Perspectives and challenges of small molecule inhibitor therapy for FLT3-mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous clonal disease characterized overall by an aggressive clinical course. The underlying genetic abnormalities present in leukemic cells contribute significantly to the AML phenotype. Mutations in FMS-like tyrosine kinase 3 (FLT3) are one of the most common genetic abnormalities identified in AML, and the presence of these mutations strongly influences disease presentation and negatively impacts prognosis. Since mutations in FLT3 were identified in AML, they have been recognized as a valid therapeutic target resulting in decades of research to develop effective small molecule inhibitor treatment that could improve outcome for these patients. Despite the approval of several FLT3 inhibitors over the last couple of years, the treatment of patients with FLT3-mutated AML remains challenging and many questions still need to be addressed. This review will provide an up-to-date overview of our current understanding of FLT3-mutated AML and discuss what the current status is of the available FLT3 inhibitors for the day-to-day management of this aggressive disease.

Novel Biological Insights and New Developments in Management of Burkitt Lymphoma and High-Grade B-Cell Lymphoma.

OPINION STATEMENT: Burkitt lymphoma (BL) is highly curable, and prompt institution of therapy is critical to achieving optimal outcomes. Although current "standard" approaches are very effective in disease eradication, treatment-related toxicity makes optimal delivery of curative therapy a challenge, especially in older and immunocompromised individuals. Reduced intensity approaches with fewer toxic complications have been the focus of some recent studies. A critical question is if they can replace "standard" approaches by maintaining high curability with improved tolerability. Additionally, new molecular insights in BL biology suggest that in the future, "targeted therapy" approaches may be feasible using small molecule inhibitors and novel strategies. Recently, a new category of aggressive lymphoma named "high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations" has been recognized. This category overlaps clinically and biologically with BL and has an inferior prognosis compared to most B-cell lymphomas, and the optimal approach to its management remains, as yet, undefined. In this review, we discuss the current landscape of BL treatment including recent results with low-intensity regimens and also consider current approaches to HGBL. We also explore how recently elucidated novel biological insights in BL biology may shape future therapeutic directions including the use of novel cellular therapy approaches.

The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia.

For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. Inhibition of various classes of αKG-dependent dioxygenases results in dramatic epigenetic changes in hematopoietic cells, which has been found to directly impair differentiation. In addition to a global dysregulation of gene expression, other mechanisms have been described through which R2-HG promotes leukemic transformation including the induction of B cell lymphoma 2 dependency and stimulation of the EglN family of prolyl 4-hydroxylases (EglN). Due to the fact that mutations in IDH1 and IDH2 are acquired early during AML clonal evolution as well as because these mutations tend to remain stable during AML progression, the pharmaceutical industry has prompted the development of specific mutant IDH enzyme inhibitors. More recently, the FDA approved the first mutant IDH2 inhibitor, enasidenib (AG-221), for patients with relapsed or refractory IDH2-mutated AML (RR-AML). This has brought a lot of excitement to researchers, clinicians, and patients, especially because the treatment of AML remains challenging and is still associated with a high mortality.

PD-1 signaling and inhibition in AML and MDS.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

Acute Myeloid Leukemia Following Myeloproliferative Neoplasms: A Review of What We Know, What We Do Not Know, and Emerging Treatment Strategies.

Acute myeloid leukemia (AML) arising from myeloproliferative neoplasms (MPNs) represents a small subtype of secondary AML (sAML). This entity is well known to be associated with poor responses to available treatment options and dismal outcomes. To date, there are no standardized treatment options and there has been very little therapeutic advancement in recent years. This is a stark contrast to other subsets of AML for which there have been significant advances in therapeutic approaches, especially for patients with targetable mutations. We aim to focus our review on the incidence, risk factors for leukemogenesis, pathogenesis, molecular landscape, and emerging therapeutic options in post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML).

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm.

Hematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2 + myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.

An atypical presentation of Sweet's syndrome in a myelofibrosis patient.

