CHRONIC MYELOID LEUKEMIA – SO MANY MUTATIONS, BUT BACK TO THE START
Author(s): ,
Carolina Pavao
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Fátima Oliveira
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Nuno Cerveira
Affiliations:
Department of Genetics,Instituto Português de Oncologia,Porto,Portugal
,
Susana Bizarro
Affiliations:
Department of Genetics,Instituto Português de Oncologia,Porto,Portugal
,
Andreia Moreira
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Ana Rita Leal
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Joana Oliveira
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Dina Rochate
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Carolina Viveiros
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Ana Luísa Araújo
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
,
Manuel R. Teixeira
Affiliations:
Department of Genetics,Instituto Português de Oncologia,Porto,Portugal
Cristina Fraga
Affiliations:
Department of Hematology,Hospital Divino Espírito Santo,Ponta Delgada,Portugal
(Abstract release date: 05/14/20) EHA Library. Pavao C. 06/12/20; 298035; PB2119
Carolina Pavao
Carolina Pavao
Contributions
Abstract

Abstract: PB2119

Type: Publication Only

Background
The tyrosine kinase inhibitors (TKIs) have been the standard treatment for chronic phase chronic myeloid leukemia (CP-CML). However, the development of BCR-ABL1 mutations can lead to treatment resistance, being a challenge to manage some patients

Aims

To share the therapeutic challenge in the presence of BCR-ABL1 mutations.

Methods
Case report.

Results

A 72-year-old Caucasian man, with history of arterial hypertension, was diagnosed on May 2009 with CP-CML BCR-ABL1 p210 positive, with an intermediate Sokal and Hasford risk. Treatment with Imatinib 400 mg qd was started with complete hematologic response on the 1st month. Due to lack of major molecular and complete cytogenetic response at 6 months, Imatinib was increased to 600 mg qd on February 2010, however, on July 2010 disease progression was observed, with a BCR/ABL transcript of 17.54%. Mutational analysis revealed the presence of a Y253F mutation and Dasatinib 100 mg qd was started on July 2010. Under Dasatinib treatment the patient did not achieved a major molecular response (MMR), so on January 2014 he was switched to Nilotinib 300mg bid which resulted in the achievement of MMR after 3 months of treatment. Then, on February 2016 loss of MMR was detected and treatment with Bosutinib 500 mg qd was initiated. MMR was obtained on September 2016 but one year later he experienced again loss of MMR, without loss of complete cytogenetic response. At this time, it was decided to maintain Bosutinib therapy, but on June 2018, BCR-ABL1 transcript levels increased from 0.3071% to 59.7019%. Treatment with Ponatinib was initiated on September 2018, but due to uncontrolled high blood pressure the patient only completed 2 months of treatment, and administration of interferon alfa-2b was initiated on January 2019. Despite this, the patient presented consistent BCR-ABL1 transcripts > 5%. At this point it was decided to retrospectively evaluate the mutational status by NGS at each time point the patient switched therapy since 2013. At the time of loss of Dasatinib response, NGS analysis showed the presence of a M244V variant (VAF=15.25%), described in the literature as conferring resistance to Imatinib and of a F317L (VAF=72.78%), reported as conferring resistance to both Imatinib and Dasatinib. When Nilotinib failed, NGS evaluation demonstrated the presence of the Y253H mutation (VAF=99.63%) described in the literature as insensitive to Imatinib and partial resistant to Nilotinib. At the time of Bosutinib failure, NGS showed the same M244V variant (VAF=99.84%) previously described. At this point, on October 2019, due to consecutive therapeutic failures, and with limited therapeutic options it was decided to restart Imatinib 400 mg qd. After 2 months of treatment, molecular evaluation showed response to treatment with BCR-ABL1 transcripts decreasing from 9.76% to 0.67%, with NGS analysis revealing the same M244V variant, although with a reduced allelic frequency (VAF=10.31%).

