes et al. J Clin Oncol. 2016;34(20):2333-40.

Proof of concept: STIM study

Mahon et al. Lancet Oncol. 2010 ;11(11):1029-1035.Etienne et al. J Clin Oncol 2017; 35(3): 298-305.

START IMATINIBBCR-ABL1

undetectable ≥ 2 years

RQ-PCR RM4.7undetectable

RQ-PCRMolecular relapse (detectable BCR-ABL1 on 2

consecutive occasions showing a significant increase in BCR-ABL1 levels of at least 1 log) triggered imatinib

resumption.

STOP IMATINIB

Treatment-free phase

STIM and STIM FUNCT00478985 and NCT02896829

≥ 3 years

100 patientsImatinib first line or after IFN-aMedian duration of imatinib: 58.8 months (35-112)Median follow-up: 77 months (9-95)

Molecular relapse-free survival at 60 months: 38% (95% CI; 29-47)

A-STIM: loss of MMR as relapse definition

D1IMATINIB Undetectable RM4.5

MR4.5≥ 2 years

RQ-PCR

STOP IMATINIB

Treatment-free phase

A-STIMClinicalTrial.gov NCT02897245

Molecular relapse: MMR lossimatinib resumption)

Rousselot et al. J Clin Oncol. 2014;32(5):424-30.

80 patientsMedian duration of imatinib: 79 months (30-145)Median follow-up: 31 months (8-92)TFR at 24 months: 61% (95% CI; 51-73)

≥ 3 years

Other imatinib discontinuation studies

Study Main inclusion criteria Definition of relapse

TWISTERImatinib ≥ 3 yearsUndetectable MR4.5 ≥ 2 years

Detectable BCR-ABL1 on 2 consecutive tests or MMR loss

STIM2(Fi-LMC)

Imatinib ≥ 3 yearsUndetectable MR4.5 ≥ 2 years

At least 1 log increase in BCR-ABL1 or MMR loss

KIDImatinib ≥ 3 yearsUndetectable MR4.5 ≥ 2 years

MMR loss

ISAVImatinib ≥ 2 yearsUndetectable MR4 ≥ 18 months

Detectable BCR-ABL1 on 2 consecutive tests and MMR loss

STIM123Imatinib ≥ 3 yearsRM4.5 ≥ 2 years

MMR loss

EUROSKITKI ≥ 2 yearsMR4 ≥ 1 year

MMR loss

Ross et al. Blood. 2013;122(4):515-22. Mahon et al. Blood (ASH 2013): abstract 654.Lee et al. Haematologica. 2016;101(6):717-23.Mori et al. Am J Hematol. 2015;90(10):910-4.

Takahashi et al. Blood (ASH 2015): abstract 4035.Mahon et al. Blood (2016): abstract 787.

EUROSKI: study design and MRFS

D1 TKI

MR4≥ 1 year

RQ-PCR

STOP TKI

Treatment-free phase (up to 3 years)

EUROSKI≥ 3 years

Molecular relapse: MMR loss (TKI reintroduction)

Imatinib, nilotinib or dasatinib 1st lineNilotinib or dasatinib ≥ 2nd line (excluding prior resistance)

MR4

Interim analysis:821 patients includedDescriptive statistics: 758 patients (imatinib 93.5%)Molecular-relapse-free survival: 755 patients

Mahon FX et al. Blood. 2016:[abstract 787].

Molecular relapse-free survival: 61% (95% CI; 58-65) at 6 months55% (95% CI; 51-58) at 12 months52% (95% CI; 48-56) at 24 months47% (95% CI; 43-51) at 36 months

EUROSKI: Factors associated with MRFSUnivariate analysis

Mahon FX et al. Blood. 2016:[abstract 787].Pfirrmann M et al. Blood. 2016:[abstract 789].

