Search

Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneous composition of these diseases has limited our understanding of these domains. The NHLBI-sponsored MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/MPN, idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with

The mismatch between the study populations participating in oncology clinical trials and the composition of the targeted cancer population requires urgent amelioration. Regulatory requirements can mandate that trial sponsors enroll diverse study populations and ensure that regulatory revue prioritizes equity and inclusivity. A variety of projects directed at increasing accrual of underserved populations to oncology clinical trials emphasize best practices: broadened eligibility requirements for trials, simplification of trial procedures, community outreach through patient navigators, decentralization of clinical trial procedures and institution of telehealth, and funding to offset costs of travel and lodging. Substantial improvement will require major changes in culture in the educational and professional practice, research, and regulatory communities and will require major increases in public, corporate, and philanthropic funding.

Supplementary Table S1

Summary:Patients with hematologic malignancies are particularly vulnerable to COVID-19 infections, and upon a pooled data analysis of 24 publications, there is evidence that they have suboptimal antibody responses to COVID-19 vaccination and boosters. To provide them the needed additional protection from COVID-19, it is imperative to achieve a 100% full immunization rate in health care workers and adult caretakers, and to foster research to test higher doses and repeated rounds of COVID-19 vaccines and the use of passive immune prophylaxis and therapy.

Frequencies of monocyte and myelomonocytic populations in the bone marrow and spleen of Flt3ITD/ITD;Dnmt3afl/fl MxCre mice and age-matched Flt3ITD/ITD;Dnmt3afl/fl and wild-type control mice by flow cytometric analyses.

Supplementary Figure S1. Dnmt3a haploinsufficiency transforms Flt3ITD MPN into an AML with clonogenic c-Kit+ leukemic stem and progenitors in the spleen. Supplementary Figure S2. Comparative patterns of differential global DNA methylation in DNMT3A-mutant human and murine AML. Supplementary Figure S3. Hematopoietic stem cells/progenitor and c-Myc signatures are upregulated in murine AML. Supplementary Figure S4. DNMT3A rescued murine Flt3ITD/ITD;Dnmt3afl/fl MxCre AML hypermethylated regions correspond to HSPC-like populations.

Purpose: After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options.Patients and Methods: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples.Results: Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2–4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/kg) was expanded with no grade 2–4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3 mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95% CI, 240–671+). Patients who achieved PSD or mCR had significantly higher frequency of T cells expressing ICOS (inducible T-cell co-stimulator).Conclusions: Our findings suggest that ipilimumab dosed at 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit. Clin Cancer Res; 24(15); 3519–27. ©2018 AACR.

Purpose: Azanucleoside DNA methyltransferase (DNMT) inhibitors are currently approved by the U.S. Food and Drug Administration for treatment of myelodysplastic syndrome. The relative contributions of DNMT inhibition and other off-target effects to their clinical efficacy remain unclear. Data correlating DNA methylation reversal and clinical response have been conflicting. Consequently, it is necessary to investigate so-called off-target effects and their impact on cell survival and differentiation.Experimental Design: Flow cytometry was used for cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation analysis. Gene expression analysis was performed using real-time PCR. DNA methylation was detected by methylation-specific PCR. Mitochondrial membrane potential was analyzed using JC-1 dye staining. Western blotting was used for quantitative protein expression analysis.Results: 5-Aza-2′-deoxycytidine (DAC) induced cell-cycle arrest and apoptosis in leukemia cells. p53 expression was dispensable for DAC-induced apoptosis. DAC induced delayed ROS accumulation in leukemia cells but not in solid tumor cells and p53 expression was dispensable for ROS increase. ROS increase was deoxycytidine kinase dependent, indicating that incorporation of DAC into nuclear DNA is required for ROS generation. ROS accumulation by DAC was caspase-independent and mediated the dissipation of the mitochondrial membrane potential. Concordantly, ROS scavengers diminished DAC-induced apoptosis. DAC induced the expression of different NADPH oxidase isoforms and upregulated Nox4 protein expression in an ATM-dependent manner, indicating the involvement of DNA damage signaling in Nox4 upregulation.Conclusion: These data highlight the importance of mechanisms other than DNA cytosine demethylation in modulating gene expression and suggest investigating the relevance of ROS accumulation to the clinical activity of DAC. Clin Cancer Res; 20(5); 1249–58. ©2014 AACR.

