Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia.

The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the heterogeneous molecular basis of the disease. Since genetic sequencing has become a standard practice, several driver mutations have been identified. Accordingly, novel targeted therapeutic agents have been developed and are now approved for the treatment of subsets of patients that carry mutations in FLT3, IDH1, and IDH2 [1, 2]. The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.

Risk factors for disease progression and treatment goals in polycythemia vera.

Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by the clonal proliferation of hematopoietic cells, leading to the overproduction of erythrocytes and the elaboration of inflammatory cytokines. Management is aimed at reducing the risk of thromboembolic events, alleviating the symptom burden, decreasing splenomegaly, and potentially mitigating the risk of disease progression. Existing treatment options include therapeutic phlebotomy and cytoreductive agents including hydroxyurea, pegylated recombinant interferon alpha 2a, ropegylated recombinant interferon alpha 2b, and ruxolitinib. We review risk factors for both thrombotic events and disease progression in patients with polycythemia vera. We discuss existing and novel therapeutic approaches to mitigate the risk of disease-related complications and progression.

Treating accelerated and blast phase myeloproliferative neoplasms: progress and challenges.

Myeloproliferative neoplasms (MPNs) are a group of clonal hematologic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). MPNs are characterized by activating mutations in the JAK/STAT pathway and an increased risk of transformation to an aggressive form of acute leukemia, termed MPN-blast phase (MPN-BP). MPN-BP is characterized by the presence of ⩾20% blasts in the blood or bone marrow and is almost always preceded by an accelerated phase (MPN-AP) defined as ⩾10-19% blasts in the blood or bone marrow. These advanced forms of disease are associated with poor prognosis with a median overall survival (mOS) of 3-5 months in MPN-BP and 13 months in MPN-AP. MPN-AP/BP has a unique molecular landscape characterized by increased intratumoral complexity. Standard therapies used in de novo acute myeloid leukemia (AML) have not demonstrated improvement in OS. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy but is associated with significant morbidity and mortality and infrequently utilized in clinical practice. Therefore, an urgent unmet need persists for effective therapies in this advanced phase patient population. Here, we review the current management and future directions of therapy in MPN-AP/BP.

Telomerase-targeted therapies in myeloid malignancies.

Human telomeres are tandem arrays that are predominantly composed of 5'-TTAGGG-3' nucleotide sequences at the terminal ends of chromosomes. These sequences serve 2 primary functions: they preserve genomic integrity by protecting the ends of chromosomes, preventing inappropriate degradation by DNA repair mechanisms, and they prevent loss of genetic information during cellular division. When telomeres shorten to reach a critical length, termed the Hayflick limit, cell senescence or death is triggered. Telomerase is a key enzyme involved in synthesizing and maintaining the length of telomeres within rapidly dividing cells and is upregulated across nearly all malignant cells. Accordingly, targeting telomerase to inhibit uncontrolled cell growth has been an area of great interest for decades. In this review, we summarize telomere and telomerase biology because it relates to both physiologic and malignant cells. We discuss the development of telomere- and telomerase-targeted therapeutic candidates within the realm of myeloid malignancies. We overview all mechanisms of targeting telomerase that are currently in development, with a particular focus on imetelstat, an oligonucleotide with direct telomerase inhibitory properties that has advanced the furthest in clinical development and has demonstrated promising data in multiple myeloid malignancies.

Plasmodium falciparum-Induced Autoimmune Hemolytic Anemia in a Pregnant Patient with Sickle Cell Disease.

