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Emerging Strategies for Managing CML in 2025

Richard A. Larson, MD

University of Chicago

March 2025

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Disclosures – Richard A. Larson, MD

​

  • Research funding to the University of Chicago:
    • Astellas
    • Biomea
    • Cellectis
    • Daiichi Sankyo
    • Novartis (asciminib)
  • Equity ownership: none
  • Royalties: UpToDate, Inc

​

​

  • Consultancy/ Honoraria:
    • Ariad/Takeda (DSMB)
    • Biomea
    • CVS/Caremark
    • Epizyme/Ipsen (DSMB)
    • Jazz Pharmaceuticals
    • Novartis (DSMB)

​

No investigational agents will be discussed.

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Agenda: addressing remaining challenges

  • Clarify patient goals (Survival &/or TFR)
  • The approved frontline therapies
  • Address toxicity, adherence, & QOL
  • Aim for Treatment-Free Remission (TFR)
  • Learn the role for asciminib

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Outcomes from major randomized frontline chronic phase CML trials

Trial (FU)

N=

Therapy

CCyR

MMR

MR4.5

PFS

OS

IRIS (10.9 y)

553

IM 400

83%

​

​

92%

83%

TOPS

(42 mos)

157

IM 400

80%

52%

​

94%

94%

319

IM 800

82%

50%

​

96%

93%

ENESTnd

(10 yr)

282

NIL 600

​

77%

54%

96%

92%

281

NIL 800

​

77%

52%

98%

96%

283

IM 400

​

60%

31%

93%

92%

DASISION

(5 yr)

259

DAS 100

​

76%

33%

85%

91%

260

IM 400

​

64%

42%

86%

90%

BFORE

(5 yr)

246

BOS 400

77%

74%

47%

93%

95%

241

IM 400

66%

65%

37%

91%

95%

Regardless of frontline TKI, Overall Survival is now >90%.

Deininger et al. Chronic Myeloid Leukemia, version 2.2021. NCCN.org; 18: 1385-1408.

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2020 European LeukemiaNet Recommendations for newly diagnosed CML

Time:  

  Optimal Response  

Warning

Failure

3 months  

BCR/ABL <10%

BCR/ABL >10%

>10% if confirmed

6 months  

BCR/ABL <1%

BCR/ABL >1-10%

BCR/ABL >10%

12 months  

BCR/ABL <0.1% (MMR) 

BCR/ABL >0.1-1%

BCR/ABL >1%

There- after, >12 months

Major Molecular Response [MMR] or better; 

Tolerating the drug;

good adherence; monitored every 3 mos

BCR/ABL >0.1%;

-7 or del(7q)

in Ph- cells

BCR/ABL >1%;

ABL mutations; New chromosome abnormalities

Baccarani et al. Blood 2013 Aug 8; 122(6): 872-884

Hochhaus, et al. Leukemia 2020 Apr; 34(4): 966-984

Resistance to:

Due to mutation in:

Dasatinib

V299L, T315I/A, F317L/V/I/C

Nilotinib

Y253H, E255K/V, T315I, F359V/I/C, G250E

Bosutinib

E255K, V299L, T315I, G250E

Ponatinib

T315M/L

Asciminib

G109D, Y115N, M244V, V289I, A337V/T, E355G, F359V, E462K, G463D/S, P465S, V468F, S501R, I502L

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Somatic mutations in 222 CML patients at diagnosis with NGS evaluation

Schonfeld et al -- ASXL1 mutations predict inferior molecular response to

nilotinib treatment in CML -- Leukemia 2022; 36: 2242-49

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Stopping TKI Therapy in CML

​

Why discontinue tyrosine kinase inhibitor (TKI) therapy?

​

  • Avoid chronic toxicities
  • Avoid late complications
  • Reduce costs

​

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Most common side-effects from TKIs in CML (early and later)

All BCR::ABL1 TKIs

Fatigue, (asymptomatic) lipase elevation

Imatinib

Gastritis, diarrhea, rash, myalgia, periorbital edema

Dasatinib

Pleural and pericardial effusions, diarrhea, bleeding; vascular events, pulmonary hypertension

Nilotinib

Hyperglycemia, rash, headache, LFT elevation; vascular events

Bosutinib

Diarrhea, LFT elevation, rash, myalgia; vascular events, effusions

Ponatinib

Dry skin, rash, LFT elevation; vascular events

Asciminib

Hypertension, rash, headache

  • Apperley. Lancet Dec 5, 2014; Steegmann et al. Leuk Lymph 2012; 53:2351.
  • Lipton et al. Long-term safety review of tyrosine kinase inhibitors in CML - What to look for when

treatment-free remission is not an option. Blood Reviews 2022

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Greatest chance for successful TKI discontinuation�

  • About 50% of patients will be candidates
  • First-line therapy, or second-line if intolerance was the only reason for changing TKI.
  • Low-risk by Sokal or ELTS scores
  • No prior treatment failure.
  • Duration of TKI therapy >5 years (>4 years for 2nd Gen TKI)
  • Duration of Deep Molecular Response (DMR) >3 years, if MR4
  • Duration of sustained DMR >2 years, if MR4.5

Hochhaus, et al. Leukemia 2020; 34: 966–984

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Will Asciminib and its novel mechanism of action change outcomes in CML?