Supplementary Methods (Flow cytometry, cell sorting and TCR sequencing); Figure S1 shows Kaplan-Meir curve; Figure S2 shows absolute lymphocyte counts (ALC); Figure S3 shows differentiation of BM T cells; Figure S4 shows absolute numbers of ICOS+ T cells; Figure S5 shows ICOS expression in bone marrow T cells; Figure S6 shows CTLA-s and PD-1 expression; Figure S7 shows T-regulatory cells (Tregs); Figure S8 shows T cell receptor diversity; Figure S9 shows the top 20 most frequent T cell clones; Table S1 shows antibodies used for correlative studies; Table S2 shows immune related adverse events for each patient

Supplemental Figure S1. A, pretreatment bone marrow samples were treated diluent (-) with 10 μM melphalan (+) for 6 h and analyzed by immmunoblotting for FANCD2, ubiquitinated FANCD2 (Ub-FANCD2) and, as a loading control, heat shock protein 90 (HSP90). Supplemental Figure S2. A, Aliquots of whole cell lysates containing 5 x 106 pretreatment marrow mononuclear cells from the indicated patients were subjected to SDS-PAGE and blotting for the indicated antigens (lanes 5-12). Supplemental Figure S3. A, PAR suppression in PBMCs at various veliparib dose levels as a function of times during therapy. B, PAR suppression in PBMCs at 2 hours post dosing on day 1 and its relationship to clinical response. C, PAR suppression as assessed in bone marrow aspirates. Supplemental Table S1. MPN-Associated Leukemia Characteristics Supplemental Table S2 Accumulation of γH2AX in Viable Peripheral Blood CD34+ Cells Following Veliparib Administration at 80 mg Twice Daily Relative to Pretreatment (Day 0) Levels of DNA Damage

PDF file - 111K, Supplementary table S1. Primers sequence used in RealTime PCR. Supplementary table S2. DAC induces G2/M arrest in leukemia cells. Supplementary table S3. Impact of DAC on the expression of ROS generating and detoxifying enzymes. Supplementary table S4. Impact of 5AC on the expression of ROS generating and detoxifying enzymes. Supplementary figure 1. CEM cells and its isogenic dck negative cells were treated with DAC 500 nM for 72 h followed by apoptosis analysis.

Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies.Experimental Design: Patients received veliparib [20–200 mg once a day on day 1 and twice daily on days 4–12 in cycle 1 (days 1–8 in cycle ≥2)] and temozolomide [150–200 mg/m2 daily on days 3–9 in cycle 1 (days 1–5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined.Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR.Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697–706. ©2016 AACR.

Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results: A total of 99 patients received veliparib 10–100 mg orally twice daily on days 1–8, 1–14, or 1–21 along with continuous infusion topotecan 1.0–1.2 mg/m2/d + carboplatin 120–150 mg/m2/d on days 3–7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage–induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27–0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899–907. ©2016 AACR.

Table S1. Changes in Proportion (%) of γH2AX-Positive Cells in Peripheral Blood upon Veliparib and Veliparib/Temozolomide Treatment Figure S1. FANCD2 monoubiquitination following ex vivo melphalan treatment of patient bone marrow cells Figure S2.Pretreatment levels of PARP1 and MGMT Figure S3.Pretreatment MGMT promoter methylation in patient peripheral blood (PB) or bone marrow (BM) AML cells Figure S4. PARP inhibition in peripheral blood cells

Supplementary Table 1 from Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies

Supplementary Figure 2 from Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies

Supplementary Figure and Table Legends 1-2 from Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies

Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematologic disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), whereas no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high-risk MDS (≥RAEB2), but not in low-risk MDS (CTNNA1 methylation might be important in the transformation of MDS to AML. CTNNA1 expression was lowest in AML/MDS patients with CTNNA1 methylation, although reduced expression was found in some patients without promoter methylation. Repressive chromatin marks (H3K27me3) at the promoter were identified in CTNNA1-repressed AML cell lines and primary leukemias, with the most repressive state correlating with DNA methylation. These results suggest progressive, acquired epigenetic inactivation at CTNNA1, including histone modifications and promoter CpG methylation, as a component of leukemia progression in patients with both 5q− and non-5q– myeloid malignancies. [Cancer Res 2009;69(21):8482–90]

Supplementary Table 2 from Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies

