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Venous thromboembolism (VTE) causes morbidity and mortality in cancer patients. The association of VTE with known risk factors in chronic lymphocytic leukemia (CLL) is not known. To examine risk factors and mortality associated with VTE in White, Black, and Asian CLL patients. The United States SEER-Medicare database (2000–2015) was used for CLL patients ≥ 65 years. Logistic regression was used to examine VTE risk factors and Cox proportional regression was used to evaluate the effect of VTE on mortality in White, Black, and Asian CLL patients. Among 34,075 CLL patients, VTE was diagnosed in 11.6 % of 31,395 White, 14.6 % of 2062 Black and 6.3 % of 618 Asian patients. Risk of having VTE was, OR a = 1.2 (95 % CI, 1.0–1.4) for Black patients and OR a = 0.5 (95 % CI, 0.4–0.7) for Asian patients compared to White patients. Anemia and heart failure were associated with VTE in all three racial cohorts and were the only risk factors in Asian patients. Other risk factors in White patients were the same as in the overall population, including hypertension, obesity, COPD, kidney disease, diabetes, hyperlipidemia, myocardial infarction, and chemotherapy. In Black patients, other risk factors were hypertension, and chemotherapy. Mortality was slightly higher with VTE in the overall population and in White patients. There was difference in VTE risk factors in White, Black, and Asian patients. VTE was marginally associated with mortality in CLL patients. Our findings may help to identify patients at higher risk of VTE in racially diverse CLL populations. • 11.7 % of CLL patients ≥ 65 years had a diagnosis of venous thromboembolism (VTE). • Black CLL patients had a higher risk of VTE than White patients. • Asian CLL patients had a lower risk of VTE than White patients. • Mortality was slightly higher in CLL patients with a diagnosis of VTE. [ABSTRACT FROM AUTHOR]

Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results. Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration. One hundred and sixty five patients were enrolled and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months, respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common. Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures.

PurposePharmacologic differentiating agents have had relatively limited clinical success outside of the use of ATRA in acute promyelocytic leukemia and DNA methyltransferase inhibitors in myelodysplastic syndromes. The differentiating effects of such agents can be enhanced in combination with lineage-specific growth factors. We developed a dose finding trial to assess toxicity, differentiating activity, and clinical impact of the combination of bryostatin-1 and GM-CSF.Experimental designPatients with poor risk myeloid malignancies were eligible to enroll in a dose finding study of continuous infusion bryostatin-1 combined with a fixed dose of daily GM-CSF. Toxicities were graded per NCI CTC version 2.0 and pharmacokinetic and correlative study samples were obtained to assess the combination's clinical and biologic differentiating effects.ResultsThirty-two patients were treated with the combination therapy and the dose determined to be most suitable for study in a larger trial was continuous infusion broystatin-1 at 16μg/m(2) for 14 days and subcutaneous GM-CSF at 125μg/m(2) daily for 14 days every 28 days. Arthralgias and myalgias limited further dose escalation. Clinically, the combination impacted differentiation with improvement of absolute neutrophil counts (p=0.0001) in the majority of patients. Interestingly, there were two objective clinical responses, including a CR after a single cycle. Both the bryostatin-1 plasma concentrations and the correlative studies supported biologic activity of the combination at the doses where clinical responses were observed.ConclusionsCombining growth factors with pharmacologic differentiating agents may increase their clinical effectiveness and further studies should focus on such combinations.

Since its introduction less than 3 years ago, imatinib mesylate (STI571) has altered the entire approach to the therapy of patients with chronic myeloid leukemia (CML). In addition to its impact on clinical practice, imatinib has also increased the focus of basic and translational CML research on enhancing the cellular effects of imatinib and preventing and overcoming resistance to the drug. Here, I summarize some recent advances in our understanding of the regulatory and signaling mechanisms of Bcr-Abl, with an emphasis on therapeutic implications.

• Infectious complications post-cladribine treatment remain high. • Primary peg-filgrastim prophylaxis compared to filgrastim given on demand. • Both types of G-CSF are justifiable, and the choice remains at the physician's discretion. Major advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening. In this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given "on demand" according to absolute neutrophil count (ANC). Medical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985–2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC < 1.0 × 10 [ 9 ]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [ 9 ]/L. The study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim "on demand" due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44). Infectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician's discretion. [ABSTRACT FROM AUTHOR]

• AML leukemia stem cells (LSC) as defined by CD34/CD38 expression, light scatter and Side Population (SP). • In CD34 positive AML therapy resistant LSC are enriched in CD34 + CD38-/SP compartment. • Frequency of these LSC decreases with decreasing CD34%, with concomitant increase of normal CD34 + CD38- SP stem cells. • Frequency of putative LSC compartment is median 5.1 per million in these CD34 positive AML. • In CD34 negative AML putative LSC compartment has CD34-CD38+/SP phenotype. Leukemic stem cells (LSCs), defined by CD34/CD38 expression, are believed to be essential for leukemia initiation and therapy resistance in acute myeloid leukemia. In addition, the side population (SP), characterized by high Hoechst 33342 efflux, reflecting therapy resistance, has leukemia initiating ability. The purpose of this study is, in both CD34-positive and CD34-negative AML, to integrate both types of LSC compartment into a new more restricted definition. Different CD34/CD38/SP defined putative LSC and normal hematopoietic compartments, with neoplastic or normal nature, respectively, were thus identified after cell sorting, and confirmed by FISH/PCR. Stem cell activity was assessed in the long-term liquid culture stem cell assay. SP fractions harbored the strongest functional stem cell activity in both normal and neoplastic cells in both CD34-positive and CD34-negative AML. Overall, inclusion of SP fraction decreased the size of the putative CD34/CD38 defined LSC compartment by a factor >500. For example, for the important CD34+CD38- LSC compartment, the median SP/CD34+CD38- frequency was 5.1 per million WBC (CD34-positive AML), and median SP/CD34-CD38+ frequency (CD34-negative AML) was 1796 per million WBC. Improved detection of LSC may enable identification of therapy resistant clones, and thereby identification of novel LSC specific, HSC sparing, therapies. [ABSTRACT FROM AUTHOR]

