A little CIN may cost a lot: revisiting aneuploidy and cancer

Despite over 100 years of study, the role of aneuploidy in cancer remains poorly understood. This review highlights the advances in understanding the causes and consequences of aneuploidy. Recent work has illuminated ways in which aneuploidy could have either tumor-promoting or tumor-suppressing effects, similar to what is known for other forms of genetic instability such as telomere attrition [Maser RS, DePinho RA: Connecting chromosomes, crisis, and cancer. Science 2002, 297:565-569]. We explore the possibility that aneuploidy could be just another type of 'mutation', with potential beneficial and deleterious effects, depending on the chromosomes involved and the specific selective pressures the cells experience. We also discuss the potential therapeutic implications of changes in physiology associated with aneuploidy

Insights into novel emerging epigenetic drugs in myeloid malignancies

Epigenetics has been defined as 'a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence' and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes encoding epigenetic modifiers are a frequent occurrence in hematologic malignancies and important in both the initiation and progression of cancer. Epigenetic modifications are also frequently reversible, allowing excellent opportunities for therapeutic intervention. The goal of epigenetic therapies is to reverse epigenetic dysregulation, restore the epigenetic balance, and revert malignant cells to a more normal condition. The role of epigenetic therapies thus far is most established in hematologic malignancies, with several agents already approved by the US Food and Drug Administration. In this review, we discuss pharmacological agents targeting epigenetic regulators

What constitutes meaningful improvement in myelodysplastic syndromes?

Myelodysplastic syndromes (MDS) are a heterogeneous spectrum of clonal stem cell disorders characterized by ineffective hematopoiesis and resulting peripheral blood cytopenias. Clinical manifestations of the disorder are varied and range from mild asymptomatic anemia to a markedly truncated life expectancy, underscoring the importance of risk-adapted therapy. MDS therapy for both lower- and higher-risk patients is an area of immense therapeutic opportunity. This is partly due to the diversity of treatment goals between patients and defining what constitutes meaningful benefit from a patient's viewpoint. Correlating metrics such as hematologic improvement or response rate to develop novel therapies can be falsely reassuring to physicians and patients, specifically if the interventions are burdensome, disconnected from a patient's sense of wellbeing and do not correlate with an improvement in quality of life or longevity. We discuss aligning drug development goals with patient goals that will lead to meaningful improvement in MDS clinical care

Hypomethylating agent based combinations in higher risk myelodysplastic syndrome

For over a decade the hypomethylating agents (HMA) azacitidine and decitabine have been the mainstay of therapy for myelodysplastic syndrome (MDS). There is a critical need to improve frontline therapy, given that only up to half of high-risk MDS patients will respond to HMA therapy, and responses are short-lived. Currently, a key strategy has been to combine HMAs with other novel agents to improve patient outcomes. While synergy of agents is the goal of combination therapy, combinations often come at the cost of increased side effects that are often intolerable in this vulnerable population. The purpose of this review is to critically examine clinically relevant HMA combinations and discuss the future of MDS management

What are the most promising new agents in myelodysplastic syndromes?

Purpose of review Myelodysplastic syndromes (MDS) are a diverse group of clonal disorders of hematopoietic stem or progenitor cells that represent the most common class of acquired bone marrow failure syndromes in adults. Despite significant improvement in the pathologic insight into this group of disorders, therapeutic options remain limited and allogeneic hematopoietic stem-cell transplantation is the only treatment that can induce long-term remission in patients with MDS. The goals of therapy for MDS are based on disease prognostication, with a focus of minimizing transfusion dependence and preserving quality of life in low-risk groups and preventing progression of disease to acute myeloid leukemia in high-risk groups. Given the dearth of approved treatment options, there is a marked need for novel therapies across the board, and there are several novel agents currently in the pipeline. Recent findings Among the promising agents with preclinical and early phase efficacy in higher risk MDS, apoptosis targeting with BCL-2 inhibitors have been a standout. There is also a keen interest in immunotherapy, and targeted agents (genetic, signaling pathways, bispecific antibodies, antibody-drug conjugates, and others described in this review). Summary In this review, we will highlight some of the promising new agents currently under investigation for the management of MDS

Advances in non-intensive chemotherapy treatment options for adults diagnosed with acute myeloid leukemia

Acute myeloid leukemia (AML) is primarily a disease of older adults. Many older patients with AML are not candidates for intensive chemotherapy regimens aimed at inducing remission before transplantation. The prognosis for this patient population remains poor, with 5-year overall survival (OS) rates of less than 10 %. At present, there is no standard of care, and clinical trials should be considered. Hypomethylating agents often are the mainstay of treatment in this setting; however, improved genetic profiling and risk stratification based on molecular, biological, and clinical characteristics of AML enhance the ability to identify an individual patient's risk and can refine therapeutic options. Over the past 2 years, several novel agents have been approved for AML patients in either the frontline or relapsed settings. Additional agents have also shown promising activity. It is becoming a challenge for physicians to navigate these different options and select the optimal therapy or combination of therapies. The aim of this review is to summarize the available information to assist with treatment decisions for leukemia patients who are not suitable for intensive chemotherapy