Manley PW, et al. Leuk Res 2020; 98:106458

ATP-competitive

binding site

Non-ATP-competitive

binding site –

myristoyl pocket locks

the inactive isoform

Imatinib

Dasatinib

Nilotinib

Ponatinib

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ASC4FIRST is a head-to-head study comparing asciminib vs �all standard-of-care TKIs in newly diagnosed patients with CML

Hochhaus A et al. N Engl J Med. 2024 Sep 12;391(10):885-898.

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Key secondary endpoints

  • MMR at week 96 with asciminib vs all investigator-selected TKIs
  • MMR at week 96 with asciminib vs investigator-selected TKIs in the imatinib stratum

Imatinib stratum: ASCIMA

2G TKI stratum: ASC2G

Asciminib (ASC) 80 mg QD

Imatinib stratum: IS-TKIIMA

2G TKI stratum: IS-TKI2G

IS-TKIs at label doses

R 1:1

N=405

Prerandomization TKI selection

  • The TKI a patient will take if randomized to the investigator-selected (IS-TKI) arm
  • Selected by the physician in consultation with the patient

Stratification �by:

  • Prerandomization TKI selection (IMA or 2G TKI)
  • ELTS risk category (high, intermediate, low)

End of study: Last Patient + 5 years

NCT04971226

Key inclusion criteria

  • Newly diagnosed Ph+ CML‑CP with no prior TKIsa
  • Age ≥18 years

Data cutoff: October 22, 2024

Primary endpoints

  • MMR at week 48 with asciminib vs all investigator-selected TKIs
  • MMR at week 48 with asciminib vs investigator-selected TKIs in the imatinib stratum

DRIVE score 3

Birhiray 2022

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Baseline characteristics were well balanced between asciminib and all IS-TKIs. Patients pre-selected for imatinib were older and had higher cardiovascular risk.

Hochhaus A et al. N Engl J Med. 2024 Sep 12;391(10):885-898.

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More patients in the imatinib than in the 2G TKI stratum were aged ≥65 years and had higher cardiovascular disease risk, reflecting physician preference for imatinib in these subgroups.

Variable

Asciminib

IS-TKIs

ASC

(n=201)

ASCIMA�(n=101)

ASC2G

(n=100)

All IS-TKIs

(n=204)

IS-TKIIMA

(n=102)

IS-TKI2G

(n=102)

Age, median (range), years

52.0 (18.0-79.0)

56.0 (21.0-79.0)

43.0 (18.0-76.0)

50.5 (19.0-86.0)

54.5 (20.0-86.0)

43.0 (19.0-83.0)

Age group, %

18 to <65 years

77.1

68.3

86.0

76.0

68.6

83.3

65 to <75 years

17.9

23.8

12.0

16.7

21.6

11.8

≥75 years

5.0

7.9

2.0

7.4

9.8

4.9

Male, %

65.2

61.4

69.0

61.3

63.7

58.8

Framingham CV risk score, %a

Low (<10%)

54.2

40.6

68.0

54.9

39.2

70.6

Intermediate (10% to 20%)

15.9

20.8

11.0

21.6

28.4

14.7

High (>20%)

29.9

38.6

21.0

23.5

32.4

14.7

ELTS, %b

Low

60.7

61.4

60.0

61.3

62.7

59.8

Intermediate

27.9

29.7

26.0

27.9

29.4

26.5

High

11.4

8.9

14.0

10.8

7.8

13.7

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Cumulative incidence of MMR continued to be higher �with asciminib than with all IS-TKIs

Cortes J et al. 2024 ASH annual meeting. Abstract 475

a Defined as the proportion of patients who achieved MMR at or before specific times. b Nonresponders were censored at their last molecular assessment date. c Discontinuation from treatment for any reason without prior achievement of MMR was considered a competing event.

Censoredb

Competing eventc

0

60

72

12

24

36

48

84

96

108

120

144

60

20

0

40

100

80

Time, weeks

Cumulative incidence of MMR, %

132

ASC

All IS-TKIs

66.5%

80.5%

46.3%

62.1%

ASC vs all IS-TKIs

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Deep molecular response rates at week 96 were higher with asciminib overall and across strata

ASC vs all IS-TKIs

ASCIMA vs IS-TKIIMA

ASC2G vs IS-TKI2G

Patients, %

MR4

MR4.5

MR4

MR4.5

MR4

MR4.5

ASCIMA (n=101)

IS-TKIIMA (n=102)

ASC2G (n=100)

IS-TKI2G (n=102)

ASC (n=201)

All IS-TKIs (n=204)

Hochhaus A et al. N Engl J Med. 2024 Sep 12;391(10):885-898.