Highlights • High clinical trial accrual volume had a modest impact on complete remission rates. • Median overall and event-free survival were similar between high and low accruing institutions. • No differences in early mortality were observed between patients treated in high versus low volume accruing institutions. Abstract Purpose To study whether institutional clinical trial accrual volume affects clinical outcomes of younger (age less than 61 years) patients with acute myeloid leukemia. Patients and methods We investigated the impact of clinical trial accrual on response rates, early mortality and survival in patients with AML enrolled between 2002 and 2009 into two parallel cooperative group clinical trials SWOG S0106/ECOG-ACRIN E1900. Institutions were classified as low- (LAIs) (≤ 9 enrolled patients) or high-accruing institutions (HAIs) (≥10 enrolled patients). Fisher's exact text and logistic regression analysis were used to analyze the response and early mortality rates. The effect of accrual volume on survival was analyzed by log-rank tests and Cox regression models. Results A total of 1252 patients from 152 institutions were included in the final analyses. The median clinical trial registrations in HAIs was 19 patients (range, 10 to 92) versus 3 (range, 1 to 9) patients in LAIs. In multivariate analyses, HAIs, as a quantitative covariate, was associated with improved complete remission rates (odds ratio (OR) 1.08, p = 0.0051), but no improvement median overall survival (HR 0.97, p = 0.065) or median event-free (hazard ratio (HR) 0.97, p = 0.05). Early mortality rates were similar between cohorts and academic affiliation had no impact on response rates or survival. Conclusion Clinical trial accrual volume, had an independent, albeit modest, impact on complete remission rates, but not on overall survival and event-free in younger patients with AML. [ABSTRACT FROM AUTHOR]

Highlights • This is the largest cohort of mast cell leukemia patients analyzed for survival. • Most mast cell leukemia patients are Caucasian, and have de novo disease. • Mast cell leukemia is associated with poor overall survival outcomes. • Chemotherapy may improve survival outcomes in subsets of mast cell leukemia patients. Abstract Introduction Mast cell leukemia (MCL) is rare and carries a poor prognosis. No standard-of-care has been established. No USA registry-based analyses have examined clinical correlates of overall survival (OS) in MCL patients, thus we aimed to do this using the Surveillance, Epidemiology, and End Results (SEER) database, and the National Cancer Database (NCDB). Materials/methods We included 25 patients from SEER, and 50 patients from NCDB diagnosed with MCL through 2015. Kaplan-Meier and multivariable regression analyses were used to assess the impact of clinical characteristics on OS in each dataset, and on a pooled cohort of both datasets. Results Median age at diagnosis for the pooled cohort was 63 years, and median OS was 9.4 months. The proportion of patients surviving 12, 36, and 60 months was 42.9%, 23.2%, and 16.6%, respectively. Males (n = 44, 58.7%) outnumbered females (n = 31, 41.3%). Caucasians formed a majority (n = 66, 88%). With Cox regression accounting for database of origin, age at and year of diagnosis, sex, race, sequence number, and receipt of chemotherapy, no variable was significantly associated with OS. However, in the same analysis, when stratified by sex, receipt of chemotherapy was associated with improved OS in males (HR = 0.41, 95% CI 0.14-0.89, p < 0.03), and poorer OS in females (HR = 3.64, 95% CI 1.07–12.44, p = 0.04). Conclusions Our study reaffirms that MCL carries a poor prognosis. Chemotherapy may improve survival in subsets of patients, though generalizability is limited by biases inherent in registry-based datasets. Due to poor outcomes for MCL patients, more study is needed to determine optimal care. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Determine unique genomic characteristics of ETP-ALL using computational modeling. • Generated disease-specific protein network maps for ETP-ALL patients. • Genomics-based classification of ETP-ALL had sensitivity and specificity of 93% and 87%. • Computational simulation of 62 ETP-ALL patients identified 87 combination therapies. • Shortlisted combinations validated by in vitro chemosensitivity assays. Abstract Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematological malignancy for which optimal therapeutic approaches are poorly characterized. Using computational biology modeling (CBM) in conjunction with genomic data from cell lines and individual patients, we generated disease-specific protein network maps that were used to identify unique characteristics associated with the mutational profiles of ETP-ALL compared to non-ETP-ALL (T-ALL) cases and simulated cellular responses to a digital library of FDA-approved and investigational agents. Genomics-based classification of ETP-ALL patients using CBM had a prediction sensitivity and specificity of 93% and 87%, respectively. This analysis identified key genomic and pathway characteristics that are distinct in ETP-ALL including deletion of nucleophosmin-1 (NPM1), mutations of which are used to direct therapeutic decisions in acute myeloid leukemia. Computational simulations based on mutational profiles of 62 ETP-ALL patient models identified 87 unique targeted combination therapies in 56 of the 62 patients despite actionable mutations being present in only 37% of ETP-ALL patients. Shortlisted two-drug combinations were predicted to be synergistic in 11 profiles and were validated by in vitro chemosensitivity assays. In conclusion, computational modeling was able to identify unique biomarkers and pathways for ETP-ALL, and identify new drug combinations for potential clinical testing. [ABSTRACT FROM AUTHOR]

