Optimal first-line treatment of chronic phase CML

순천향대학교병원

김 경 하

** Frontline approval of bosutinib on December 2017

Baccarni et al., Blood 2013;122:872-84. Courtesy of Dr DK Kim

Advances in CML treatment, particularly regarding TKI, mandate

regular updating of concepts and management

Response Criteria in CML

100%

10%

1%

0.1%

0.01%

0.001%

Diagnostic

1 log reduction

2 log reduction

3 log reduction

4 log reduction

5 log reduction

4.5 log reduction

~ MCyR (≤ 35% Ph+ in BM), 2nd line

~ CCyR (0% Ph+ in BM), Front line

MMR or MR3.0, Front line

MR4.0 (most reliable deep response)

MR5.0 or CMR

MR4.5, reliable parameter for CMR 0.0032%

International scale Log scale Definition of Response

• Imatinib

• Dasatinib

• Nilotinib

• Bosutinib

• Radotinib

Frontline treatment options

Selecting a frontline treatment

• Efficacy of TKI in first-line clinical trials

• Patient’s age

• Patient’s comorbidities

• TKI toxicity profile

• Adherence

• Risk score

• BCR-ABL transcript type

• Additional chromosomal abnormalities (ACAs)

Pro

bab

ility

of

surv

ival

Time from onset of imatinib therapy (years)

BCR-ABL/ABL<9.8% OS= 93.3%

BCR-ABL/ABL>9.8% OS= 56.9%

p<0.0001

Survival According to MR at 3 months: 282 Patients Treated with Imatinib 1st-line

Marin D, et al. J Clin Oncol 2012;30(3):232-8.

Individualized TKI selection - Efficacy

10%

CMR according to the BCR-ABL transcript level at 3 months

BCR-ABL/ABL≤0.61% (n=57), CMR = 84.7%

BCR-ABL/ABL>0.61% (n=222), CMR of 1.5%

p<0.0001

Individualized TKI selection - Efficacy

Inci

de

nce

of

CM

R

Marin D, et al. J Clin Oncol 2012;30(3):232-8.

Time from onset of imatinib therapy (years)

1%

Summary of pivotal phase III trials of approved TKI for

the frontline treatment of CML

Jabbour and Kantarjian. Am J Hematol 2018;93:442-59

High-dose imatinib and imatinib based

combinations : CML-study IV (10yr survival results)

Hehlmann et al. Leukemia 2017;31:2398-406

ASH 2017 # 897

Overall survival

Multivariate analysis for impact on survival (n= 1252)

Hehlmann et al. Leukemia 2017;31:2398-406

ASH 2017 # 897

Conclusions

- IM 400 mg monotherapy provides close to normal life expectancy

- Survival between IM400mg and any experimental arm was not different

DASISION 5 yr follow-up:

Cumulative MMR/ MR 4.5 rates over time

Cortes, et al. J Clin Oncol 2016;34:2333-40

ENESTnd 5 yr follow-up:

Cumulative MR 4.5 rates over time

A Hochhaus, et al. Leukemia 2016;30:1044-54

Takahashi, et al. Cancer 2016;122:3336-43

Propensity score matching analysis of dasatinib and

nilotinib as a frontline therapy with CML-CP

Cortes, et al. J Clin Oncol 2018;36:231-7

BEFORE 1 yr follow-up: Molecular response

RERISE 3 yr follow-up:

Cumulative MMR Rates over time

ASH 2017 # 317

Selecting a frontline treatment

• Efficacy of TKI in first-line clinical trials

• Patient’s age

• Patient’s comorbidities

• TKI toxicity profile

• Adherence

• Risk score

• BCR-ABL transcript type

• Additional chromosomal abnormalities (ACAs)

Bower et al. J Clin Oncol 2016;34:2851-7

Patient ≤ 50 yrs → Expected survival ≥ 30yrs

Durable CMR → Therapy discontinuation !!!

Elderly patients

Discontinuation → Less important

Swedish Cancer

Registry : 2662 CML pts

Published clinical studies of TKI discontinuation in patients with CP-CML

ASH 2017# Education

Selecting a frontline treatment

• Efficacy of TKI in first-line clinical trials

• Patient’s age

• Patient’s comorbidities

• TKI toxicity profile

• Adherence

• Risk score

• BCR-ABL transcript type

• Additional chromosomal abnormalities (ACAs)

