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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. Patients and Methods: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. Results: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%. Conclusions: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Background: Patients with acute myeloid leukemia (AML) face an abrupt life-threatening illness and experience immense physical and psychological symptoms. However, no data describe how patients with AML cope longitudinally with their illness or the relationship between longitudinal coping and outcomes. Methods: We conducted a secondary analysis of longitudinal data from 160 patients with high-risk AML enrolled in a supportive care intervention trial to describe coping strategies longitudinally across the illness course. We used the Brief COPE questionnaire, the Hospital Anxiety and Depression Scale, the Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, and the Functional Assessment of Cancer Therapy-Leukemia to measure coping strategies, psychological distress, and quality of life (QoL) at baseline and at weeks 2, 4, 12, and 24 after diagnosis. Electronic health records were used to assess healthcare utilization and end-of-life (EoL) outcomes, and multivariate analyses were used to assess the relationship between coping and outcomes. Results: Longitudinal utilization of approach-oriented coping strategies was significantly associated with less distress (anxiety: β, –0.18; PPPPPPP=.049). Conclusions: Longitudinal use of approach-oriented coping strategies was associated with less psychological distress, better QoL, and a lower likelihood of ICU admission, suggesting a possible target for supportive oncology interventions. Coping strategies did not impact EoL outcomes, and further research is needed to elucidate which patient factors impact EoL decision-making.

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 ( ClinicalTrials.gov )

Representativeness of Study Participants

Supplemental Figure 2: Overall and progression-free survival for patients according to NPM1 mutational status

Purpose:Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML.Methods:We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib.Results:Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%.Conclusions:Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Supplemental Figure 1: Overall and progression-free survival for patients, according to whether the transplant followed first line or second line treatment.

BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantation. This case illustrates that next-generation sequencing approaches designed to discover cryptic gene fusions can benefit patients with Ph-like ALL.

PURPOSE The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti–SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses ( P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type ( P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses ( P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research.

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

TP53-mutated acute myeloid leukaemia (AML) is associated with an adverse prognosis and poor response to traditional chemotherapy regimens. Next-generation sequencing (NGS) is considered the gold standard method to determine TP53-mutational status; however, molecular assays are costly and time-consuming. In contrast, immunohistochemistry (IHC) can be performed within 1 day of biopsy. We sought to determine an optimal threshold of staining with p53 IHC to predict TP53-mutational status.We identified 142 consecutive patients with newly diagnosed AML with concurrent NGS analysis diagnosed between 2019 and 2020. All cases were stained for p53 IHC and images were scored for the percent of strongly stained p53+ cells by a combination of manual counting and image analysis. We then correlated percent positive staining with mutational status and clinical outcomes. We determined that a threshold of ≥7% strongly stained cells by p53 IHC correlated with the presence of a TP53 mutation with a sensitivity of 67%, specificity of 100%, positive predictive value of 100% and negative predictive value of 90%. TP53 mutation and the presence of ≥7% staining by IHC were associated with shorter overall survival by univariate analysis (P 0.01).If the limitations of this study are carefully considered, our findings suggest that p53 protein expression as evaluated by IHC could be used to rapidly predict TP53-mutational status with high specificity and assist in risk stratification in newly diagnosed AML.

