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ASH 2013: CML Relevant Abstracts
Authors: S Branford, N Roberts, DT Yeung, et al
'..........Our data confirms the importance of achieving BCR-ABL values of 10% or below at 3 mo after starting therapy. Based on the 3 mo assessment, the prognosis was significantly superior for these pts. Progression before the 6 mo time point occurred in 4% of pts with BCR-ABL >10% at 3 mo. However, the vast majority of pts with >10% at 3 mo continued therapy and the 6 mo BCR-ABL assessment provided important long-term prognostic information. Any reduction below 10% at 6 mo led to significantly superior outcomes, approximating those with optimal response at 3 mo. The impact and optimal timing of therapeutic intervention for pts in the poor risk category at 3 mo still needs to be determined in prospective studies and may require large patient cohorts. However, pts who are >10% at both 3 and 6 mo have inferior outcomes and are undoubtedly in need of a therapy change.'
https://ash.confex.com/ash/2013/webprogram/Paper58808.html
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257 Nilotinib Exerts Direct Pro-Atherogenic and Anti-Angiogenic Effects On Vascular Endothelial Cells: A Potential Explanation For Drug-Induced Vasculopathy In CML.
Authors: H Emir, K Albrecht-Schgoer, K Huber, et al
'.... As assessed by immunohistochemistry using antibodies against KIT and mast cell tryptase, we also found that in our CML patients, nilotinib induces an almost complete depletion of KIT+ mast cells, a cell type that serves as unique source of heparin and uncomplexed tPA and has been implicated as a major repair cell in vascular disorders. However, imatinib was also found to induce mast cell depletion in our patients with CML. Neither nilotinib nor imatinib showed in vitro or in vivo effects on platelet adhesion or platelet aggregation. In conclusion, nilotinib exerts multiple effects on vascular endothelial cells and other perivascular cells such as mast cells, presumably through multiple mechanisms and targets. We hypothesize that these effects may contribute to nilotinib-induced vasculopathy in CML.'
https://ash.confex.com/ash/2013/webprogram/Paper57422.html
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379 Disease Relapse After TKI Discontinuation In CML Is Related Both To Low Number and Impaired Function Of NK-Cells:Data From Euro-SKI
Authors: MM Ilander, U Olsson-Strömberg, H Lähteenmäki, et al
'Background: The inhibition of oncogenic BCR-ABL1 kinase with tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of CML. Recent reports suggest that approximately 40 % of CML patients who have achieved optimal therapy response (complete molecular remission, CMR) can stop imatinib treatment without recurrence of detectable BCR-ABL1 transcripts. However, no predictive prognostic factors for successful therapy discontinuation have yet been identified. We therefore set up an immunological substudy in the ongoing pan-European EURO-SKI stopping study. We aimed to identify predictive biomarkers for relapse and non-relapse after TKI discontinuation. In addition, we aimed to understand more on the mechanisms of immune surveillance in CML and to study the effects of TKI treatment on the immune system......'
'Conclusions: The NK-cell numbers and their function may predict disease relapse after TKI discontinuation. This may have impact on the future stopping trials. In addition, it further illustrates the importance of the immune system in the successful long-term treatment of CML.'
https://ash.confex.com/ash/2013/webprogram/Paper60147.html
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381 Loss Of Major Molecular Response As a Trigger For Restarting Tyrosine Kinase Inhibitor Therapy In CP-CML Patients Who Have Stopped Imatinib After Durable Undetectable Minimal Residual Disease
Authors: P Rousselot, A Charbonnier, P Cony-Makhoul, et al
'More than half of patients with chronic phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy.
A multicenter observational study (A-STIM, According to STop IMatinib) evaluating MMR persistence was conducted in 80 CP-CML patients who had stopped imatinib after prolonged confirmed CMR (24 months or more). Patients with confirmed CMR with 1 or 2 occasional weak positive samples before study entry were also considered eligible. CMR was defined as undetectable BCR-ABL transcript with a sensitivity of at least 40000 amplified copies of the ABL control gene, in accordance with the level of sensitivity routinely applied within laboratories participating in the French GBMHM Network.
Results: Median time from imatinib initiation to discontinuation was 79 months (range 30-145), median duration of CMR before imatinib discontinuation was 41 months (24-96), and median follow-up after discontinuation was 31 months (8-92).
Twenty-nine patients (36%) lost MMR after a median of 4 months off-therapy (2-17). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25%-46%) at 12 months and 36% (95% CI, 26%-47%) at 24 months whereas probability of losing CMR was estimated as 51% at 12 months (95% CI, 41%-63%) and 54% at 24 months (95% CI, 44%-66%). Fifty two percent of the patients met the criteria for cCMR but experienced occasional BCR-ABL positivity (unstable cCMR). Those patients were not at higher risk of losing MMR as compared to patients with stable cCMR.
This observation may potentially increase by two-fold the number of patients eligible for TKI discontinuation. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ 2 consecutive positive values) were observed in 31% of patients after imatinib discontinuation. Using cell sorting in three fluctuating patients, we were able to confirm that BCR-ABL signal was mostly present in the CD15 positive fraction, demonstrating first that BCR-ABL residual signal was not related to long living lymphoid cells and second that residual CML cells retain a clonogenic potential. Treatment-free remission was estimated as 64% (95% CI, 54%-75%) at 12 and 24 months and 61% (95% CI, 51%-73%) at 36 months. Treatment was resumed in 31 patients after loss of MMR. Twenty-three patients regained CMR4.5 and 8 patients are in MMR under therapy after 2+ to 17+ months. Median to time to a second CMR was estimated as 7.3 months in retreated patients.
Conclusion: The probability of losing MMR after imatinib discontinuation was estimated as 36% in the long-term. Loss of MMR is a practical and safe criterion for restarting therapy in CML patients with prolonged CMR and could be used for future discontinuation studies.'