Targeted therapies have delivered great efficacy benefits for patients with some hematologic cancers. However, with treatment paradigms typically based on ongoing therapy until loss of response, these benefits can be accompanied by clinical and financial toxicities. Imatinib and later-generation tyrosine kinase inhibitors (TKIs) have revolutionized outcomes for patients with chronic myeloid leukemia (CML), and their use has shaped our thinking about how to deploy truly targeted therapies for greatest benefit. Increasingly, attention has turned to whether imatinib can be ceased indefinitely in patients who have achieved a durable deep remission where BCR-ABL1 transcripts are undetectable. The pioneering Stop Imatinib (STIM1) trial by a group of French investigators revealed that approximately 40 percent of deep responders with undetectable BCR-ABL1 transcripts could maintain remission for more than one year after cessation of imatinib.1 Although these data were independently confirmed by other groups, doubts about the long-term safety of this approach have delayed its introduction into routine clinical practice.
Now, Dr. Gabriel Etienne and colleagues have reported the long-term follow-up of the 100 patients who discontinued imatinib in the STIM1 trial. After a median follow-up of more than six years after imatinib discontinuation, molecular recurrence-free survival was 38 percent at five years. Molecular recurrence was defined as at least two positive reverse transcriptase–polymerase chain reaction results showing a significant increase (>10-fold) on consecutive assessments, or loss of a major molecular response (MMR; BCR-ABL1 ≤0.1%). Molecular recurrence was observed in 61 patients and occurred within one to seven months of discontinuation in 58 of these patients (95%). No patient had molecular recurrence beyond two years, and 55 of 57 patients who resumed imatinib re-achieved an undetectable BCR-ABL1 state. No patient has experienced progression of CML, and of the four deaths on study, none were related to CML. Intriguingly, three of four patients who refused retreatment with imatinib have maintained very low levels of BCR-ABL1 transcript (i.e., maintained MMR) without intervention. Long-term follow-up of patients without molecular recurrence revealed that intermittently positive tests for BCR-ABL1 transcripts at very low levels occurred in some patients.
Dr. Amy Hughes and colleagues have begun to address the question of whether restoration of immune function may help explain maintenance of treatment-free molecular responses. They conducted a cross-sectional survey of innate and adaptive immune cell numbers and function in small cohorts of patients at diagnosis, on TKIs before achieving MMR, on TKIs at MMR or deeper response (BCR-ABL1 ≤0.0032%), and in treatment-free sustained transcript-negative remission. At diagnosis, immune-inhibitory cells (such as myeloid-derived suppressor cells, and PD-1–expressing T cells) and functions were increased compared to blood from healthy donors, while innate effector natural killer (NK) cells and cytotoxic T-lymphocyte responses to leukemia-associated antigens were reduced. TKI therapy was associated with normalization of immune-inhibitory cell numbers, but only in patients with deep molecular responses. Restoration of effector NK cell and T-cell immune responses was also only seen in patients with deep molecular responses. Longitudinal sampling was reported for eight patients and confirmed the observations in the cross-sectional survey. For patients with treatment-free molecular response, the same pattern of immune restoration was observed as seen in deep molecular responders receiving ongoing TKIs. The authors hypothesise that in the setting of high leukemic cell load at diagnosis, immunosuppressive mechanisms, mediated in part by increased myeloid-derived suppressor cells that are part of the leukemic cell clone, predominate and serve to inhibit NK cell cytotoxicity and limit cytotoxic T lymphocyte immune responses via the aberrantly expressed PD-1/PD-L1 pathway. When TKI therapy reduces the leukemic cell load, suppressor cell activity, and PD-1 expression, there is consequent reactivation of the immune effector response. Normalization of immune effector responses seem to be most consistently observed when leukemic burden has fallen more than 4 logs or is undetectable.
In Brief
These long-term safety data from Dr. Etienne and colleagues confirm that molecular progression is rare if it is not observed within the first two years off imatinib. Further, molecular recurrence can be effectively treated by resumption of TKI therapy, without significant risk of later failure. Together with less mature, but highly consistent data from other trials, these findings mean that cessation of imatinib should be considered in patients with long-standing deep molecular responses. Regular monitoring of BCR-ABL1 transcripts as outlined in the article is necessary, especially in the first year. For patients with chronic low-grade toxicity from imatinib, the ability to safely attempt cessation without compromise of long-term outcomes will be a substantial relief. Many pragmatic questions remain unanswered however, and are the subject of ongoing investigations. How low does the transcript level need to be before a trial of cessation should occur, and for how long should that depth of response be maintained? Do the results apply similarly to patients receiving other TKIs? What distinguishes those patients who have molecular recurrence from those who do not? What role does the immune system play in maintaining remissions? The data from Dr. Hughes and colleagues at least establish that patients who achieve a deep molecular response to imatinib (and other TKIs) have a normalization of key aspects of their innate and adaptive immune systems that can be maintained without ongoing TKI therapy. But whether re-establishment of immunity is central to the ability to stop imatinib successfully is unknown. Hence, the spotlight will stay on the treatment of CML while we learn how best to select responding patients for discontinuation of targeted therapy, and how to augment responses to enable successful discontinuation in a larger proportion of patients with deep molecular remissions.
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Competing Interests
Dr. Roberts indicated no relevant conflicts of interest.
