Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.
BACKGROUND Significantly elevated telomerase activity (TA) has been found in samples from patients with almost all malignant hematologic diseases. The impact of elevated TA on the course of pediatric patients with acute myeloid leukemia (P‐AML) is unknown. METHODS Using a modified polymerase chain reaction‐based, telomeric repeat‐amplification protocol assay, the authors measured TA in bone marrow samples from 40 patients with P‐AML and, for comparison, in 65 adult patients with AML (A‐AML), excluding patients with French–American–British M3 disease. The results were correlated with patient characteristics and survival. RESULTS TA in patients with P‐AML was significantly lower compared with TA in patients with A‐AML (P = 0.005). Patients who had P‐AML with low TA had a projected 5‐year survival rate of 88%, whereas patients who had P‐AML with high TA had a projected 5‐year survival rate of 43% (P = 0.009). Conversely, patients who had A‐AML with very high TA (upper quartile) had significantly longer survival compared with patients who had A‐AML with lower TA (P = 0.03). There was no correlation between complete remission rate or disease free survival and TA in P‐AML or A‐AML. In the A‐AML group, when patients were separated by cytogenetic findings (poor prognosis vs. others), it was found that TA was significantly lower in patients with a poor prognosis, but the prognostic value of TA was not independent of cytogenetic status. CONCLUSIONS The current results suggest, that for patients with P‐AML, bone marrow TA is a highly significant prognostic factor. Cancer 2003;97:2212–7. © 2003 American Cancer Society. DOI 10.1002/cncr.11313
Circulating cell-free DNA (ccfDNA) allows for noninvasive peripheral blood sampling of cancer-associated mutations and has established clinical utility in several solid tumors. We performed targeted next-generation sequencing of ccfDNA and bone marrow at the time of diagnosis and after achieving remission in 22 patients with acute myeloid leukemia (AML). Among 28 genes sequenced by both platforms, a total of 39 unique somatic mutations were detected. Five mutations (13%) were detected only in ccfDNA, and 15 (38%) were detected only in bone marrow. Among the 19 mutations detected in both sources, the concordance of variant allelic frequency (VAF) assessment by both methods was high (R2 = 0.849). Mutations detected in only 1 source generally had lower VAF than those detected in both sources, suggesting that either method may miss small subclonal populations. In 3 patients, sequencing of ccfDNA detected new or persistent leukemia-associated mutations during remission that appeared to herald overt relapse. Overall, this study demonstrates that sequencing of ccfDNA in patients with AML can identify clinically relevant mutations not detected in the bone marrow and may play a role in the assessment of measurable residual disease. However, mutations were missed by both ccfDNA and bone marrow analyses, particularly when the VAF was <10%, suggesting that ccfDNA and bone marrow may be complementary in the assessment and monitoring of patients with AML.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell–like compared with the germinal-center B-cell–like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.
Background: Heat shock protein 90 supports the function of client proteins in multiple myeloma (MM) including IL-6 and IGF-R1. Inhibition of HSP90 leads to protein degradation and apoptosis of MM cells, including patient-derived cells resistant to bortezomib or immunomodulators. KOS-953, a new formulation of 17-AAG, is a potent HSP90 inhibitor in phase 1 and 2 trials that suppresses cell surface expression of IL-6, IGF-R1 and their downstream signaling molecules, including the PI-3K/Akt/IKK-a and Ras/Raf/MAPK pathways. In vivo, KOS-953 extends the survival of mice after MM cells are injected and home to the marrow (>250 days in KOS-953-treated mice vs 29 days in the control group; p=0.0001). Aims: To define the MTD, toxicity, PK and pharmacodynamics of KOS-953 in patients (pts) with relapsed and relapsed, refractory MM. Methods: Pts receive an IV infusion of KOS-953 twice weekly for 2 out of 3 weeks. PK and PD are performed following the 1st and 4th infusion. Parent drug and its active metabolite are quantified in plasma. PD is assessed in bone marrow aspirates (BM) with MM cells examined for apoptosis, proliferation, pAKT, and change in HSP, IL-6 and IGF-R1 expression. Peripheral blood lymphocytes (PBLs) are assayed for change in HSP70/90 levels. Response is assessed by EBMT criteria. Results: Twenty -two pts (6 F/16 M; median age 64 yrs; median number of prior regimens 4, range 2–19; 41% prior SCT, 100% prior thalidomide, 82% prior bortezomib) were enrolled in 4 dose levels (150, 220, 275 and 340 mg/m2). Two episodes of DLT have been observed (both G3–4 elevations in liver transaminases): one pt at 220 mg/m2 with hepatic infiltration with MM (who