Highlights • Green tea extract inhibited the growth of human myeloid leukemia cells. • Green tea extract had differential effects on pRb and phosphor-pRb. • Green tea extract inhibited E2F DNA binding activity. • The inhibitory effect appeared receptor tyrosine kinase-independent. Abstract Both inhibitory and stimulatory effect of EGCG on cancer cells have been reported, which often is linked to receptor tyrosine kinase signaling. In this study, we present evidence that green tea extract and its chemical component, Epigallocatechin-3-gallate (EGCG), inhibit growth of human myeloid leukemia cells through the regulation of pRb synthesis and formation of pRb-E2F complexes. Addition of green tea extract to the culture of TF-1a and MV4-11 myeloid leukemia cells significantly inhibited their proliferation with a substantial portion of cell death being observed. The green tea extract and EGCG had no significant effect on the expression of G1 CDKs and the CDK inhibitors but downregulated the formation of pRb-CDKs. Surprisingly, the expression of pRb was markedly upregulated while the phosphorylation of pRb downregulated. The upregulation of pRb was blocked by pre-treatment with cycloheximide, a protein synthesis inhibitor, suggesting a requirement of protein synthesis. In agreement with these results, pRb-E2F complexes were upregulated and E2F DNA binding activity decreased. Since both TF-1a and MV4-11 are factor-independent cell lines, the upregulation of pRb-E2F complexes and inhibition of DNA binding activity by green tea extract is most likely through a receptor tyrosine kinase-independent pathway. We also found that the stem/progenitor cells derived from these two leukemia cell lines are more sensitive to the inhibitory effect of green tea extract. Our result suggests that concentrated green tea extract and EGCG may have potential for clinical investigation as an inducer of cancer cell death. [ABSTRACT FROM AUTHOR]

A national cooperative group trial was conducted in 153 patients with chronic myelogenous leukemia (CML) in chronic phase treated with oral pulse busulfan to determine if oral vitamin A can increase the time to blast crisis and enhance survival of patients. Patients diagnosed within 1 year and in the chronic phase of CML were randomized to receive oral pulse busulfan or the alkylator plus continuous oral vitamin A. Distributions of clinical progression and overall survival were estimated using the method of Kaplan and Meier. Associations of these endpoints with treatment and other patient characteristics were analyzed using the proportional hazards regression method of Cox. Both regimes were well tolerated. Patients in the busulfan plus vitamin A arm had somewhat longer durations of clinical progression-free survival (median 46 months) and overall survival (51 months) compared to those in the busulfan arm (medians 38 and 44 months). However, the differences were not statistically significant (one-tailed P = 0.11 for clinical progression-free survival, 0.081 for survival). After adjustment for significant factors identified in an additional exploratory multivariate analysis, risk of clinical progression or death was 53% (P = 0.022) greater and risk of death 60% (P = 0.014) greater among busulfan patients. Given the relatively large though non-significant difference between treatment arms, the limited statistical power of the study, and the likelihood that oral vitamin A may not be the most effective means of delivering retinoid therapy, we conclude that further investigation of retinoids in chronic phase CML is warranted.

Highlights • BRD2 and BRD4 were increased in I-BET151-resistant U937 (U937R) cells. • Constitutive activation of the NF-κB signaling pathway was induced in U937R cells. • IKK inhibitor VII restored the sensitivity to I-BET151 in U937R cells. • IKK inhibitor VII synergistically enhanced the antitumor activity of I-BET151. Abstract Novel epigenetic therapies targeting bromodomain and extra-terminal (BET) family proteins have shown therapeutic efficacy in diverse hematologic malignancies and solid cancers. However, the mechanism of resistance remains poorly understood. In the present study, we evaluated the mechanism of resistance to the BET inhibitor I-BET151 and its signaling pathway to overcome resistance in U937 cells. Treatment with 10 μM I-BET151 significantly induced growth inhibition, apoptosis, and cell cycle modulation, including increases in sub-G1 and G1 phases and decreases in S and G2/M phases, in U937 cells. However, no significant changes in these factors were detected in I-BET151-resistant U937 (U937R) cells. Combined treatment with I-BET151 and IKK inhibitor VII synergistically induced apoptosis in U937 and U937R cells. Increased expression of bromodomain-containing protein (BRD) 2, BRD4, and nuclear NF-κBp65 proteins was detected in U937R cells. IKK inhibitor VII inhibited the activation of NF-κBp65 protein in the nuclear fraction of U937R cells. These findings suggest that resistance to I-BET151 in U937R cells is related to constitutive activation of the NF-κB signaling pathway via increased expression of both BRD2 and BRD4. Targeting the NF-κB signaling pathway may be an effective therapeutic strategy to enhance or restore the sensitivity to I-BET151 in U937 cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Decellularized Wharton’s jelly matrix (DWJM) can be used to culture leukemia. • Leukemia cells cultured in DWJM demonstrate increased ALDH expression. • Leukemia cells cultured in DWJM demonstrate increased N -cadherin expression. • Leukemia cells cultured in DWJM demonstrate increased drug resistance. • DWJM could serve as an ECM-based model to study AML stem cell-like behavior. Abstract Acute myeloid leukemia (AML) relapse results from the survival of chemotherapy-resistant and quiescent leukemia stem cells (LSC). These LSCs reside in the bone marrow microenvironment, comprised of other cells and extracellular matrix (ECM), which facilitates LSC quiescence through expression of cell adhesion molecules. We used decellularized Wharton’s jelly matrix (DWJM), the gelatinous material in the umbilical cord, as a scaffolding material to culture leukemia cells, because it contains many components of the bone marrow extracellular matrix, including collagen, fibronectin, lumican, and hyaluronic acid (HA). Leukemia cells cultured in DWJM demonstrated decreased proliferation without undergoing significant differentiation. After culture in DWJM, these cells also exhibited changes in morphology, acquiring a spindle-shaped appearance, and an increase in the ALDH+ cell population. When treated with a high-dose of doxorubicin, leukemia cells in DWJM demonstrated less apoptosis compared with cells in suspension. Serial colony forming unit (CFU) assays indicated that leukemia cells cultured in DWJM showed increased colony-forming ability after both primary and secondary plating. Leukemia cell culture in DWJM was associated with increased N-cadherin expression by flow cytometry. Our data suggest that DWJM could serve as an ECM-based model to study AML stem cell-like cell behavior and chemotherapy sensitivity. [ABSTRACT FROM AUTHOR]

