Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Abstract

Patients with chronic myeloid leukemia (CML) who have achieved a complete molecular response (CMR) defined by no detectable BCR-ABL mRNA on imatinib (IM) treatment often ask whether it is necessary for treatment to continue. We now know that approximately 40% of patients with a stable CMR for at least 2 years are able to stop IM treatment and remain in molecular remission for at least 2 years. This exciting observation has raised hopes that many patients can be cured of CML without the need for transplantation and its attendant risks. One might argue that for many patients maintenance therapy with IM or an alternative kinase inhibitor is so well tolerated that there is no imperative to stop treatment; however, chronic medical therapy may be associated with impaired quality of life and reduced compliance. Inferences about the biology of CML in patients responding to kinase inhibitors can be drawn from clinical experience, molecular monitoring data, and experimental observations. We summarize this information herein, and propose 3 possible pathways to "cure" of CML by kinase inhibitors: stem-cell depletion, stem-cell exhaustion, and immunological control.

Cancer stem cell definitions and terminology: the devil is in the details

“…In AML, it has been reported that [94][95][96][97] . Conversely, in chronic phase CML, the persistence of a detectable (that is, substantial) population of primitive (presumably pre-malignant) CML stem cells is not predictive of relapse 98 . Routine assays for MRD used clinically may, however, be unable to distinguish a new (often indolent or pre-malignant) subclone from the original dominant one.…”

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider?

“…[14][15][16]23,24,30,32,34,[37][38][39] Comparing patients in Table 1 (clinical trials) and Table 2 (case series), it is apparent that durable stable CMR before discontinuation is important to limit molecular relapse. Multivariate analyses have identified factors associated with molecular relapse and with prolonged TFR.…”

“…30,31 All additional publications and abstracts addressing the topic of TKI discontinuation in CML directly were reviewed. [32][33][34][35][36][37][38] …”

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

“…Based on the sustained, deeper molecular responses observed in patients treated with TKIs, investigators became interested in the possibility of TFR. TFR studies have garnered interest among patients and physicians for various reasons, including the desire to avoid chronic low-grade adverse events and late-emerging toxicities, the potential for resistance, issues with compliance, safety concerns with pregnancy, cost, and patient motivation to live drug free [36]. Because data from TFR studies are still limited, TFR should currently be attempted only in the setting of a clinical trial, with strict molecular monitoring of patients [7,11].…”

“…Before the era of BCR-ABL1 TKIs, IFN with or without cytarabine was the most commonly used treatment in patients with CML [36]. Studies demonstrated that IFN conferred a survival advantage over conventional chemotherapy [37].…”