Hematopoietic cell transplantation (HCT) is a common therapy for the treatment of neoplastic and metabolic disorders, hematological diseases, and fatal immunological deficiencies. HCT can be ...subcategorized as autologous or allogeneic, with each modality being associated with their own benefits, risks, and post-transplant complications. One of the most common complications includes acute kidney injury (AKI). However, diagnosing HCT patients with AKI early on remains quite difficult. Therefore, this evidence-based guideline, compiled by the Pediatric Continuous Renal Replacement Therapy (PCRRT) working group, presents the various factors that contribute to AKI and recommendations regarding optimization of therapy with minimal complications in HCT patients.
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of ...pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical ...annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
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•Acute myeloid leukemia patient cohort with clinical, molecular, drug response data•Validation and discovery of diverse biological features of drug response•Broad mapping of tumor cell differentiation state affecting response to drugs•Modeling reveals a strong and targetable determinant of clinical outcome
Bottomly et al. present a functional genomic resource composed of molecular, clinical, and drug response data on acute myeloid leukemia patient specimens. Through integration of all of these data, they identify genetic and cell differentiation state features that predict drug response, and they utilize modeling to identify targetable determinants of clinical outcome.
Patterns of Venetoclax Sensitivity in Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is predominantly a disease of older adults. The 5-year overall survival is 70-91%, depending on ...Rai/Binet stage at diagnosis (80% overall), and although a subset of CLL takes a very indolent course, it can be aggressive as well. Disease course and responsiveness to therapeutic agents may be predictable, to some degree, based on specific genetic lesions or other patient population characteristics. Monotherapies targeting specific cell pathways are rapidly increasing in prevalence. Ibrutinib (Bruton tyrosine kinase inhibitor) has shown promise as a single agent as well as in combination with other agents. In particular, ibrutinib has shown efficacy in combination with venetoclax (inhibitor of cell death suppressor BCL2). This combination appears to be particularly potent in patients with a del(11q) karyotype. Cytogenetic information is used already in several other leukemias to inform prognosis and treatment. Although CLL is a disease of monoclonal proliferation, precise definition of the diseased clone will allow for more individualized treatment. Stratification of drug sensitivity based on genetic and cytogenetic features will directly affect patient outcomes in CLL.
Primary patient mononuclear cells (from either peripheral blood or bone marrow) were plated ex vivo with a panel of 49 drug combinations and the 16 respective single agents (SA) in 384-well plates using 10,000 cells/well. Drugs were tested in 7-point concentration series; wells with drug combinations were added at fixed molar ratios. Cell viability was assessed after a 72 hour culture period. In this assay, primary cells maintain viability but do not proliferate. In CLL, the most frequent mutations were: del(17p); del(11q); del(13q14); trisomy 12; complex karyotype (at least three chromosomal aberrations).
Selected analysis of these data from 157 unique patients were performed by isolating the most potent inhibitors (defined by lowest median AUC) either as a single agent or in combination with known treatments. These were evaluated with nonparametric tests (Kruskal-Wallace, Mann-Whitney, Spearman rank coefficient) on the statistical software Prism. By subdividing the data by available genetic and cytogenetic information, patterns that have not been previously described in the literature emerged.
In the cohort of patients with any karyotypic abnormality (not complex karyotype), SA venetoclax and the combination of venetoclax-ibrutinib (VEN/IBRUT) were equivalently effective with no significant difference in efficacy observed between SA venetoclax and the combination. As previously described, del(11q) independently predicts increased efficacy of SA venetoclax and VEN/IBRUT, and this efficacy was validated by ex vivo potency here as well. However, we show that male gender is an independent predictor of potency in both SA venetoclax and VEN/IBRUT as well.
Interestingly, doramapimod (an inhibitor of p38 MAP kinase) was not particularly potent as a SA, however, the combination of venetoclax-doramapimod (VEN/DORA) proved to be the most potent of all combinations tested, more potent than even VEN/IBRUT. This effect could not be replicated in any subgroup, as VEN/DORA samples for the entire cohort were relatively limited (n=31).