Highlights • CDX2 could be used as a specific diagnostic marker in acute leukemias, such as ALL and AML. • The prognosis role of CDX2 has been indicated in some studies, but the findings are controversial. • It seems to be of great clinical interest for assessment of minimal residual diseases. • We have comprehensively evaluated the clinical significance of CDX2 in leukemia. Abstract CDX2 gene encodes a transcription factor involved in primary embryogenesis and hematopoietic development; however, the expression of CDX2 in adults is restricted to intestine and is not observed in blood tissues. The ectopic expression of CDX2 has been frequently observed in acute myeloid and lymphoid leukemia which in most cases is concomitant with poor prognosis. Induction of CDX2 in mice leads to hematologic complications, showing the leukemogenic origin of this gene. CDX2 plays significant role in the most critical pathways as the regulator of important transcription factors targeting cell proliferation, multi-drug resistance and survival. On the whole, the results indicate that CDX2 has the potential to be suggested as the diagnostic marker in hematologic malignancies. This review discusses the role of aberrant expression of CDX2 in the prognosis and the response to treatment in patients with different leukemia in clinical reports in the recent decades. The improvement in this regard could be of high importance in diagnosis and treatment methods. [ABSTRACT FROM AUTHOR]

Background High Risk (HR) or Very High Risk (VHR) acute lymphoblastic leukemia (ALL) treated with 4 drug induction chemotherapy is often associated with adverse events. The aim of this study was to identify risk factors associated with a prolonged inpatient length of stay LOS during induction chemotherapy. Procedure Data from patients (N = 73) (age<21 years) was collected through a retrospective chart review. Univariable and multivariable logistic regression was used to test for statistical significance. The overall survival and disease (leukemia)-free survival were analyzed using the Kaplan–Meier method and log-rank test. Results Of the 73 patients, 42 (57%) patients were discharged on day 4 of induction (short LOS, group A), while 31 (43%) patients (group B) experienced a prolonged LOS or an ICU stay (16 ± 27.7 days, median hospital stay = 8 days vs 4 days (group A), p = 0.02) due to organ dysfunction, infectious or metabolic complications. Group B patients were more likely to have a lower platelet count, serum bicarbonate, and a higher blood urea nitrogen (BUN) on day 4 of treatment (OR = 4.52, 8.21, and 3.02, respectively, p < 0.05). Multivariable analysis identified low serum bicarbonate (p = 0.002) and a platelet count<20,000/μL (p = 0.02) on day 4 of induction to be predictive of a prolonged LOS. Twenty six (group A (n = 16, 36%) and B (n = 11, 35%), p = 0.8) patients experienced unplanned admissions, within 30 days of discharge. Conclusions A significant proportion of newly diagnosed HR or VHR pediatric ALL patients experience a prolonged LOS and unplanned re-admissions. Aggressive discharge planning and close follow up is indicated in this cohort of patients. [ABSTRACT FROM AUTHOR]

Background Therapy related myeloid neoplasm (t-MN) is an emerging challenge in the current era. However, real world data on its incidence and survival at the population level remains sparse. Methods Using Surveillance Epidemiology and End Results (SEER-18) database, we identified patients aged ≥20 years with pathologically confirmed t-MN diagnosed between the years 2001–2014 and actively followed. Incidence rate per 100,000 population and incidence rate ratio (IRR) were calculated. Overall survival (OS) was calculated by Kaplan-Meier method with determinants analyzed by Cox proportional hazard regression method. Results A total of 1093 patients with a median age of 65 years were identified. Overall incidence of t-MN was 0.13 cases/100,000 population and showed significant variations with age, race and the period of diagnosis. Two year OS significantly declined with increasing age (51.3% in age group 20–39, 33.9% in age group 40–59, 19.3% in age group 60–79 and 0% in age ≥ 80, p < 0.01). OS has improved over period (year 2001–2007 − 22.1% vs. year 2008–2014 −26.9%, p = 0.01). On multivariate analysis, increasing age was associated with significantly higher mortality. Compared to the period 2001–2007, a significantly lower risk for mortality was seen in the period 2008–2014 (HR 0.73, CI 0.58–0.92, p < 0.01). Conclusions Incidence of t-MN has significantly increased in the last decade. Although OS at the population level is improving over time, outcomes of this disorder continue to remain poor, highlighting the need for novel therapies. [ABSTRACT FROM AUTHOR]

