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.
Following the recent isolation of monolayer CrI3 (ref. 1), many more two-dimensional van der Waals magnetic materials have been isolated2–12. Their incorporation in van der Waals heterostructures ...offers a new platform for spintronics5–9, proximity magnetism13 and quantum spin liquids14. A primary question in this field is how exfoliating crystals to the few-layer limit influences their magnetism. Studies of CrI3 have shown a different magnetic ground state for ultrathin exfoliated films1,5,6 compared with the bulk, but the origin is not yet understood. Here, we use electron tunnelling through few-layer crystals of the layered antiferromagnetic insulator CrCl3 to probe its magnetic order and find a tenfold enhancement of the interlayer exchange compared with bulk crystals. Moreover, temperature- and polarization-dependent Raman spectroscopy reveals that the crystallographic phase transition of bulk crystals does not occur in exfoliated films. This results in a different low-temperature stacking order and, we hypothesize, increased interlayer exchange. Our study provides insight into the connection between stacking order and interlayer interactions in two-dimensional magnets, which may be relevant for correlating stacking faults and mechanical deformations with the magnetic ground states of other more exotic layered magnets such as RuCl3 (ref. 14).
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.
Biochar amendments can reduce nitrate (NO3) leaching in agricultural soil. It has been hypothesized that functional groups on the biochar surface from oxidation can increase NO3 sorption. This study ...evaluates the effect of chemical oxidation of biochar on NO3 sorption characteristics. Eight biochars, made from wood and corn cobs, underwent sodium hypochlorite (NaClO) and hydrogen peroxide (H2O2) oxidation and then assessed for NO3 sorption capacity using batch isotherm methods. The unoxidized and oxidized biochar produced at low temperatures (400 °C) had no significant NO3 sorption. Oxidized biochars produced at higher temperatures (600 °C and 700 °C) had calculated maximum NO3 sorption capacities (Smax) ranging from 0.50 to 3.97 mg NO3-N g-1. Biochar oxidations with 50 mmol NaClO g-1 (N50) in combination with an acid wash (AW) had the largest estimated sorption capacities of 3.68, 3.97, and 1.46 mg NO3-N g-1 for CTN50,AW, BW3N50,AW, and CC3N50,AW, respectively. Sorption capacity of wood-based biochars was higher than corn cob biochars due to increased oxidation as measured by total acid group content (TAGC). Wood biochar Smax values were correlated with ΔTAGC (R2 = 0.86), with a slope of 1.2 μmol NO3-N μmol TAGC-1 suggesting that cationic bridging of NO3 to oxidized sites is the primary mechanism for NO3 sorption.
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•Chemical oxidation of biochar via NaClO and H2O2 can increase TAGC of biochar.•TAGC following oxidation increases as pyrolysis production temperature increases.•NMR and FTIR spectrums support hypothesis that oxygenated functional groups increase as a result of NaClO and H2O2 oxidation.•Oxidation of biochar increases NO3 sorption.•TAGC and NO3 sorption capacity were correlated, suggesting a cation bridging mechanism between oxidized surface sites and NO3.
Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study ...of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
Our group previously demonstrated that M-protein light chain (LC) glycosylation can be detected on routine MASS-FIX testing. Glycosylation is increased in patients with immunoglobulin LC amyloidosis ...(AL) and rarely changes over the course of a patient's lifetime. To determine the rates of progression to AL and other plasma cell disorders (PCDs), we used residual serum samples from the Olmsted monoclonal gammopathy of undetermined significance (MGUS) screening cohort. Four-hundred and fourteen patients with known MGUS were tested by MASS-FIX, and 25 (6%) were found to have glycosylated LCs. With a median follow-up of surviving patients of 22.2 years, the 20-year progression rates to a malignant PCD were 67% (95% CI 29%, 84%) and 13% (95% CI 9%, 18%) for patients with and without glycosylated LCs, respectively. The risk of progression was independent of Mayo MGUS risk score. The respective rates of progression to AL at 20 years were 21% (95% CI 0.0%, 38%) and 3% (95% CI 0.6%, 5.5%). In summary, monoclonal LC glycosylation is a potent risk factor for progression to AL, myeloma, and other PCDs, an observation which could lead to earlier diagnoses and potentially reduced morbidity and mortality.
We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain ...(HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5-3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1-3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.
We studied 351 patients with smoldering multiple myeloma (SMM) in whom the underlying primary molecular cytogenetic subtype could be determined based on cytoplasmic immunoglobulin fluorescent in situ ...hybridization studies. Hundred and fifty-four patients (43.9%) had trisomies, 127 (36.2%) had immunoglobulin heavy chain (IgH) translocations, 14 (4%) both trisomies and IgH translocations, 53 (15.1%) no abnormalities detected and 3 (0.9%) had monosomy13/del(13q) in the absence of any other abnormality. Among 127 patients with IgH translocations, 57 were t(11;14), 36 t(4;14), 11 musculoaponeurotic fibrosarcoma (MAF) translocations, and 23 other or unknown IgH translocation partner. Time to progression (TTP) to symptomatic multiple myeloma was significantly shorter in patients with the t(4;14) compared with patients with t(11;14), median 28 versus 55 months, respectively, P=0.025. The median TTP was 28 months with t(4;14) (high-risk), 34 months with trisomies alone (intermediate-risk), 55 months with t(11;14), MAF translocations, other/unknown IgH translocations, monosomy13/del(13q) without other abnormalities, and those with both trisomies and IgH translocations (standard-risk), and not reached in patients with no detectable abnormalities (low-risk), P=0.001. There was a trend to shorter TTP with deletion 17p (median TTP, 24 months). Overall survival from diagnosis of SMM was significantly inferior with t(4;14) compared with t(11;14), median 105 versus 147 months, respectively, P=0.036.
Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to ...determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2-3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007, who had testing for circulating PCs using an immunofluorescent assay and adequate follow-up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5 × 10(6)/l and/or >5% PCs per 100 cytoplasmic immunoglobulin (Ig)-positive peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 24%, respectively, P=0.001. Corresponding rates for progression within 3 years were 86% versus 34%, respectively, P<0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2-3 years following diagnosis.
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