Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in CML

Madrid, June 2017 – With a recurrence-free rate of 76%, the 24 months findings of the British Destiny study showed better results than in comparable studies, which may be an effect of a stepwise TKI withdrawal after initial dose reduction. These results were presented at the 22^nd Congress of the European Hematology Association (EHA)¹.

The British De-Escalation and Stopping Therapy with Imatinib, Nilotinib or sprYcel (DESTINY) study investigated treatment de-escalation before a complete cessation, in patients in not only stable molecular response (MR)⁴, but also those in stable major molecular response (MMR) less than MR⁴.

There are large numbers of studies on treatment-free remission with imatinib and second generation TKI’s, “but none of these numerous studies assessed what happened if we stop treatment in patients who have a good response and are in stable major molecular response, but not necessarily in stable MR⁴”, reported Dr Richard Clark from the University of Liverpool (UK) who presented the 24 month data at EHA.

Study entry required; CML in first chronic phase, TKI treatment for at least 3 years, and only one TKI treatment change and then only if due to intolerance. “The eligibility criteria are nearly identical to those in the EURO-SKI study, with the exception that we also have patients in MR but not necessarily in MR⁴”, explained Dr Clark. MMR in the 12 months before trial entry must have been ≤0.1%; those with all results ≤ 0.01% were allocated to the ‘stable MR⁴’ group; the remainder to the ‘MMR, but not MR⁴’ group.

TKI treatment was reduced to half the standard dose (imatinib 200mg daily, dasatinib 50mg daily, or nilotinib 200mg twice daily) for the first 12 months followed by complete treatment cessation. The 12 months de-escalation results² on half-dose therapy have already been published in the Lancet Haematology journal showing that molecular recurrence was lower in patients with stable MR⁴ at entry than in those in MMR, but not MR⁴.

Now 24 months efficacy and safety data are available for all 174 patients. Patients in stable MR⁴ showed a recurrence-free survival (RFS) of 76% for the overall 24 months (90% CI: 71-83%). RFS in patients in stable MMR, but not MR⁴ was 39% for the overall 24 months (90% CI: 29-52%); p = < 0.001).

According to Clark the 24 month RFS of 76% for patients in stable MR⁴ appears better than in comparable studies and the initial 12 months of dose reduction may be responsible for the better results. “Possible mechanisms might include improved compliance in the few months prior to stopping, or an undefined effect of the leukemic stem cell or anti-leukemic immune response”, suggested Dr Clark.

1. Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukemia (CML): Year 2 results in the British Destiny Study (R. Clark), abstract presented by R. Clark during the 22nd Congress of the European Hematology Association (EHA), June 22-25, 2017 in Madrid, Spain.
2. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Clark R et al. Lancet Haematol, May 2017

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