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Graubert, Timothy

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Graubert

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Timothy

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Graubert, Timothy

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2016 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.e46094e4-3df0-42d0-8554-e2099e606c80

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    Dynamic Changes in the Clonal Structure of MDS and AML in Response to Epigenetic Therapy
    (2016) Uy, Geoffrey L.; Duncavage, Eric J.; Chang, Gue Su; Jacoby, Meagan A.; Miller, Christopher A.; Shao, Jin; Heath, Sharon; Elliott, Kevin; Reinick, Teresa; Fulton, Robert S.; Fronick, Catrina C.; O’Laughlin, Michelle; Ganel, Liron; Abboud, Camille N.; Cashen, Amanda F.; DiPersio, John F.; Wilson, Richard K; Link, Daniel C.; Welch, John S.; Ley, Timothy J.; Graubert, Timothy; Westervelt, Peter; Walter, Matthew J.
    Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (i.e., mutations) for at least one year without disease progression. Using an ultra-sensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years prior to their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
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    Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia
    (Ferrata Storti Foundation, 2017) Fathi, Amir; Wander, Seth; Blonquist, Traci M.; Brunner, Andrew; Amrein, Philip; Supko, Jeffrey; Hermance, Nicole M.; Manning, Amity L.; Sadrzadeh, Hossein; Ballen, Karen K.; Attar, Eyal C.; Graubert, Timothy; Hobbs, Gabriela; Joseph, Christelle; Perry, Ashley M.; Burke, Meghan; Silver, Regina; Foster, Julia; Bergeron, Meghan; Ramos, Aura Y.; Som, Tina T.; Fishman, Kaitlyn M.; McGregor, Kristin L.; Connolly, Christine; Neuberg, Donna; Chen, Yi-Bin
    Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring “5+2” reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68–96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33–81%) and 42% (90% CI 17–65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).