BACKGROUND Sickle cell disease (SCD) is an autosomal recessive hereditary condition characterized by chronic hemolytic anemia and painful vaso-occlusive episodes. Homozygous sickle cell patients are at increased risk of morbidity and mortality from malaria. Autoimmune hemolytic anemia (AIHA) secondary to, or in the setting of, malarial infection is rare. In our case, the concurrence of Plasmodium falciparum malarial parasitemia and AIHA led to severe hemolytic anemia with an extensive packed red blood cell transfusion requirement. The patient's underlying SCD also contributed to the severity of the anemia and persistence of the malarial infection. CASE REPORT We report the case of a 29-year-old woman in the second trimester of pregnancy, with a history of SCD, who presented with severe anemia beyond her typical baseline in the setting of P. falciparum malaria. Hemolysis markers, including lactate dehydrogenase and bilirubin, were elevated. Direct Coombs testing was positive for IgG and C3 antibodies. Treatment with antimalarial agents and steroids led to clinical improvement and eventual clearance of the parasitemia. CONCLUSIONS Our patient's clinical course was most compatible with P. falciparum malaria-induced AIHA. Although she received a short course of steroids, it was treatment and clearance of the parasitemia that led to resolution of the hemolysis and a return to baseline hemoglobin levels. While the exact mechanism of AIHA in malaria is not well characterized, several unique mechanisms have been proposed and should be considered in cases of P. falciparum malaria manifesting with particularly severe hemolytic anemia.

Contemporary and future strategies in polycythemia vera.

Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher morbidity and mortality compared to the general population due to increased risk of thrombosis, hemorrhage, and well-characterized microvascular and constitutional symptoms. There is also a propensity to transform to myelofibrosis and to an aggressive form of acute leukemia, further increasing morbidity and mortality. Current management is aimed at reducing the risk of thromboembolic events and improving symptom burden; however, none of the existing therapies have proven the ability to deplete the underlying malignant clone, or definitively reduce the risk of disease, progression leaving a large area of unmet need. In this review, we highlight the pathophysiology of PV, current management and limitations therein. We propose highly debated clinical practices that require further investigation. We conclude by discussing therapies in development and how these may fill unmet needs and be incorporated into the future PV treatment paradigm.

Novel Therapies in Myelofibrosis: Beyond JAK Inhibitors.

PURPOSE OF REVIEW: To discuss the current treatment paradigm, review novel targets, and summarize completed and ongoing clinical trials that may lead to a paradigm shifts in the management of myelofibrosis (MF). RECENT FINDINGS: In addition to the recent approval and ongoing late-stage development of multiple novel JAK inhibitors, recent clinical studies demonstrate therapeutic potential of targeting multiple alternate proteins and pathways including BET, MDM2, telomerase, BCL2, LSD1, PI3K, SMAC, and PTX2 in patients with MF. MF is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells and bone marrow fibrosis often causing cytopenias, extramedullary hematopoiesis resulting in hepatosplenomegaly, and increased pro-inflammatory cytokine production driving systemic symptoms. A significant proportion of morbidity and mortality is related to the propensity to transform to acute leukemia. Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, due to the high associated mortality, this treatment is not an option for the majority of patients with MF. Currently, there are three targeted Food and Drug Administration (FDA)-approved therapies for MF which include ruxolitinib, fedratinib, and pacritinib, all part of the JAK inhibitor class. Many patients are unable to tolerate, do not respond, or develop resistance to existing therapies, leaving a large unmet medical need. In this review, we discuss the current treatment paradigm and novel therapies in development for the treatment of MF. We review the scientific rationale of each targeted pathway. We summarize updated clinical data and ongoing trials that may lead to FDA approval of these agents.

Novel therapeutics and targets in myelofibrosis.

Myelofibrosis is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells, bone marrow fibrosis and cytopenias, extramedullary hematopoiesis and hepatosplenomegaly, increased pro-inflammatory cytokine production, and systemic symptoms. Patients with MF also have a propensity toward leukemic transformation. Allogeneic hematopoietic stem cell transplantation (aHCT) is the only curative therapy for patients with MF; however, transplant-related morbidity and mortality precludes this option for the majority of patients. In the last decade, two targeted therapies have been approved for the treatment of MF, both JAK2 inhibitors, ruxolitinib and fedratinib. Despite the clinical efficacy of these two compounds in terms of splenomegaly and symptom burden reduction, there remain many areas of unmet need in the treatment of myelofibrosis. In this review, we discuss the limitations of currently approved treatment options and novel therapeutic targets with drug candidates in late-stage (phase II or III) clinical development for the treatment of MF. We delve into the mechanism of action and scientific rational of each candidate agent as well as the available clinical data, and ongoing trials that could lead to the approval of some of these novel therapies.