NAMPT (Nicotinamide phosphoribosyltransferase) catalyses the rate-limiting step in the NAD biosynthesis from nicotinamide and thereby regulates the activity of NAD-dependent enzymes. Cancer cells are highly dependent on NAD for energy and DNA repair processes and are assumed to be more susceptible to an inhibition of NAD synthesis than non-transformed cells. We aimed to investigate whether or not inhibition of NAMPT with its specific inhibitor FK866 can sensitize leukemia cells for chemotherapeutic agents. NAMPT protein abundance, enzymatic activity and NAD concentrations were significantly higher in Jurkat and Molt-4 leukemia cell lines compared to normal peripheral blood mononuclear cells. Combination of etoposide and FK866 caused increased cell death in leukemia cell lines compared to etoposide alone. Etoposide decreased protein abundance of NAD-dependent deacetylases SIRTUIN1. After combining etoposide and FK866 treatment SIRTUIN2 was further decreased and accumulation and acetylation of the downstream target p53 was further enhanced in MOLT4 cells. Concomitantly, protein abundance of p21 and cleaved BAX was increased. Targeting NAMPT could be a novel therapeutic strategy to enhance the efficacy of chemotherapeutic agents such as etoposide against leukemia. [ABSTRACT FROM AUTHOR]

Fast identification of BCR-ABL fusion genes is critical for precise diagnosis, risk stratification and therapy scheme selection in leukemia. More convenient methods are needed for quickly detection of the BCR-ABL fusion genes. Multiplex fluorescent reverse transcription quantitative real-time PCR (Multiplex RT-qPCR) methods are developed for detection of the at least 14 subtypes of BCR-ABL fusion genes in one tube at a time by using patients’ bone marrow samples. The new Multiplex RT-qPCR method could quickly detect BCR-ABL fusion genes with sensitivity up to 10–10 6 copies. It can detect the fusion genes in patients’ bone marrow samples containing any subtypes of the major bcr (M-bcr) e13a2, e14a2, e13a3 and e14a3, the minor bcr (m-bcr) e1a2 and e1a3, the micro bcr (μ-bcr) e19a2 and e19a3, and the nano bcr (n-bcr) e6a2 and e6a3. The specificity is comparable to the FISH methods. The cutoff for clinical diagnosis of BCR-ABL(+) is also determined by testing in clinical chronic myeloid leukemia samples. This is a new fast method with high sensitivity and specificity for clinical detection of BCR-ABL fusion genes. It will benefit the precise diagnosis, targeted therapy and minimal residual disease (MRD) monitoring in leukemia. [ABSTRACT FROM AUTHOR]

Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial’s statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) failure is often seen in leukemia patients, indicating an abnormal hematopoietic process. However, hematopoiesis in leukemic milieus is largely unknown. In the present study, we utilized one of the most frequent leukemogenic translocations MLL-AF9 to induce leukemia and investigated the hematopoiesis and the activity of hematopoietic stem and progenitor cells (HSPCs) in a leukemic milieu. We found that the phenotypes of the non-leukemic population in leukemic BM were drastically different than normal BM, including blockage of differentiation and a drastically reduced Lin-/Sca+/c-kit+ (LSK) population that contains all HSPCs in leukemic BM. Further, transplantation assays demonstrated that stem cell function of HSPCs from leukemic BM was significantly compromised. Intriguingly, BM from a patient-derived xenograft leukemia model and from immunocompromised mice transplanted with murine MLL-AF9 cells, showed comparable percentage of hematopoietic stem cells (HSCs) to normal controls, indicating that an immunocompetent microenvironment is critical for leukemia-induced loss of HSPCs. Mechanistically, we found that the non-leukemic cells from leukemic BM possessed a more inflammatory profile than either leukemic cells or normal BM counterparts. Co-culturing or co-transplantation with non-leukemic cells from leukemic BM impaired the stem cell function of normal HSPCs in vitro and in vivo respectively, suggesting that the highly inflammatory non-leukemic population in leukemic BM not only is functionally abnormal but displayed a ‘leukemia-like’ characteristic. Finally, we tested the effect of the anti-inflammation drug diclofenac on leukemia mice. However, no phenotypic changes of HSPCs were observed upon diclofenac treatment due to only mild repression of inflammatory genes by diclofenac, further indicating that inflammation is a powerful negative regulator of HSPCs. Together, our results suggest that leukemia impairs normal hematopoiesis and inflammation as well as immune cells play a critical role in leukemia-induced BM failure. [ABSTRACT FROM AUTHOR]

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4 mg/m 2 per day for 5–7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n = 45) or with ATO (n = 38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4 days, 10 days and 28 days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0–24 days) and day 3 (range: 0–27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score = 4, the consumption of transfused platelets was less in the RIF group than that in the ATO group ( P = 0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels ( P = 0.028) was observed in the RIF group compared with that in the ATO group ( P = 0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients. [ABSTRACT FROM AUTHOR]

Inhibition of WEE1 is emerging as a promising chemosensitization strategy in many cancers including acute leukemia. Our lab and others have demonstrated that a small-molecule inhibitor of WEE1, AZD1775, sensitizes acute leukemia cells to cytarabine; however, a mechanism of combinatorial activity has remained elusive. Thus, we sought to determine the relative contribution of WEE1 targets CDK1 and CDK2 to the combinatorial activity of AZD1775 and cytarabine. To accomplish this, we expressed “WEE1 resistant” CDK1 (CDK1-AF) and CDK2 (CDK2-AF) constructs in a T-ALL cell line. Expression of CDK1/2-AF together, but neither alone, enhanced the anti-proliferative effects, DNA damage and apoptosis induced by cytarabine. Furthermore, pharmacologic inhibition of CDK1 alone or CDK1 and CDK2 together reduced the combinatorial activity of AZD1775 and cytarabine. Thus, increased activity of both CDK1 and CDK2 in response to WEE1 inhibition is necessary for the combinatorial activity of AZD1775 and cytarabine. This suggests the role of WEE1 in cells with accumulated DNA damage extends beyond regulation of CDK1 and the G2/M checkpoint and highlights the importance of WEE1 in mediating progression through the cell cycle. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EV) are nano-sized membrane enclosed vehicles that are involved in cell-to-cell communication and carry cargo that is representative of the parent cell. Recent studies have highlighted the significant roles leukemia EVs play in tumor progression, and ways in which they can lead to treatment evasion, thus meriting further investigation. Leukemia EVs are involved in crosstalk between the leukemia cell and its surroundings, transforming it into a cancer favorable microenvironment. Due to the diverse biological content found in leukemia EVs, they have an assortment of effects on the cells they interact with and can be harnessed as candidates for diagnostic and therapeutic treatments. This review focuses on EVs in the context of leukemia and the means by which they modulate their microenvironment, hematopoiesis, and the immune system to facilitate malignancy. We will also address current and prospective EV-based therapeutics. [ABSTRACT FROM AUTHOR]

