Korea’s experience of TFR in CML

Hawk Kim, M.D., Ph.D.Division of Hematology

Gachon University Gil Medical CenterGachon University College of Medicine

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Hawk Kim

I currently have, or I have had in the past two years, an affiliation or financial interest with business corporation(s):

(1) Consulting fees, patent royalties, licensing fees ： No

(2) Research fundings; Yes, Novartis, Celgene, Janssen, Shinpoong

(3) Others No

Discontinuation of Imatinib

Michor F et al. Nature 2005, 435: 1267-70

IFN cessation

• 7 patients free from hematological relapse despite detectable MRD

• 21 patients stopped IFN with a median follow up after discontinuation of IFN treatment of 8 years (mean 9, range 5-18)

• In 9 of them the persistence of leukemic cells after discontinuation of IFN without CML relapse is demonstrated by RQ-PCR

Mahon FX, et al. J Clin Oncol 2002;20:214-220.

STIM study: Cumulative incidence of molecular relapse

Mahon et al. Lancet Oncol. 2010; 11: 1029-1035

Early Korean data

Leukemia Research 36 (2012) 689–693

Acta Haematol 2016;135:133–139

Am J Hematol 2013; 88(6):449-54

KIDS study

Probabilities for UMRDProbabilities for sustained MMR

Am J Hematol 2013; 88(6):449-54

KIDS study

Probabilities for UMRDProbabilities for sustained MMR

Am J Hematol 2013; 88(6):449-54

KIDS follow up

Haematologica. 2016 Jun; 101(6): 717–723.

KIDS follow up

Haematologica. 2016 Jun; 101(6): 717–723.

Probability of sustained MMR and UMRD

Hurdles in performing TFR

• It is usually not recommended outside of clinical trial• Many different expert recommendations in details• BCR/ABL1 RQ-PCR

– Standardization & quality control– International scale issues– Long turnaround time– Deep molecular response: MR4.0IS vs. MR4.5IS

– UMRD: MR4.3IS vs. MR4.5IS

Criteria for stopping TKIs

Curr. Treat. Options in Oncol. (2018) 19: 15; Blood. 2016;128(1):17–23.; Ann Oncol. 2017;28(suppl_4):iv41–51.NCCN Clinical practice guidelines in oncology. Chronic Myeloid Leukemia Version I2018 - July 26, 2017.

ASTER

• Korean study– IM: Retrospective & prospective– 2G TKI: on going

• RQ-PCR– Difficulty in availability of standard lab for IS – Ipsogen KIT: MR4.3IS

• Real-world data is important

Objectives

• Aim: To find out the success rate of TFR in real clinical practice in CML

• End points– Primary: Molecular relapse-free survival (MR3.0IS)– Secondary: BCR/ABL1 RQ-PCR method, TKI cessation criteria,

risk factors for TFR failure

Patients’ characteristics

Characteristics No. of Patients Characteristics No. of PatientsGender (M/F) 48 (50.5) / 47 (49.5) TKIsPhase Imatinib 73 (76.8)

Unknown 1 (1.1) Nilotinib 11 (11.6)CP 89 (93.7) Dasatinib 9 (9.5)AP 5 (5.3) Radotinib 2 (2.1)

Sokal score Prior interferon therapy 7 (7.4)Unknown 21 (22.1) Prior HCT 2 (2.1)Low 24 (25.3) In-house PCR lab 70 (73.7)Intermediate 39 (41.1) International scale PCR 95 (100)High 11 (11.6) Ipsogen PCR kit 95 (100)

Hasford score TFR criteriaUnknown 43 (45.3) MR4.0 27 (28.4)Low 29 (30.5) MR4.3 68 (71.6)Intermediate 20 (21.1) Median RangeHigh 3 (3.2) Age (Years) 48.0 18-72

EUTOS score Duration of TKI therapy (Years) 7.4 0.51-16.87Unknown 43 (45.3) Duration of MR3.0 (Years) 6.4 0.25-15.15Low 41 (43.2) Duration of UMRD (Years) 5.8 0.25-15.15High 11 (11.6) Months to achieve UMRD 12.5 2.1-100.8

