Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

Abstract

The primary goal of tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukemia is survival, which is achieved by the vast majority of patients. The initial response to therapy provides a sensitive measure of future clinical outcome. Measurement of BCR-ABL1 transcript levels using real-time quantitative polymerase chain reaction standardized to the international reporting scale is now the principal recommended monitoring strategy. The method is used to assess early milestone responses and provides a guide for therapeutic intervention. When patients successfully traverse the critical first 12 months of TKI therapy, most will head towards another milestone response, deep molecular response (DMR, BCR-ABL1 ≤0.01%). DMR is essential for patients aiming to achieve treatment-free remission and a prerequisite for a trial of TKI discontinuation. The success of discontinuation trials has led to new treatment strategies in order for more patients to reach this milestone response. DMR has been incorporated into endpoints of clinical trials and is considered by some expert groups as the optimal treatment response. But is DMR a stable response and does it provide the ultimate protection against TKI resistance and death? Do we need to increase the sensitivity of detection of BCR-ABL1 to better identify the patients who would likely remain in treatment-free remission after TKI discontinuation? Is it necessary to switch current TKI therapy to a more potent inhibitor if the goal is to achieve DMR? These are issues that I will explore in this review.

IRF4 Gene Expression on the Trail of Molecular Response: Looking at Chronic Myeloid Leukemia from Another Perspective

“…IRF4 expression tends to normalize in patients achieving MR. Interestingly, CML cases in MR4.5 and MR5 show comparable values to those in the HC group, while a mild downregulation is still evident in patients in MR3 and MR4. On the one hand, these findings are in line with the concept that patients achieving the greatest degree of MR are the best candidates for TKI discontinuation [15,23,24]; on the other hand, even a residual presence of the BCR-ABL transcript, as expressed by MR3 and, frequently, MR4, is associated with a significant IRF4 downregulation. A correlation analysis between the IS and IRF4 values confirmed this close association.…”

Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial

“…This suggests that a follow-up ≤60 months may be insufficient to adequately assess the proportion of patients achieving sustained DMR. However, the rate observed with bosutinib by five years was similar to imatinib by eight years, suggesting (with acknowledgement of caution in comparison across studies) that treatment with second-generation TKIs may allow patients to achieve a sustained DMR faster, as would be expected based on the earlier achievement of DMR with second-generation TKIs [ 15 ]. This study also confirmed the achievement of BCR::ABL1 transcript level ≤10% at three months as predictive of sustained MR 4 , as previously suggested in studies with other TKIs [ 15 ].…”

Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia

“…Indeed, the majority of AML samples remain cytokine-dependent for growth, and FLT3 inhibitors may target this necessary growth signal. Although we do not yet know whether the synergy we observed with the drug combination ex vivo will translate into more durable responses in patients, studies in other disease types suggest that treatments delivering deeper up-front responses often improve response duration 52,53 . Ultimately, this question will be best answered by evaluation in an early-stage clinical trial with accompanying monitoring of minimum residual disease.…”