Blood cancers

Life After Stopping TKIs study shows discontinuation feasible in select CML patients

Thursday, 26 Nov 2020

Discontinuation of tyrosine kinase inhibitors (TKIs) is feasible in patients with chronic myeloid leukaemia (CML) who have sustained a deep molecular response and is associated with significant improvements in patient reported outcomes, data from the LAST (Life After Stopping TKIs) trial shows.

The US study included 172 patients with chronic-phase CML who had a minimum of three years treatment with imatinib, dasatinib, nilotinib, or bosutinib and had continuous documented BCR-ABL less than 0.01% by polymerase chain reaction (PCR) for at least 2 years; and no previous TKI resistance.

Results showed that of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response (MMR), and 104 (60.8%) achieved treatment free remission (TFR); 59 patients (34.5%) had molecular recurrence (MRec; defined as loss of major molecular response [BCR-ABL1 International Scale ratio >0.1%]), and 67 (39.2%) restarted therapy.

Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec.

Half of patients with BCR-ABL1 detectable by real-time PCR had molecular recurrence (14 of 28); 64.3% of patients (36 of 56) with BCR-ABL1 undetectable by real-time PCR but detectable by ddPCR had molecular recurrence. Only 10.3% of patients (9 of 87) with BCR-ABL1 undetectable by both ddPCR and real-time PCR had molecular recurrence.

Patient-reported outcomes were assessed 12 months after discontinuation and showed that of the 112 patients in TFR, 90 (80.4%) had a clinically meaningful improvements in fatigue, 39 (34.8%) in depression, 98 (87.5%) in diarrhoea, 24 (21.4%) in sleep disturbance, and 5 (4.5%) in pain.

“The LAST study demonstrates that patients with undetectable BCR-ABL1 by ddPCR had a very high chance of maintaining MMR, with modest improvements in patient reported outcomes.

“Our results provide important new information to inform the discussion between patients with CML and clinicians about the risks and benefits of TKI discontinuation and the potential to assess TKI cessation more accurately,” the study authors concluded in their paper published in JAMA Oncology. 

In an accompanying editorial Theodore Braun and Brian Druker from Knight Cancer Institute, Oregon Health & Science University in Portland, said fatigue, sleep disruption and depression were common among patients with CML but it was often difficult to establish the association between treatment and symptoms.

“These findings provide objective evidence that important measures of quality of life do improve off of therapy,” they wrote.

However, they noted that while the results of the LAST study were intriguing, as ddPCR was only available in a few centres and this was a relatively small study, additional validation studies were necessary.

“If validated, a critical question is determining what about these patients allows them to achieve TFR…through an understanding of the mechanisms that allow TFR, it might be possible to develop strategies to allow more patients with CML to get to TFR and enjoy the benefits of being off therapy,” they wrote.

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