Three ADCs: Mylotarg, Besponda and Lumoxiti have improved overall survival and event=free survival as well as reduced relapse in 3 types of Leukaemia: AML, ALL and HCL, respectively. Lessons from these three SOC successful ADCs should guide other new ADCs in addressing the ADC-related off target toxicity due to the cytotoxic payload that limits their therapeutic index by using the successful approach of administrating lower doses in a fractionated regimen over time in separate days of the cycle to reduce the severity and frequency of the ADC-related serious toxicities that include ocular damage, long-term peripheral neuropathy and hepatic toxicity etc. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. The chemotherapeutic effect on survival remains unclear, and feasible standardized response criteria are yet to be established. We aimed to evaluate the chemotherapeutic response and its effect on survival in patients with JMML. A retrospective registry was reviewed for children diagnosed with JMML between 2000 and 2019. Response was assessed according to the criteria proposed by the International JMML Symposium in 2007 (criteria I) and the updated version in 2013 with its modifications (criteria II). A total of 73 patients were included in this study. Complete response (CR) rates were 46.6% and 28.8% using the criteria I and criteria II, respectively. A platelet count ≥ 40 × 109/L at diagnosis was associated with higher CR rates using the criteria II. Patients with criteria I-based CR had a better overall survival (OS) than those without CR (81.1% vs. 49.1% at 5 years). Patients with criteria II-based CR showed better OS (85.7% vs. 55.5% at 5 years) and event-free survival (EFS) (71.1% vs. 44.7% at 5 years) than those without CR. Additionally, a trend toward better EFS was observed in patients with criteria II-based CR than in those with criteria I-based CR but without criteria II-based CR (71.1% vs. 53.8% at 5 years). Chemotherapeutic response is associated with better survival outcomes. Along with splenomegaly, the addition of platelet count recovery, existence of extramedullary leukemic infiltration, and more stringent leukocyte counts to the response criteria allows for a more sensitive prediction of survival outcomes. • Standardized response criteria are yet to be established in treatment of JMML. • Complete response was assessed by the two criteria (criteria I and II). • A platelet count ≥40×109/L at diagnosis was associated with higher CR rates. • Patients with criteria II-based CR showed better OS and EFS than those without. • More stringent response criteria might be helpful in predicting survival outcomes. [ABSTRACT FROM AUTHOR]

Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution—60 (44%) tax A cases and 76 (56%) tax B cases—differed from that of a previous report from Kagoshima Prefecture in mainland Japan ( tax A, 10%; tax B, 90%). A comparison of the clinical outcomes of 45 patients ( tax A, 14; tax B, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for tax A (50% and 35%, respectively) were lower than those for tax B (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of tax A compared with tax B was 2.68 (95% confidence interval, 0.87–8.25; P = 0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL. [ABSTRACT FROM AUTHOR]

The c-Rel transcription factor is a unique member of the NF-kB family that has a role in apoptosis, proliferation and cell survival. Overexpression of c-Rel is detected in many human B cell tumors, including B-cell leukemia and several cancers. The study aimed to investigate the effects of c-Rel siRNA on the proliferation and apoptosis of relapsed pre-B acute leukemia cells. The c-Rel siRNA was transfected into Leukemia cells using an Amaxa cell line Nucleofector kit L (Lonza). Quantitative real-time RT-PCR (qRT-PCR) and western blot were done to measure the expression levels of mRNA and protein, respectively. The flow cytometry was used to analyze the effect of c-Rel siRNA on the apoptosis and proliferation of Leukemia cells. Observed c-Rel expression in the 5 pre-B Acute lymphoblastic leukemia (ALL) patients were higher than the normal cells. The c-Rel siRNA transfection significantly blocked the expression of c-Rel mRNA in a time-dependent manner, leading to a strong growth inhibition and enhanced apoptosis (P < 0.05). Our results demonstrated that c-Rel plays a fundamental role in the survival. Therefore, c-Rel can be considered as an attractive target for gene therapy in ALL patients. Also siRNA-mediated silencing of this gene may be a novel strategy in ALL treatment. [ABSTRACT FROM AUTHOR]

Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene - rearranged acute lymphoblastic leukemia ( MLL + ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL + ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)β1 mRNA levels in MLL + ALL cells, we extensively examined the effect of TGFβ1 on the cell cycle progression and chemosensitivity in MLL + ALL cells, and found that TGFβ1 stimulation induced MLL + ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL. Thus, it is likely that TGFβ1 and FL, both abundantly produced by bone marrow stromal cells, function in a coordinated manner to render MLL + ALL cells chemoresistant, which should lead to the development of minimal residual disease (MRD) resulting in relapse. The use of inhibitors against FLT3 and TGFβ1 may become a useful strategy for eradicating MRD in MLL + ALL. [ABSTRACT FROM AUTHOR]

