Citations

Abstract Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting.

Abstract Background: Associations of medical history, lifestyle, and family history of hematological disorders with risk of chronic lymphocytic leukemia (CLL) have been previously established (1), but these exposures have not been well-studied as contributing factors to CLL prognosis. Here we investigate the association of these exposures with time to first treatment (TTFT) in 730 CLL patients. Methods: Newly diagnosed CLL patients seen at the Mayo Clinic between 2002 and 2012 were enrolled. CLL was defined according to the 1996 NCI-Working Group criteria (2). Risk factor data (including body mass index, smoking, alcohol use, sun exposure, having lived on a farm, any allergy, asthma, eczema, blood transfusion, diabetes, rheumatoid arthritis, and family history of hematological malignancy) were collected from self-administered questionnaires. Clinical and prognostic characteristics for CLL were extracted from medical records. Analyses were performed using Cox regression with first treatment as the event. Hazard ratios (HR) and 95% confidence intervals were estimated. We used Bonferroni correction for multiple testing with statistical significance at 0.004. Results: The median age at CLL diagnosis was 63 years (range 36 - 89); 65% were male, and 95% had a Rai stage< III. The median follow up time was 6.3 years, and 40% received treatment. In unadjusted analyses, patients with any history of allergies had significantly longer TTFT (HR = 0.66, 95% CI: 0.51-0.85, P = 0.001). We also observed borderline significance with history of asthma (HR = 0.53, 95% CI: 0.34-0.85, P = 0.008). These associations held after adjusting for important prognostic factors including age, sex, Rai stage, and IGVH mutational status. The other risk factors had non-significant associations (P>0.1). Conclusions: We observed an improved CLL prognosis in patients with a history of any allergies or asthma. These results were independent of other prognostic markers and suggest that an overactive IgE level from environmental exposures may provide insight into the progression of CLL. Literature Cited 1. Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, et al. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014 Aug;2014(48):41-51. 2. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7. Citation Format: Sara Beiggi, James M. Foran, O’Byrne Megan, Celine M. Vachon, Timothy G. Call, Neil E. Kay, Tait D. Shanafelt, James R. Cerhan, Susan L. Slager. Medical history, lifestyle, and family history exposures and chronic lymphocytic leukemia outcome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3453.

BACKGROUNDRAS/RAF/mitogen‐activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen‐activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.METHODSThis phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild‐type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).RESULTSThe most commonly reported treatment‐related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS‐mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies.CONCLUSIONSThe selective, single‐agent activity of trametinib against RAS‐mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871–9. © 2016 American Cancer Society.

BACKGROUNDNational Cancer Institute (NCI)/National Comprehensive Cancer Network (NCCN)–designated cancer centers (CCs) offer patients state‐of‐the‐art treatment, but their impact on multiple myeloma (MM) patient outcomes has not been evaluated.METHODSAdult MM patients diagnosed between 1973 and 2011 were identified from the Surveillance, Epidemiology, and End Results database and were stratified by the county of residence at the time of diagnosis and the year of CC designation. The influence of NCI/NCCN CC access, race, and the year of diagnosis on overall survival (OS) was evaluated with a Cox regression model.RESULTSA statistically significant OS improvement was noted in patients diagnosed after 1995 with access to 2 or more NCI CCs overall (P = .002 for 1996‐2002; P < .001 for 2003‐2011) and by race for whites (hazard ratio [HR] for 1996‐2002, 0.85; 95% confidence interval [CI], 0.78‐0.91; HR for 2003‐2011, 0.85; 95% CI, 0.79‐0.91) but not for nonwhites. For NCCN access, improvement was seen in 1996‐2002 (P = .003), in 2003‐2011 (P < .001), and by race for whites (HR, 0.917; 95% CI, 0.88‐0.95) and nonwhites (0.94; 95% CI, 0.89‐0.99), but within nonwhites, this was true only for African Americans (AAs; HR, 0.88; 95% CI, 0.81‐0.97) and not for Asians, Hispanics, or Native Americans.CONCLUSIONSImprovement in OS was seen in MM patients diagnosed after 1995 with access to 1 NCCN CC or 2 or more NCI CCs. NCI access benefited only whites, whereas NCCN access benefited only white and AA patients. No OS benefit was seen for any subgroup with access to only 1 NCI center. Eliminating racial disparities in health care access and utilization is needed to improve outcomes. Cancer 2016;122:618–625. © 2015 American Cancer Society.

It is important to separate socioeconomic factors affecting health care quality from confounders related to patients’ baseline status or disease biology when studying disparities in lymphoma survival.

Purpose Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL. Patients and Methods Eligible patients were adults with newly diagnosed untreated stages II to IV CD20 + DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP. Results In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively). Conclusion R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.

Key Points Patients living in low SES neighborhoods had worse survival after DLBCL. Disparity was most striking in younger (non-Medicare) patients and after the introduction of rituximab.

SummaryMultiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL2 and MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Thus, we investigated the anti‐tumour effects of a pan‐BCL2 inhibitor, AT‐101, which has high binding specificity for BCL2 and MCL1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL2 family members. AT‐101 was able to downregulate BCL2 and MCL1 in all plasma cell cancer models and induced apoptotic cell death in a caspase‐dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL2 downregulation were further potentiated when AT‐101 was combined with lenalidomide/dexamethasone (LDA). NanoString nCounter mRNA quantification and Ingenuity Pathways Analysis revealed differential changes in the CCNA2, FRZB, FYN, IRF1, PTPN11 genes in LDA‐treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT‐101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy.