320 results on '"Karp JE"'
Search Results
2. A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia
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Lancet, JE, Ravandi, F, Ricklis, RM, Cripe, LD, Kantarjian, HM, Giles, FJ, List, AF, Chen, T, Allen, RS, Fox, JA, Michelson, GC, and Karp, JE
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- 2011
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3. MDR modulation in acute myelogenous leukemia: is it dead?
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Karp, JE
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- 2001
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4. Abstract S3-5: Myelodysplatic syndrome and/or acute myelogenous leukemia (MDS and/or AML) after a breast cancer diagnosis: the National Comprehensive Cancer Network (NCCN) experience.
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Karp, JE, primary, Blackford, A, additional, Visvanathan, K, additional, Rugo, HS, additional, Moy, B, additional, Goldstein, LJ, additional, Stockerl-Goldstein, K, additional, Neumayer, L, additional, Langbaum, TS, additional, Hughes, ME, additional, Weeks, JC, additional, and Wolff, AC, additional
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- 2012
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5. Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia
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Schneider, E, primary, Cowan, KH, additional, Bader, H, additional, Toomey, S, additional, Schwartz, GN, additional, Karp, JE, additional, Burke, PJ, additional, and Kaufmann, SH, additional
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- 1995
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6. Adult acute leukemia: a need for continued translational research [letter]
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Geller, RB, primary and Karp, JE, additional
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- 1994
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7. Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia
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Kaufmann, SH, primary, Karp, JE, additional, Jones, RJ, additional, Miller, CB, additional, Schneider, E, additional, Zwelling, LA, additional, Cowan, K, additional, Wendel, K, additional, and Burke, PJ, additional
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- 1994
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8. Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies.
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Bose P, Perkins EB, Honeycut C, Wellons MD, Stefan T, Jacobberger JW, Kontopodis E, Beumer JH, Egorin MJ, Imamura CK, Douglas Figg W Sr, Karp JE, Koc ON, Cooper BW, Luger SM, Colevas AD, Roberts JD, Grant S, Bose, Prithviraj, and Perkins, Edward B
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Purpose: Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies.Methods: In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.Results: A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.Conclusions: This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease. [ABSTRACT FROM AUTHOR]- Published
- 2012
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9. New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia.
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Tiu RV, Gondek LP, O'Keefe CL, Huh J, Sekeres MA, Elson P, McDevitt MA, Wang XF, Levis MJ, Karp JE, Advani AS, Maciejewski JP, Tiu, Ramon V, Gondek, Lukasz P, O'Keefe, Christine L, Huh, Jungwon, Sekeres, Mikkael A, Elson, Paul, McDevitt, Michael A, and Wang, Xiao Fei
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- 2009
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10. Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia.
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Schimmer AD, Estey EH, Borthakur G, Carter BZ, Schiller GJ, Tallman MS, Altman JK, Karp JE, Kassis J, Hedley DW, Brandwein J, Xu W, Mak DH, LaCasse E, Jacob C, Morris SJ, Jolivet J, Andreeff M, Schimmer, Aaron D, and Estey, Elihu H
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- 2009
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11. Novel postremission strategies in adults with acute myeloid leukemia.
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Lancet JE, Karp JE, Lancet, Jeffrey E, and Karp, Judith E
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- 2009
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12. Management of infections in neutropenic patients: new opportunities and emerging challenges.
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Karp JE, Merz WG, and Dick JD
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- 1994
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13. Asynchronous antigen expression in B lineage acute lymphoblastic leukemia
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Hurwitz, CA, Loken, MR, Graham, ML, Karp, JE, Borowitz, MJ, Pullen, DJ, and Civin, CI
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Cell surface phenotypes of 113 B lineage acute lymphocytic leukemia (ALL) cases, defined by the presence of HLA-DR and at least one B-cell- specific antigen (either CD19, CD20, or CD22), were compared with antigen-defined stages of normal B lymphocyte development. The cases were first evaluated for expression of HLA-DR, CD19, CD34, CD10, CD20, and CD22 by indirect one-color immunofluorescence. Pairwise comparisons of cell surface marker expression were performed for each leukemic sample: no correlations were observed for paired antigen expression on the leukemic samples using antigens expressed either early or late during normal B lymphoid development. Complete immunophenotypes of the cases were then compared with normal B-cell developmental stages. Sixteen different complete immunophenotypes were observed on the leukemias that were not found in normal marrow; at least 78% of the cases demonstrated such “asynchronous” combinations of B lymphoid- associated differentiation antigens. Several samples were subsequently studied by two-color immunofluorescence, and the presence of doubly labeled cells with “asynchronous” antigen combinations was confirmed. These results indicate that the majority of B lineage leukemias exhibit “developmental asynchrony,” as compared with normal marrow B cells. The data further suggest that ALL cases do not accurately represent cells arrested at the stage where the leukemogenic event occurred. Rather, ALL appears to be a disease in which there may be maturation of leukemic blasts; but this maturation is “asynchronous” when compared with the normal developmental process.
