Type 1 diabetes is a chronic disease characterized by abnormal metabolism and hyperglycemia due to insulin deficiency. There is a rapid decline in insulin production due to autoimmune destruction of the pancreatic beta cells. Partial remission (honeymoon phase) of type 1 diabetes is common in children and young adults with newly diagnosed type 1 diabetes. There is temporary restoration of beta cell function such that little or no exogenous insulin is required. Stopping insulin therapy soon after an emergency admission requiring intravenous insulin and subsequent subcutaneous insulin therapy can be frightening for both patient and healthcare provider. Affected patients require education and support during this period. This report describes a case of a 28-year-old man who presented to the emergency department with features of type 1 diabetes and diabetic ketoacidosis. He was treated with intravenous fluids and intravenous insulin and discharged on a subcutaneous insulin regimen. Despite testing positive for several types of islet cell autoantibodies, the patient was able to stop insulin therapy within three months of diagnosis. The patient maintained a self-initiated low-carbohydrate diet, regular weight-reducing exercise, and normal glucose levels without the need for insulin therapy. The honeymoon phase of type 1 diabetes, latent autoimmune diabetes, and ketosis-prone type 2 diabetes are discussed as important differential diagnoses.

Clinical factors alone do not enable us to differentiate which patients will maintain treatment-free remission (TFR) from those who are likely to relapse. Thus, patient-specific factors must also play a role. This review will update the reader on the most recent studies presenting biological factors that can help predict tyrosine kinase inhibitor (TKI) discontinuation success.
Cellular and molecular factors with a suggested role in TFR include immune factors and leukemic stem cell (LSC) persistence; the BCR::ABL1 transcript type, halving time, and BCR::ABL1 DNA and RNA positivity; as well as other molecular factors such as somatic mutations, RNA expression, and telomere length. Our review presents several biomarkers with predictive value for TFR but also highlights areas of unmet need. Future discontinuation guidelines will likely include biological factors for the personalization of TFR prediction. However, it will be important that such advances do not prevent more patients from making a TKI discontinuation attempt.

Introduction: Tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, have significantly prolonged the overall survival of patients affected by chronic myeloid leukemia (CML) and changed drastically the outcome. Evidences from several studies suggest that in patients who have achieved a sustained, stable and deep molecular response, TKI treatment can be safely discontinued with a close subsequent monitoring. Thus, a stable deep molecular response (DMR) has become a feasible treatment goal in CML. Areas covered: In this review, the main findings extrapolated from sponsored and real-life evidences regarding TKI discontinuation were discussed, through a broad research on Medline, Embase and archives from EHA and ASH congresses (including words such as discontinuation, treatment-free remission, TFR, etc). Moreover, suggestions emerged from international guidelines about treatment-free remission (TFR) are presented. Expert opinion: With the growing availability of clinical trials and real-life data on TFR, in recent years the possibility of offering to CML patients a safe, informed and shorter path to TFR, through the achievement of a stable deep molecular response (DMR), has become an increasing option. However, many controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication and optimal strategies aimed at achieving a successful TFR.

As it is recommended that most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. The MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. Overall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1699 chronic myeloid leukemia patients were included in this analysis. The overall mean TFR rate at 24 months after entering TFR phase was 55% [95% confidence interval (CI) 0.51-0.58]. Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24 months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12 months (60.2% vs. 49.9%). Our results suggest that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better may account for approximately 60% of the TFR rate at 24 months after stopping TKI.

Background: A new goal in treatment of chronic myeloid leukemia (CML) in patients with stable deep molecular response (DMR) is maintaining durable treatment-free remission (TFR) after discontinuing tyrosine kinase inhibitor (TKI) treatment. Methods: We conducted a systematic review and meta-analysis focusing on the efficacy and safety of TKI discontinuation but also exploring the factors contributing to successful TFR. Results: The search yielded 10 trials including 1,601 patients. For patients who discontinued TKIs, the estimated weighted mean incidence of major molecular relapse was 16% (95%CI: 11-21), 34% (95%CI: 29-38), 39% (95%CI: 35-43) and 41% (95%CI: 36-47) at 3, 6, 12, and 24 months, respectively. Of these, 39, 82, and 95% of molecular losses occurred within the first 3, 6, and 12 months. In safety analysis, among patients without TFR, 98% (95% CI: 96-100) were sensitive to TKI retreatment. No new safety issues were identified except TKI withdrawal syndrome, which appeared during the early TFR phase, with a weighted mean incidence of 27% (95%CI: 19-35). Our subgroup analysis suggested better TFR associated with interferon therapy (P = 0.007), depth of molecular response (P = 0.018) and duration of DMR (P < 0.001). Conclusions: TFR as an extension of an approach to optimize management of CML is clinically feasible in approximately 59% of patients with sufficient TKI response. In the remaining 41% of patients with molecular relapse, discontinuing TKIs had no negative impact on clinical outcomes. Given the high heterogeneity among studies, the role of these predictors for successful TFR still requires further investigation.