Discontinuation of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia: a Review of the Biological Factors Associated with Treatment-Free Remission.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Presence of Myeloid Mutations in Patients with Chronic Myeloid Leukemia Increases Risk of Cardiovascular Event on Tyrosine Kinase Inhibitor Treatment.

For chronic myeloid leukemia (CML) patients with a known risk of cardiovascular events (CVE), imatinib is often recommended for first-line tyrosine kinase inhibitor (TKI) treatment rather than a second-generation TKI (2G-TKI) such as nilotinib or dasatinib. To date, very few studies have evaluated the genetic predisposition associated with CVE development on TKI treatment. In this retrospective study of 102 CML patients, 26 CVEs were reported during an average follow-up of over 10 years. Next-generation sequencing identified pathogenic/likely pathogenic mutations in genes associated with myeloid malignancies in 24.5% of the diagnostic samples analyzed. Patients with a recorded CVE had more myeloid mutations (0.48 vs. 0.14, p = 0.019) and were older (65.1 vs. 55.7 years, p = 0.016). Age ≥ 60 years and receiving a 2G-TKI in first-line were CVE risk factors. The presence of a pathogenic somatic myeloid mutation was an independent risk factor for CVE on any TKI (HR 2.79, p = 0.01), and significantly shortened the CV event-free survival of patients who received first-line imatinib (by 70 months, p = 0.011). Indeed, 62% of patients on imatinib with mutations had a CVE vs. the 19% on imatinib with a mutation and no CVE. In conclusion, myeloid mutations detectable at diagnosis increase CVE risk, particularly for patients on imatinib, and might be considered for first-line TKI choice.

Predictive indicators of successful tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia.

Clinical trials have demonstrated that some patients with chronic myeloid leukemia (CML) treated for several years with tyrosine kinase inhibitors (TKIs) who have maintained a molecular response can successfully discontinue treatment without relapsing. Treatment free remission (TFR) can be reached by approximately 50% of patients who discontinue. Despite having similar levels of deep molecular response and an identical duration of treatment, the factors that influence the successful discontinuation of CML patients remain to be determined. In this review we will explore the factors identified to date that can help predict whether a patient will successfully achieve TFR. We will also discuss the need for the identification of predictive biomarkers associated with a high probability of achieving TFR for the future personalized identification of patients who are suitable for the discontinuation of TKI treatment.

Thrombotic Risk Detection in Patients with Polycythemia Vera: The Predictive Role of DNMT3A/TET2/ASXL1 Mutations.

The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006-1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of ≥1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15-11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort.

Additional evidence that the rat renal interstitium contracts in vivo.

We recently provided highly suggestive preliminary evidence that the renal interstitium contracts reactively in vivo. We demonstrated that renal medullary direct interstitial volume expansion (rmDIVE = 100 µl bolus infusion of 0.9% saline (SS)/30 s) brought about a biphasic renal interstitial hydrostatic pressure (RIHP) response which was abolished when dibutyryl-cAMP was concomitant and interstitially infused. To assess more deeply the feasibility of the concept that the renal interstitium contracts in vivo, two experimental series (S1, S2) were performed in hydropenic rats subjected to acute left renal-denervation, hormonal clamping, and control of renal arterial pressure. In S1, RIHP and renal outer medullary blood flow (RoMBF) were continuously measured before and after a sudden micro-bolus (5µl) injection, into the renal medullary interstitium, of SS containing α-trinositol (α-TNS, anti-inflammatory drug) to either two doses 2 or 4 mM (SS + 2 α-TNS and SS + 4 α-TNS groups). No overall differences between groups in either ΔRIHP or %ΔRoMBF time courses were found; however, in the SS + 2 α-TNS group the data were less scattered and the ΔRIHP time course tended to peak faster and then persisted there, so that, this α-TNS dose was selected for S2. In S2, RIHP and RoMBF were similarly measured in rats randomly assigned to three groups: the CTR group (sham time-control), SS group (SS alone), and SS + α-TNS group. The micro-bolus injection of SS alone (SS group) was unable to increase ΔRIHP. The group with no micro-bolus injection (CTR group) experienced a decrease in ΔRIHP. The micro-bolus injection of SS + 2 α-TNS was accompanied by a differential increase in ΔRIHP (vs. CTR and SS groups). These responses were not associated with differential changes among groups in %ΔRoMBF or hemodilution parameters. These results provide additional evidence that the renal interstitium contracts in vivo.