N=448 N=405

Duration of imatinib treatment Duration of MR4 during imatinib

No difference in outcome between patients with an undetectable MR4.5and those with a detectable MR4.5 at inclusion

2nd generation TKI discontinuation studiesStudy Main criteria for TKI discontinuation Definition of relapse

DADIDasatinib 2nd line ≥ 1 yearUndetectable BCR-ABL1 (< 0.0069% IS)

BCR-ABL1 ≥ 0.0069% IS

STOP 2G-TKI(Fi-LMC)

TKI ≥ 3 years, undetectable MR4.5 ≥ 2 yearsDasatinib or nilotinib

MMR loss

DASFREE(BMS)

Dasatinib 1st or 2ne line (excluding prior resistance) 2 yearsMR4.5 ≥ 1 year

MMR loss

ENESTop(Novartis)

No MR4.5 before nilotinibNilotinib 2nd line ≥ 3 years - MR4.5 ≥ 1 year

MMR loss or confirmed MR4 loss

D-STOPUndetectable MR4 (< 0.01% IS) on TKIDasatinib ≥ 2 years - Undetectable MR4 (< 0.01% IS) ≥ 2 years

Detectable BCR-ABL1 transcripts (2 consecutive tests 1 month apart)

ENESTFreedom(Novartis)

Nilotinib 1st line ≥ 3 yearsMR4.5 ≥ 1 year

MMR loss

ENESTPath(Novartis)

CCyR but no MR4 before nilotinibNilotinib 2nd line ≥ 2 or 3 years - MR4 ≥ 1 year

MMR loss or confirmed MR4 loss

STAT2MR4.5 on prior TKI (imatinib, nilotinib or dasatinib)Nilotinib ≥ 2 years - MR4.5 ≥ 2 years

Confirmed MR4.5 loss (2 consecutive tests)

NILSTMR4.5 on prior TKI (imatinib, nilotinib)Nilotinib ≥ 2 years - MR4.5 ≥ 2 years

MR4.5 loss

Imagawa et al. Lancet Haematol. 2015;2(12):e528-35.Rea et al. Blood. 2016 Dec 8. pii: blood-2016-09-742205. DASFREE ClinicalTrials.gov Identifier: NCT01850004

ENESTop ClinicalTrials.gov Identifier: NCT01698905ENESTfreedom ClinicalTrials.gov Identifier: NCT01784068Kumagai et al. Blood (ASH) 2016: abstract 791.

ENESTPath ClinicalTrials.gov Identifier: NCT01743989Takahashi et al. Haematologica (EHA) 2016: abstract P229.Kadowaki et al. Blood (ASH) 2016: abstract 709.

STOP 2G-TKI study

STARTIMA

NILO or DASA uMR4.5DEEP MOLECULAR RESPONSE

(uMR4.5 for ≥ 2 y)

RQ-PCR uMR4.5 RQ-PCR (Molecular relapse: loss of MMR: 2G-TKI resumption)

STOP NILOor DASA

Treatment-free phase up to 5 years

STOP 2G-TKIIRB 00006477 Registration n°15-050

≥ 3 years

Rea et al. Blood. 2016 Dec 8. pii: blood-2016-09-742205. [Epub ahead of print]

Interim analysis:60 patients includedMinimum follow-up of 12 months (median 47, range: 12-65)Median duration of TKI: 76 months (36-153)

2G TKI discontinuation:factors associated with TFR

STOP 2G-TKI DADI

Imagawa et al. Lancet Haematol. 2015;2(12):e528-e535.Rea et al. Blood. 2016 Dec 8. pii: blood-2016-09-742205. [Epub ahead of print]

ENESTop and ENESTfreedom

Hughes et al. Haematologica (EHA) 2016: abstract LB237.Saglio et al. Haematologica (EHA) 2016: abstract LB618.

ENESTop:

126 patients in the treatment-free phaseMinimum follow-up 48 weeksMedian duration of TKI: 87.7 months (49-171)Median duration of nilotinib: 53 months (37-109)Relapse = loss of MMR or confirmed loss of MR4

ENESTfreedom:

190 patients in the treatment-free phaseMedian duration of nilotinib: 43.5 months (32.9-88.7)Minimum follow-up 48 weeksRelapse = loss of MMR

TFR at 48 weeks: 57.9% (95% CI, 48.8%-66.7%)

TFR at 48 weeks: 51.6% (95% CI; 44.2-58.9)

DASFREE - first interim analysis

Interim analysis: 30 patients in MR4.5 ≥1 year who stopped dasatiniband had a follow-up of ≥1 year (over a total of 84 patients enrolled)

Relapse = loss of MMR

Shah et al. Blood (ASH) 2016: abstract 1895.