Although this analysis has inherent limitations, including underpowered data to analyze in less frequent cytogenetic events (e.g. del(6q)), we did find significant patterns of potency. These may or may not translate to clinical efficacy in CLL and do not address any potential toxicity. However, these data suggest future directions for more targeted research on these drugs and drug combinations.
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Tyner:Petra:Research Funding;Janssen:Research Funding;Seattle Genetics:Research Funding;Incyte:Research Funding;Genentech:Research Funding;Constellation:Research Funding;AstraZeneca:Research Funding;Aptose:Research Funding;Gilead:Research Funding;Takeda:Research Funding;Syros:Research Funding;Agios:Research Funding;Array:Research Funding.Druker:EnLiven:Consultancy, Research Funding;Gilead Sciences:Consultancy, Membership on an entity’s Board of Directors or advisory committees;Cepheid:Consultancy, Membership on an entity’s Board of Directors or advisory committees;Dana-Farber Cancer Institute:Patents & Royalties;Bristol-Myers Squibb:Research Funding;Blueprint Medicines:Consultancy, Current equity holder in private company, Membership on an entity’s Board of Directors or advisory committees;Aptose Therapeutics Inc. (formerly Lorus):Consultancy, Current equity holder in publicly-traded company, Membership on an entity’s Board of Directors or advisory committees;ARIAD:Research Funding;Third Coast Therapeutics:Membership on an entity’s Board of Directors or advisory committees;The RUNX1 Research Program:Membership on an entity’s Board of Directors or advisory committees;Pfizer:Research Funding;Patient True Talks:Consultancy;Oregon Health & Science University:Patents & Royalties;Novartis Pharmaceuticals:Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding;MolecularMD (acquired by ICON):Consultancy, Current equity holder in publicly-traded company, Membership on an entity’s Board of Directors or advisory committees;Millipore (formerly Upstate Biotechnology):Patents & Royalties;VB Therapeutics:Membership on an entity’s Board of Directors or advisory committees;Vivid Biosciences:Membership on an entity’s Board of Directors or advisory committees;ALLCRON:Consultancy, Membership on an entity’s Board of Directors or advisory committees;Amgen:Current equity holder in publicly-traded company, Membership on an entity’s Board of Directors or advisory committees;Aileron Therapeutics:Membership on an entity’s Board of Directors or advisory committees;Merck & Co:Patents & Royalties;McGraw Hill:Patents & Royalties;GRAIL:Consultancy, Current equity holder in private company, Membership on an entity’s Board of Directors or advisory committees;Henry Stewart Talks:Patents & Royalties;Iterion Therapeutics (formerly Beta Cat Pharmaceuticals):Membership on an entity’s Board of Directors or advisory committees;Leukemia & Lymphoma Society:Research Funding.
Micro-Abstract High dose therapy for light chain amyloidosis (AL) was performed in 31 patients at a single institution. This is a retrospective study, describing the outcomes of patients with and ...without cardiac involvement, patients not pre-treated as well as those that received induction chemotherapy. Bortezomib is well tolerated and results in higher overall response rates and shorter time to hematologic response.
Abstract 3957
Currently used clinical prognostic markers for patients with multiple myeloma (MM) such as the international staging system (ISS) and cytogenetics are inadequate predictors of response ...and survivorship after hematopoietic stem cell transplant (HSCT). Recently published large studies of HSCT as consolidation after primary therapy have demonstrated 3-year progression free survival (PFS) and overall survival (OS) rates of 45% and 78% respectively after tandem HSCT (BMT CTN 0102; Krishnan, Lancet Onc, 2011) and median time to progression of 46 and 27 after single autologous transplant, with and without lenalidomidemaintenance (CALGB 10104; McCarthy, NEJM, 2012). These studies (which include patients in the current cohort) have established expected PFS and OS benchmarks that allow identification of higher risk subsets.
The aim of this study is to describe and further sub- stratify patients with high-risk myeloma (HRMM), with the goal to identify ‘higher' risk groups that may benefit from alternative treatment strategies.
A retrospective cohort study of HRMM patients who received an HSCT at OHSU between 01/01/2001 and 12/31/2011 was performed. We defined HRMM by the following: FISH and cytogenetic findings of del17p, t(4:14), t(14;16), t(14;20), chromosome (ch) 1 abnormalities, del 13q by cytogenetics; the presence of multiple extra-medullary plasmacytomas; plasmablastic morphology; higher ISS categories (II and III); Salmon- Durie(S-D) stages 2 and 3; recurrence or less than a partial remission (PR) to 2 consecutive lines of therapy prior to HSCT.
