Michael Gary Martin

Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 and its Active N-oxide Metabolite TG100855

TG100435 ([7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) is a novel multitargeted, orally active protein tyrosine kinase inhibitor. The inhibition constants (Ki) of TG100435 against Src, Lyn, Abl, Yes, Lck, and EphB4 range from 13 to 64 nM. TG100435 has systemic clearance values of 20.1, 12.7, and 14.5 ml/min/kg and oral bioavailability of 74%, 23%, and 11% in mouse, rat, and dog, respectively. Four oxidation metabolites of TG100435 have been found in human, dog, and rat in vitro and in vivo. The ethylpyrrolidine N-oxide of TG100435 is the predominant metabolite (TG100855; [7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine) in human, dog, and rat. TG100855 is 2 to 9 times more potent than the parent compound. Flavin-containing monooxygenases are the primary enzymes mediating the biotransformation. Significant conversion of TG100435 to TG100855 has been observed in rat and dog after oral administration. Systemic exposure of TG100855 is 1.1- and 2.1-fold greater than that of TG100435 in rat and dog after oral dosing of TG100435. Since TG100435 is predominantly converted to the more potent N-oxide metabolite across species in vivo and in vitro, the overall tyrosine kinase inhibition in animal models may be substantially increased after oral administration of TG100435.

Hospital volume and acute myeloid leukemia mortality in Medicare beneficiaries aged 65 years and older

To the editor:nnAcute myeloid leukemia (AML) is a fast-growing and lethal malignancy of the blood and bone marrow, with a 5-year mortality rate of 75%.[1][1],[2][2] Between disease onset and chemotherapy treatment, patients often experience adverse symptoms, such as bleeding and infection, which can

Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of cytokine-driven immune activation. Cardinal features include fever, hemophagocytosis, hepatosplenomegaly, lymphocytic infiltration, and hypercytokinemia that result in multisystem organ dysfunction and failure. Familial HLH is genetically driven, whereas secondary HLH (SHL) is caused by drugs, autoimmune disease, infection, or cancer. SHL is associated with worse outcomes, with a median overall survival typically of less than 1 year. This reflects difficulty in both diagnostic accuracy and in establishing reliable treatments, especially in cases of malignancy-induced SHL, which have significantly worse outcomes. Malignancy-induced HLH is seen almost exclusively with hematologic malignancies, constituting 97% of cases in the literature over the past 2 years. In these situations, the native immune response driven by CD8 T cells produces an overabundance of T helper 1 cytokines, notably interferon-γ, tumor necrosis factor-α, and interleukin-6, which establish a positive feedback loop of inflammation, enhancing replication of hematologic malignancies while leaving the host immune system in disarray. In this paper, we present 2 case studies of secondary HLH driven by HM, followed by a review of the literature discussing the cytokines driving HLH, diagnostic criteria, and current treatments used or undergoing investigation.

JAK Pseudokinase Domain Variants Highlight nRTK VUSs Identified with Next-Generation Sequencing in Solid Tumor Patients

Non-receptor tyrosine kinase (nRTK) pathways are aberrantly activated in cancer, and mutations in nRTKs have potential therapeutic and prognostic importance. Consisting of 10 families, the 32 known human nRTKs each include a TKD made of N and C-terminal lobes necessary for catalytic activity, as well as varying regulatory regions including Src homology 2 (SH2) and 3 (SH3), and in the case of the Janus kinases a PSKD which is also bi-lobed [1]. Tumor profiling with NGS enables the entire coding sequence of numerous genes to be evaluated, thus facilitating the identification of novel nsSNPs in nRTKs. We reviewed advanced breast, colon and lung cancer patients treated at West Cancer Center (Memphis, Tennessee) from 2013 to 2015 who received tumor profiling including NGS with a 592 cancer-related gene panel from Caris Life Sciences (Phoenix, Arizona). Caris NGS searched 14 nRTKs: ABL1, ABL2, AKT1, AKT2, AKT3, BTK, JAK1, JAK2, JAK3, SRC, CDK4, CDK6, CDK12, PIK3CA. All mutations test-defined as either pathogenic (PATH) or nonsynonymous single nucleotide variants deemed variants of undetermined significance (VUS) were included. All variants had >99% detection confidence based upon allele frequency and amplicon coverage. In order to classify VUS, in silico analysis with PolyPhen-2 was utilized to predict pathogenicity [2]. Any VUS predicted-damaging with in silico analysis we denote VUSp. VUSs were then classified as occurring within or outside of the TKD; PSKD lesions were also detailed for JAK1–3. 346 patients (79 breast, 110 colon and 157 non-small cell lung cancer (NSCLC)) were identified. The cohort had a median age of 61 years (range 26–86). 58% were female; 62% were Caucasian and 35% African-American. 245 variants were found, with 200 VUS and 45 PATHs. PATHs were seen in 2 genes: PIK3CA (21 breast, 13 colon, 5 NSCLC) and AKT1 (6 breast). 168/346 (49%) patients had ≥1 nRTK lesion. 52/200 (26%) VUS were VUSp and spread amongst 48 patients (5 breast, 13 colon and 30 NSCLC). VUSp were found in 13/14 nRTKs (excluding AKT1) with median 3 (range 0– 10). The most numerous VUSp by gene were JAK3 (10), ABL1 (8), JAK2 (5), BTK (5) and CDK12 (5). By cancer type, the most-frequently mutated nRTKs were: SRC (2/2 VUS were VUSp) and ABL2 (1/5) in breast, ABL1 (5/10), JAK3 (3/27) and CDK12 (2/8) in colon, and JAK3 (6/20), BTK (5/ 8), ABL1 (3/12) and JAK2 (3/11) in NSCLC. Of 180 VUS with in silico results, 68% were outside of the TKD (29/122 VUSp), 23% TKD-restricted (13/42) and 9% in PSKD of JAK1–3 (11/16). Of note, 44 unique VUS were found in JAK1–3, with a total 18 VUSp (3 JAK1, 5 JAK2 and 10 JAK3). 12/18 JAK VUSp were NSCLC, including 9 PSKD, 2 FERM (4.1, Ezrin, Radixin,Moesin) and 1 TKD variants (Table 1). Comprised of 4 regions including N-terminal FERM and SH2 domains and C-terminal PSKD and TKD, the JAK family is known to harbor oncogenic mutations in myeloproliferative neoplasms (e.g. V617F in JAK2), other hematologic malignancies and several solid cancers [1].While described in all 4 domains, the majority of activating JAK mutations focus in the N-lobes of the PSKD and TKD, which normally form an autoinhibitory * Matthew K. Stein mkstein@westclinic.com

