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C. Michel et al.
Figure 3. Probabilities of molecular relapse-free survival after dose reduc- tion to imatinib at 400 mg/day. At 12 and 36 months, horizontal crossbars indicate the upper and lower limit of the 95% confidence interval (CI) for the esti- mated probability.
RFS 12 months after stopping high-dose treatment was 98% (95%CI: 87-99%), whereas it was 65% [95%CI: 34- 84%; HR: 0.096 (95%CI: 0.014-0.449)] for the 15 patients who were only on high-dose treatment for 9 months or less after achieving MMR (Figure 4B).
Discussion
The concept of starting CML therapy upfront with more potent BCR-ABL inhibition than is achievable with 400 mg imatinib has been introduced to prevent early dis- ease progression and induce deep MR faster and more effectively.2 However, it is not known in which patients and when after the initiation of a more potent BCR-ABL kinase inhibition (second/third-generation TKI or 800 mg imatinib) a deep MR can be maintained after de-escalation to 400 mg imatinib.
Trials investigating dose reductions are rare. In the DES- TINY study, the dose of second-generation TKIs was reduced to half the respective standard dose.28 However, in terms of BCR-ABL inhibitory potency, even reduced second-generation TKI doses such as those used in the DESTINY trial demonstrate significantly more BCR-ABL inhibition than 400 mg imatinib. To our knowledge, a con- trolled switch from highly potent BCR-ABL kinase inhibi- tion with 800 mg imatinib or second/third-generation TKI to 400 mg/day imatinib has never been performed prospectively.
On the other hand, a reduction of imatinib treatment intensity to 400 mg is frequently required in patients who achieve a deep MR but experience toxicities or acquire/ have worsening comorbidities of a type that prevents the further use of second-generation TKI. Furthermore, those
patients with deep MR who relapse after TKI cessation or who do not wish to discontinue their TKI, and therefore require life-long TKI therapy, are all candidates for a dose de-escalation to imatinib 400 mg.
Here, we studied the stability of a deep MR in patients of the German CML-Study IV who had MMR or better response for at least 6 months when they reduced ima- tinib from 800 mg to 400 mg per day. We wished to gain insight into whether treatment duration with 800 mg ima- tinib has an impact on subsequent maintenance of deep MR with imatinib at the 400 mg standard dose. We also searched for clinical variables associated with mainte- nance of at least MMR after dose reduction of imatinib.
We found that, if BCR-ABL-monitoring once every three months is ensured, imatinib dose reduction from 800 mg to 400 mg/day in patients with stable MMR did not compromise efficacy or risk sustained MMR in most patients, as only two of seven patients who had lost MMR on 400 mg imatinib required a rescue treatment with more potent BCR-ABL-kinase inhibitors. This also suggests that if standard dose imatinib treatment and BCR-ABL moni- toring are ensured, a single loss of MMR might not require immediate re-intensification of TKI treatment.29 Secondly, despite only 7 events, statistical modeling suggested that achieving an MMR within 13 months under 800 mg ima- tinib, as well as staying on 800 mg imatinib for at least 9 months after achievement of MMR, are both good predic- tors of a successful continuous MMR maintenance under the standard imatinib dose of 400 mg.
Interestingly, with the exception of WBC count, all other prognostic markers identified for a successful ima- tinib dose reduction have previously also been reported as predictors for treatment-free remission (TFR).7,22,27,30 Based on this, it is tempting to speculate that the biology of TFR
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haematologica | 2019; 104(5)