Outcome measures included PFS and OS. Descriptive statistical analysis was conducted for all primary and secondary endpoints, patients' individual and clinical characteristics, and gene profiles. Kaplan-Meier method was used to estimate the OS and PFS function. Log-rank test was used to assess whether the survival function differs across the groups. Factors that are significantly associated with the primary and secondary endpoints were identified using univariateanalysis. Multivariate analysis is ongoing.
Patient and HSCT characteristics are found in table 1.Table 1n = 252CharacteristicNo%Age at transplant, yearsMedian59Range30–79Male Sex16264ISS stageII8945III4724Salmon-Duriestage25723314558Genetic abnormalitiesdel (13q) cytogenetics3011t(4;14)218del(17p)187t(14;16)41t(14;20)10.3ch 1 abnormality*219Plasmablastic morphology62Multiple extramedullary plasmacytomas187Prior therapiesMedian2Range1–9<PR to 2 conventional lines of therapy prior to HSCT249HSCT total273Single Autologous242Tandem7Allogeneic24Sibling14MUD9Syngeneic1Indication for HSCTInduction20776Salvage6624Post HSCT maintenance5119Lenalidomide19Bortezomib2Steroids12Thalidomide18*Ch 1 abnormalities were heterogenous and included 8 deletions (1q x1, 1p x7); 4 additions (1p x2, 1q x2); 5 translocations (t1;4, t1;8, t1;19, t1;10 x2) and 4 with multiple abnormalities.
With a median follow up of 40 months, relapse occurred in 127 patients, of which 77 (60%) occurred within 18 months post HSCT. Median PFS and OS are 22.3 (95% CI: 19.7 – 29.3) and 56.67 (95% CI: 40.1–69.9) months respectively. The 2-year PFS and OS rates were 47%, and 72% respectively.
Univariate data analysis revealed the following factors that are highly associated with reduced PFS: del 17p (2- year PFS 26.2%; p= 0.09); ch 1 abnormalities (27.4%; p=0.0026); recurrence or < PR after 2 consecutive lines of chemotherapy prior to HSCT (27.5%; p= 0.07). For patients with chromosome 1 abnormalities, the presence of del 13q by cytogenetics further decreased the PFS (22%; p= 0.04;)(Figure 1). Factors associated with highly with a reduced OS are: ch 1 abnormalities (2-year OS 52.5%; p=0.0042); both chromosome 1 and del13q (46.2%; p=0.0016) and having multiple extra-medullary plasmacytomas (55.2%; p= 0.026 (Figure 2).
Within the broad group of HRMM, certain groups have significantly inferior outcomes post HSCT, the worst being those with recurrence or < PR to 2 consecutive lines of chemotherapy prior to HSCT, those with any ch 1 abnormality and particularly those with additional del 13q by cytogenetics. Investigation of novel therapeutic and more aggressive strategies is warranted in these groups. Display omitted Display omitted
Scott:Genzyme: Research Funding; Millenium: Speakers Bureau.
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•We study variation in mobility measurements on organic films.•Values extracted by different scientists typically vary by about a factor of 3.•We propose a protocol that drastically ...reduces this variation.•Control of film thickness and electrode quality are also important factors.
Charge carrier mobility is a figure of merit commonly used to rate organic semiconducting materials for their suitability in applications such as solid-state lighting or photovoltaics. Although large variations are found in published mobility values on identical materials, there is little open discussion in the literature of the reproducibility of these results. We address this with an interlaboratory study of mobility measurements performed on a set of organic semiconductors using the space-charge limited current method. We found mobility measured on nominally identical devices could vary by more than one order of magnitude, with the largest sources of variation being poor electrodes and film thickness variation. Moreover, we found that mobility values extracted from identical data by different scientists would typically vary by a factor of 3. We propose a protocol for analysis and reporting that was found to reduce this analysis variation to as little as 20%. We also present general guidelines for improving the reproducibility of benchmark mobility measurements.
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