Purpose Cytosine arabinoside (AraC) remains the backbone of most treatment regimens for acute myeloid leukemia (AML). Incorporation of AraC into DNA activates checkpoint kinase 1 (Chk1), leading to cell-cycle arrest and diminished AraC cytotoxicity, which can be reversed by the selective Chk1 inhibitor MK-8776. Building on a Phase I trial, we conducted a phase II trial comparing timed sequential AraC with or without MK-8776. Methods Patients with relapsed or primary refractory AML were randomized 1:1 to receive either AraC with MK-8776 (Arm A); or AraC alone (Arm B). Results 32 patients were treated: 14 assigned to Arm A and 18 to Arm B. There were 5 (36%) complete responses (CR/CRi) and 1 (7%) partial response (PR) in Arm A, and 8 (44%) CR/CRis and 1 (6%) PR in Arm B. Median survival did not differ significantly between the two groups (5.9 months in Arm A vs. 4.5 months in Arm B). MK-8776 led to a robust increase in DNA damage in circulating leukemic blasts as measured by increased γ-H2AX (16.9% ± 6.1% prior and 36.4% ± 6.8% at one hour after MK-8776 infusion, p = 0.016). Conclusion Response rates and survival were similar between the two groups in spite of evidence that MK-8776 augmented DNA damage in circulating leukemic blasts. Better than expected results in the control arm using timed sequential AraC and truncated patient enrollment may have limited the ability to detect clinical benefit from the combination. [ABSTRACT FROM AUTHOR]

Background Current results regarding treatment outcomes in acute myeloid leukemia (AML) point to significant differences between low- and middle-income countries (LMIC) and high-income countries (HIC). Excluding well-known socioeconomic issues, genetic markers important for prognosis have not been properly incorporated into the clinical practice so far and their usefulness outside of well-controlled clinical trials remain unknown. Methods Here, we assessed the clinical significance of the European LeukemiaNet (ELN) recommendations in 196 consecutive patients with AML in a real-life setting. All patients were younger than 60 years of age (49% male) and treated with conventional chemotherapy for induction and consolidation in three Brazilian Institutions that well represent Brazilian geographic and socioeconomic diversity. Findings Multivariable analysis showed that ELN recommendations had a slight association with complete remission achievement (odds ratio: 0.74, 95% confidence interval, CI: 0.53-1.01; P = 0.06), but were independently associated with poor overall survival (OS) (hazard ratio, HR: 1.3, 95% CI: 1.1-1.54; P = 0.002), disease-free survival (DFS) (HR: 1.42, 95% CI: 1.03-1.95; P = 0.028) and event-free survival (EFS) (HR: 1.24, 95% CI: 1.06-1.47; P = 0.007), considering initial leukocyte counts and age as confounders. ELN recommendations had no impact on cumulative incidence of relapse ( P = 0.09). Interpretation Our results suggest that within the context of LMIC, the prognostic markers recommended by ELN may be useful to predict patient’s clinical outcomes; however, the OS, DFS and EFS were shorter than the reported in Europe and US for the respective risk groups. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is frequently treated with induction and consolidation chemotherapy. Consolidation chemotherapy can be delivered on an ambulatory basis, requiring some patients to travel long distances for treatment at specialized centers. We developed a shared care model where patients receive consolidation chemotherapy at a quaternary center, but post-consolidation supportive care at local hospitals. To evaluate the impact of our model on patient travel and outcomes we conducted a retrospective analysis of AML and acute promyelocytic leukemia patients receiving consolidation over four years at our quaternary center. 73 patients received post-consolidation care locally, and 344 at the quaternary center. Gender, age and cytogenetic risk did not significantly differ between groups. Shared care patients saved mean round trip distance of 146.5 km ± 99.6 and time of 96.7 min ± 63.4 compared to travelling to quaternary center. There was no significant difference in overall survival between groups, and no increased hazard of death for shared care patients. 30, 60, and 90 day survival from start of consolidation was 98.6%, 97.2%, and 95.9% for shared care and 98.8%, 97.1%, and 95.3% for quaternary center patients. Thus, a model utilizing regional partnerships for AML post-consolidation care reduces travel burden while maintaining safety. [ABSTRACT FROM AUTHOR]

Mast cell leukemia (MCL) is a very rare subtype of systemic mastocytosis (SM). We have identified 13 such patients (5.9%) among 218 patients with SM seen at our institution between 1994 and 2016. Patients with MCL had poor survival (median 31.6 months); response to various therapies was rare and not durable. Clinical course may be affected by concurrent associated hematologic neoplasm and different genetic profiles. More research is required to decipher this rare and enigmatic SM subtype. [ABSTRACT FROM AUTHOR]

The aberrant expression or mutation of CFTR has been shown to be involved in several tumors, but how mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains unclear. Here, we report the interaction between CFTR and HDAC2, and its involvement in the development of Ph+ leukemia. We first detected the physical interaction and co-localization of CFTR and HDAC2 in Ph+ leukemia cell lines. And treatment with CFTRinh-172, a CFTR inhibitor, reduced the expression of HDAC2 protein in K562 and SUP-B15 cells, which could be partially recovered by MG132, a proteasome inhibitor. Additionally, high expression levels of HDAC2 protein were observed in CFTR cDNA transfected HEK-293 and Ba/F3 cells. Next, we found that HDAC2 bound in the promoter region of the PTEN gene, and treatment with HDAC2 inhibitor or CFTRinh-172 resulted in an increase in PTEN mRNA and protein levels and a decrease in PDK1 and mTOR (downstream signaling of PTEN) activity. Finally, the MTT assay revealed that CFTRinh-172 could strengthen the anti-proliferation effect of HDAC2 inhibitor on Ph+ leukemia cells. Altogether, this study provides strong evidence that high-expression CFTR plays an important role in the development of Ph+ leukemia through the HDAC2-mediated PTEN pathway. [ABSTRACT FROM AUTHOR]

