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E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy Treatment-free remission (TFR) is a new therapy goal for patients with chronic phase chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs), with approximately 40% sustaining deep molecular responses after stopping treatment.1-3 However, it is difficult to predict precisely who will achieve TFR and the subject remains controversial.3 We present data from 64 patients who stopped TKI therapy. Data show a significant association between the type of BCR-ABL1 transcript and age on the probability of TFR.Subjects were in 1 st chronic phase and had a deep molecular response (≥MR4 on the International Scale) for one year or more before stopping TKI therapy, equivalent to the eligibility criteria of the Euro-Ski trial. 4Molecular response level was calculated by standard criteria 5 and molecular relapse defined as loss of MR3. Time to molecular relapse was measured from the date of TKI discontinuation to the first of 2 or more consecutive quantitative real-time polymerase chain reaction (qRT-PCR) assessments confirming less than MR3.Treatment-free remission was defined as the interval between the date of stopping TKI therapy and the date of molecular relapse or, if this did not happen, the date of last contact. Continuous variables were dichotomized to assess prognostic values for TFR using the median value. Sensitivity analysis was performed for these variables excluding outlier values. To explore the impact of age, we interrogated cut-off points at the median age (51 years) and at ages 40 and 60 years. P<0.05 (two-tailed) was considered significant. Potential predictive variables for TFR were analyzed in univariate analysis using the KaplanMeier method. Only statistically significant variables were included in multivariate analysis using a Cox proportional hazard regression model. Subject-, disease-and therapy-related variables before stopping TKI therapy are shown in Table 1. Median follow up from stopping TKI therapy was 26 months (range 6-121 months). Forty-one subjects [64%; 95% confidence interval (CI): 53, 75%)] stopped TKI because of intolerance, 7 (11%; 95%CI: 5, 19%) in order to conceive, and 16 (25%; 95%CI: 14, 36%) were elected to stop treatment on achieving a sustained deep response. At the time of discontinuing TKI, 32 subjects (50%; 95%CI: 38, 63%) were receiving imatinib and 32 (50%; 95%CI: 38, 63%), dasatinib or nilotinib. The frequency of patients with e13a2 (42%) or e14a2 transcripts (58%) is similar to that reported within the European LeukemiaNet (ELN) registry, at 45% and 55%, respectively. 6Thirty-seven subjects (58%; 95%CI: 45, 70%) remain in molecular remission at a median of 26 months (range 7-64 months) after stopping TKI therapy. The 3-year actuarial probability of TFR is 53% (95%CI: 38, 66%). Twenty-seven subjects (42%; 95%CI: 30, 55%) had a molecular relapse at a median of four months (range 1...

June 2018 was the 20th anniversary of the clinical use of the first tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia. Since then, the change in prognosis for patients with this disease is one of the major success stories of modern cancer medicine. The dilemmas that face physicians and patients are no longer only those concerned with delaying inevitable progression to the terminal blastic phase or selecting the individuals most likely to benefit from allogeneic stem-cell transplantation; rather, they are now focused also on the choice of TKI, the management of comorbidities and adverse effects, strategies to improve quality of life, and the appropriateness of a trial of therapy discontinuation. Interestingly, with 4 TKIs approved for frontline use, the choice of initial therapy continues to cause controversy, a situation made more complicated by the tantalizing prospect of treatment-free remission. In this manuscript, we will explore the factors influencing this decision and try to provide a pragmatic and clinically applicable solution.

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91Á9%), MR3 was maintained at median follow-up of 27Á3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last followup. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74Á1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.

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Summary The clinical outcome of chronic myeloid leukaemia patients has vastly improved since the introduction of tyrosine kinase inhibitor treatment, with a significant proportion of patients able to achieve treatment‐free remission. However, studies have shown that patients with the e13a2 transcript were less likely to achieve major molecular response compared to those with e14a2 transcripts. Most quantitative polymerase chain reaction (PCR) assays for detection of the BCR–ABL1 fusion gene do not differentiate between the two transcripts and we therefore hypothesised that technical bias linked to the qPCR assay could partially explain the discrepancy in outcomes. We designed an e14a2‐specific assay and identified no difference in results compared to an e13a2 standard assay. We then demonstrated that the commercial e14a2 standards were causing a significant overestimation of the e13a2 transcripts. Finally, we reviewed patient management after the qPCR values were corrected, using our new evaluation. We concluded that despite statistically significant differences in qPCR results, there was no impact on patient management or outcome. We conclude that, at least in our institution, it would be inappropriate to perform separate assays for patients with e13a2 or e14a2.

The COVID-19 pandemic is a serious healthcare challenge, leading to more than 5 million deaths worldwide so far. The rapid advent of modern messenger RNA-and adenovirus DNA vector-based anti-SARS-CoV-2 vaccines has already been associated with a significant reduction in the rate of COVID-19 deaths. 1 Haematological malignancies and/or their treatments are linked to impaired immunocompetence, which has been highlighted by recent reports of severe COVID-19 outcomes 2 and poor responses to SARS-CoV-2 vaccines. 3,4 Interestingly, patients with chronic myeloid leukaemia (CML) on BCR-ABL1 tyrosine kinase inhibitors (TKI) seem to have less severe COVID-19 compared to patients with other haematological cancers. 5 Also, although TKI have been reported to be immunosuppressive, 6,7 two recent prospective studies demonstrated that CML patients on TKI can mount an early immune response after the first dose of BNT162b2 (Pfizer-BioNTech). 8,9 We are conducting a prospective observational study (CML-Co-vax) at our centre, of which the primary objective is the evaluation of the seroconversion rate and the median anti-SARS-CoV-2 receptor binding domain (RBD) antibody level in CML patients on TKI compared to healthy subjects (HS), at early and late time points after the first and the second dose of SARS-CoV-2 vaccines. Patients and HS were assessed serially at baseline (T0), day +21 ± 7 (T1), day +49 ± 7 (T2) after the first dose, day +21 ± 7 (T3) and day +90 ± 20 (T4) after the second dose. Both groups received two doses of either BNT162b2 or ChAdOx1 nCov-19 (Oxford-AstraZeneca) vaccine 6-12 weeks apart (in accordance with UK government recommendations).Inclusion criteria were CML in chronic phase, current treatment with TKI and in at least complete cytogenetic remission. Exclusion from the study was determined by previous PCR-or serology-confirmed COVID-19 or by anti-SARS-CoV-2 immunisation with any of the available vaccines.Seroconversion for anti-RBD was confirmed using the Imperial double antigen-binding enzyme-linked immunosorbent assay (Imperial Hybrid DABA), which detects total anti-RBD with a specificity of 100% and a sensitivity of 98.9%. 10 All subjects gave their informed consent for participation in the study, which was approved by the Health Research Authority (IRAS ID: 289527) and by the Research Ethics

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