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- 1988
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14. In vivo cell growth and pharmacologic determinants of clinical response in acute myelogenous leukemia
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Karp, JE, Donehower, RC, Enterline, JP, Dole, GB, Fox, MG, and Burke, PJ
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A predictable increase in the proliferative rate of malignant cells remaining after initial cytoreduction in vivo forms the rationale for timed sequential therapy (TST) with 1-B-D-arabinofuranosylcytosine (ara- C) for adult acute myelogenous leukemia (AML). The relationship between in vivo leukemic cell growth, intracellular ara-C metabolism, and clinical response to ara-C-containing TST was evaluated by comparing AML marrow cell growth kinetic and biochemical pharmacologic determinants obtained before therapy (day 0) and at the predicted peak of in vivo postdrug residual tumor proliferation (day 8). Serial measurements of DNA synthesis and net intracellular ara-C metabolism demonstrated marked increases in both determinants in day 8 residual tumor when compared with the pretreatment cells for newly diagnosed adults achieving complete remission but not for TST-refractory patients. The interrelationship of AML cell proliferation and biochemical pharmacology together quantitate cytotoxicity measured by both achievement and duration of remission and serve to predict eventual clinical outcome in response to TST with ara-C where both growth and favorable pharmacokinetics are intrinsic to the success of the drug schedule.
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- 1989
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15. A rationale for sequential high-dose chemotherapy of leukemia timed to coincide with induced tumor proliferation
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Burke, PJ, Vaughan, WP, and Karp, JE
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- 1980
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16. Induction of serum stimulation and plasma cell proliferation during chemotherapy of multiple myeloma
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Karp, JE, Burke, PJ, and Humphrey, RL
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Sequential sera from 45 patients with multiple myeloma (MM) and from 6 patients with solid tumors but normal bone marrows who received cyclophosphamide, 15 mg/kg/day for 4 days, were assayed for their effects on tritiated thymidine (3H-TdR) incorporation by normal bone marrow cells and malignant plasma cells. Pretreatment sera from 23 of the 45 patients with MM inhibited normal marrow cell proliferation relative to the effects of normal sera. Of these 45 sera, 30 inhibited plasma cell proliferation. This humoral inhibition was overcome by the induction of humoral stimulation at a predictable time during chemotherapy. The sera obtained sequentially from patients with MM and patients with normal bone marrows increased 3H-TdR uptake by both cell types by days 12–15 of therapy. Sequential changes in malignant marrow plasma cell 3H-TdR labeling indices paralleled the changes in serum activity, with an increased tumor cell growth fraction occurring at the time of peak serum stimulatory activity. The relationship between serum stimulation and malignant plasma cell proliferation was confirmed in vitro.
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- 1977
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17. Relationship of the hematopoietic cycle to the combined activities of a stimulator and a short-lived inhibitor
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Burke, PJ and Karp, JE
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Substances that circulate in the blood following drug-induced bone marrow aplasia produce a biphasic curve of DNA synthesis in cells in liquid and semisolid cultures which reflect relative concentrations of these growth regulators of hematopoiesis. This net effect magnified by induced marrow failure in human, rat, and mouse is a sinusoidal curve that is the reciprocal of the WBC. Generated in the bone marrow, humoral stimulating activity (HSA) produces peak growth of colonies in agar (CFU-GM) during the proliferative phase of bone marrow recovery, whereas humoral inhibitory activity (HIA), present at the time of marrow maturation, suppresses colony growth. Split femurs from rats given cyclophosphamide (CY) and killed at regular intervals condition media that affect DNA synthesis in a fashion similar to that of HSA-HIA in the rats' sera. In Dexter cultures, HSA is derived from the adherent rather than the hematopoietic cell, whereas HIA is produced by that nonadherent cell. Animals treated with a lethal dose of busulfan (BU) produce large amounts of HSA in vivo until death. Those transplanted with adherent bone marrow cells depleted of hematopoietic cells on day 1 after BU also die, whereas those given nonadherent marrow cells survive and generate HIA at the time of bone marrow recovery. HSA and media conditioned by bone marrow stromal cells causes an increase in spleen colonies (CFU-S), as does HIA. These studies support the contention that the net effect of putative regulators of hematopoiesis, measured in the drug-perturbed state, consist of a constantly present stimulator emanating from bone marrow stroma, and a variable inhibitor produced by maturing hematopoietic bone marrow cells.
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- 1987
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18. Correlation of drug-perturbed marrow cell growth kinetics and intracellular 1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult acute myelogenous leukemia
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Karp, JE, Donehower, RC, Dole, GB, and Burke, PJ
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To define the relationship between leukemic cell growth, intracellular metabolism of 1-B-D-arabinofuranosylcytosine (ara-C), and the clinical response to timed sequential induction therapy with ara-C in adult acute myelogenous leukemia (AML), growth kinetic and biochemical pharmacologic determinants were examined in AML bone marrow populations. Leukemic blasts from 45 previously untreated patients obtained prior to therapy were cultured in vitro in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). Cell populations cultured in HSA demonstrated both increased proliferation, as measured by both [3H]dThd incorporation into DNA and [3H]dThd leukemic blast labeling index, and greater [3H] ara-C leukemic blast labeling index relative to cells maintained in APS. HSA-cultured marrow cells from the 31 patients who achieved complete remission with ara-C-containing therapy demonstrated enhanced intracellular formation of ara-C 5'-triphosphate over three hours and retention of this active form during one subsequent hour in drug-free medium relative to cells maintained in APS. In contrast, cells from the 14 nonresponsive patients demonstrated no such HSA- induced increases in intracellular ara-C metabolism. These studies of human AML marrow cells identify behavior patterns of ara-C activation and net metabolism in the kinetically perturbed, proliferative state that may discriminate clinical sensitivity from clinical resistance to ara-C-based timed sequential therapy. Sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA- perturbed growth and pharmacologic parameters, while refractory cells demonstrate uncoupling of these determinants in the growth-stimulated state. These in vitro measurements may further serve as a template for prediction of clinical outcome to timed sequential therapy with ara-C, where both pharmacologic and cytokinetic determinants of response are intrinsic to the success of the designed drug scheduling.