The National Heart, Lung, and Blood Institute National MDS Natural History Study (NCT02775383) is a prospective cohort study enrolling cytopenic patients with suspected myelodysplastic syndromes (MDS) to evaluate factors associated with disease. Here, we sequenced 53 genes in bone marrow samples harvested from 1,298 patients diagnosed with myeloid malignancy, including MDS and non-MDS myeloid malignancy, or alternative marrow conditions with cytopenia based on concordance between independent histopathologic reviews (local, centralized, and tertiary to adjudicate disagreements when needed). We developed a novel two-stage diagnostic classifier based on mutational profiles in 18 of 53 sequenced genes that were sufficient to best (1) predict a diagnosis of myeloid malignancy and (2) within those with a predicted myeloid malignancy, predict whether they had MDS. The classifier achieved a PPV of 0.84 and NPV of 0.8 with an AUROC of 0.85 when classifying patients as myeloid vs. no myeloid malignancy based on VAFs in 17 genes and a PPV of 0.71 and NPV of 0.64 with an AUROC of 0.73 when classifying patients as MDS vs. non-MDS malignancy based on VAFs in 10 genes. We next assessed how this approach could complement histopathology to improve diagnostic accuracy. For 99 of 139 (71%) patients (PPV of 0.83 and NPV of 0.65) with local and centralized histopathologic disagreement in myeloid vs. no myeloid malignancy, the classifier-predicted diagnosis agreed with the tertiary pathology review (considered the internal gold standard). An online version of the classifier that can be used with either VAFs or binary mutation profiles is available at https://thenationalmdsstudy.net.

BackgroundDisparities in cancer outcomes persist for underserved populations; one important aspect of this is limited access to promising early phase clinical trials. To address this, the National Cancer Institute–funded Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. We report the tools developed and accrual metrics of the initial year of CATCH-UP.2020 with a focus on racial, ethnic, geographic, and socioeconomically underserved populations.MethodsCATCH-UP.2020 is a P30 supplement awarded to 8 National Cancer Institute–designated cancer centers with existing resources to rapidly open and accrue to Experimental Therapeutics Clinical Trials Network (ETCTN) trials with emphasis on engaging patients from underserved populations. Sites used patient-based, community-based, investigator-based, and program-based tools to meet specific program goals.ResultsFrom September 2020 to August 2021, CATCH-UP.2020 sites opened 45 ETCTN trials. Weighted average trial activation time for the 7 sites reporting this was 107 days. In the initial year, sites enrolled 145 patients in CATCH-UP.2020 with 68 (46.9%) representing racial, ethnic, rural, and socioeconomically underserved populations using the broader definition of underserved encompassed in the grant charge. During the initial year of CATCH-UP.2020, a time impacted by the COVID-19 pandemic, 15.8% (66 of 417) and 21.4% (31 of 145) of patients enrolled to ETCTN trials at network and at CATCH-UP sites, respectively, were from racial and ethnic minority groups, a more limited definition of underserved for which comparable data are available.ConclusionTargeted funding accelerated activation and accrual of early phase trials and expanded access to this therapeutic option for underserved populations.

Patients with classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary and secondary myelofibrosis (MF), are known to have an increased risk of second malignancies (SMs). Hydroxyurea (HU) is a guideline-recommended cytoreductive therapy for patients at high risk for MPNs. Controversy exists as to whether HU use is associated with a higher risk of SMs, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We conducted a retrospective cohort study of older patients diagnosed with MPN (age ≥66 years) between 2010 and 2017 and included the data in the Surveillance, Epidemiology, and End Results Medicare-linked database. Multivariable competing risk analyses adjusting for patient characteristics were used to assess the impact of HU on the development of SM. We identified 4023 patients (1688 with PV, 1976 with ET, and 359 with MF) with a median age of 77 (interquartile range [IQR], 71-83) years at the time of MPN diagnosis. After a median follow-up of 3.25 (IQR, 2.10-5.00) years, 489 patients developed an SM (346 solid, 73 lymphoid, and 70 myeloid malignancies). The cumulative incidence probability of SM was 19.88% (95% confidence interval [CI], 17.16%-22.75%) among 2683 HU users and 22.31% (95% CI, 17.51%-27.47%) among 1340 nonusers, respectively (Gray’s test, P < .01). We did not identify significant differences in the incidence of solid or hematologic SMs, including AML/MDS (hazard ratio, 1.33; 95% CI, 0.77-2.29; P = .30), between HU users and nonusers. Our results suggest that the use of HU does not increase the risk of SM in older patients with MPN.

The hypomethylating agents (HMAs) azacitidine and decitabine have been the de facto standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive therapy. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 2263 older adults (age ≥66 years) diagnosed with AML during 2005-2015 who received a first-line HMA; 1154 (51%) received azacitidine, and 1109 (49%) received decitabine. Median survival from diagnosis was 7.1 and 8.2 months (P < .01) for azacitidine- and decitabine-treated patients, respectively. Mortality risk was higher with azacitidine vs decitabine (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.01-1.21; P = .02). The findings were similar when evaluating only patients completing ≥4 cycles (42% of patients treated with either azacitidine or decitabine). These findings lost significance when evaluating those completing a standard 7-day schedule of azacitidine (34%) vs 5-day schedule for decitabine (66%) (HR, 0.95; 95% CI, 0.83-1.08; P = .43). Red blood cell (RBC) transfusion independence (TI) was achieved in one-third of patients with no difference between the 2 HMAs. In conclusion, the majority of older AML patients did not receive the minimum of 4 cycles of HMA often needed to elicit clinical benefit. We observed no clinically meaningful differences between azacitidine- and decitabine-treated patients in their achievement of RBC TI or survival.

