MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib
M Agrawal1, B Hanfstein1, P Erben1
1III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
Abstract:
In the face of competing tyrosine kinase inhibitors (TKIs), identification of chronic myeloid leukemia (CML) patients expecting favorable response to second-line treatment is warranted. At the time of imatinib resistance, the investigation of multidrug-resistance protein 1 (MDR1) and BCR-ABL yielded the following results: (i) Patients with high MDR1 transcript levels showed superior response at 48 months as compared with low-level MDR1 patients: major molecular response (MMR) in 41% vs 16% (P=0.014), complete cytogenetic response (CCyR) in 58% vs 39% (P=0.044), and progression-free survival (PFS) in 67% vs 46% (P=0.032). (ii) Patients with BCR-ABL(IS) <28% achieved higher MMR rates (48% vs 21%, P=0.009). (iii) PFS at 48 months was associated with in vitro resistance of BCR-ABL kinase domain mutations: 63% (no mutation) vs 61% (sensitive, intermediately sensitive or unknown IC50 (median inhibitory concentration)) vs 23% (resistant, P=0.01). (iv) Single-nucleotide polymorphisms (SNPs) at positions 1236 and 2677 were associated with higher MDR1 expression in comparison to wild type. (v) Nilotinib was able to impede proliferation of MDR1-overexpressing imatinib-resistant cells. High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment.
Insights
High multidrug-resistance protein 1 (MDR1) expression in chronic myeloid leukemia (CML) patients predicts better response to second-line nilotinib. This identifies CML patients with MDR1-mediated imatinib resistance who may benefit from nilotinib therapy.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Chronic myeloid leukemia (CML) treatment often involves tyrosine kinase inhibitors (TKIs).
- Identifying patients likely to respond to second-line therapy after imatinib resistance is crucial.
- Multidrug-resistance protein 1 (MDR1) and BCR-ABL are implicated in imatinib resistance.
Purpose of the Study:
- To investigate the role of MDR1 and BCR-ABL in predicting response to second-line treatment in imatinib-resistant CML patients.
- To evaluate the efficacy of nilotinib in MDR1-overexpressing, imatinib-resistant CML cells.
Main Methods:
- Analysis of MDR1 transcript levels and BCR-ABL mutations in CML patients.
- Correlation of these markers with treatment response, including major molecular response (MMR), complete cytogenetic response (CCyR), and progression-free survival (PFS).
- In vitro assessment of nilotinib's effect on MDR1-overexpressing imatinib-resistant cells.
Main Results:
- High MDR1 transcript levels correlated with superior MMR (41% vs 16%), CCyR (58% vs 39%), and PFS (67% vs 46%) at 48 months.
- BCR-ABL(IS) <28% was associated with higher MMR rates (48% vs 21%).
- Progression-free survival was significantly lower in patients with resistant BCR-ABL kinase domain mutations (23%) compared to others (61-63%).
- Single-nucleotide polymorphisms (SNPs) at positions 1236 and 2677 were linked to higher MDR1 expression.
- Nilotinib inhibited the proliferation of MDR1-overexpressing imatinib-resistant cells.
Conclusions:
- High MDR1 gene expression can identify CML patients whose imatinib resistance is primarily due to increased drug efflux.
- These patients may achieve a favorable response to second-line nilotinib treatment.
- MDR1 expression and BCR-ABL mutations are important predictive markers for CML treatment outcomes.
