Genetic Mutations May Impact Effectiveness of Ponatinib in Patients with CML

Although progress has been made in increasing the treatment options available to patients with chronic myeloid leukemia (CML), many patients still relapse – most commonly due to the acquisition of BCR-ABL1 mutations that impair drug binding. Patients with the highly resistant T315I mutation also experience poor outcomes with first- and second-generation tyrosine kinase inhibitors (TKIs). However, emerging data show that common mutations, including T315I, are sensitive to the third-generation TKI ponatinib, and these in vitro sensitivity profiles have translated into therapeutic success in these patients.

A report published in Blood further suggests that ponatinib could overcome the mechanisms of resistance that led to inferior responses with older-generation TKIs.
Wendy T. Parker, PhD, from the Department of Genetics and Molecular Pathology of the Centre for Cancer Biology in Adelaide, Australia, and colleagues investigated the impact of these and other low-level mutations on the response to ponatinib in CML patients who were resistant or intolerant to other TKIs.

This phase II study included 363 TKI-resistant patients who were enrolled in the Ponatinib Ph+ALL and CML Evaluation (PACE) trial, including 231 patients with chronic-phase CML (CP-CML).

Mass-spectrometry analysis of patients’ peripheral blood samples was performed at baseline (before ponatinib treatment), and patients were followed for a minimum of 22 months after treatment initiation. Mutation analysis was conducted again at the end of treatment.

“Our data suggest that sensitive BCR-ABL1 mutation analysis could be used to guide therapy adjustment after TKI failure,” Dr. Parker told ASH Clinical News. “Additionally, chronic-phase CML patients with T315I plus additional mutations may benefit from close monitoring during ponatinib therapy, experimental approaches, or hematopoietic cell transplant to reduce the risk of TKI failure.”

Investigators detected a total of 243 mutations (28 different types) in 196 patients:

  • CP-CML: n=114
  • Accelerated-phase CML: n=39
  • Blastic-phase CML: n=29
  • Ph+ ALL: n=14

Seventeen types of low-level mutations (those below the detection limit of 0.05% to 0.2% mutant), were detected in 53 patients:

  • CP-CML: n=28
  • Accelerated-phase CML: n=12
  • Blastic-phase CML: n=8
  • Ph+ ALL: n=5

T315I was the most common mutation detected at baseline and was present at a substantially higher frequency than in other cohorts of TKI-resistant patients,” Dr. Parker and co-authors wrote.

Of the 231 patients with CP-CML, 137 (59%) achieved a major cytogenetic response (MCyR) and 109 (47%) had treatment failure. See TABLE for specific responses to ponatinib as classified by mutation type. Notably, response rates did not differ substantially between CP-CML patients with different BCR-ABL1 mutation types.

The researchers also examined any emergence of new BCR-ABL1 mutations during treatment with ponatinib, finding 44 new mutations in 34 patients (18%). Of the newly discovered mutations, seven were detected at low-level by mass-spectrometry at baseline. “Our method was able to show a significant correlation between detection of low-level BCR-ABL1 mutants and subsequent clonal expansion in patients treated with TKIs,” Dr. Parker said.

Patients with more than one mutation at baseline were also more likely to gain new mutations during ponatinib therapy than those with one or no mutations (33% vs. 10%, respectively; p=0.05). This finding was also observed in patients with advanced-phase disease (40% vs. 20%; p=0.18).

Sixty-three patients with CP-CML had a T315I mutation (27%) and, overall, these patients had superior responses. However, those with T315I as the sole mutation detected (n=43; 19%) had significantly better responses and outcome compared with those with T315I plus additional mutations (n=20; 9%).

Rates of cytogenetic and molecular responses for those with T135I only versus additional mutations were:

  • MCyR by 12 months: 79% vs. 50% (p=0.03)
  • Complete cytogenetic response by 18 months: 74% vs. 45% (p=0.01)
  • Major molecular response by 18 months: 63% vs. 35% (p=0.07)

The probability of failure-free and progression-free survival at 18 months was also higher (86% and 88% vs. 55% and 63%, respectively; p=0.02 and p=0.09, respectively).

Ponatinib was also effective in CP-CML patients without the T315I mutation, but who had inferior responses to treatment with second-generation TKIs (nilotinib and/or dasatinib) following imatinib-resistance with multiple mutations.

Given that the number of mutations detectable by mass-spectrometry after TKI resistance was associated with response to ponatinib treatment, this approach could be used to refine the therapeutic approach, the authors noted.

“Response to ponatinib for CP-CML patients without the T315I mutation was similar, regardless of the number or type of mutations detected,” Dr. Parker explained. “This suggests that ponatinib may be a particularly effective therapeutic option for patients with multiple mutations (without T315I), as this subset of patients had substantially inferior response when treated with second-generation TKIs.”

However, the results of this study are limited by the complex relationship between baseline factors and the ultimate success of ponatinib therapy in the salvage setting; therefore, the authors wrote “definitive identification of the major determinants of variation in treatment response is difficult for this heavily pre-treated patient population.”


Reference

Parker WT, Yeung DTO, Yeoman AL, et al. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood. 2016 January 14. [Epub ahead of print]

TABLE. Best Responses to Ponatinib Treatment by Mutation
Mutation No Response Partial Cytogenic Response Complete Cytogenic Response Major Molecular Response
M244V

(n=7)

1

(14%)

1

(14%)

2

(28%)

3

(42%)

G250E

(n=13)

3

(23%)

1

(7%)

3

(23%)

6

(46%)

Y253H

(n=3)

1

(33%)

0

(0%)

1

(33%)

1

(33%

E255V

(n=4)

1

(25%)

1

(25%)

2

(50%)

0

(0%)

E255K

(n=9)

2

(22%)

0

(0%)

2

(22%)

5

(55%)

V299L

(n=6)

3

(50%)

0

(0%)

1

(16%)

2

(33%)

T315I

(n=63)

18

(28%)

2

(3%)

8

(12%)

35

(55%)

F317L

(n=26)

13

(50%)

1

(3%)

1

(3%)

11

(42%)

F359C

(n=4)

3

(75%)

1

(25%)

0

(0%)

0

(0%)

F359I

(n=4)

0

(0%)

2

(50%)

0

(0%)

2

(50%)

F359V

(n=12)

6

(50%)

2

(16%)

1

(8%)

3

(25%)

H396R

(n=4)

2

(50%)

0

(0%)

0

(0%)

2

(50%)

E459K

(n=4)

1

(25%)

0

(0%)

0

(0%)

3

(75%)

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