Real World Outcomes of Liposomal Daunorubicin and Cytarabine Versus 7+3 in Patients with Secondary Acute Myeloid Leukemia

Introduction: Liposomal daunorubicin and cytarabine (CPX-351) was approved based on data which showed improved overall survival (9.56 v 5.95 months; p = .003) and remission rates (47.7% v 33.3%; p = .016) compared to conventional cytarabine and daunorubicin (7+3) chemotherapy in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients receiving CPX-351 had prolonged time to neutrophil and platelet count recovery compared to 7+3, which was not associated with adverse outcomes (Lancet et al, JCO 2018). Based on these data, our center adopted CPX-351 as a first-line agent in this patient population. Considering the significant cost differences and delays in count recovery, we conducted a comparison of outcomes in patients who received CPX-351 versus 7+3 at our center. Methods: The objective of this study was to compare efficacy and safety of CPX-351 versus 7+3 in patients with sAML. Primary outcome was response rate as defined by CR or CRi. Secondary outcomes included duration of neutropenia, incidence of invasive fungal infections (IFIs), and number of patients proceeding to allogeneic hematopoietic cell transplant (HCT). Patients with sAML receiving induction with 7+3 (daunorubicin dosed at 60 or 90 mg/m2 per treating physician's discretion) or CPX-351 from July 2014 to April 2020 were reviewed. Secondary AML was defined as: AML with a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), AML with myelodysplasia-related changes, or therapy-related AML. Patients with prior myeloproliferative neoplasms, myelofibrosis, or FLT3 mutations were excluded. Patient characteristics were summarized using descriptive statistics (TABLE 1) including mean for continuous measures and proportions and frequencies for categorical measures. The association between continuous variables and patient groups were assessed using ANOVA or Student's t-test. The associations between categorical variables and patient groups were evaluated using Chi-square test. Results: Over the study period, 65 patients with sAML received induction therapy with either CPX-351 (n = 31) or 7+3 (n = 34). Of these, 61 patients had an evaluable bone marrow biopsy at count recovery. The data is summarized in Table 2. The response rates (CR or CRi) were no different (36% 7+3 vs 36% CPX-351, p = 0.958) among the study population. Longer duration of neutropenia was observed with CPX-351 (33 days 7+3 vs 47 days CPX-351, p = 0.026). More patients in the 7+3 arm proceeded to allogeneic HCT; however, this was not statistically significant (59% 7+3 vs 39% CPX-351, p = 0.105). In an efficacy subgroup analysis of patients with TP53 mutation, there was no difference in response rates (33% 7+3 vs 11% CPX-351, p = 0.224). There was no difference in IFI between the groups (38% 7+3 vs 42% CPX-351, p = 0.761). Upon further analysis of IFI characteristics, there was no difference in choice of mold-active vs non mold-active prophylaxis (ppx) and the incidence of IFIs (40% mold ppx vs 39% non-mold ppx, p = 0.91). Patients with baseline neutropenia prior to induction did not have increased risk of IFIs (65% 7+3 vs 74% CPX-351, p = 0.626). Additionally, there were no between group differences in incidence of IFIs in patients who were neutropenic prior to induction. Conclusions: In the evaluable dataset of patients receiving 7+3 or CPX-351, there was no difference in CR/CRi rate between the two subgroups. There was a longer duration of neutropenia in the CPX-351 group without increased incidence of IFI. However, we report a higher incidence of IFI compared to the study population in Lancet et al (18% Lancet vs 40% Miami) despite appropriate anti-fungal prophylaxis, which may be due to patient selection on the clinical trial, demographic differences (e.g., age, ethnicity), or locoregional environmental factors. In our population, a greater percentage of patients who received 7+3 proceeded to allogeneic HCT. While this study was not powered to detect a significant difference between the two regimens and these findings require validation in larger cohorts, they do not support superior outcomes in patients who receive CPX-351. Data on differences in hospital costs will also be presented. Future directions include a larger multi-center real-world analysis to evaluate patient outcomes, safety, and the financial implications of these two regimens. Disclosures Watts: Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptevo Therapeutics: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees

Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes

Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer cells defined mechanisms that suppress multipolar mitoses. In addition to proteins that organize microtubules at the spindle poles, we identified novel roles for the spindle assembly checkpoint, cortical actin cytoskeleton, and cell adhesion. Using live cell imaging and fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. These findings may identify cancer-selective therapeutic targets: HSET, a normally nonessential kinesin motor, was essential for the viability of certain extra centrosome-containing cancer cells. Thus, morphological features of cancer cells can be linked to unique genetic requirements for survival