ELN Treatment Milestones in Chronic Myeloid Leukemia Are Prognostic for Achieving Deep Molecular Response and Treatment-Free Remission in Routine Care: Results of the German CML Registry
Authors: Kohlbrenner Katharina , Galuschek Norbert , Fabarius Alice , Reiser Marcel , Fenchel Klaus , Esseling Eva , Göhler Thomas , Kühn Ralf-Bodo , Depenbusch Reinhard , Talah Azeh Ivo , Engel Erik , Hansen Richard , Hanel Mathias , Jehner Paul , Abu-Samra Maisun , Ritter Markus , Gattermann Norbert , Pelz Henning , Fuxius Stefan , Oswald Burkhard , Baerlocher Gabriela M , Brümmendorf Tim H. , Heim Dominik , le Coutre Philipp , Burchert Andreas , Niederwieser Dietger , Tesch Hans , Hofmann Wolf-Karsten , Hochhaus Andreas , Hehlmann Rüdiger , Saussele Susanne 
Published: December 2023

Introduction: Tyrosine kinase inhibitor (TKI) induced molecular response (MR) within the first months after diagnosis of chronic myeloid leukemia (CML) is critical for long-term outcome prediction.
Aim: To analyze the prognostic relevance of MR according to European Leukemia Net (ELN) treatment milestones in CML patients in routine care.
Methods: Within the German CML registry, adult patients (pts) with CML newly diagnosed between 2013 and 2019 were registered and followed annually. Endpoints included time to MR, progression and death. MR was analyzed according to the ELN recommendations 2013 with the focus on the BCR::ABL1 (International Scale, IS) milestones 10% (EMR, early molecular response) at 3 months (M3), 1% (MR 2) at 6 months (M6) and 0.1% (MMR, major molecular response) at 12 months (M12) using the cumulative incidence function. MR at milestones were correlated to achievement of DMR (deep molecular remission, defined as BCR::ABL1 IS&lt; 0.01%).
Results: A total of 540 pts have been registered from 91 centers. Thirty pts had to be excluded (inclusion failure), 510 pts were evaluable for baseline analyses and 490 pts for MR analyses. Median age at diagnosis was 59 years (range 16-100), 264 pts of 510 pts (52%) were male. Median follow-up was 5.4 years. First-line treatment included imatinib ([n=209 (42%)], nilotinib [n=141 (29%)], dasatinib [n=146 (29%)], HU only (n=2 (0,4%)], and was unknown for 12 pts. In total, 473 (97%) of 490 pts achieved an EMR after a median of 3 months (mth) [range (r) 0-55 mth], 461 (94%) pts MR 2 [median 5 mth (1-67 mth)], and 446 (91%) pts MMR [median of 9 mth (1-82 mth)]. DMR was achieved in a total of 384 (78%) pts after a median of 15 mth (1-96 mth) of which at least 282 (58%) had a MR level according to MR 4.5 (BCR::ABL1 &lt;0.0032%). Milestones M3, M6, and M12 were achieved in 245 (50%), 292 (60%), and 297 (61%) pts, respectively (see Table). DMR was achieved in 208 (85%), 259 (89%) and 277 (93%) pts who reached M3, M6, and M12, respectively. In all other pts only 176 (72%), 125 (63%), and 107 (55%) pts achieved DMR.
61 (12%) pts stopped TKI-treatment with the aim of treatment-free remission (TFR). Of these pts, 40 (66%), 47 (77%), and 52 (85%) pts achieved M3, M6, and M12 before TKI stop, respectively. 26 (43%) pts lost MMR in TFR.
Progression to either accelerated phase (AP) or blast phase (BP) was documented for 9 patients (6 BP, 3 AP). Progression was more frequent in pts without achievement of milestones. At M3 2.4% vs. 1.2%, M6 3.5% vs. 0.7% and M12 4.7% vs. 0% of pts progressed. 48 deaths were reported. Only one death was clearly CML-related. This pt reached M3 but not M6 and M12, and died in BP.
7 pts developed BCR::ABL1 mutations. According to milestones, mutations were found in 1.2%, 1%, and 1% with achievement of M3, M6 and M12 vs. 1.6%, 1.5%, and 1.6% of pts not achieving the respective milestones. In addition, 126 pts (29%) lost MMR without being in TFR regardless of whether the milestones had been reached or not. Reasons for MMR-loss were variable (dose-reduction because of intolerance, incompliance, age) so that no correlation to treatment milestones can be made.
Conclusion: Achieving ELN milestones in CML in routine care demonstrated a better outcome for pts with higher DMR rates, lower rates for progression rates and kinase domain mutations. DMR is of importance for stopping treatment in CML. Consequently, the rate of pts who could start TFR after achieving the ELN-milestones was 2-3 times higher than of pts who failed milestones or with unknown MR results.