A 46-year-old man with no significant medical history presented to haematology with symptoms of fatigue, dyspnoea on exertion and weight loss. Physical examination revealed a lesion on the right shin and splenomegaly. Labs were significant for leucocytosis with immature components, thrombocytosis and 3% peripheral blasts on smear. A bone marrow biopsy confirmed a diagnosis of myelofibrosis (MF). Dynamic International Prognosis Scoring system was 2. He was started on ruxolitnib, with decitabine added subsequently prior to definitive therapy with an allogenic haematopoietic stem cell transplant. His course with decitabine was complicated with febrile neutropaenia with multiple tender erythematous plaques unresponsive to antibacterial and antifungal coverage. A skin biopsy showed neutrophilic dermatitis, consistent with a diagnosis of Sweet's syndrome (SS) and empirical treatment with glucocorticoids was initiated resulting in resolution of symptoms. This report reviews the literature for cases of SS in the setting of MF.

Chronic Myeloid Leukemia as Secondary Malignancy Following the Treatment of Hodgkin Lymphoma: A Case Series.

Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.

Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy.

Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the onco-metabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years.

Bariatric venous thromboembolism prophylaxis: an update on the literature.

Introduction: Rates of obesity have been increasing worldwide and with the current situation obesity now represents an epidemic. Bariatric surgery is one the most effective ways to help reduce weight and sustain weight loss. Venous thromboembolism is a major cause of morbidity and mortality among bariatric surgery patients with no clearly established guidelines on prophylaxis. Areas covered: In this review the authors summarize clinical studies evaluating unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in bariatric surgery patients. The authors present studies that assessed venous thromboembolic (VTE)-related risk stratification but also various dosing regimens of heparin products in this population of patients. Moreover, the authors will also present the feasibility of using direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) prevention along with providing a summary of few current guidelines for VTE prevention in bariatric surgery patients. Expert opinion: Based on the data presented in this review, the authors conclude that LMWHs may be better options than UFH for VTE prophylaxis in bariatric surgery patients. We also conclude that risk stratifying bariatric patients may be a better approach when deciding on the best thromboprophylaxis modality, dose and duration.

Sinusoidal Obstruction Syndrome (Veno-occlusive Disease) Following Hematopoietic Stem Cell Transplant: Insights and Therapeutic Advances.

Hepatic sinusoidal obstruction syndrome (SOS) is a rare fatal clinical entity seen following hematopoietic stem cell transplant (HSCT). It is more commonly reported to occur following allogeneic HSCT compared to autologous HSCT. Historically, it is known as hepatitis following HSCT. It is thought that endothelial damage to the hepatic venules leading to occlusion of the terminal hepatic venules and hepatic sinusoids is the trigger for the development of SOS. Several risk factors have been associated with this condition. Some of these risk factors are patient related while others are transplant process related. Given the high mortality of this condition, early identification of high-risk patients with severe disease is of utmost importance. The management of SOS varies depending on the severity of the disease. Mild to moderate disease has a good outcome with supportive measures alone, while severe presentation of the disease requires a more aggressive management. Defibrotide is the only Food and Drug Administration-approved therapy and it is reserved for severe cases of SOS. The role of defibrotide as a prophylactic therapy remains under investigation.

Post-Transfusion Purpura: A Case Report of an Underdiagnosed Phenomenon.

Post-transfusion purpura is a rare transfusion-related complication that often goes undiagnosed. It is due to alloimmunization against platelet antigens which leads to acute profound thrombocytopenia following the transfusion of any platelet-containing product (red blood cells or platelets). It is commonly seen in multiparous women. Here, we report a case of post-transfusion purpura in a 56-year-old multiparous woman who developed acute thrombocytopenia seven days following a packed red blood cell transfusion. We will discuss the clinical presentation, diagnosis, workup and treatment of this rare disease. It is important to recognize this entity separately and to include it in the differential diagnosis of acute thrombocytopenia after a recent blood transfusion. Treatment for this condition consists of intravenous immunoglobulins, corticosteroids or plasmapheresis.