Conclusion
Evaluating the mutational status of CML patients with signs of therapy resistance is an important component of disease monitoring, potentially facilitating selection of subsequent therapies. Our results suggest that, in opposition to what has been described in the literature, the M244V mutation seems to confer resistance to Bosutinib but remains sensible to Imatinib. In addition, this case report highlights the impact that sequential therapy can have on the selection of different clones with different mutations, with the patient responding to a treatment to which it was initially resistant.

Session topic: 15. Myeloproliferative neoplasms - Biology & Translational Research

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Drug resistance

Abstract: PB2119

Type: Publication Only

Background
The tyrosine kinase inhibitors (TKIs) have been the standard treatment for chronic phase chronic myeloid leukemia (CP-CML). However, the development of BCR-ABL1 mutations can lead to treatment resistance, being a challenge to manage some patients

Aims

To share the therapeutic challenge in the presence of BCR-ABL1 mutations.

Methods
Case report.

Results

A 72-year-old Caucasian man, with history of arterial hypertension, was diagnosed on May 2009 with CP-CML BCR-ABL1 p210 positive, with an intermediate Sokal and Hasford risk. Treatment with Imatinib 400 mg qd was started with complete hematologic response on the 1st month. Due to lack of major molecular and complete cytogenetic response at 6 months, Imatinib was increased to 600 mg qd on February 2010, however, on July 2010 disease progression was observed, with a BCR/ABL transcript of 17.54%. Mutational analysis revealed the presence of a Y253F mutation and Dasatinib 100 mg qd was started on July 2010. Under Dasatinib treatment the patient did not achieved a major molecular response (MMR), so on January 2014 he was switched to Nilotinib 300mg bid which resulted in the achievement of MMR after 3 months of treatment. Then, on February 2016 loss of MMR was detected and treatment with Bosutinib 500 mg qd was initiated. MMR was obtained on September 2016 but one year later he experienced again loss of MMR, without loss of complete cytogenetic response. At this time, it was decided to maintain Bosutinib therapy, but on June 2018, BCR-ABL1 transcript levels increased from 0.3071% to 59.7019%. Treatment with Ponatinib was initiated on September 2018, but due to uncontrolled high blood pressure the patient only completed 2 months of treatment, and administration of interferon alfa-2b was initiated on January 2019. Despite this, the patient presented consistent BCR-ABL1 transcripts > 5%. At this point it was decided to retrospectively evaluate the mutational status by NGS at each time point the patient switched therapy since 2013. At the time of loss of Dasatinib response, NGS analysis showed the presence of a M244V variant (VAF=15.25%), described in the literature as conferring resistance to Imatinib and of a F317L (VAF=72.78%), reported as conferring resistance to both Imatinib and Dasatinib. When Nilotinib failed, NGS evaluation demonstrated the presence of the Y253H mutation (VAF=99.63%) described in the literature as insensitive to Imatinib and partial resistant to Nilotinib. At the time of Bosutinib failure, NGS showed the same M244V variant (VAF=99.84%) previously described. At this point, on October 2019, due to consecutive therapeutic failures, and with limited therapeutic options it was decided to restart Imatinib 400 mg qd. After 2 months of treatment, molecular evaluation showed response to treatment with BCR-ABL1 transcripts decreasing from 9.76% to 0.67%, with NGS analysis revealing the same M244V variant, although with a reduced allelic frequency (VAF=10.31%).

Conclusion
Evaluating the mutational status of CML patients with signs of therapy resistance is an important component of disease monitoring, potentially facilitating selection of subsequent therapies. Our results suggest that, in opposition to what has been described in the literature, the M244V mutation seems to confer resistance to Bosutinib but remains sensible to Imatinib. In addition, this case report highlights the impact that sequential therapy can have on the selection of different clones with different mutations, with the patient responding to a treatment to which it was initially resistant.

Session topic: 15. Myeloproliferative neoplasms - Biology & Translational Research

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Drug resistance

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