Median follow up duration after TKI cessation: 10.2 (0.9-171.4) months

Treatment-free remission; Loss of MR3.0IS or Restarting TKIs

• 3M; 84.8%• 6M; 69.9%• 9M; 56.9%• 12M; 51.1%• 2Y; 46.9%• 5Y; 46.9%

Treatment-free remission; Loss of UMRD

• 3M; 75.3%• 6M; 60.3%• 9M; 48.1%• 12M; 48.1%• 2Y; 48.1%• 5Y; 48.1%

Treatment-free remission; Loss of MR3.0IS

• 3M; 86.9%• 6M; 73.0%• 9M; 64.2%• 12M; 58.3%• 2Y; 58.3%• 5Y; 58.3%

TFR by different criteria

TFR UMRD MR3 MR3/TKI

3M 75.3% 86.9% 84.8%

6M 60.3% 73.0% 69.9%

9M 48.1% 64.2% 56.9%

12M 48.1% 58.3% 51.1%

2Y 48.1% 58.3% 46.9%

5Y 48.1% 58.3% 46.9%

0%

20%

40%

60%

80%

100%

0M 3M 6M 9M 12M 2Y 5Y

Loss of UMRD

Loss of MR3.0

Loss of MR3.0 or Restating TKI

11.4% difference

TFR loss

• Median time to TFR loss: 4.4 (1.84-110.52) months• Reasons for TFR loss

– Loss of MR3.0IS: 35 (85.4%)– Loss of UMRD: 2 (4.9%)– TKI discontinuation syndrome: 2 (4.9%)– Impending loss of MR3.0IS: 2 (4.9%)

• Regain of MR3.0IS: 34/41 (82.9%)– Lost to follow up after CVA (n=1)– Not starting TKI yet (n=1)– Short follow up duration (n=5)

MR3.0IS re-achievement

Months after TKI restart

Predictive factors for TFRTFR criteria MR3/TKI UMRD MR3Male 0.906 0.180 0.771

Age≤50y 0.771 0.861 0.964

b3a2 transcript 0.757 0.983 0.586

Sokal Low/Int 0.218 0.348 0.088

Hasford Low/Int 0.634 0.462 0.687

EUTOS Low 0.771 0.285 0.701

CP by ELN 0.035 0.208 0.082

2G TKIs 0.086 0.489 0.117

TKI dose intensity ≥100% 0.654 0.165 0.464

Prior IFN 1.000 0.440 1.000

Prior HCT 1.000 1.000 1.000

Time to MR3.0IS≤12M 0.567 0.215 0.834

Time to UMRD≤12M 0.315 0.076 0.501

No other prior TKI 1.000 0.731 1.000

TKI duration≥5Y 0.174 0.672 0.363

MR3.0IS duration≥5Y 0.303 0.639 0.706

UMRD duration≥5Y 0.784 0.564 0.474

Health-related profiles after IM cessation

Leuk Lymphoma. 2015 Jun 12:1-7

Contributing factors

Leuk Lymphoma. 2015 Jun 12:1-7

Lab change after IM cessation

Leuk Lymphoma. 2015 Jun 12:1-7

ASTER-C

• A Study of Treatment-free remission Evaluation in Real-world chronic myeloid leukemia; Estimated Cost-effectiveness analysis (ASTER-C)

• Theoretical calculation of costs of various TKIs under Korean CML epidemiology considering maximal possible TFR

Assumptions

• Total numbers of annual newly-diagnosed CML patients were adopted from national cancer registration database.

• TFR will be started after achieving MR4.5 and lasting for 3 years. • All achieved adequate conditions try TFR.• The proportion of MR4.5 was adopted from phase III studies of imatinib (IM), nilotinib

(NIL) and dasatinib (DAS). • TKI management followed life-long Markov model. • TFR success rates were assumed as 50% in all TKIs.• PCR monitoring costs are not included.• Willingness to pay (WTP) was calculated for beneficial effects of patients who have

achieved TFR and taking no TKIs as 2 times of gross domestic product per capita. • Cost of progression was calculated based on the study by Jabbour et al. • Patients older than 79y was not included in this study because TFR benefit is not

considered in this age group. • Duration of treatment and TFR was calculated separately according to age groups. • We assumed that taking KTI lasted life-long until median life expectancy in Korea

(80.87 years).