Cortes J et al. 2024 ASH annual meeting. Abstract 475

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MMR rates at week 96 were higher with asciminib than with all IS-TKIs across all demographic and prognostic subgroups

Hochhaus A et al. N Engl J Med. 2024 ;391(10):885-898.

Cortes J et al. 2024 ASH annual meeting. Abstract 475

15

-50

0

100

50

38.1 (11.6 to 64.7)

31.0 (13.5 to 48.5)

15.5 (4.6 to 26.5)

5/22 (22.7)

20/57 (35.1)

81/125 (64.8)

14/23 (60.9)

37/56 (66.1)

98/122 (80.3)

High

Intermediate

Low

53.3 (19.9 to 86.7)

16.0 (−5.2 to 37.3)

20.6 (10.1 to 31.2)

4/15 (26.7)

21/34 (61.8)

81/155 (52.3)

8/10 (80.0)

28/36 (77.8)

113/155 (72.9)

≥75 years

65 to 75 years

18 to 65 years

Age category

16.7 (−55.8 to 89.1)

26.8 (14.4 to 39.2)

16.7 (2.9 to 30.4)

2/4 (50.0)

53/110 (48.2)

51/90 (56.7)

2/3 (66.7)

81/108 (75.0)

66/90 (73.3)

Others

White

Asian

Race and ethnicity

21.3 (9.7 to 32.9)

24.0 (9.2 to 38.7)

64/125 (51.2)

42/79 (53.2)

95/131 (72.5)

54/70 (77.1)

Male

Female

Sex

22.2 (13.0 to 31.3)

106/204 (52.0)

149/201 (74.1)

All patients

ELTS based on randomization data

Risk difference

(95% CI)

All IS-TKIs

n/N (%)

ASC

n/N (%)

Subgroup

Favors ASC

Favors all IS-TKIs

20.8 (3.0 to 38.7)

34.1 (13.2 to 55.0)

18.0 (5.6 to 30.4)

26/48 (54.2)

18/44 (40.9)

62/112 (55.4)

45/60 (75.0)

24/32 (75.0)

80/109 (73.4)

High

Intermediate

Low

Framingham 10-year CV risk category

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Safety and tolerability continued to be more favorable with asciminib than with imatinib and 2G TKIs by the week 96 cutoff

Hochhaus A et al. N Engl J Med. 2024 Sep 12;391(10):885-898.

Cortes J et al. 2024 ASH annual meeting. Abstract 475

16

ASC

(n=200)

IMA

(n=99)

2G TKIs

(n=102)

Patients, %a

ASC

(n=200)

IMA

(n=99)

2G TKIs

(n=102)

ASC

(n=200)

IMA

(n=99)

2G TKIs

(n=102)

Grade ≥3 AEs

AEs leading to

discontinuation

AEs leading to dose

adjustment/interruption

  • The median average daily dose was 80 mg/day with ASC, 400 mg/day with IMA, 600 mg/day with NIL, 100 mg/day with DAS, and 316 mg/day with BOS
  • The hazard ratio for time to treatment discontinuation due to AEs (TTDAEs) for asciminib vs 2G TKIs was 0.46 (95% CI, 0.21-1.02)
    • There was a 54% lower risk of discontinuation due to AEsb with asciminib compared with 2G TKIs

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Conclusions from the ASC4FIRST trial

  • Asciminib continued to demonstrate superior efficacy vs all IS-TKIs, and MMR rates as high as 76.2% were observed in the imatinib stratum.
  • DMR rates at week 96 remained higher with asciminib than with all IS-TKIs.
    • Whether this will lead to a higher percentage of successful TFR is uncertain.
  • Asciminib’s safety and tolerability profile continued to be better than that of imatinib and 2G TKIs, and was consistent with its known safety profile.
    • Twice the proportion of patients discontinued all IS-TKIs due to AEs compared with asciminib.
    • The frequency of arterial occlusive events and mutations remains to be determined.
  • Asciminib’s favorable benefit-risk profile compared with all IS-TKIs, imatinib, and 2G TKIs in patients with newly diagnosed CML-CP resulted in FDA accelerated approval for frontline treatment.

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Frontline Asciminib: ASCEND-CML study (ALLG CML 13)

Yeung et al. Asciminib monotherapy as frontline treatment. Blood November 2024; 144:1993.

  • Asciminib 40 mg BID or 80 mg once daily; 7 increased to 80 mg BID
  • Median follow up of 21 months
  • 82 of 101 patients are still taking asciminib
  • One patient had lymphoid blast crisis; one had cerebrovascular event

Progression free survival

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Take Home Points

  • Design treatment around the patient’s goals
  • To avoid resistance or recurrence:
    • Ensure daily dosing of TKI
    • Manage and minimize side-effects
    • Monitor adherence and response (every 3 months)
  • Consider prospective discontinuation (>5 years on TKI):
    • More successful if initial low-risk scores
    • Durable deep molecular remission
  • Await longer follow-up results of asciminib trials

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Thank you.

​

​

rlarson@uchicago.edu