Blood cancers

No room for complacency on molecular monitoring in CML

In the era of potent TKI therapy the importance of regular high-quality molecular monitoring is more important than ever in patients with chronic myeloid leukaemia (CML), Australian haematologists say.

The availability of potent TKI agents that achieve good long-term disease control should not lull clinicians into a false sense of complacency about the need to monitor treatment responses and adjust therapy according to Dr Naranie Shanmuganathan and Dr Timothy Hughes of the South Australian Health and Medical Research Institute (SAHMRI).

Writing in the journal Blood, they say that with treatment-free remission (TFR) now being adopted as the main goal of CML therapy, it is essential that patients have monitoring to ensure they are achieving specific time-dependent molecular milestones, to identify those at risk of poor compliance and therapy failure.

“Because of the abundance of therapies available for patients with CML and the excellent outcomes achieved in most cases, there is a danger that CML may be regarded as an easy disease to treat, even by the non-expert,” they write.

“This attitude can leave the high-risk and complex patient vulnerable to inadequate attention to toxicity issues, delayed therapeutic responses resulting in nonoptimal management, and inferior outcomes.

In their article they say the gold standard for monitoring of molecular responses to TKI therapy is measurement of BCR-ABL1 messenger RNA expression through reverse transcription quantitative polymerase chain reaction (RT-qPCR).

They describe the importance of assessing patients at critical milestones in first-line CML therapy with three month monitoring intervals, and the definitions of optimal, ‘warning’ (formerly suboptimal) and failure responses.

“Early detection of rising BCR-ABL1 values or failure to achieve predetermined milestones should trigger a thorough evaluation regarding compliance,” they suggest.

“KD mutation analysis may be required, and if patients fail therapy, a switch to a more potent TKI is required,” they say.

According to their review article, three-month BCR-ABL1 testing is generally recommended after TKI initiation until stable MMR [major molecular response] is achieved followed by three- to six month testing thereafter. The depth and duration of a deep molecular response have become the new therapeutic targets in patients considered for TFR.

And for patients attempting TFR, they note that molecular relapse after TKI discontinuation is mainly within the first 6 months. Therefore the recommended molecular monitoring should be monthly BCR-ABL1 testing for the first six to 12 months followed by 3-month testing thereafter.

With TFR now regarded as a safe and feasible option, therapeutic goals have shifted for many patients to include the potential for an “operational cure” for CML, they say.

“Achievement of sustained deep molecular response correlates with TFR success, and maximising DMR through appropriate therapy selection has become an increasingly important therapeutic target,” they conclude.

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