Disseminated intravascular coagulation-like reaction following rituximab infusion.

Rituximab generally is a well-tolerated medication used in a variety of haematological and autoimmune conditions. The safety profile of the medication has been reviewed in the literature. Infusion reactions due to cytokine release are the most common side effects. With the increased use of rituximab, there is an increase incidence of cytopenias, most commonly thrombocytopenia and leucopenia. Coagulopathy is quite rare, reported previously in four cases in the literature. We highlighted the clinical course of a 39-year-old patient with precursor B-cell acute lymphoblastic leukaemia who was started on rituximab infusion. The patient developed a cytokine-release syndrome with haemodynamic instability, followed by rapid-onset cytopenias and disseminated intravascular coagulation abnormalities characterised by coagulopathy with fibrinolysis and mucocutaneous bleeding. The report is followed by a review of the literature. It is important to recognise rituximab-induced coagulopathy early as part of the differential diagnosis of thrombocytopenia and disseminated intravascular coagulation following rituximab administration.

Acute Graft Versus Host Disease: A Comprehensive Review.

Acute graft versus host disease (aGVHD) remains the second leading cause of death following allogeneic hematopoietic stem cell transplant (AHSCT). Over the last five years, the progress in understanding the pathophysiology of this immune based-process helped redefine graft versus host reaction and opened new possibilities for novel preventive and therapeutic approaches. The evolution in the field of immunology widened the horizons for hematopoietic stem cell transplant leading to the availability of different stem cell sources for potential graft and incorporation of novel conditioning regimens. There is conflicting data about the impact of the graft source and the conditioning regimen used in the process of AHSCT on the incidence of aGVHD. Many studies have reported increased risk of chronic GVHD (cGVHD) and to a less extent aGVHD with the use of peripheral blood stem cell and bone marrow compared to umbilical cord stem cell. The conditioning regimen, either myeloablative, non-myeloablative or reduced intensity may have different impact on the incidence of GVHD. Several preventive modalities have been adopted by different transplant centers but, to date, there is no standardized regimen. As for treatment, immunosuppression using steroids remains the first line of intervention. Several novel therapeutic options are being investigated for treatment of steroid-refractory aGVHD including the use of mesenchymal stem cells, anti thymocyte globulin and extra corporeal photophoresis. This review discusses the pathophysiology, risk factors, clinical features, and advances in the diagnosis, prevention and treatment of aGVHD.

Immune-based Therapies for Non-small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related death worldwide. Treatment of non-small cell lung cancer has evolved tremendously over the past decade. Specifically, immune checkpoint inhibitors have become an increasingly interesting target of pharmacological blockade. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination with other therapies. Vaccination in non-small cell lung cancer is also an emerging field of research that holds promising results for the future of immunotherapy in non-small cell lung cancer. This review presents a concise update on the most recent data regarding the role of checkpoint inhibitors as well as vaccination in non-small cell lung cancer.

Integrating Genomics in Myelodysplastic Syndrome to Predict Outcomes After Allogeneic Hematopoietic Cell Transplantation.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic neoplastic disorders most commonly occurring in the elderly population; MDS has a tendency to progress to acute leukemia. Although epigenetic therapies have improved the outcomes of MDS patients, allogeneic hematopoietic cell transplantation remains the only curative option. Molecular characterization of MDS using next-generation sequencing has expanded not only the knowledge on MDS but also the depth of understanding of evolution and contribution of recurrent somatic mutations in precursor conditions. Rapidly evolving genomic information on MDS may provide clinicians with better risk stratification tools and may also aid in supplying useful information to allow comprehensive therapeutic decision making for MDS patients. In this concise review, we summarize the current knowledge and understanding of recurrent somatic mutations in MDS and discuss salient genomic information predicting response and influencing therapeutic outcomes in the context of allogeneic hematopoietic cell transplantation, as well as the potential application of these findings into future clinical practice.