Adverse effects of BCR-ABL1 inhibitors

Pleural/Lung problems

Dasatinib Dasatinib

Imatinib

Nilotinib

Cytopenias

Imatinib

Fluid retention

Nilotinib

Hyperglycemia Skin changes

Imatinib

Nilotinib

PAOD

Nilotinib

Steegmann JL et al., Leuk Lymphoma, 2012; 53:2351-61. Courtesy of Dr DK Kim

Unique profiles of clinically overt recurrent nonhematologic AEs in

patients with CML treated with BCR/ABL1-targeting TKIs

++, >20% of patients in at least 2 different studies

+, >5% of patients win at least 2 different studies

+/-, 1-5% in at least 1 study

-.<1%

Peter Valent et al. Blood 2015;125(6):901

Risk factors predisposing for the development of VAEs

Peter Valent et al. Blood 2015;125(6):901

Risk factors predisposing for the development of pleural effusion

Peter Valent et al. Blood 2015;125(6):901

Selecting a frontline treatment

• Efficacy of TKI in first-line clinical trials

• Patient’s age

• Patient’s comorbidities

• TKI toxicity profile

• Adherence

• Risk score

• BCR-ABL transcript type

• Additional chromosomal abnormalities (ACAs)

• adherence rates ↓ response rate ↓ survival rate ↓

Beaumont JL, et al. Blood. 2011;118(21):471 [abstract 1025].

Marin et al. J Clin Oncol. 2010;28(14):2381-2388.

Adherence is the critical factor for response

Administration of TKI

Imatinib Qd, with a meal

Dasatinib Qd, with no meal

Nilotinib Bid, fasting two hours before and one hour after each dose

Bosutinib Qd, with a meal

Radotinib Bid, fasting two hours before and after each dose

Ponatinib Qd, with or without a meal

Selecting a frontline treatment

• Efficacy of TKI in first-line clinical trials

• Patient’s age

• Patient’s comorbidities

• TKI toxicity profile

• Adherence

• Risk score

• BCR-ABL transcript type

• Additional chromosomal abnormalities (ACAs)

Calculation of relative risk

http://www.leukemia-net.org/content/leukemias/cml/cml_score/ http://www.leukemia-net.org/content/leukemias/cml/eutos_score/

SOKAL HASFORD EUTOS

Age 0.116 (age -43.4) 0.666 when age≥50 Non applicable

Spleen (cm below

costal margin, max

distance)

0.0345 (spleen-7.51) 0.042 x spleen 4 × spleen

Platelet (x 109/L) 0.188[(platelet count ÷ 700)2 -

0.563]

1.0956 when platelet

count >1,500

Non applicable

Blood myeloblasts (%) 0.0887 × (myeloblasts - 2.10) 0.0584 blast cells Non applicable

Blood basophils (%)

Non applicable 0.20399 when

basophils >3%

7 × basophils

Blood eosinophils (%) Non applicable 0.0413 × eosinophils Non applicable

Relative risk Exponential of the total Total x 1000 Total

LOW <0.8

≤780

≤87

INTERMEDIATE 0.8-1.2

781-1480 Non applicable

HIGH >1.2 >1480 >87 Sokal JE et al, Blood 1984; 63: 789-799

Hasford J et al, JNTL Cancer Inst 1998; 90: 850-858

Hasford J et al. Blood 2011;118:686-92

low Int High

16.9-25.6% ↑ 17.3-27.7% ↑ 19.2-21.8% ↑

2G TKI → more beneficial in patients with intermediate or high risk disease

Saglio and Jabbour. Leukemia & Lymphoma 2017

Response according to risk score assessment

Selecting a frontline treatment

• Efficacy of TKI in first-line clinical trials

• Patient’s age

• Patient’s comorbidities

• TKI toxicity profile

• Adherence

• Risk score

• BCR-ABL transcript type

• Additional chromosomal abnormalities (ACAs)

Impact of BCR-ABL transcript type on outcome in

patients with chronic-phase CML treated with tyrosine

kinase inhibitors

Jain et al. Blood 2016; 127:1269-75

** two most common transcripts: e13a2 (B2a2) and e14a2 (b3a2)

Jain et al. Blood 2016; 127:1269-75

b2a2 b3a2

Molecular responses (≤10% or ≤1%) for BCR-ABL at 3 and 6months

according to the type of BCR-ABL transcript (e13a2, e14a2, or both)

Jain et al. Blood 2016; 127:1269-75

Factors predictive of EFS including the type of BCR-ABL transcripts

Characteristics of CP-CML patients with major-route ACAs

Fabarius et al. Blood 2011; 118:6760-8

** Conclusion

Major route ACA at diagnosis are associated with a negative impact on survival

and signify progression to the AP/BP

Fabarius et al. Blood 2011; 118:6760-8

Cumulative incidences of MMR for patients with t(9;22), t(v;22), and

minor- and major-route ACAs

Conclusions

• A balance between the achievements of an early

response, long-term outcomes, potential AEs, and a

patient’s lifestyle are all key components for successful

therapy.

• Special considerations for patient-TKI pairing include

comorbidities, concomitant medications, age and sex,

risk factors, BCR-ABL1 transcript type and ACAs

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