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- 1987
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19. Two-cycle timed-sequential chemotherapy for adult acute nonlymphocytic leukemia
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Vaughan, WP, Karp, JE, and Burke, PJ
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Based on a series of clinical and laboratory studies of leukemia cell kinetics and responses to chemotherapy, we have developed an intensive timed-sequential regimen of daunorubicin and high-dose infusion 1-beta- D-arabinofuranosyl cytosine for the treatment of adult acute nonlymphocytic leukemia. Of the first 34 patients achieving complete remission (CR) with a single cycle of this therapy, four (12%) remain in complete remission without further therapy after a minimum of five years of follow-up. Treatment of relapsed patients with a second course of the same regimen at relapse and no chemotherapy in second remission increased to seven (21%) the number of patients expected to remain in remission for four years or more from their last chemotherapy. Beginning in 1980, however, we gave all consenting adults a second cycle of this chemotherapy in early first remission. Of the first 25 patients treated with a second cycle of this chemotherapy in early first remission, there was one toxic death, but 11 patients (44%) remain in CR with a median follow-up of almost three years.
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- 1984
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20. A two-step timed sequential treatment for acute myelocytic leukemia
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Geller, RB, Burke, PJ, Karp, JE, Humphrey, RL, Braine, HG, Tucker, RW, Fox, MG, Zahurak, M, Morrell, L, and Hall, KL
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Since 1980, adults with acute myelocytic leukemia (AML) have been treated on two clinical studies using intensive timed sequential therapy. All patients ages 16 to 80, including those with secondary AML (SAML) and those with AML preceded by a hematologic disorder (AHD), were treated, regardless of medical complications at the time of diagnosis. The first study combined high doses of cytarabine (ara-C, AC) and daunorubicin (DRN, D) in sequence (Ac2-D-Ac) and resulted in a complete remission rate of 55%. A group of these patients selected by functional status was able to receive a second course of therapy in remission, which resulted in a disease-free survival (DFS) of greater than 40% at 7 years. Because of toxicity in that study, 114 patients were entered on a second trial initiated 4 years ago, using a less aggressive first course, with amsacrine, to achieve a stable remission (Ac2-D-Amsa). This first treatment was followed by a more intensive second course (Ac6-D-Ac). With this two-step approach, a higher complete remission (CR) rate (76% for de novo AML and 54% for SAML-AHD) was achieved, and more patients were able to receive the second course of therapy. At the current median follow-up of 26 months, the median duration of DFS and overall survival are 11 and 14 months for patients with de novo AML. Age less than or equal to 55 is the most significant prognostic factor for both prolonged DFS and overall survival, with median durations of 17 and 18 months, respectively, for these younger patients. Patients with SAML-AHD remain relatively refractory to treatment despite aggressive chemotherapy, with median durations of DFS and overall survival of 9 months and 5 months, respectively.
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- 1989
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21. Humoral factors in aplastic anemia: relationship of liver dysfunction to lack of serum stimulation of bone marrow growth in vitro
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Karp, JE, Schacter, LP, and Burke, PJ
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- 1978
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22. Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation
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Karp, JE, Humphrey, RL, and Burke, PJ
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Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor- risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4–21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.
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- 1981
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23. Fibrinogen-fibrin degradation products and fibrinolysis following exercise in humans
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Karp, JE, primary and Bell, WR, additional
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- 1974
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24. CT of invasive pulmonary aspergillosis
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Kuhlman, JE, primary, Fishman, EK, additional, Burch, PA, additional, Karp, JE, additional, Zerhouni, EA, additional, and Siegelman, SS, additional
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- 1988
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25. Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy for prior malignancy.
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Vaughan WP, Karp JE, and Burke PJ
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- 2008
26. Systematic review and meta-analysis: Prognostic impact of time from diagnosis to treatment in patients with acute myeloid leukemia.
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Franco S, Geng X, Korostyshevskiy V, Karp JE, and Lai C
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- Humans, Middle Aged, Aged, Prognosis, Remission Induction, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
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Background: Acute myeloid leukemia (AML) has been considered an oncologic emergency that requires initiation of chemotherapy immediately after diagnosis. With the introduction of novel targeted therapies, there is a potential benefit associated with delaying definitive treatment for identification of actionable therapeutic targets. Unfortunately, cytogenetic/molecular testing can take >7 days to return, and there is not a consensus regarding the prognostic impact of time from diagnosis to treatment (TDT) in AML., Methods: A literature review and meta-analysis of studies done to date that evaluate TDT was conducted. Studies that reported baseline characteristics, TDT, and outcomes for patients with AML were selected. Outcomes included overall survival (OS), complete remission (CR), and mortality. Studies that measured CR rates within each TDT range and data to calculate odds ratios were included in the meta-analysis. The remaining outcomes were synthesized descriptively for literature review., Results: Thirteen studies were identified, which comprised a total of 14,946 patients. Median TDT values were between 1 and 8 days. Several studies found a significant association between prolonged TDT and older age and lower proliferation burden. Four of 11 studies did not detect a significant relationship between TDT and OS. No studies found a significant association between TDT and early death. Six of eight studies did not find a significant association between TDT and CR rate. The meta-analysis found a significant association between prolonged TDT and decreased achievement of CR (p < .05)., Conclusions: Results were highly variable but suggest it may be feasible to pursue cytogenetic/molecular testing in patients who are clinically stable, particularly in those aged 60 years and older., (© 2023 American Cancer Society.)
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- 2023
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27. Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification.