Clinical Utility of Fedratinib in Myelofibrosis.

Myelofibrosis (MF) is a clonal hematologic malignancy characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms with a propensity towards leukemic transformation. Constitutive activation of the JAK/STAT pathway is a well-described pathogenic feature of MF. Allogeneic stem cell transplant is the only curative therapy, but due to high morbidity and mortality this option is not available for most patients. There are two approved targeted therapy options for MF, ruxolitinib and fedratinib. In this review, we discuss the clinical utility of fedratinib in the myelofibrosis treatment paradigm. Fedratinib has shown impressive pre-clinical and clinical efficacy in patients with untreated MF as well as in those with ruxolitinib intolerance and those with relapsed/refractory MF. Here, we review the pre-clinical and clinical trials that led to the approval of fedratinib, and the ongoing late-phase trials. We highlight several areas regarding the clinical utility of fedratinib that remain unanswered. We discuss the limitations of fedratinib and address areas that are understudied and require further clinical evaluation and research. The approval of fedratinib has provided a significant expansion to the very limited treatment armamentarium available to patients with MF.

Incorporation of Novel therapies for the treatment of acute myeloid leukemia: a perspective.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases that poses an array of therapeutic challenges. For decades two chemotherapeutic agents, cytarabine and daunorubicin, remained the backbone of AML therapy protocols. However, since 2017 nine novel therapies have been approved for the management of AML. With the rapid expansion of therapeutic options, hematologists must adapt their practice to optimize the benefits of these novel therapy options and minimize treatment toxicity. Here, we discuss the novel therapies that have changed the standard of care in management of patients with AML. We summarize the pivotal clinical trials that lead to the approval of these agents, and ongoing trials evaluating additional potential indications. We discuss several promising therapy candidates and their corresponding clinical trials. We discuss therapeutic strategies to incorporate these therapies into practice and pose unanswered questions that have arisen along with the expansion of treatment options.

Surveillance after resection of vestibular schwannoma: measurement techniques and predictors of growth.

OBJECTIVES: To compare different methods of measuring tumor growth after resection of vestibular schwannoma and to identify predictors of growth. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center, inpatient surgery with ambulatory follow-up. PATIENTS: All patients who underwent vestibular schwannoma resection by the senior author from September 1991 to April 2012 and had two or more postoperative MRI scans. INTERVENTIONS: Vestibular schwannoma resection. Measurement of tumor size and enhancement pattern on postoperative magnetic resonance imaging scans. MAIN OUTCOME MEASURES: Tumor size as measured in one (linear), two (planar), and three (volumetric) dimensions using standard radiology workstation tools versus time elapsed since surgical resection. RESULTS: Eighty-eight patients were included with mean follow-up of 3.9 years. Linear measurement of tumor size was found to have modest correlation with planar and volumetric measurements. Excellent correlation was found between the planar and volumetric methods. Nodular enhancement increased risk for tumor growth (OR 6.25, p = 0.03 on planar analysis). If there was growth, tumors with nodular enhancement typically showed increase in size beginning 2 years postoperatively, whereas those with linear or no enhancement were typically stable in size through 5 years. Younger age and larger preoperative tumor size were also risk factors for growth (OR 0.9/p = 0.01 and OR 1.09/p = 0.02). CONCLUSION: Simple planar measurement is an efficient method that correlates well with the more time-consuming volumetric method. The major risk factor for tumor growth is nodular enhancement on a baseline scan, a finding that warrants annual MRI beginning 2 years postoperatively. Younger age and larger preoperative size minimally increased risk of growth.

Controlled branching of polyglycidol and formation of protein-glycidol bioconjugates via a graft-from approach with "PEG-like" arms.

The control of the branching in polyglycidols as semibranched alternatives to traditional polyglycidols is presented. The relative abundance of dendritic carbons is lowered by five-fold compared to hyperbranched polyglycidols. It is the first example of tailoring the branching in polyglycidol and creating protein-glycidol bioconjugates as alternatives to pegylated biostructures.