Outcomes od BCR-ABL mutated chronic myeloid leukemia patients who have failed tyrosine kinase inhibitors

This study aimed to investigate the frequency of BCR-ABL kinase domain mutation detection and its prognostic significance in patients with chronic-phase chronic myeloid leukemia (CP-CML) treated with tyrosine kinase inhibitors (TKIs). 

This study concluded that early mutation detection and use of 2nd and 3rd generation TKIs can reverse the worst outcomes associated with BCR-ABL kinase domain mutations.  

The BCR-ABL gene is a cancer gene which produces the BCR-ABL protein. The BCR-ABL protein is known as a tyrosine kinase. This protein allows cancer cells to grow and divide. Tyrosine kinase inhibitors (TKIs) are a treatment that works by blocking the tyrosine kinase protein. This stops the growth and division of cancer cells.  

However, if the BCR-ABL kinase domain (BCR-ABL-KD) becomes mutated (abnormal), the TKI will no longer work. This is called TKI resistance. The outcomes for patients with BCR-ABL-KD mutations were unknown.  

This study involved 253 patients with CP-CML who had at least one mutation analysis. 187 of these patients were early CP (ECP) and 66 were late CP (LCP). 88% of the patients were treated with imatinib (Gleevec) as the first TKI treatment.  

32% of patients had BCR-ABL-KD mutations. The BCR-ABL-KD mutation was found in 57% of patients who progressed to accelerated or blastic phases (AP-BP) of CML. The BCR-ABL-KD mutation was found in 47% of patients who lost a complete hematologic response (response to treatment as seen in the blood).  

The BCR-ABL-KD mutation was found in 29% of patients who failed to achieve complete cytogenetic response (CCyR – no Philadelphia chromosomes left). The BCR-ABL-KD mutation was found in 35% of patients who lost prior CCyR. 

The BCR-ABL-KD mutation was found in 16% of patients who failed to achieve a major molecular response (MMR – no BCR-ABL gene left). The BCR-ABL-KD mutation was found in 26% of patients who lost prior MMR. 

Overall survival (OS) and frequency of CML-related death were correlated with the disease phase regardless of the absence or presence of the mutation. LCP mutated patients had a worse outcome than ECP mutated patients. 

This study concluded that early mutation detection combined with the use of 2nd and 3rd generation TKIs can reverse the worst outcome associated with BCR-ABL-KD mutations whatever the mutation subgroup in patients with CP-CML.