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Hochman MJ, Othus M, Hasserjian RP, Ambinder A, Brunner A, Percival MM, Hourigan CS, Swords R, DeZern AE, Estey EH, and Karp JE
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- Humans, Prognosis, Risk Factors, Mutation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Neoplasms, Second Primary complications, Hematologic Diseases complications
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Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML., (© 2023. The Author(s).)
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- 2023
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28. Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase I Oncology Trials.
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Frankel PH, Groshen S, Beumer JH, Cleveland L, Kim ES, and Karp JE
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- Humans, Medical Oncology, Informed Consent, Neoplasms drug therapy
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- 2023
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29. Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.
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Doucette K, Percival ME, Williams L, Kandahari A, Taylor A, Wang S, Ahn J, Karp JE, and Lai C
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- Adolescent, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Hypoalbuminemia chemically induced, Hypoalbuminemia metabolism, Hypoalbuminemia pathology, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Hypoalbuminemia mortality, Leukemia, Myeloid, Acute drug therapy, Serum Albumin analysis
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Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker., (© 2021 John Wiley & Sons, Ltd.)
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- 2021
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30. The spectrum of genetic mutations in myelodysplastic syndrome: Should we update prognostication?
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Cook MR, Karp JE, and Lai C
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The natural history of patients with myelodysplastic syndrome (MDS) is dependent upon the presence and magnitude of diverse genetic and molecular aberrations. The International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R) are the most widely used classification and prognostic systems; however, somatic mutations are not currently incorporated into these systems, despite evidence of their independent impact on prognosis. Our manuscript reviews prognostic information for TP53, EZH2, DNMT3A, ASXL1, RUNX1, SRSF2, CBL, IDH 1/2, TET2, BCOR, ETV6, GATA2, U2AF1, ZRSR2, RAS, STAG2, and SF3B1. Mutations in TP53, EZH2, ASXL1, DNMT3A, RUNX1, SRSF2, and CBL have extensive evidence for their negative impact on survival, whereas SF3B1 is the lone mutation carrying a favorable prognosis. We use the existing literature to propose the incorporation of somatic mutations into the IPSS-R. More data are needed to define the broad spectrum of other genetic lesions, as well as the impact of variant allele frequencies, class of mutation, and impact of multiple interactive genomic lesions. We postulate that the incorporation of these data into MDS prognostication systems will not only enhance our therapeutic decision making but lead to targeted treatment in an attempt to improve outcomes in this formidable disease., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2021
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31. Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia.
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Carraway HE, Sawalha Y, Gojo I, Lee MJ, Lee S, Tomita Y, Yuno A, Greer J, Smith BD, Pratz KW, Levis MJ, Gore SD, Ghosh N, Dezern A, Blackford AL, Baer MR, Gore L, Piekarz R, Trepel JB, and Karp JE
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- Adult, Aged, Benzamides administration & dosage, Clofarabine administration & dosage, Female, Follow-Up Studies, Histone Deacetylase Inhibitors therapeutic use, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Pyridines administration & dosage, Salvage Therapy, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Lineage, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local drug therapy, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Purpose: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL., Experimental Design: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m
2 /day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy., Results: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined., Conclusion: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted., (Copyright © 2021. Published by Elsevier Ltd.)- Published
- 2021
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32. Genetics of donor cell leukemia in acute myelogenous leukemia and myelodysplastic syndrome.
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Williams L, Doucette K, Karp JE, and Lai C
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- Humans, Tissue Donors, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes therapy
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapeutic modality for patients with acute myelogenous leukemia (AML) with poor risk features. Nonetheless, roughly 30% of such patients have leukemia recurrence and up to 2% of these are donor-derived leukemias, in which malignancy develops in the donor's transplanted cells, despite extremely low rates of leukemia in the donors themselves. Notably, over 20% of these malignancies carry chromosome 7 abnormalities nearly all of which are monosomies. Recent advances in whole exome and genome sequencing have allowed for detection of candidate genes that likely contribute to the development of AML in donor cells (donor leukemia, DCL). These genes include CEBPA, GATA2, JAK2, RUNX1, DDX41, EZH2, IDH1/2, DNMT3A, ASXL1, XPD, XRCC3, and CHEK1. The potential roles of variants in these genes are evaluated based on familial clustering of MDS/AML and corresponding animal studies demonstrating their leukemogenic nature. This review describes the spectrum of genetic aberrations detected in DCL cases in the literature with regard to the character of the individual cases, existing family cohorts that carry individual genes, and functional studies that support etiologic roles in AML development. DCL presents a unique opportunity to examine genetic variants in the donors and recipients with regards to progression to malignancy.
- Published
- 2021
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33. CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia.
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Ding H, Vincelette ND, McGehee CD, Kohorst MA, Koh BD, Venkatachalam A, Meng XW, Schneider PA, Flatten KS, Peterson KL, Correia C, Lee SH, Patnaik M, Webster JA, Ghiaur G, Smith BD, Karp JE, Pratz KW, Li H, Karnitz LM, and Kaufmann SH
- Subjects
- Animals, Apoptosis, Cell Proliferation, Female, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred NOD, Mice, SCID, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha genetics, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 2 antagonists & inhibitors, Gene Expression Regulation, Neoplastic drug effects, Leukemia, Myeloid, Acute drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Pyrazines pharmacology, Pyrazoles pharmacology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro , including TP53 -null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo . In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2-AP1- TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo . Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand-induced killing that can potentially be exploited for acute leukemia treatment. SIGNIFICANCE: This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically., (©2021 American Association for Cancer Research.)
- Published
- 2021
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34. Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.
