European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Increasing thermal stress for tropical coral reefs: 1871-2017.

Tropical corals live close to their upper thermal limit making them vulnerable to unusually warm summer sea temperatures. The resulting thermal stress can lead to breakdown of the coral-algal symbiosis, essential for the functioning of reefs, and cause coral bleaching. Mass coral bleaching is a modern phenomenon associated with increases in reef temperatures due to recent global warming. Widespread bleaching has typically occurred during El Niño events. We examine the historical level of stress for 100 coral reef locations with robust bleaching histories. The level of thermal stress (based on a degree heating month index, DHMI) at these locations during the 2015-2016 El Niño was unprecedented over the period 1871-2017 and exceeded that of the strong 1997-1998 El Niño. The DHMI was also 5 times the level of thermal stress associated with the 'pre-industrial', 1877-1878, El Niño. Coral reefs have, therefore, already shown their vulnerability to the modest (~0.92 °C) global warming that has occurred to date. Estimates of future levels of thermal stress suggest that even the optimistic 1.5 °C Paris Agreement target is insufficient to prevent more frequent mass bleaching events for the world's reefs. Effectively, reefs of the future will not be the same as those of the past.

Large-scale bleaching of corals on the Great Barrier Reef.

In 2015-2016, record temperatures triggered a pan-tropical episode of coral bleaching. In the southern hemisphere summer of March-April 2016, we used aerial surveys to measure the level of bleaching on 1,156 individual reefs throughout the 2,300 km length of the Great Barrier Reef, the world's largest coral reef system. The accuracy of the aerial scores was ground-truthed with detailed underwater surveys of bleaching at 260 sites (104 reefs), allowing us to compare aerial and underwater bleaching data with satellite-derived temperatures and with associated model predictions of bleaching. The severity of bleaching on individual reefs in 2016 was tightly correlated with the level of local heat exposure: the southernmost region of the Great Barrier Reef escaped with only minor bleaching because summer temperatures there were close to average. Gradients in nutrients and turbidity from inshore to offshore across the Great Barrier Reef had minimal effect on the severity of bleaching. Similarly, bleaching was equally severe on reefs that are open or closed to fishing, once the level of satellite-derived heat exposure was accounted for. The level of post-bleaching mortality, measured underwater after 7-8 months, was tightly correlated with the aerial scores measured at the peak of bleaching. Similarly, reefs with a high aerial bleaching score also experienced major shifts in species composition due to extensive mortality of heat-sensitive species. Reefs with low bleaching scores did not change in composition, and some showed minor increases in coral cover. Two earlier mass bleaching events occurred on the Great Barrier Reef in 1998 and 2002, that were less severe than 2016. In 2016, <9% of scored reefs had no bleaching, compared to 42% in 2002 and 44% in 1998. Conversely, the proportion of reefs that were severely bleached (>60% of corals affected) was four times higher in 2016. The geographic footprint of each of the three events is distinctive, and matches satellite-derived sea surface temperature patterns. Our aerial surveys indicate that past exposure to bleaching in 1998 and 2002 did not lessen the severity of bleaching in 2016. This data set of aerial bleaching scores provides a historical baseline for comparison with future bleaching events. No copyright restrictions apply to the use of this data set other than citing this publication.

The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment.

Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

TGF-α and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy.

Early molecular response (EMR, BCR-ABL1 (IS)⩽10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early, 3 months may be too late for effective therapeutic intervention. Here, we employed multiplex cytokine profiling of plasma samples to test newly diagnosed CP-CML patients who subsequently received imatinib treatment. A wide range of pro-inflammatory and angiogenesis-promoting cytokines, chemokines and growth factors were elevated in the plasma of CML patients compared with that of healthy donors. Most of these normalized after tyrosine kinase inhibitor treatment while others remained high in remission samples. Importantly, we identified TGF-α and IL-6 as novel biomarkers with high diagnostic plasma levels strongly predictive of subsequent failure to achieve EMR and deep molecular response, as well as transformation to blast crisis and event-free survival. Interestingly, high TGF-α alone can also delineate a poor response group raising the possibility of a pathogenic role. This suggests that the incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy intensity to be individualized early according to the cytokine-risk profile of the patient.

Global marine protected areas do not secure the evolutionary history of tropical corals and fishes.

Although coral reefs support the largest concentrations of marine biodiversity worldwide, the extent to which the global system of marine-protected areas (MPAs) represents individual species and the breadth of evolutionary history across the Tree of Life has never been quantified. Here we show that only 5.7% of scleractinian coral species and 21.7% of labrid fish species reach the minimum protection target of 10% of their geographic ranges within MPAs. We also estimate that the current global MPA system secures only 1.7% of the Tree of Life for corals, and 17.6% for fishes. Regionally, the Atlantic and Eastern Pacific show the greatest deficit of protection for corals while for fishes this deficit is located primarily in the Western Indian Ocean and in the Central Pacific. Our results call for a global coordinated expansion of current conservation efforts to fully secure the Tree of Life on coral reefs.

OCT1 and imatinib transport in CML: is it clinically relevant?

Imatinib is a highly effective therapy for chronic phase-chronic myeloid leukaemia (CP-CML) patients; however, responses to frontline imatinib are variable. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter involved in imatinib uptake into CML cells. Furthermore, variation in the efficiency of imatinib influx via OCT1 has been demonstrated to result in the inter-patient variation observed in primary response to imatinib. Although studies have questioned the role of OCT1 in imatinib influx, these have been largely performed in non-clinical settings. Measuring both OCT1 mRNA levels and the functional activity of OCT1 in primary leukaemic cells has been demonstrated to predict molecular response and outcome in imatinib-treated CP-CML patients in several independent studies. Here, the role of OCT1 and OCT1 genetic variants in imatinib uptake and response prediction is summarised and data generated from model systems assessing the role of OCT1 in imatinib transport is discussed.

BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase.

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia.

Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.

Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib.

The efflux transporters adenosine triphosphate (ATP)-binding cassette (ABC)B1 and ABCG2 have been demonstrated to interact with the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib. However, although some studies conclude that TKIs are substrates of one or both transporters, other studies demonstrate only an inhibitory function. This variation is probably due to differences in the concentration of TKIs assayed and the experimental systems used. This article examines the evidence for clinically relevant interactions between three currently approved TKIs and ABCB1/ABCG2.

BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance.

BACKGROUND: BCR-ABL1 mutation analysis is recommended for chronic myeloid leukaemia patients. However, mutations may become undetectable after changing therapy, and it is unknown whether they have been eradicated. METHODS: We examined longitudinal data of patients with imatinib-resistant mutations, which became undetectable by Sanger sequencing to determine whether mutations could reappear, and the related circumstances. RESULTS: Identical imatinib- and nilotinib-resistant mutations reappeared following further therapy changes in five patients, and was associated with subsequent nilotinib resistance in four. CONCLUSION: The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors.