How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Ultrasound-Guided Scalp Blocks for an Awake Craniotomy: A Case Report.

Ultrasound-guided scalp blocks may revolutionize regional anesthesia for neurosurgery. In this report, we demonstrate that ultrasound-guided scalp blocks can be used effectively for a craniotomy. A 48-year-old patient with a brain tumor at the motor cortex was scheduled for an awake craniotomy. Ultrasound-guided scalp blocks targeting the bilateral supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, greater auricular, lesser occipital, greater occipital, and third occipital nerves were performed. A total of 29 mL of levobupivacaine 0.3% was used. No additional local anesthetic agent was given for skull pinning, skin incision, or the craniotomy. Postoperatively, the patient remained pain-free, and she was discharged without complications.

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.

PURPOSE: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) 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 mIDH1 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%). mIDH1 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 mIDH1 mutation clearance.

Efficacy and safety of nilotinib 300 mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study.

BACKGROUND: Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. METHODS: This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of ≤0.0032% on the International Scale) by 24 months. RESULTS: Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib-intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300 mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300 mg bid. CONCLUSION: Nilotinib 300 mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses.

Cellular Immunotherapy for Hematologic Malignancies: Beyond Bone Marrow Transplantation.

Immunotherapy has changed treatment practices for many hematologic malignancies. Even in the current era of targeted therapy, chemotherapy remains the backbone of treatment for many hematologic malignancies, especially in acute leukemias, where relapse remains the major cause of mortality. Application of novel immunotherapies in hematology attempts to harness the killing power of the immune system against leukemia and lymphoma. Cellular immunotherapy is evolving rapidly for high-risk hematologic disorders. Recent advances include chimeric antigen-receptor T cells, mesenchymal stromal/stem cells, dendritic cell tumor vaccines, cytokine-induced killer cells, and virus-specific T cells. The advantages of nontransplantation cellular immunotherapy include suitability for patients for whom transplantation has failed or is contraindicated, and a potentially less-toxic treatment alternative to transplantation for relapsed/refractory patients. This review examines those emerging cellular immunotherapies that are changing treatment paradigms for patients with hematologic malignancies.

Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia.

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.

The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study.

Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5-21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1-5 and 8-9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia.

In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0-25 mg, days 5-25) in combination with azacitidine (50-75 mg/m(2) , days 1-5) every 28 d, was explored in 40 patients with acute myeloid leukaemia (AML) in complete remission after chemotherapy. Eligibility included AML in first complete remission (CR1) with adverse risk karyotype (n = 8), fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (n = 5), age ≥60 years (n = 31) or AML in second remission (CR2) (n = 14). Dose-limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR1, median relapse-free (RFS) and overall survival (OS) was 12 and 20 months, respectively. In CR2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT3-ITD and nucleophosmin (NPM1) mutation; none have relapsed and all are still alive after 17-39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A)-positive disease, resulting in sustained remission in patients with concurrent NPM1 mutation. Azacitidine/lenalidomide as maintenance therapy for high-risk AML warrants further exploration.

Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients.

A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFNγ production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome.

Day-case re-do varicose vein surgery.

OBJECTIVE: To assess whether re-do varicose vein surgery as a day case is feasible and safe. METHODS: Data were collected retrospectively on 70 consecutive patients (77 legs) undergoing re-do sapheno-femoral or sapheno-popliteal ligation by consultant surgeons as day cases. Follow-up was by structured telephone interview. RESULTS: The 70 patients comprised 53 females and 17 males. Median age and body mass index were 47.5 years and 27, respectively. All patients were ASA Grade I or II. Median operating time was 75 min (range 25-140). Of the 70 patients intended to be treated as day cases, four (5.7%) were admitted overnight. There were no were re-admissions nor did any patient develop deep vein thrombosis. Eleven per cent developed wound infection and 4% transient lymphatic leakage. Overall, 91% of patients were pleased with the initial surgical result but this decreased to 81% in the longer term. Eighty-nine per cent would have their surgery performed again as a day case. CONCLUSION: Re-do sapheno-femoral or sapheno-popliteal can be performed safely as a day case.

Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients.

PURPOSE: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2(+) Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2(+) Tregs. EXPERIMENTAL DESIGN: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2(+) Tregs were analyzed subsequently. RESULTS: We report that TNFR2(+) Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2(+) Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2(+) Tregs were associated with increases in Interferon (IFN)-γ and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs. CONCLUSIONS: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2(+) Tregs, resulting in clinical benefits within patients with AML.

C-terminal ß9-strand of the cyclic nucleotide-binding homology domain stabilizes activated states of Kv11.1 channels.

Kv11.1 potassium channels are important for regulation of the normal rhythm of the heartbeat. Reduced activity of Kv11.1 channels causes long QT syndrome type 2, a disorder that increases the risk of cardiac arrhythmias and sudden cardiac arrest. Kv11.1 channels are members of the KCNH subfamily of voltage-gated K(+) channels. However, they also share many similarities with the cyclic nucleotide gated ion channel family, including having a cyclic nucleotide-binding homology (cNBH) domain. Kv11.1 channels, however, are not directly regulated by cyclic nucleotides. Recently, crystal structures of the cNBH domain from mEAG and zELK channels, both members of the KCNH family of voltage-gated potassium channels, revealed that a C-terminal ß9-strand in the cNBH domain occupied the putative cyclic nucleotide-binding site thereby precluding binding of cyclic nucleotides. Here we show that mutations to residues in the ß9-strand affect the stability of the open state relative to the closed state of Kv11.1 channels. We also show that disrupting the structure of the ß9-strand reduces the stability of the inactivated state relative to the open state. Clinical mutations located in this ß9-strand result in reduced trafficking efficiency, which suggests that binding of the C-terminal ß9-strand to the putative cyclic nucleotide-binding pocket is also important for assembly and trafficking of Kv11.1 channels.

