Maximilian Stahl

Epigenetics in Cancer: A Hematological Perspective.

For several decades, we have known that epigenetic regulation is disrupted in cancer. Recently, an increasing body of data suggests epigenetics might be an intersection of current cancer research trends: next generation sequencing, immunology, metabolomics, and cell aging. The new emphasis on epigenetics is also related to the increasing production of drugs capable of interfering with epigenetic mechanisms and able to trigger clinical responses in even advanced phase patients. In this review, we will use myeloid malignancies as proof of concept examples of how epigenetic mechanisms can trigger or promote oncogenesis. We will also show how epigenetic mechanisms are related to genetic aberrations, and how they affect other systems, like immune response. Finally, we will show how we can try to influence the fate of cancer cells with epigenetic therapy.

Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes

ABSTRACT Introduction: Epigenetic changes and mutations in epigenetic modifiers characterize and likely drive many cases of acute myeloid leukemia and myelodysplastic syndrome. Development of DNA methyltransferase inhibitors has been most successful in these diseases. While many epigenetic marks are potential targets of cancer therapies, histone deacetylase inhibitors (HDACi) have undergone the most advanced development to date. Area Covered: In this review, the authors describe and discuss the biology and the clinical results of HDAC inhibitors in the settings of myeloid malignancies. Expert opinion: While significant results have been achieved in lymphoma and myeloma, efficacy remains limited in myeloid malignancies for both single agent and HDACi based combination regimens. The redundancy and the pleiotropic activity of HDACi (on both histone and non-histone proteins) are key factors that have limited to date the selection of patients and the design of robust biomarkers. Recent advances in biology (mechanisms of resistance, immunology) and the design of a more specific third generation of HDACi are two important features that will drive the future clinical development of HDACi in myeloid malignancies.

Clinical response to ruxolitinib in CSF3R T618-mutated chronic neutrophilic leukemia

Dear Editor, Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only about 200 patients described to date meeting the World Health Organization (WHO) criteria and the recently reported CSF3R T618I mutation. Diagnosis of CNL using the World Health Organization 2008 criteria[1] requires a WBC count of ≥25 × 10/L, ≥80 % segmented/band neutrophils, absence of dysgranulopoiesis, exclusion of genetic drivers that are known to occur in others MPNs (such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements), and <10 % immature myeloid cells [2]. Previously, CNL was often confused with chronic myeloid leukemia (CML), atypical CML (aCML), or chronic myelomonocytic leukemia (CMML); however, this changed with the identification of oncogenic mutations in the granulocyte colony-stimulating 3 factor receptor (CSF3R) gene in approximately 83 % of WHO-defined CNL patients [3]. CSF3R mutations in CNL are either nonsense or frameshift mutations truncating the cytoplasmic tail (truncation mutations) or point mutations in the extracellular domain (membrane proximal mutations) [3, 4]. Truncation mutations are sensitive to dasatinib in vitro, while membrane proximal mutations show ligand-independent signaling through the JAKSTAT pathway and cells harboring this mutation are sensitive to Jak1/2 inhibitors in vitro. Additional observations from Mayo Clinic showed that concomitant SETBP1 and ASXL1 mutations in CNL patients with a CSF3R mutation help to further distinguish CNL from aCML and are associated with poorer outcomes [5]. There is as yet limited clinical experience with ruxolitinib in patients with CNL, given the low prevalence of the disease [6, 7]. After the initial case reported by Maxson et al., Dao et al. presented the case of another patient with CNL and a CSF3RT618I mutation who experienced reduction in hepatosplenomegaly and * Maximilian Stahl maximilian.stahl@yale.edu

Emerging biological therapies for the treatment of myelodysplastic syndromes

ABSTRACT Introduction: No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure. Areas covered: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche. Expert opinion: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.

Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications

Myelosysplastic syndromes (MDS) include a heterogeneous group of clonal myeloid neoplasms characterized by ineffective hematopoiesis leading to blood cytopenias and a variable risk of progression into acute myeloid leukemia (AML). Although the hypomethylating agent azacitidine prolongs survival among patients with higher risk (HR)‐MDS compared with conventional care, no drug has been shown conclusively to prolong survival or delay progression to AML among patients with lower‐risk MDS (LR‐MDS). Lenalidomide is the drug with the most impressive clinical activity in the subset of anemic LR‐MDS patients who harbor a deletion of the long arm of chromosome 5 (5q−), where it leads to high rates of transfusion independence and cytogenetic responses. Furthermore, lenalidomide delays progression to AML and prolongs survival among responders. In this article, we review the recently recognized mechanisms of action of lenalidomide and discuss the most recent clinical data regarding its use in patients with both 5q− MDS as well as non‐5q− MDS. Finally, we forecast the future directions to improve the efficacy of lenalidomide in MDS with and without 5q−. Cancer 2017;123:1703–1713.

Hypomethylating agents in combination with histone deacetylase inhibitors in higher risk myelodysplastic syndromes: Is there a light at the end of the tunnel?