1220 4 86 10

30 25 19 19Number of patients at risk

Rel

apse

-fre

e Su

rviv

al (

%)

Time (Months)

63%

0

10

20

30

40

50

60

70

80

90

100

77%

Patients on first-line dasatinib (n = 14)

Patients on subsequent lines of dasatinib(n = 16)

RFS, % (95% CI)

at 6 months 86 (45, 96) 69 (41, 86)

at 12 months 71 (41, 88) 56 (30, 76)

Attempting TFR: safety in clinical studies

• Resistance after resumption of the same TKI has not been reported yet with the exception of 1 case in ENESTstop.

• Blast crisis seems exceptional and has been reported in 1 case (sudden blast crisis after imatinib resumption in A-STIM).

• The “TKI withdrawal syndrome “ consisting in musculoskeletal pain and/or arthralgia soon after treatment discontinuation is frequent (~30% of patients) but benign and transient.

Hughes et al. Haematologica (EHA) 2016: abstract LB237.Rousselot et al. J Clin Oncol. 2014;32(5):424-30.Richter et al. J Clin Oncol. 2014; 32(25): 2821-23.Lee et al. Haematologica 2016; 101(6): 717-23.

Molecular response after therapy resumption

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 1140.0001

0.001

0.01

0.1

1

10

100

Months since imatinib initiation

BC

R-A

BL1

% IS

Stop IMATINIB(STIM2)

Start IMATINIB 400mg QD

Restart IMATINIB 400mg QD

MMR level

MR4.5 level

Undetectable BCR-ABL1with at least 32000 copies of ABL1

STIM2 ClinicalTrials.gov Identifier:NCT01343173

MMR loss

IMATINIB 300mg QD

2nd attempt to stop TKI:RESTIM

Observational study69 patientsFailure of a first attempt to stop imatinib or 2G TKI (loss of MMR 60%, loss of uMR4.5 40%)Median duration of TKI rechallenge: 32 months (6-72)Median duration of uMR4.5 after TKI rechallenge: 25 months (4-62)Relapse = loss of MMR

Legros et al. Blood. 2012;120(9):1959-60.Pagilardini et al. Blood (ASH) 2016: abstract 788.

Treatment-free remission ≠ cure• In the absence of CML relapse after TKI discontinuation:

The BCR-ABL1 gene is still present.

BCR-ABL1 transcripts are detectable in CD34+ cell-derived CFC (colony forming cells) and LT-CIC (long-term culture-initiating cells).

BCR-ABL1 transcripts can be detected at low levels in the blood.

Ross et al. Blood. 2013;122(4):515-22.Mahon et al. Lancet Oncol. 2010 ;11(11):1029-35.Chomel et al. Oncotarget. 2016 ;7(23):35293-301.Chomel et al. Blood. 2011 ;118(13):3657-60. Rousselot et al. J Clin Oncol. 2014;32(5):424-30.

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 1200.0001

0.001

0.01

0.1

1

10

100

Months since CML diagnosis

Stop IMATINIB(EUROSKI)

Start IMATINIB 400mg QD

Undetectable BCR-ABL1with at least 32000 copies of ABL1

BC

R-A

BL1

% IS

MMR level

MR4.5 level

Reasons to aim at TFR in clinical practice

To avoid worrying side effects including those predisposing to other chronic diseases.

To get rid of low grade but chronic side effects.

To become free from daily constraints of medication intake.

Not to care anymore about drug-drug/food-drug interactions.

Fight against cost burden of targeted therapy borne by society or individuals.

Steegmann JL, et al. Leukemia. 2016;30(8):1648-1671.Rea D. Ann Hematol. 2015;94 Suppl 2:S149-158.Palani R, et al. Ann Hematol. 2015;94 Suppl 2:S167-176.Jiang Q, et al. J Cancer Res Clin Oncol. 2016;142(7):1539-1547.

TKI discontinuation in clinical practice:The Australian point of view

Hughes TP, Ross DM. Blood. 2016;128(1): 17-23.