The association between cytomegalovirus (CMV) reactivation and relapse risk has not been evaluated in relation to T cell depletion strategies. We evaluated 93 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and analyzed the association between T cell depletion strategies with the cumulative incidence of relapse and CMV reactivation. A total of 33% of patients who received ATG vs. 34% who received alemtuzumab developed CMV reactivation. The cumulative incidence of relapse was 3% at 1 year and 20% at 3 years in patients with CMV reactivation vs. 30% at 1 year and 38% at 3 years in patients without CMV reactivation (p = 0.02). When analyzed separately, this effect persisted in the myeloid, but not the lymphoid group. There was a numerical trend towards increased non-relapse mortality (NRM) in patients with CMV reactivation, especially in the myeloid group. The choice of T cell depleting agent and the rate of CMV reactivation were not associated with different overall survival (OS) rates. These results suggest that the choice of T cell depletion strategy may have similar effects on rates of CMV reactivation, disease relapse, and survival. Further studies examining these variables in patients not exposed to in-vivo T cell depleting agents may be of interest. [ABSTRACT FROM AUTHOR]

Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes. The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload. In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events. In the present report, we detail findings from the final analysis at 5 years. We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not. Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease. Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy. Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification. [ABSTRACT FROM AUTHOR]

Telomeres are structures confined at the ends of eukaryotic chromosomes. With each cell division, telomeric repeats are lost because DNA polymerases are incapable to fully duplicate the very ends of linear chromosomes. Loss of repeats causes cell senescence, and apoptosis. Telomerase neutralizes loss of telomeric sequences by adding telomere repeats at the 3′ telomeric overhang. Telomere biology is frequently associated with human cancer and dysfunctional telomeres have been proved to participate to genetic instability. This review covers the information on telomerase expression and genetic alterations in the most relevant types of hematological diseases. Telomere erosion hampers the capability of hematopoietic stem cells to effectively replicate, clinically resulting in bone marrow failure. Furthermore, telomerase mutations are genetic risk factors for the occurrence of some hematologic cancers. New discoveries in telomere structure and telomerase functions have led to an increasing interest in targeting telomeres and telomerase in anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Cell signalling, which is often derailed in cancer, is a network of multiple interconnected pathways with numerous feedback mechanisms. Dynamics of cell signalling is intimately regulated by addition and removal of phosphate groups by kinases and phosphatases. We examined expression of members of the PTP4A family of phosphatases across acute leukemias. While expression of PTP4A1 and PTP4A2 remained relatively unchanged across diseases, PTP4A3 showed marked overexpression in ETV6-RUNX1 and BCR-ABL1 subtypes of precursor B cell acute lymphoblastic leukemia. We show that PTP4A3 is regulated by the ETV6-RUNX1 fusion, but noticed no marked impact on cell viability either after PTP4A3 silencing or treatment with a PTP4A3 inhibitor. Regulation of PTP4A3 expression is altered in specific subgroups of acute leukemias and this is likely brought about by expression of the aberrant fusion genes. [ABSTRACT FROM AUTHOR]

Purpose Identify AML patients most likely to respond to CPX-351, a nano-scale liposome formulation containing cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio. Methods We examined the ex vivo cytotoxic activity of CPX-351 against leukemic cells isolated from 53 AML patients and an additional 127 samples including acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative neoplasms, or chronic lymphocytic leukemia/lymphoma. We assessed activity with respect to common molecular lesions and used flow cytometry to assess CPX-351 cellular uptake. Results AML specimen sensitivity to CPX-351 was similar across conventional risk groups. FLT3-ITD cases were five-fold more sensitive to CPX-351. CPX-351 was active across other indications with nearly all cases exhibiting IC 50 values markedly lower than reported 72-h plasma drug concentration in patients receiving CPX-351. The range and distribution of CPX-351 IC 50 values were comparable for AML, CLL, and ALL, whereas MDS/MPN cases were less sensitive. CPX-351 uptake analysis revealed a correlation between uptake of CPX-351 and cytotoxic potency. Conclusions Our findings are consistent with clinical data, in which CPX-351 activity is retained in high-risk AML patients. Ex vivo analysis of cytotoxic potency may provide a means to identify specific AML subsets, such as FLT3-ITD, that benefit most from CPX-351 and warrant additional clinical evaluation. [ABSTRACT FROM AUTHOR]

Patients with acquired and inherited bone marrow failure syndromes (BMFS) have ineffective hematopoiesis due to impairments of the hematopoietic stem cell compartment. Common manifestations of BMFS include varying degrees of peripheral blood cytopenias and, sometimes, progression to acute myelogenous leukemia. Research efforts have been made all over the world to improve understanding of the pathogenesis of these diseases and their clinical implications. The Aplastic Anemia and MDS International Foundation (AAMDSIF) is an independent nonprofit organization whose mission is to help patients and family members cope with BMFS. Here, we summarize recent scientific discoveries in several BMFS that were presented at the fifth International Bone Marrow Failure Disease Scientific Symposium 2016 that AAMDSIF sponsored on March 17–18, 2016, in Rockville, Maryland. [ABSTRACT FROM AUTHOR]