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Zeidner JF, Knaus HA, Zeidan AM, Blackford AL, Montiel-Esparza R, Hackl H, Prince GT, Gondek LP, Ghiaur G, Showel MM, DeZern AE, Pratz KW, Douglas Smith B, Levis MJ, Gore S, Coombs CC, Foster MC, Streicher H, Karp JE, Luznik L, and Gojo I
- Subjects
- Adult, Aged, Cytarabine administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Hexosamines administration & dosage, Humans, Immunomodulation drug effects, Induction Chemotherapy methods, Male, Maximum Tolerated Dose, Middle Aged, Remission Induction, Thalidomide administration & dosage, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immunologic Factors administration & dosage, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Thalidomide analogs & derivatives
- Abstract
An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m
2 /day IV continuous infusion days 1-3, daunorubicin 45 mg/m2 IV days 1-3, etoposide 400 mg/m2 IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4+ and CD8+ peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4+ and CD8+ T cells.- Published
- 2020
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35. Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse?
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Estey E, Karp JE, Emadi A, Othus M, and Gale RP
- Subjects
- Benzimidazoles pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cytarabine pharmacology, Daunorubicin pharmacology, Gemtuzumab pharmacology, Glycine analogs & derivatives, Glycine pharmacology, Humans, Phenylurea Compounds pharmacology, Pyridines pharmacology, Randomized Controlled Trials as Topic, Staurosporine analogs & derivatives, Staurosporine pharmacology, Sulfonamides pharmacology, United States, United States Food and Drug Administration, Antineoplastic Agents pharmacology, Drug Approval, Leukemia, Myeloid, Acute drug therapy
- Abstract
Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particularly older ones, for whom current therapy is unsatisfactory, or simply not given, these approvals raise several concerns. Although the venetoclax and glasdegib approvals were for persons considered "unfit" for intensive induction, the criteria for fitness were not well defined (age ≥75 per se being insufficient) and are frequently subjective, making it likely that many subjects in the venetoclax and glasdegib registration trials were fit for intensive induction; for example, none had performance status 3-4. Fitness must be assessed together with the potential efficacy of a proposed therapy. We note the modest complete remission rates and durations in the venetoclax + hypomethylating agent trial. Although these formed the basis for FDA approval, it is unclear that better results might not have obtained with more intense induction, as several studies, with considerably longer-follow up, have suggested. Hence, we question the venetoclax (and glasdegib) approvals absent randomized comparisons with intense induction. Given the uncertain relation in older individuals between survival and complete remission (CR), much less responses less than CR, we are skeptical of the sole use of these responses in the ivosidenib and venetoclax approvals; we also question the use of survival, without event-free survival, in the glasdegib approval. Noting the midostaurin and CPX-351 approvals included populations not participating in the registration studies we suggest means to address this issue as well as those involving fitness, randomization, and endpoints.
- Published
- 2020
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36. Population pharmacokinetics and exposure-response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias.
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Singh R, Mehrotra S, Gopalakrishnan M, Gojo I, Karp JE, Greer JM, Chen A, Piekarz R, Kiesel BF, Gobburu J, Rudek MA, and Beumer JH
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Alkylating pharmacokinetics, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Incidence, Leukemia, Myeloid, Acute pathology, Male, Maryland epidemiology, Middle Aged, Models, Statistical, Mucositis chemically induced, Poly(ADP-ribose) Polymerase Inhibitors administration & dosage, Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics, Prognosis, Tissue Distribution, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzimidazoles administration & dosage, Benzimidazoles pharmacokinetics, Leukemia, Myeloid, Acute drug therapy, Mucositis epidemiology, Temozolomide administration & dosage, Temozolomide pharmacokinetics
- Abstract
Purpose: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design., Methods: Population pharmacokinetic analysis was performed using Phoenix
® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR ), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival., Results: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure., Conclusions: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.- Published
- 2019
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37. A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.
- Author
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Litzow MR, Wang XV, Carroll MP, Karp JE, Ketterling RP, Zhang Y, Kaufmann SH, Lazarus HM, Luger SM, Paietta EM, Pratz KW, Tun HW, Altman JK, Broun ER, Rybka WB, Rowe JM, and Tallman MS
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carboplatin administration & dosage, Carboplatin adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Disease-Free Survival, Etoposide administration & dosage, Etoposide adverse effects, Female, Flavonoids administration & dosage, Flavonoids adverse effects, Follow-Up Studies, Gastrointestinal Diseases chemically induced, Hematologic Diseases chemically induced, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Mitoxantrone administration & dosage, Mitoxantrone adverse effects, Piperidines administration & dosage, Piperidines adverse effects, Recurrence, Remission Induction, Sirolimus administration & dosage, Sirolimus adverse effects, Topotecan administration & dosage, Topotecan adverse effects, Tumor Lysis Syndrome etiology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Salvage Therapy adverse effects
- Abstract
To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
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38. Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy.