Background: LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 dose escalation study of oral LY3410738 in patients (pts) with R/R IDH1/2m hematologic cancers. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in IDH1/2m R/R AML (NCT04603001). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 114 pts including 108 R/R AML pts received LY3410738 dosed at 5-600 mg QD or 40-300 mg BID. Pts were median 73 years of age (range, 22-92) with a median of 2 prior therapies (range, 1-10); 29% received a prior IDH inhibitor and 58% a prior BCL2 inhibitor. Median time on treatment was 2.3 months (range, 0.1-15). No DLTs or treatment related deaths were observed. Treatment emergent adverse events ≥20% were diarrhea (22%), fatigue (21%), and anemia (20%). Differentiation syndrome was reported in 11 pts (10%); 4 grade 1/2 (4%), 7 grade 3 (6%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Responses were observed in both IDH1m and IDH2m AML (Table). Higher doses were required for IDH2m AML, especially IDH2 R140m pts. Efficacy appears higher in venetoclax naïve pts and limited in IDH inhibitor pre-treated pts. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1m R132, IDH2m R172, and IDH2m R140 mutations. Preliminary efficacy was also seen in all genotypes, in a dose dependent manner. RP2D evaluation is ongoing. Table: Response in R/R AML IDH Inhibitor Naive (N=68) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=13) Prior Venetoclax (n=19) Total (N=32) Low Dosesa (n=5) (High Dosesb) Total (N=13) Low Dosesa (n=9) (High Dosesb) Total (N=23) No prior Venetoclax (n=3) Prior Venetoclax (n=5) No prior Venetoclax (n=6) Prior Venetoclax (n=8) CR+CRh, n (%) 5 (38%) 2 (11%) 7 (22%) - 3 (100%) 2 (40%) 5 (38%) - 2 (33%) - 2 (9%) CR, n (%) 3 (23%) 2 (11%) 5 (16%) - 2 (67%) 2 (40%) 4 (31%) - 2 (33%) - 2 (9%) CRh, n (%) 2 (15%) - 2 (6%) - 1 (33%) - 1 (8%) - - - - CRc (CR+CRh+CRi/CRp), n (%) 6 (46%) 6 (32%) 12 (38%) - 3 (100%) 3 (60%) 6 (46%) - 2 (33%) - 2 (9%) MFLS, n (%) 1 (8%) 3 (16%) 4 (13%) 2 (40%) - - 2 (15%) 1 (11%) - - 1 (4%) IDH Inhibitor Pre-Treated (N=33) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=2) Prior Venetoclax (n=8) Total (N=10) Low Dosesa (n=6) (High Dosesb) Total (N=8) Low Dosesa (n=4) (High Dosesb) Total (N=15) No prior Venetoclax (n=1) Prior Venetoclax (n=1) No prior Venetoclax (n=3) Prior Venetoclax (n=8) CR+CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CR, n (%) - - - - - - - - - - - CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CRc (CR+CRh+CRi/CRp), n (%) - - - - - - - 1 (25%) - 1 (13%) 1 (7%) MLFS, n (%) - - - - - - - - - - - Among the 108 treated R/R AML pts, 101 were efficacy evaluable (42 IDH1 R132, 21 IDH2 R172, 38 IDH2 R140); 68 pts were IDH inhibitor naïve and 33 had received a prior IDH inhibitor treatment. Efficacy evaluable pts are those who had completed the first bone marrow assessment or had discontinued treatment prior to first bone marrow assessment aTotal daily low doses: ≤75 mg Arm A, ≤30 mg Arm B bTotal daily high doses: ≥150 mg Arm A, ≥60 mg Arm B Arm A: not requiring a strong CYP3A4 inhibitor Arm B: requiring a strong CYP3A4 inhibitor Citation Format: Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Maël Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, Eytan M. Stein. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT026.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Background Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. Methods Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. Results Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of “abnormal” results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. Conclusion Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

We developed a direct mapping approach to overlay the image of a polycrystalline perovskite film obtained from the transient absorption microscope (TAM) with that from the scanning electron microscope (SEM). By mapping these imaging data pixel by pixel, we are able to observe the relaxation dynamics of the photo-generated charge carriers on varied regions of the film. The carrier relaxation dynamics contain a dominated single-exponential decay component owing to the recombination of charge carriers. The lifetime distribution of charge recombination shows a bimodal feature, for which the rapid and slow distributions are assigned as free and trapped carriers, respectively. The charge recombination was slower in the grain boundary (GB) region than in the grain interior (GI) region. The small grains have longer lifetimes than the large grains for the crystal size smaller than 500 nm. Therefore, GB with retarded charge recombination might play a positive role in a perovskite solar cell.

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

Key Points A novel PCM1-FGFR1 gene rearrangement was identified in a patient with a myeloid neoplasm with eosinophilia. Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, resulted in a durable complete hematologic and cytogenetic remission.

Applying a two-step procedure and solvent engineering we fabricated a stable tin-based perovskite, formamidinium-tin-triiodide (FASnI3) solar cell for lead-free photovoltaic applications. The first...

The effects of additives SnF2 (10 %) and EDAI2 (1 %) on the dynamics of carrier relaxation of formamidinium tin triiodide (FASnI3) perovskite were studied using femtosecond transient absorption spe...

Summary Background Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial. Methods The multicentre, open-label, phase 1–2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60–300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov , NCT01915498 , status ongoing but closed to recruitment. Findings 17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5–73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8–23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2–15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3–4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28–77]), with a median duration of response of 9·2 months (95% CI 1·0–not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5–32·3), and median event-free survival was 11·0 months (1·5–16·7). Interpretation Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful. Funding Celgene and Agios Pharmaceuticals.

A far-field optical microscope (OM) is a powerful noninvasive, nondestructive tool to study sub-micrometer structures and organisms, which has been used for decades to study the interactions betwee...

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 x 10(9)/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those >= 65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.

A 44-year-old woman with a prior history of myxoid liposarcoma who was previously treated with radiation, chemotherapy, and resection, was admitted with syncope and pancytopenia. She was diagnosed with a high-grade therapy-related myelodysplastic syndrome and treated with decitabine. Her disease soon progressed to overt acute myeloid leukemia (AML). She was treated with cytotoxic chemotherapy including cytarabine and topotecan, but she was not a candidate for further anthracycline exposure given her prior treatment for sarcoma and concern for cardiotoxicity. Her AML was refractory to two sequential induction regimens. Given that targeted genomic sequencing had revealed a