Early experience with cytoreduction and hyperthermic intraperitoneal chemotherapy at a newly developed center for peritoneal malignancy

BackgroundnCytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has improved outcomes for patients with peritoneal carcinomatosis (PC). We present our experience from a newly developed peritoneal surface malignancy program.nnnMethodsnAn IRB approved retrospective review was performed for the first 50 patients treated with CRS/HIPEC with clinicopathologic data described.nnnResultsnPatients treated with CRS/HIPEC were Caucasian (64%), female (66%) with a median age of 53 years (range, 11-73 years). Primary pathology included: appendix (40%, n=20), ovary (20%, n=10), colon (14%, n=7), desmoplastic small round cell tumor (14%, n=7) or other (12%, n=6). The median peritoneal cancer index (PCI) score was 15.5 (range, 1-39) and 92% underwent complete cytoreduction (CCR 0/1). Median hospital length of stay was 9.0 days (range, 6-35 days). Eight patients (16%) suffered major morbidity with 2 (4%) 30-day mortalities.nnnConclusionsnShort-term outcomes observed after CRS/HIPEC in a newly developed center for PC are consistent with published higher volume center experiences.

Desmoplastic small round cell tumor: A nationwide study of a rare sarcoma

Desmoplastic small round cell tumor (DSRCT) is a rare peritoneal surface malignancy. Current research is limited by the scarcity of this disease.

A Phase 1/2 Study of evofosfamide, A Hypoxia-Activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.

Purpose: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Patients and Methods: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2–15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined. Results: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. Conclusions: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.

Correction to: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung

In the original publication, the sixth author name was published incorrectly as Matthew Stein. The correct author name should read as Matthew K Stein.

Role Of Early Evaluation For Clonal Heterogeneity In Acute Myeloid Leukemia

A 67-year-old Caucasian male presented with a chief complaint of shortness of breath and fatigue. Initial laboratory evaluation revealed hyperleukocytosis with WBC count of 76,000/mcL and 83% blasts. He immediately received leukapheresis for respiratory symptoms. Bone marrow biopsy and peripheral blood flow cytometry confirmed a diagnosis of acute myeloid leukemia (AML) with normal cytogenetics. Fluorescence in-situ hybridization (FISH) study of the bone marrow was negative for t(8;21), t(15;17), inv(16) and abnormalities of Mixed Lineage Leukemia. Mutation analysis by PCR (Quest Diagnostics, AML Prognostic Panel) showed mutations in nucleophosmin (NPM1) gene and internal tandem duplication in the FMS-like Tyrosine Kinase 3 gene (FLT3-ITD) but wild-type for CCAAT/enhancer binding protein α gene (CEBPA). The patient received induction chemotherapy with cytarabine and idarubicin (7+3). Day-14bone marrow biopsy showed a hypocellular marrow with no morphologic evidence of residual AML. Cytogenetic analysis was unsuccessful due to lack of metaphases. Repeat mutational analysis was also completed on the day-14 bone marrow sample and was found to be positive for FLT3-ITD but negative for NPM1. The day-30 bone marrow biopsy showed evidence of residual AML with normal cytogenetics and 67% blasts. He subsequently underwent salvage chemotherapy with cladribine, cytarabine and filgrastrim (CLAG regimen). Despite salvage chemotherapy his follow-up 1Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 2Division of Hematology & Oncology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 3The West Cancer Center, Memphis, TN