- Author
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Knaus HA, Berglund S, Hackl H, Blackford AL, Zeidner JF, Montiel-Esparza R, Mukhopadhyay R, Vanura K, Blazar BR, Karp JE, Luznik L, and Gojo I
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cytokines immunology, Cytokines metabolism, Female, Gene Expression, Humans, Immunophenotyping, Immunotherapy, Ki-67 Antigen metabolism, Leukemia, Myeloid, Acute immunology, Lymphocyte Activation drug effects, Male, Middle Aged, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor drug effects, Programmed Cell Death 1 Receptor metabolism, Receptors, OX40 drug effects, Up-Regulation drug effects, Antineoplastic Agents immunology, CD8-Positive T-Lymphocytes drug effects, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: Our understanding of phenotypic and functional signatures of CD8+ T cell dysfunction in acute myeloid leukemia (AML) is limited. Deciphering these deranged T cell functional states and how they are impacted by induction chemotherapy is essential for incorporation of novel immune-based strategies to restore and maintain antileukemia immunity., Methods: We utilized high-dimensional immunophenotyping, gene expression, and functional studies to characterize peripheral blood and bone marrow CD8+ T cells in 72 AML patients at diagnosis and after induction chemotherapy., Results: Our data suggest that multiple aspects of deranged T cell function are operative in AML at diagnosis, with exhaustion and senescence being the dominant processes. Following treatment, the phenotypic and transcriptional profile of CD8+ T cells diverged between responders and nonresponders. Response to therapy correlated with upregulation of costimulatory, and downregulation of apoptotic and inhibitory, T cell signaling pathways, indicative of restoration of T cell function. In functional studies, AML blasts directly altered CD8+ T cell viability, expansion, co-signaling and senescence marker expression. This CD8+ T cell dysfunction was in part reversible upon PD-1 blockade or OX40 costimulation in vitro., Conclusion: Our findings highlight the uniqueness of AML in sculpting CD8+ T cell responses and the plasticity of their signatures upon chemotherapy response, providing a compelling rationale for integration of novel immunotherapies to augment antileukemia immunity., Funding: This work was supported by the Leukemia & Lymphoma Society grant no. 6449-13; NIH grants UM1-CA186691 and R01-HL110907-01; the American Society for Blood and Marrow Transplantation New Investigator Award/Gabrielle's Angel Foundation; the Vienna Fund for Innovative Cancer Research; and by fellowships from the Wenner-Gren Foundation and the Swedish Society for Medical Research.
- Published
- 2018
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39. Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML).
- Author
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Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, and Karp JE
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Female, Flavonoids administration & dosage, Flavonoids adverse effects, Humans, Male, Middle Aged, Mitoxantrone administration & dosage, Mitoxantrone adverse effects, Piperidines administration & dosage, Piperidines adverse effects, Risk Factors, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality
- Published
- 2018
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40. Exposure-Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies.
- Author
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Mehrotra S, Gopalakrishnan M, Gobburu J, Ji J, Greer JM, Piekarz R, Karp JE, Pratz KW, and Rudek MA
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles adverse effects, Benzimidazoles pharmacokinetics, Carboplatin administration & dosage, Carboplatin adverse effects, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Hematologic Neoplasms pathology, Humans, Male, Middle Aged, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics, Topotecan administration & dosage, Topotecan adverse effects, Benzimidazoles administration & dosage, Hematologic Neoplasms drug therapy, Poly(ADP-ribose) Polymerase Inhibitors administration & dosage
- Abstract
Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated a 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure-response analysis to inform the phase II trial design. Experimental Design: Pharmacokinetic, efficacy, and safety data from 95 patients, who were administered 10 to 100 mg b.i.d. doses of veliparib for either 8, 14, or 21 days with T+C, were utilized for exposure-efficacy (objective response and overall survival) and exposure-safety (≥grade 3 mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment, and number of prior therapies. Results: The odds of having objective response were 1.08-fold with 1,000 ng/hr/mL increase in AUC, 1.8-fold with >8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN), and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1,000 ng/hr/mL increase in AUC, 39% with >8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥grade 3 mucositis increased by 29% with 1,000 ng.h/mL increase in AUC. Conclusions: Despite shallow exposure-efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC
50 Shallow exposure-mucositis relationship also supports the 80-mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg b.i.d. for at least 14 days in combination with T+C is recommended to be studied in MPN patients. Clin Cancer Res; 23(21); 6421-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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41. Timed sequential therapy for acute myelogenous leukemia: Results of a retrospective study of 301 patients and review of the literature.
- Author
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Norsworthy KJ, DeZern AE, Tsai HL, Hand WA, Varadhan R, Gore SD, Gojo I, Pratz K, Carraway HE, Showel M, McDevitt MA, Gladstone D, Ghiaur G, Prince G, Seung AH, Benani D, Levis MJ, Karp JE, and Smith BD
- Subjects
- Adult, Aged, Female, Humans, Induction Chemotherapy, Male, Middle Aged, Propensity Score, Retrospective Studies, Young Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute drug therapy
- Abstract
Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004-2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20-74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31-45%) and 32% (95% CI 27-38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC≥50×10
9 /L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9-4.0), and 1.6 (95% CI 0.7-3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7+3., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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42. Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia.
- Author
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Webster JA, Tibes R, Morris L, Blackford AL, Litzow M, Patnaik M, Rosner GL, Gojo I, Kinders R, Wang L, Doyle LA, Huntoon CJ, Karnitz LM, Kaufmann SH, Karp JE, and Smith BD
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Checkpoint Kinase 1 antagonists & inhibitors, Cytarabine adverse effects, Drug Resistance, Neoplasm drug effects, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Pyrazoles adverse effects, Pyrimidines adverse effects, Antineoplastic Agents administration & dosage, Cytarabine administration & dosage, Leukemia, Myeloid, Acute drug therapy, Pyrazoles administration & dosage, Pyrimidines administration & dosage
- Abstract
Purpose: Cytosine arabinoside (AraC) remains the backbone of most treatment regimens for acute myeloid leukemia (AML). Incorporation of AraC into DNA activates checkpoint kinase 1 (Chk1), leading to cell-cycle arrest and diminished AraC cytotoxicity, which can be reversed by the selective Chk1 inhibitor MK-8776. Building on a Phase I trial, we conducted a phase II trial comparing timed sequential AraC with or without MK-8776., Methods: Patients with relapsed or primary refractory AML were randomized 1:1 to receive either AraC with MK-8776 (Arm A); or AraC alone (Arm B)., Results: 32 patients were treated: 14 assigned to Arm A and 18 to Arm B. There were 5 (36%) complete responses (CR/CRi) and 1 (7%) partial response (PR) in Arm A, and 8 (44%) CR/CRis and 1 (6%) PR in Arm B. Median survival did not differ significantly between the two groups (5.9months in Arm A vs. 4.5 months in Arm B). MK-8776 led to a robust increase in DNA damage in circulating leukemic blasts as measured by increased γ-H2AX (16.9%±6.1% prior and 36.4%±6.8% at one hour after MK-8776 infusion, p=0.016)., Conclusion: Response rates and survival were similar between the two groups in spite of evidence that MK-8776 augmented DNA damage in circulating leukemic blasts. Better than expected results in the control arm using timed sequential AraC and truncated patient enrollment may have limited the ability to detect clinical benefit from the combination., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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43. Population pharmacokinetics and site of action exposures of veliparib with topotecan plus carboplatin in patients with haematological malignancies.