Myelodysplastic syndromes (MDS) are genetically, biologically, and clinically very heterogeneous. Although allogeneic stem cell transplantation (alloSCT) remains the only intervention with a potential for cure, less than 5% of patients undergo transplantation because of age and comorbidities. Before the approval of hypomethylating agents (HMAs), patients with higher-risk (HR)-MDS had a median overall survival (OS) of< year. The approval of the 2 HMAs azacitidine and decitabine in the United States in 2004 and 2006, respectively, represented a major milestone in the management of MDS. Those 2 drugs result in objective hematologic responses in 40% to 50% of patients, including a 10% to 15% complete remission (CR) rate and an improved quality of life. Furthermore, in the case of azacitidine, OS improved by a median of 9.5 months (24.5 vs 15 months) over conventional care regimens (CCR) in the landmark randomized phase 3 clinical trial AZA-001. Indeed, a Surveillance, Epidemiology, and End Results-based analysis indicates that the OS of patients with HR-MDS in the United States has improved over the last 15 years. The use of HMAs as the frontline therapy for patients with HR-MDS nonetheless leaves a lot to be desired. HMAs require 4 to 6 months of therapy before the lack of a response can be determined, and approximately one-half of patients never respond. The majority of those who do respond would progress in less than 18 months, and patients with primary or secondary resistance to HMAs have a dismal OS, with a median of 4 to 6 months. Furthermore, population-based studies not only observed a substantially worse median OS with azacitidine than reported in the AZA-001 trial (median OS, 13-17 and 24.5 months, respectively), but some analyses have even questioned the OS advantage of azacitidine in HR-MDS. Despite extensive clinical research, and compared with the many new agents approved in other hematologic malignancies, such as multiple myeloma and chronic lymphocytic leukemia, 10 years have passed since decitabine was approved without any new drug approvals in the MDS world. With no drugs to outperform HMAs in the upfront setting and no drugs to improve OS in the post-HMA failure setting to date, a big focus in the MDS research community has been on identifying HMA-based combination regimens that could improve the clinical outcomes of patients compared with HMA monotherapy. The goals of combinationbased strategies are to increase the response rate, deepen and/or accelerate responses, and eventually improve clinical survival over HMA monotherapy without significantly increasing toxicity. One of the commonly used combinationbased approaches revolves around targeting the epigenetic dysregulation that has been recognized as a central mechanism in the pathogenesis of MDS and its progression to acute myeloid leukemia (AML), and has been associated with worse survival. Both DNA promoter hypermethylation as well as post-translational modification of histone tails (eg, deacetylation) lead to transcriptional silencing of tumor-suppressor genes and genes involved in differentiation and apoptosis. Preclinical evidence supported synergy between HMAs and histone deacetylase (HDAC) inhibitors. Compared with HMAs, monotherapy with HDAC inhibitors has had only limited efficacy in phase 1 and 2 clinical studies in both HR-MDS and AML. Therefore, extensive trials of combined HMAs and HDAC inhibitors have been taking place. Although early phase trials of these combinations had promising results, phase 2, randomized clinical trials to date have failed to demonstrate a significant improvement in response rates or survival when azacitidine was combined with the HDAC

A call for action: Increasing enrollment of untreated patients with higher-risk myelodysplastic syndromes in first-line clinical trials

Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher‐risk myelodysplastic syndromes (HR‐MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real‐life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24‐month median survival observed with azacitidine in the landmark AZA‐001 trial has not been replicated in population‐based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR‐MDS is significantly lower than what was observed in the AZA‐001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front‐line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR‐MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider‐scale enrollment in front‐line HR‐MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy. Cancer 2017;123:3662–3672.

Management of lower-risk myelodysplastic syndromes without del5q: current approach and future trends

ABSTRACT Introduction: Myelodysplastic syndromes (MDS) are characterized by progressive bone marrow failure manifesting as blood cytopenia and a variable risk of progression into acute myeloid leukemia. MDS is heterogeneous in biology and clinical behavior. MDS are generally divided into lower-risk (LR) and higher-risk (HR) MDS. Goals of care in HR-MDS focus on changing the natural history of the disease, whereas in LR-MDS symptom control and quality of life are the main goals. Areas covered: We review the epidemiology, tools of risk assessment, and the available therapeutic modalities for LR-MDS. We discuss the use of erythropoiesis stimulating agents (ESAs), immunosuppressive therapy (IST), lenalidomide and the hypomethylating agents (HMAs). We also discuss the predictors of response, combination treatment modalities, and management of iron overload. Lastly, we overview the most promising investigational agents for LR-MDS. Expert commentary: It remains unclear how to best incorporate a wealth of new genetic and epigenetic prognostic markers into risk assessment tools especially for LR-MDS patients. Only a subset of patients respond to current treatment modalities and most responders eventually lose their response. Once standard therapeutic options fail, management becomes more challenging. Combination-based approaches have been largely unsuccessful. Among the most promising investigational are the TPO agonists, TGF- β pathway inhibitors, telomerase inhibitors, and the splicing modifiers.

Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities.

The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.

Novel Therapies for Acute Myeloid Leukemia: Are We Finally Breaking the Deadlock?

Acute myeloid leukemia (AML) is one of the best studied malignancies, and significant progress has been made in understanding the clinical implications of its disease biology. Unfortunately, drug development has not kept pace, as the ‘7+3’ induction regimen remains the standard of care for patients fit for intensive therapy 40 years after its first use. Temporal improvements in overall survival were mostly confined to younger patients and driven by improvements in supportive care and use of hematopoietic stem cell transplantation. Multiple forms of novel therapy are currently in clinical trials and are attempting to bring bench discoveries to the bedside to benefit patients. These novel therapies include improved chemotherapeutic agents, targeted molecular inhibitors, cell cycle regulators, pro-apoptotic agents, epigenetic modifiers, and metabolic therapies. Immunotherapies in the form of vaccines; naked, conjugated and bispecific monoclonal antibodies; cell-based therapy; and immune checkpoint inhibitors are also being evaluated in an effort to replicate the success seen in other malignancies. Herein, we review the scientific basis of these novel therapeutic approaches, summarize the currently available evidence, and look into the future of AML therapy by highlighting key clinical studies and the challenges the field continues to face.