Emerging cell cycle inhibitors for acute myeloid leukemia.

INTRODUCTION: AML therapy remains very challenging despite our increased understanding of its molecular heterogeneity. Outcomes with chemotherapy and targeted therapy remain poor. Targeting cell cycle regulators might complement chemotherapy and targeted therapy and help in improving outcomes. Areas covered: Here we cover the pre-clinical and clinical data for both for cyclin dependent kinase (CDK) and cell-cycle checkpoint inhibitors. While CDK inhibition can inhibit proliferation, checkpoint inhibitors can facilitate cell cycle progression in presence of DNA damage and can induce mitotic catastrophe. Expert opinion: Though the preclinical data for cell cycle inhibitors in AML is compelling, the clinical translation so far has proven to be challenging. This is a reflection of the complexity of both, AML and cell cycle regulators. However, early introduction of cell-cycle active agents in combination with chemotherapy or targeted agents, identifying right sequence of use and identifying right biomarkers might pave the way into successful clinical translation.

Investigational Janus kinase inhibitors in development for myelofibrosis.

INTRODUCTION: Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail. NS-018 and INCB039110, selective inhibitors of JAK2 and JAK1, respectively, are also discussed. Finally, the JAK2 inhibitors no longer in clinical development are summarized in tabular form. Expert opinion: The different agents evaluated clearly differ in their kinomes, toxicity profiles and potential for myelosuppression. If approved, the JAK2-specific non-myelosuppressive inhibitor pacritinib could fulfill a major unmet need, that of patients with significant cytopenias. However, toxicity concerns persist. The data from the pivotal trials of momelotinib do not support its approval, although improvement of anemia is an important benefit. Selective JAK1 inhibition alone is unlikely to succeed in myelofibrosis. In these circumstances, rational ruxolitinib-based combinations may represent the best way forward.

Pharmacotherapy of relapsed/refractory chronic lymphocytic leukemia.

INTRODUCTION: The treatment of relapsed/refractory (RR) CLL has been revolutionized by the advent of the new oral inhibitors of B-cell receptor (BCR) signaling and the pro-survival protein, B-cell lymphoma 2 (BCL2). Additionally, new and more potent monoclonal antibodies against CD20 have replaced/may replace rituximab in many settings. Areas covered: Herein, we review the entire therapeutic landscape of RR CLL, with particular attention to the new small-molecule kinase inhibitors and BH3-mimetics. We discuss preclinical data with these agents in CLL, cover available efficacy and safety information, and examine potential resistance mechanisms and possible rational combinations to circumvent them. Expert opinion: The availability of potent and selective inhibitors of BCR signaling and of the anti-apoptotic functions of BCL2 has enormously enhanced our therapeutic armamentarium, with unprecedented efficacy now observed in patients who historically had poor outcomes with chemoimmunotherapy (CIT), e.g., those with deletion 17p/11q and/or IGHV-unmutated disease. The next challenge is to optimally sequence these agents and develop rational combinations that will hopefully lead to deeper and more durable remissions than ever seen before. Indeed, long term relapse free survival, already achievable with CIT in patients with genetically favorable-risk disease, now appears to be a realistic possibility for most patients with CLL.

Therapy-related myelodysplastic syndromes, or are they?

The incidence of therapy-related myelodysplastic syndromes (t-MDS) is increasing as the number of cancer survivors is increasing. While t-MDS is currently defined descriptively by prior receipt of chemotherapy and/or radiotherapy, some forms of MDS that occur post localized radiation monotherapy, biologically and clinically resemble de novo (d)-MDS more than t-MDS, and therefore may not be truly therapy-related. Although patients with t-MDS, as a group, fare worse than patients with d-MDS, a variation in individual outcomes of patients with t-MDS has increasingly been appreciated. As such, accurate risk stratification is important for counseling of patients and for clinical decision making. Most of the current clinical tools used for prognostication in t-MDS were developed for d-MDS and were not specifically validated in patients with t-MDS. The management of patients with t-MDS remains challenging, highlighting the importance of developing effective prevention strategies as well as newer, targeted, and rationally-designed therapeutic interventions.

New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities.

Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. The clinical heterogeneity in MDS is a reflection of its molecular heterogeneity. Better understanding of aberrant epigenetics, dysregulation of immune responses, and del(5q) MDS has provided the rationale for well-established treatments in MDS. Further understanding of abnormal signal transduction and aberrant apoptosis pathways has led to development of new rational therapies that are in advanced phases of clinical translation. This review seeks to describe recent developments in our understanding of the pathogenesis of MDS and the potential therapeutic implications of these observations.

The clinical use of DNA methyltransferase inhibitors in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. Patients with higher risk MDS have dismal outcomes and treatment options are very limited. Aside from allogeneic hematopoietic cell transplantation, the only potentially curative treatment, DNA methyltransferase inhibitors (DNMTIs) are the only intervention that prolongs overall survival in patients with higher risk MDS. The clinical use of DNMTIs in MDS was one of the earliest successful attempts at epigenetic reprogramming of cancer. In this review, we discuss the clinical use of DNMTIs in MDS highlighting the current challenges and controversies and future directions of research needed to explore the full therapeutic potential of these agents.

Clinical utility of lenalidomide in the treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of acquired clonal hematopoietic disorders characterized by peripheral blood cytopenias, paradoxical BM hypercellularity, ineffective hematopoiesis, and increased risk of leukemic transformation. Risk stratification, using different prognostic scores and markers, is at the core of MDS management. Deletion 5q [del(5q)] MDS is a distinct class of MDS characterized by the haploinsufficiency of specific genes, microRNAs, and proteins, which has been linked to increased sensitivity to the drug lenalidomide. Phase II and III clinical trials have demonstrated the efficacy of lenalidomide in improving clinical outcomes of patients with del(5q) MDS, including reduction in red blood cell transfusion requirements and improvements in quality of life. Lenalidomide has also demonstrated some activity in non-del(5q) lower-risk MDS as well as higher-risk MDS, especially in combination with other agents. In this paper, we review the pathogenesis of del(5q) MDS, the proposed mechanisms of action of lenalidomide, the major clinical trials that documented the activity of lenalidomide in different MDS populations, potential predictors of benefit from the drug and suggested mechanisms of resistance, and the use of combination strategies to expand the clinical utility of lenalidomide in MDS.

Histoplasma epiglottitis in a patient with Crohn's disease maintained on infliximab, prednisone, and azathioprine.

Crohn's disease is associated with treatment and non-treatment infectious complications. Among the treatment-related infectious complications, Histoplasma infection is interesting because of significant overlap between its symptoms and Crohn's disease exacerbation. It is often mistaken as Crohn's disease exacerbation. We present a case of disseminated histoplasmosis presenting as Histoplasma epiglottitis in a patient with Crohn's disease maintained on infliximab, prednisone, and azathioprine.