Kinase Domain Mutation Testing and Clinical Outcome in a Nationwide Chronic Myeloid Leukemia Patient Population

Background: ABL1 kinase domain mutations (KDM) are associated with resistance to tyrosine kinase inhibitors (TKI) and inferior outcome in chronic myeloid leukemia (CML) patients. Current guidelines recommend KDM testing in case of failure or resistance during TKI treatment. In this analysis, we aimed to assess (1) the clinical practice of KDM testing in the Netherlands, (2) the observed responses to subsequent TKI in the presence of a KDM in relation to the in vitro half-maximal inhibitory concentration (IC50)-values, and (3) the clinical outcome of patients for whom KDM testing was done.

Methods: Data were obtained from a nationwide population based CML registry (Pharos-HemoBase) and six CML-reference centers in the Netherlands. We included adult Ph+ CML patients who were treated with a TKI and who had at least one KDM analysis after December 2005, when second generation TKI became available in the Netherlands. Reasons for KDM testing were categorized in three main groups based on the pattern of TKI failure: (1) primary resistance (no response), (2) suboptimal response and (3) loss of response. A suboptimal response was defined as failure to achieve the ELN response milestones, but with the achievement of at least 1-log BCR::ABL1 reduction. Loss of response was defined as losing a previously achieved ELN response milestone. A cox regression model was used for the survival analysis.

Results: A total of 391 KDM analyses performed in 275 patients between December 2015 and March 2022 were included. When focusing on CP CML, most KDM analyses were performed because of a suboptimal TKI response (n=155), however in only nine (6%) a KDM was detected. In patients with primary TKI resistance, a KDM was detected in 17 of 81 analyses (21%). The highest yield of KDM was in patients losing a previously achieved response with 43 of 89 (49%) of analyses showing a mutation. Twenty-five KDM analyses were performed outside the context of TKI failure (e.g. BCR::ABL1 fluctuations but no loss of MMR, molecular relapse after a TFR attempt) and in none of them a mutation was detected.

In total, 84 KDM were detected (panel A). Sixty-nine (25%) patients harbored at least one KDM of whom 24 the T315I mutation and eight a compound mutation. Most KDM analyses were done with Sanger Sequencing (SS).

Fifty-four TKI treatment lines were assessable for response for patients who harbored a KDM with known in vitro IC50-values for predicted effectiveness of TKI. Of the patients who were treated with a TKI with a good predicted response, 34 of 42 (81%) indeed obtained a durable major molecular response, while seven patients experienced failure (4 no response, 3 loss of response). In patients who were treated with a TKI for which intermediate sensitivity was predicted, 4 of 6 (67%) responded well. In patients who were treated with a TKI for which resistance was predicted, only 3 of 6 (50%) responded.

Progression to advanced stage disease (AP/BC), hematopoietic stem cell transplantation (HSCT) and death occurred more often in patients with a KDM compared to patients without a KDM: AP/BC in 25 (36%) versus 29 (14%) patients, HSCT in 20 (29%) versus 43 (21%), death in 26 (38%) versus 29 (14%) and CML-related death in 12 (17%) versus 10 (5%), respectively. Ten-year overall survival (OS) after the first KDM analysis was 49% versus 82% in patients with versus without a KDM, respectively, with a median follow-up of 7.2 years (panel B). The HR of harboring a KDM for OS was 0.355 (95% CI, 0.209-0.603; p<0.001). After correction for age, sex, disease phase and Sokal score, the HR was 0.356 (95% CI, 0.182-0.696; p=0.003).

Discussion: This is the first study describing the nationwide practice of KDM testing and assessing the clinical outcome of patients with a KDM in relation to IC50-values. More than 70% of the KDM were detected in patients with primary TKI resistance or in patients who lost a previously achieved response. Observed responses to TKI after the detection of a KDM were mainly in accordance with expected responses based on the IC-value, supporting the use of these in vitro derived predictions in clinical practice. In line with previous studies, the presence of a KDM translated in inferior outcomes with higher prevalence of progressive disease and (CML-related) death.

Janssen:Uppsala County Council: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy; Incyte Biosciences Benelux BV: Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Avillion: Research Funding; Ellipses Pharma: Research Funding; Roche: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Westerweel:Novartis: Research Funding.