Life-time Markov model

Estimation of annual new chronic myeloid leukemia patients

Age (yr) Cases (2008-2012) Estimated annual cases %0-14 41 9 2.0

15-34 421 85 20.935-49 551 111 27.350-64 546 110 27.165-79 391 79 19.4>80 66 14 3.3

Total 2,016 404 100

Cost estimation of imatinib

Age (year) No TFR cost (₩) TFR (person-year) WTP (₩) Progression cost (₩)

0-14 9,401,955,232.61 99.93195 6,241,551,839.67 -

15-34 66,045,704,215.14 698.36425 43,618,449,048.02 -

35-49 60,077,279,681.12 591.46905 36,941,986,393.07 -

50-64 37,303,173,147.24 313.8905 19,604,979,465.81 -

65-79 10,824,371,272.84 29.90545 1,867,835,226.51 -

Total 183,652,483,549 1,734 108,274,801,973 29,186,127,588.24

Cost estimation of nilotinib

Age (year) No TFR cost (₩) TFR (person-year) WTP (₩) Progression cost (₩)

0-14 14,295,819,020 164.9241 10300832914

15-34 103,966,188,627 1155.9915 72200941475

35-49 95,212,522,681 985.1139 61528264732

50-64 59,909,641,616 530.739 33148907650

65-79 18,288,163,192 61.2171 3823498922

Total 291,672,335,136 2,898 181,002,445,694 19,867,187,107.44

Cost estimation of dasatinib

Age (year) No TFR cost (₩)) TFR (person-year) WTP (₩) Progression cost (₩)

0-14 12,982,248,352 128.1843 8,006,137,711.53

15-34 94,182,122,142 898.2545 56,103,198,496.20

35-49 85,867,146,193 765.0897 47,785,988,610.69

50-64 53,559,987,154 411.697 25,713,779,904.57

65-79 15,818,964,316 46.8233 2,924,490,658.44

Total 262,410,468,158 2,250 140,533,595,381 23,804,776,233.26

Comparison of TKI costs

TKI Total cost (₩) WTP (₩) Net cost (₩) Net/TotalImatinib 212,838,611,137 108,274,801,973 104,563,809,164 49.1%Nilotinib 311,539,522,243 181,002,445,694 130,537,076,549 41.9%Dasatinib 286,215,244,391 140,533,595,381 145,681,649,010 50.9%

ASTER-S

• On-line survey for TFR practice in CML• Members of The Korean Society of Hematology CML

Working Party• 26 responses

What’s your specialty? Annual newly-diagnosed CML

Pediatrics

Internal medicine 0-55-10≥10

ASTER-S

In-house lab for BCR/ABL1 Lab kit for BCR/ABL1

Yes

No

Others

Ipsogen Kit

International scale available? Do you know TFR?

Yes

No SomeVery well

I don’t knowHeard about that.

RQ-PCR minimal condition for TFR Duration after achieving minimal RQ-PCR

2Y1Y

4Y3Y

MR4.3MR4.5

MR3.0MR4.0

5Y

Did you experience TFR?

NoYes

Reasons for not trying TFRTFR- Not experienced

Higher success rate More safe More experiences More clinical trial data Others

Relapse risk Not necessary Tolerable TKIs Patient’s anxiety Need for more study Not reliable PCR Others

What’s required for TFR trial?

Do you recommend TFR?TFR-Experienced

I recommend actively.I recommend sometimes.I discuss. But, not actively recommend.Only when a patient wants it.

Barriers in TFR

Patient’s disagree Not reliable PCR TKI discontinuation syndrome Monitoring No advantage of TFR

TFR-Experienced

Will you try TFR?

I’ll try actively.I’ll try sometimes.I’ll consider when data are enough.I’ll not consider it.

YesNo

TFR- Not experienced TFR-Experienced

Summary

• Korea’s experiences of TFR seems quite comparable with current studies.

• TFR in real practice– MR4.3IS by commercial BCR/ABL1 RQ-PCR kit is able to be

used for the practice.– No clear predictive clinical factors; need for longer follow-up– Safely restarting TKI is possible

• Costs of TKIs by considering TFR– Imatinib is still effective– 2G TKIs can be cost effective

• Current concepts of TFR in Korean need for improvement.

Acknowledgement

• ASTER– Chul Won Jung

• Dept of Medicine, Samsung Medical Center Sungkyunkwan Univ. School of Medicine

– Deog-Yeon Jo• Department of Internal Medicine, College of Medicine, Chungnam National University

– Jee Hyun Kong• Wonju Severance Christian Hospital

– Hyewon Lee• National Cancer Center

– Eun-Ji Choi• Department of Hematology, Asan Medical Center

• ASTER-C– Bora Nam, MBA, Ph.D.

• Dongkuk University

– Jinseob Kim, MD, MPH• ANPANMAN Co., Ltd.

• ASTER-S– Members of The Korean Society of Hematology Chronic Myeloid Leukemia Working Party