Factors that influence pain intensity and fentanyl requirements after a gynecologic laparotomy.

The association between pain intensity and its control by intravenous patient-controlled analgesia (IV-PCA) with fentanyl after a laparotomy for cystectomy/salphingoophorectomy, myomectomy, or hysterectomy was investigated. IV fentanyl infusion was administered to patients (n = 94) at 3 µg/kg/h to provide intraoperative analgesia after induction of general anesthesia. Postoperative fentanyl requirements were quantified via IV-PCA, and the amounts of rescue fentanyl required both during and after surgery were recorded. Mean values for PCA use as well as the visual analog scores (VAS) for pain were documented for up to 24 hours. The association between postoperative fentanyl requirements and VAS were then analyzed by using Mann-Whitney or Kruskal-Wallis tests. Patients with lower midline incisions had greater degrees of pain (p < .05) during the first 16 hours after surgery but did not consume more fentanyl compared with patients with Pfannenstiel incisions. Subjects who underwent operations lasting >4 hours required more rescue fentanyl during surgery (p < .05). However, this group consumed less fentanyl during the first 4 hours after surgery (p < .05). The demand at the fourth 4-hour period was lower among subjects undergoing myomectomy compared with cystectomy/salphingoophorectomy or hysterectomy (p = .045). Only a poor correlation was observed between pain intensity and analgesic usage. Postoperative pain intensity is influenced by the type of surgical incision but not the type of gynecologic surgery nor the duration of surgery. The relationship between subjective pain ratings with analgesic consumption is weak. Prolonged intraoperative administration of continuous IV fentanyl infusion may reduce fentanyl requirements in the immediate postoperative period.

Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels.

Human ether-a-go-go-related gene (hERG) potassium channels exhibit unique gating kinetics characterized by unusually slow activation and deactivation. The N terminus of the channel, which contains an amphipathic helix and an unstructured tail, has been shown to be involved in regulation of this slow deactivation. However, the mechanism of how this occurs and the connection between voltage-sensing domain (VSD) return and closing of the gate are unclear. To examine this relationship, we have used voltage-clamp fluorometry to simultaneously measure VSD motion and gate closure in N-terminally truncated constructs. We report that mode shifting of the hERG VSD results in a corresponding shift in the voltage-dependent equilibrium of channel closing and that at negative potentials, coupling of the mode-shifted VSD to the gate defines the rate of channel closure. Deletion of the first 25 aa from the N terminus of hERG does not alter mode shifting of the VSD but uncouples the shift from closure of the cytoplasmic gate. Based on these observations, we propose the N-terminal tail as an adaptor that couples voltage sensor return to gate closure to define slow deactivation gating in hERG channels. Furthermore, because the mode shift occurs on a time scale relevant to the cardiac action potential, we suggest a physiological role for this phenomenon in maximizing current flow through hERG channels during repolarization.

Anesthesia for massive retrosternal goiter with severe intrathoracic tracheal narrowing: the challenges imposed -A case report-.

Anesthetic management of patients with mediastinal masses remains challenging as acute cardiorespiratory decompensation may follow induction of anesthesia. We describe a 57 year old lady with massive retrosternal goiter and severe intrathoracic tracheal compression who had a total thyroidectomy. Comprehensive contingency plans were an essential prerequisite for successful management of difficult airway, including multidisciplinary involvement of otorhinolaryngologic and cardiothoracic surgeons preparing for rigid bronchoscopy and cardiopulmonary bypass. Awake oral fiberoptic intubation was performed under dexmedetomidine sedation. Severe tracheal narrowing necessitated usage of a 5.0 mm uncuffed flexometallic endotracheal tube. Anesthesia was maintained with sevoflurane and dexmedetomidine infusion with target controlled infusion of remifentanil as analgesia. No muscle relaxant was given. Surgical manipulation led to intermittent total tracheal compression and inadequate ventilation. The tumor was successfully removed via the cervical approach. A close working relationship between anesthesiologists and surgeons was the key to the safe use of anesthesia and uneventful recovery of this patient.

The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.

Human ether-à-go-go-related gene (hERG) K(+) channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4-S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4-S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4-S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4-S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4-S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4-S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel.

The epigenomics revolution in myelodysplasia: a clinico-pathological perspective.

Rapid advances in molecular technologies are continually re-shaping the way we view and understand the mechanisms driving oncogenesis. The last decade has witnessed unparalleled change in the biology and therapy of the myelodysplastic syndromes (MDS), a heterogeneous collection of clonal myeloid disorders characterised by ineffective haematopoiesis and susceptibility to acute leukaemia transformation. Pivotal studies demonstrating the positive effects of hypomethylating agents on clinical outcome have brought an 'epigenomics revolution' to this disease, emphasising the importance of epigenetic mechanisms to the underlying pathogenesis of MDS. One of the most important future challenges in the MDS field will be to determine whether epigenetic therapies can be made more 'targeted' through identification of biomarkers which define subsets of patients most likely to benefit from treatment. A wave of novel mutations have recently been reported in MDS and other myeloid disorders, several of which regulate endogenous methylation networks within cells (including TET2, DNMT3A, IDH and EZH2). The relevance of these lesions in being able to predict response to epigenetic modulators and their correlation with epigenetic signatures in MDS are beginning to emerge.