- Author
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Mehrotra S, Gopalakrishnan M, Gobburu J, Greer JM, Piekarz R, Karp JE, Pratz K, and Rudek MA
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzimidazoles analysis, Benzimidazoles therapeutic use, Carboplatin pharmacokinetics, Carboplatin therapeutic use, Drug Dosage Calculations, Drug Resistance, Neoplasm, Female, Humans, Leukemia blood, Male, Maximum Tolerated Dose, Middle Aged, Models, Biological, Poly(ADP-ribose) Polymerase Inhibitors analysis, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Topotecan pharmacokinetics, Topotecan therapeutic use, Young Adult, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Benzimidazoles pharmacokinetics, Leukemia drug therapy, Neoplasm Recurrence, Local drug therapy, Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics
- Abstract
Aims: Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukaemia, and compare veliparib concentration in various biological matrices., Methods: A population pharmacokinetic model was developed and effect of age, body size indices, sex, creatinine clearance (CrCL) and co-administration of T + C on the pharmacokinetics of veliparib were evaluated. The final model was qualified using bootstrap and quantitative predictive check. Linear regression was conducted to correlate concentrations of veliparib in various biological matrices., Results: A two compartment model with first-order absorption with T
lag described veliparib pharmacokinetics. The apparent clearance (CL/F) and volume (Vc /F) were 16.5 l h-1 and 122.7 l, respectively. The concomitant administration of T + C was not found to affect veliparib CL/F. CrCL and lean body mass (LBM) were significant covariates on CL/F and Vc/F, respectively. While a strong positive relationship was observed between veliparib concentrations in plasma and bone marrow supernatant, no correlation was observed between plasma and peripheral blood or bone marrow blasts., Conclusions: Consistent with veliparib's physiochemical properties and its elimination mechanism, LBM and CrCL were found to affect pharmacokinetics of veliparib while concomitant administration of T + C did not affect veliparib's CL/F. Plasma concentrations were found to be a reasonable surrogate for veliparib concentrations in peripheral blood and bone marrow supernatant but not blasts. The current model will be utilized to conduct exposure-response analysis to support dosing recommendations., (© 2017 The British Pharmacological Society.)- Published
- 2017
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44. Exposure-Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients.
- Author
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LaCerte C, Ivaturi V, Gobburu J, Greer JM, Doyle LA, Wright JJ, Karp JE, and Rudek MA
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols blood, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Biomarkers, Pharmacological blood, Cytarabine administration & dosage, Cytarabine blood, Cytarabine pharmacokinetics, Drug Administration Schedule, Female, Flavonoids blood, Flavonoids pharmacokinetics, Humans, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute pathology, Male, Maximum Tolerated Dose, Middle Aged, Mitoxantrone administration & dosage, Mitoxantrone blood, Mitoxantrone pharmacokinetics, Piperidines blood, Piperidines pharmacokinetics, Vidarabine administration & dosage, Vidarabine blood, Vidarabine pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Flavonoids administration & dosage, Leukemia, Myeloid, Acute drug therapy, Piperidines administration & dosage, Vidarabine analogs & derivatives
- Abstract
Purpose: To elucidate any differences in the exposure-response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure. Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound flavopiridol AUC were explored using recursive partitioning. Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3). Conclusions: Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m
2 /day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2 /day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592-600. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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45. Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: Interplay between hematologic and solid neoplastic clones and their microenvironments.
- Author
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Ding J, Karp JE, and Emadi A
- Subjects
- Animals, Biomarkers, Tumor immunology, Cell Line, Tumor, Hematologic Neoplasms enzymology, Hematologic Neoplasms pathology, Humans, Isoenzymes immunology, Neoplasms enzymology, Neoplasms pathology, Tumor Microenvironment, Hematologic Neoplasms immunology, L-Lactate Dehydrogenase immunology, Neoplasms immunology
- Abstract
Metabolism of neoplastic cells is shifted toward high glucose uptake and enhanced lactate production. Lactate dehydrogenase (LDH), which is comprised of two major subunits, LDH-A and LDH-B, reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. LDH-A has a higher affinity for pyruvate and is a key enzyme in the glycolytic pathway. Elevated LDH is a negative prognostic biomarker not only because it is a key enzyme involved in cancer metabolism, but also because it allows neoplastic cells to suppress and evade the immune system by altering the tumor microenvironment. LDH-A alters the tumor microenvironment via increased production of lactate. This leads to enhancement of immune-suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and dendritic cells (DCs); and inhibition of cytolytic cells, such as natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). By promoting immune-suppression in the tumor microenvironment, LDH-A is able to promote resistance to chemo/radio/targeted therapy. Here we discuss the evidence that LDH is both a metabolic and an immune surveillance prognostic biomarker and its elevation is harbinger of negative outcome in both solid and hematologic neoplasms.