TKI discontinuation in clinical practice:food for thoughts from the ELN

Saußele S, et al. Leukemia. 2016; 30(8): 1638-1647.

Patient selection for TKI discontinuation in clinical practice: provisional choices of

the FiLMC

FAVORABLE CONDITIONS

≥18 years old at CML diagnosisCharacterized M-bcr transcriptsAny Sokal risk groupChronic phase First line imatinib for at least 5 yearsOptimal responseMR4.5 for at least 2 years

WITH CAUTION

First line dasatinib or nilotinibDasatinib or nilotinib 2nd or subsequent line due to prior intoleranceAll favorable conditions with the exception of type of TKI treatment

NOT RECOMMENDED IN CLINICAL PRACTICE

<18 years old at CML diagnosis (enroll patients in pediatric TFR studies)History of accelerated phase or blast crisisNon major-type bcr-abl or untyped transcriptsBosutinib and ponatinibHistory or suboptimal response or resistance or bcr-abl mutationTreatment duration less than 5 years, less than a MR4.5 or MR4.5 duration < 2 years

DASISION AND ENESTnd

Dasatinib100mg QD

N=259

Imatinib400mg QD

N=260

Nilotinib300mg BID

N=282

Imatinib400mg QD

N=283

Still on initial therapy

61% 63% 59.9% 49.8%

MMR by 5 years 76%* 42% 77%* 60%

MR4.5 by 5 years 42%* 33% 54%* 31%

On study AP/BC 4.6% 7.3% 10/282 21/283

5-year OS on study 91% 90% 93.7% 91.7%

5-year PFS on study 85%** 86%** 92.2%*** 91%***

**PFS: survival without loss of CHR, increase in Ph+ metaphases to ≥30% from nadir, AP/BC or death ***PFS: survival without AP/BC or death

*versus imatinib: statistically significant

Cortes et al. J Clin Oncol. 2016;34(20):2333-40.Hochhaus et al. Leukemia. 2016;30(5):1044-54.

Prognostic scoresCytogenetic markers

Chronic phase CML: TKI choice in thefirst line setting

CP-CML characteristics

AgeFunctional statusComorbidities …

Patient factors

Treatment efficacyDeath due to CML

Global Outcome

TKI choiceTreatment toxicity

Non-CML-related eventsDeath not due to CML

Optimal comorbidity management

Adapted from Rea D. iCMLf / Max Foundation: Forum for Physicians from Emerging Economic Regions: Managing the high risk CML patientSan Diego, USA, December 2, 2016

TKI efficacy and safety profile

Optimal TKI usage

Different outcome after TKI discontinuation: why?

STOP TKI

TKI-ONDeep molecular

response

HSC

LSC

HSC

HC

LC

HC

HC

HC

LC

LC

HC

TKI-OFF

Sustained deepmolecular response

CML relapse:Original clone?Resistant subclone?

STOP TKI

Inter individualHeterogeneity in:

Hematopoietic niche?LSCs properties?Immune response?

Zhang et al. J Clin Invest. 2016;126(3):975-91.Tarafdar et al. Blood 2017; 129(2):199-208.

Altering signaling pathwaysWnt/b catenin, HedgehogPP2A, JAK/STATAlox5, FoxO, PMLPI3K/AKT/mTOR, ATM/p53, Notch …

Modifying DNA/RNADemethylationHDAC inhibition, siRNA

Targeting surface markersCD26, IL1RAP, CD25, IL3-R …

Modifying interactionswith the nicheCXCR4/SDF1 axis

Stimulating autophagy

Immune control(including IFN-a)

BCR-ABL+LSC

TFR: should we aim at targeting of LSC?

Conclusion and perspective

• Maximum protection from blast crisis remains an essential goal in CML management and requires an optimal response.

• TKI discontinuation may be successful in patients with deep and durable molecular responses but best pre requisite in terms of depth and duration of molecular response and duration of therapy are not completely known.

• Nevertheless, recommendations on attempting TFR in clinical practice will be provided soon by the ELN. The French CML group will also provide national recommendations.

• Further research is needed in order to better understand underlying mechanisms leading to treatment-free relapse and to increase access to TFR strategies.

TFR