continued with G1-2 elevations following dose reduction) and 1/6 pts at 340 mg/m2. Assessment of 420 mg/m2 is planned. Overall, G ≥ 3 drug-related toxicity was rare, consisting of AST/ALT (n=3), anemia, vomiting, memory impairment and rash (n=1 in each case). Common G1-2 drug related toxicity included diarrhea (n=9), fatigue (n=6), elevated transaminases (n=5), myalgias (n=5), infusional reactions (n=5) and rash (n=4). Elimination half-life (parent) equaled 2.8±1.0 hrs (5.1+/−1.0 hrs for the metabolite). Clearance equaled 45.0±3.0 L/hr with Vss 137±43 L. No change in PK was observed comparing the 1st and 4th infusion. At 340 mg/m2: AUCtot and Cmax were 18997 ng/mL*hr and 9355 ng/mL (parent); 13121 ng/mL*hr and 1644 ng/mL (metabolite). For the parent, AUC and Cmax increased linearly with dose. Comparing BMs (screening and 4 hr following 1st dose), CD138+ cells showed decreased pAKT (p=0.04) and increased apoptosis (p=0.06). PBLs showed reactive induction of HSP70 following KOS-953. Responses include 1 MR (150 mg/m2); 1 PR (220 mg/m2); 1 PR (340 mg/m2 with confirmation pending). An additional 6 pts have stable disease (≥ 3 cycles). Conclusions: KOS-953 has been successfully dose escalated from 150 - 340 mg/m2 with manageable toxicity and without treatment-emergent neuropathy. PK studies show linear kinetics, supporting further dose escalation to define MTD. PD studies suggest activity in heavily pre-treated MM patients, with clinical benefit (PR/MR or SD) observed in 9/22 pts (41%).
Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology; however, these biological subgroups overlap clinically. Using machine learning, we developed an approach to stratify patients with DLBCL into four subgroups based on survival characteristics. This approach uses data from the targeted transcriptome to predict these survival subgroups. Using the expression levels of 180 genes, our model reliably predicted the four survival subgroups and was validated using independent groups of patients. Multivariate analysis showed that this patient stratification strategy encompasses various biological characteristics of DLBCL, and only TP53 mutations remained an independent prognostic biomarker. This novel approach for stratifying patients with DLBCL, based on the clinical outcome of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, can be used to identify patients who may not respond well to these types of therapy, but would otherwise benefit from alternative therapy and clinical trials.
4092 Background: The adhesion molecule CD11b, which associates with the beta2-integrin to form the Mac-1 complex, is expressed in monocytic leukemias as well as other myeloid leukemias. Its expression on the lekemic cells has been reported to correlate with more aggressive course in adult patients with AML. The clinical relevance of CD11b expression in pediatric AML is not known. More importantly, the clinical relevance of CD11b expression on pediatric AML when these patients are treated with allogeneic hematopoietic stem cell transplant (HSCT). We investigated whether HSCT can modify the expected adverse effects of CD11b expression in pediatric AML patients. Methods: Immunophenotype data of 62 pediatric patients with AML, all treated with allogeneic HSCT, was reviewed. The expression of the CD11b on the blast population as determined by flow cytometry was correlated with clinical data and outcome. The median age of patients was 8 years (range: 8 months–14 years) and included 47 (76%) patients transplanted in their first complete remission (CR1). Fourty six (74%) of all patients had intermediate-risk cytogenetics and the remaining (26%) had adverse-risk cytogenetic abnormalities. Results: Twenty five (40%) of all studied patients expressed CD11b on the surface of the blasts at diagnosis. Patients with CD11b expression had significantly shorter overall survival (P=0.038) with median survival of approximately 11 months while the median survival in the CD11b negative patients has not been reached. Similarly, CD11 positive patients had significantly shorter event free survival (EFS) (P=0.03). When we considered only patients treated with HSCT in CR1, the OS and EFS for the CD11b positive patients were both significantly shorter (P=0.04 and P=0.05, respectively). Multivariate analysis including CD11b expression and cytogenetic risk identified CD11b expression as an independent prognostic factor for survival and EFS, while cytogenetic-risk stratification became no longer a predictor. Conclusion: Our data suggests that the expression of CD11b in pediatric AML is a significant independent poor prognostic factor and HSCT does not change this trend. Most of the CD11b positive patients die in their first year after HSCT and the management of these patients should be modified to address the biological basis of this subset of AML that expresses CD11b adhesion molecule. Disclosures: No relevant conflicts of interest to declare.
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