Clinical Lymphoma, Myeloma & Leukemia, Vol.21, Suppl.1 - September 2021

S152 CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. CML patients who fail their first second-generation TKI for true resistance need a more potent therapy. In these patients, the key issues to consider are the indication of early allogeneic hematopoietic stem cell transplantation or the use of a further TKI. Selection of the next line of treatment after second-generation TKI resistance should be individualized and must be based on patient-specific factors including cytogenetics, mutation profile, comorbidities, age, history of AEs with prior TKI therapy, and risk profile for AEs on specific TKIs. 1,6 Treatment-free remission A significant proportion of patients will achieve a DMR defined as BCR-ABL1 levels of MR4 and MR4.5 on the IS with TKIs. An attempt at treatment discontinuation can be considered, if sustained DMR of sufficiently long duration has been achieved. The first prospective proof of concept for stopping TKI treatment was the Stop Imatinib 1 (STIM1) trial which showed that 38% of the patients maintained a molecular remission after a median follow-up of 77 months. Since then, multiple trials have been conducted or are still ongoing, each of which used slightly different entry criteria and different triggers for restarting the TKI, but loss of MMR has been established as the trigger to restart therapy. After stopping nilotinib or dasatinib as either first or second-line therapy, the probability of maintaining TFR has been ~50%, similar to the results after stopping imatinib. Different prognostic factors for TFR success have been reported. Longer durations of TKI therapy and DMR and prior treatment with IFN were identified in EURO-SKI, of these, duration of DMR seemed to be the most important factor. A characteristic hyperinflammatory syndrome of musculoskeletal and/or joint pain beginning the first weeks or months after TKI discontinuation has been reported in about 20–30% of patients. In most patients the symptoms are mild and self-limited, but some patients may require temporary anti-inflammatory treatment. 1 Stem cell surveillance and eradication In TKI-resistant CML, STAT3 inhibition was shown to reduce malignant cell survival. JAK1 was identified as the STAT3- activating kinase. Combined inhibition of BCR-ABL1 and JAK1 further reduced colony forming units from murine and human CML cells. Fc gamma receptor IIb (Fc  RIIb, CD32b) was shown to be critical in stem cell resistance. Hence, targeting Fc  RIIb downstream signaling, using a BTK inhibitor, provides a promising therapeutic approach. Levels of BCL2-related anti-apoptotic proteins are reported to be expressed at higher levels in CML stem cells compared with normal stem cells and is further increased in blast crisis. Inhibiting BCL2 increases killing of CML stem cells by TKIs in models. BCL2 inhibition might be an option to target persisting CML stem cells unresponsive to BCR-ABL1 TKIs. Numerous studies have assessed immune parameters in patients prior to or in TFR, and identified associations bet-ween cellular immune parameters and TFR, including higher numbers of NK cells, and lower numbers of T regulatory cells and CD86+ plasmacytoid dendritic cells. These data argue for immunological control of residual CML in patients with successful TFR. Early studies with IFN in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFN were able to sustain durable remissions after discontinuing therapy. Studies investigating the combination of IFN with nilotinib or dasatinib and the maintenance treatment with IFN are ongoing. For any attempt to enhance stability of TFR the effect should be balanced against risk of additional side effects by the immune activation of the block of BCR-ABL1 independent pathways. Acknowledgements I am very grateful to the 34 global CML experts participating in the ELN recommendations panel 2020. References 1. Hochhaus A, Baccarani M, Silver RT, Schiffer C, 2. Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–984. 3. Pfirrmann M, Clark RE, Prejzner W, Lauseker M, Baccarani M, Saussele S, et al. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia. Leukemia. 2020 Aug;34(8):2138-2149. 4. Hehlmann R, Voskanyan A, Lauseker M, Pfirrmann M, Kalmanti L, Rinaldetti S, et al. High-risk additional chromosomal abnormalities at low blast counts herald death by CML. Leukemia. 2020 Aug;34(8):20 7 4-2086. 5. Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST, et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019 Aug;33(8):1835-1850. 6. Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29(5):999- 1003. 7 . Hochhaus A, Breccia M, Saglio G, García-Gutiérrez V, Réa D, Janssen J, et al. Expert opinion-management of chronic myeloid leukemia after resistance to second- generation tyrosine kinase inhibitors. Leukemia. 2020 Jun;34(6):1495-1502.