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- 2017
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46. Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells from Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.
- Author
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Knorr KL, Finn LE, Smith BD, Hess AD, Foran JM, Karp JE, and Kaufmann SH
- Subjects
- Cell Count, Cell Death drug effects, Cell Survival drug effects, Cyclopentanes pharmacology, Cytarabine pharmacology, Hematopoietic Stem Cells drug effects, Humans, Pyrimidines pharmacology, Cyclopentanes therapeutic use, Hematopoietic Stem Cells pathology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes pathology, Pyrimidines therapeutic use
- 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. Stem Cells Translational Medicine 2017;6:840-850., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Published
- 2017
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47. A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.
- Author
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Pratz KW, Rudek MA, Gojo I, Litzow MR, McDevitt MA, Ji J, Karnitz LM, Herman JG, Kinders RJ, Smith BD, Gore SD, Carraway HE, Showel MM, Gladstone DE, Levis MJ, Tsai HL, Rosner G, Chen A, Kaufmann SH, and Karp JE
- Subjects
- Adult, Aged, Benzimidazoles administration & dosage, Benzimidazoles adverse effects, Benzimidazoles pharmacokinetics, Carboplatin administration & dosage, Carboplatin adverse effects, Carboplatin pharmacokinetics, Disease-Free Survival, Dose-Response Relationship, Drug, Drug-Related Side Effects and Adverse Reactions pathology, Fanconi Anemia Complementation Group D2 Protein genetics, Female, Humans, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic pathology, Male, Middle Aged, Poly (ADP-Ribose) Polymerase-1 genetics, Topotecan administration & dosage, Topotecan adverse effects, Topotecan pharmacokinetics, Leukemia, Biphenotypic, Acute drug therapy, Leukemia, Myelomonocytic, Chronic drug therapy, Myeloproliferative Disorders drug therapy, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors
- Abstract
Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML). Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m
2 /d + carboplatin 120-150 mg/m2 /d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2 /d + carboplatin 150 mg/m2 /d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders. Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899-907. ©2016 AACR ., (©2016 American Association for Cancer Research.)- Published
- 2017
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48. A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia.
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Gojo I, Beumer JH, Pratz KW, McDevitt MA, Baer MR, Blackford AL, Smith BD, Gore SD, Carraway HE, Showel MM, Levis MJ, Dezern AE, Gladstone DE, Ji JJ, Wang L, Kinders RJ, Pouquet M, Ali-Walbi I, Rudek MA, Poh W, Herman JG, Karnitz LM, Kaufmann SH, Chen A, and Karp JE
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzimidazoles administration & dosage, Benzimidazoles adverse effects, Benzimidazoles pharmacology, DNA Methylation drug effects, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Dacarbazine administration & dosage, Dacarbazine adverse effects, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Drug Synergism, Esophagitis chemically induced, Female, Histones metabolism, Humans, Kaplan-Meier Estimate, Leukemia, Myelomonocytic, Chronic drug therapy, Male, Middle Aged, Mucositis chemically induced, Neoplasm Proteins analysis, Neoplasm Proteins antagonists & inhibitors, Phosphorylation drug effects, Poly (ADP-Ribose) Polymerase-1 analysis, Poly(ADP-ribose) Polymerase Inhibitors administration & dosage, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Promoter Regions, Genetic drug effects, Promoter Regions, Genetic genetics, Protein Processing, Post-Translational drug effects, Remission Induction, Salvage Therapy, Temozolomide, Tumor Suppressor Proteins genetics, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies., Experimental Design: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle ≥2)] and temozolomide [150-200 mg/m
2 daily on days 3-9 in cycle 1 (days 1-5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined., Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR., Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697-706. ©2016 AACR., Competing Interests: The authors of this manuscript report no relationship to disclose. The data in this manuscript were in part presented in the abstract/poster form at the American Society of Hematology Meeting, December 5–8, 2015, Orlando, FL, (©2016 American Association for Cancer Research.)- Published
- 2017
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49. Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms.
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Pratz KW, Koh BD, Patel AG, Flatten KS, Poh W, Herman JG, Dilley R, Harrell MI, Smith BD, Karp JE, Swisher EM, McDevitt MA, and Kaufmann SH
- Subjects
- Antineoplastic Agents therapeutic use, BRCA1 Protein genetics, Benzimidazoles adverse effects, Benzimidazoles pharmacology, DNA Damage, DNA Methylation, DNA Repair, Drug Tolerance genetics, Genomics methods, Humans, Janus Kinase 2 genetics, Mutation, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders drug therapy, Myeloproliferative Disorders genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Rad51 Recombinase genetics, Rad51 Recombinase metabolism, Antineoplastic Agents adverse effects, Drug Hypersensitivity etiology, Myeloproliferative Disorders complications, Poly(ADP-ribose) Polymerase Inhibitors adverse effects
- Abstract
Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo, Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays., Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes., Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. ©2016 AACR., Competing Interests: No conflicts of interest exist for any authors of this manuscript., (©2016 American Association for Cancer Research.)
- Published
- 2016
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50. When the Minimal Becomes Measurable.
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Hourigan CS, Goswami M, Battiwalla M, Barrett AJ, Sheela S, Karp JE, and Lai C
- Published
- 2016
- Full Text
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