Mutations in the tumor suppressor gene TP53 are detected in 5–10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n=75; 90%) and therapy-related malignancies (n=32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT.

Cytarabine-anthracycline based intensive induction chemotherapy (IC) remains the standard of care for remission induction among fit patients with newly diagnosed acute myeloid leukemia (AML) in the United States (US). However, the mortality rate outside of clinical IC trials, predictors of death, and resource utilization during admission for IC have not been thoroughly examined. We used the Premier Healthcare database to identify adult patients (aged 18-89 years) treated with cytarabine-anthracycline-based IC during their first recorded inpatient stay for AML during the contemporary period of 2010 to 2017. We identified factors associated with inpatient death or discharge to hospice, using multivariable logistic regression models. We also assessed the patterns of inpatient healthcare resource utilization. A total of 6442 patients with AML from 313 hospitals who were treated with IC were identified. Median age was 61 years (interquartile range [IQR], 50-68 years), and 56% were men. Median length of stay was 29 (IQR, 25-38) days, with rates of in-hospital death and discharge to hospice of 12.3% and 3.7% (17.9% and 6.3% among patients aged ≥65 years), respectively. Predictors of in-hospital death or discharge to hospice included older age, geographic region, and lower hospital volume. During admission, 28.0%, 12.6%, and 4.0% of patients required treatment in intensive care units, mechanical ventilation, and dialysis, respectively. Despite improvements in supportive care in the contemporary era, inpatient mortality during first hospitalization for adult patients with AML treated with IC in the US remains high particularly among older patients.

Introduction: The myelodysplastic syndromes (MDS) vary in their risk of disease progression; progression includes increasingly severe bone marrow failure, reclassification as acute myeloid leukemia...

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 x 10(9)/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those >= 65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.

Introduction: Myelodysplastic Syndrome (MDS) represents a group of cancers characterized by abnormal blood cell formation and maturation, leading to various degrees of cytopenias and potential transformation to acute myeloid leukemia. Deletion of the long arm of chromosome 5 (del(5q)) is the most common clonal chromosomal anomaly in MDS, yet the population in this disease subtype is quite heterogeneous. This manuscript analyzes literature on high-risk MDS with del(5q) abnormalities.Areas covered: The paper will review outcomes with lenalidomide among high-risk MDS patients with del(5q). It will discuss the implications of harboring TP53 gene mutations, and share the data for allogeneic hematopoietic stem cell transplantations in this setting. Finally, the report evaluates the risk of disease progression in these patients.Expert commentary: Improved characterization of MDS has enhanced our understanding of patients with anomalies involving del(5q). Emerging literature is exploring combination therapy beyond lenalidomide, and next-generation sequencing may identify secondary mutations that could be an additional avenue for treatment.

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m(2)/day IV continuous infusion days 1–3, daunorubicin 45 mg/m(2) IV days 1–3, etoposide 400 mg/m(2) IV days 8–10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4(+) and CD8(+) peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4(+) and CD8(+) T cells.

Agent Orange (AO) was the dominant weaponized herbicide employed by the United States (US) military during the Vietnam war. AO, however, was found to be regularly contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin known; furthermore, AO was commonly diluted in the field with other aromatic hydrocarbons to assist with delivery mechanisms. Unbeknownst to the US military and the millions exposed, these events have likely contributed to the development of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that has affected many veterans. Null studies regarding an association between AO exposure and AML/MDS are limited in their methodology and application. The acknowledgement that the known carcinogen TCDD was a contaminant in AO when paired with a strong biological plausibility for its leukemogenicity and an observed increased risk of AML/MDS in TCDD-exposed individuals should suffice to establish causal association and that veterans to whom this might apply should be awarded appropriate indemnity.

The Bcl-2 family small molecule inhibitor navitoclax is being clinically evaluated to treat multiple cancers including lymphoid malignancies and small cell lung cancer. A sensitive and reliable method was developed to quantitate navitoclax in human plasma using liquid chromatography with tandem mass spectrometry to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of navitoclax and the internal standard, navitoclax-d8, was achieved with a Waters Acquity UPLC BEH C18 column using isocratic flow over a 3 minute total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of navitoclax. The assay range was 5-5000 ng/mL and proved to be accurate (89.5-104.9%) and precise (CV ≤11%). Long-term frozen plasma stability for navitoclax at -70°C has been determined for at least 34 months. The method was applied for the measurement of total plasma concentrations of navitoclax in a patient with receiving a 250 mg daily oral dose.