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Dive into the research topics where Joshua F. Zeidner is active.

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Featured researches published by Joshua F. Zeidner.


Haematologica | 2015

Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia

Joshua F. Zeidner; Matthew C. Foster; Amanda Blackford; Mark R. Litzow; Lawrence E. Morris; Stephen A. Strickland; Jeffrey E. Lancet; Prithviraj Bose; M. Yair Levy; Raoul Tibes; Ivana Gojo; Christopher D. Gocke; Gary L. Rosner; Richard F. Little; John J. Wright; L. Austin Doyle; B. Douglas Smith; Judith E. Karp

Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011–July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18–70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 days 1–2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/−5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.


Leukemia Research | 2015

Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia

Joshua F. Zeidner; Judith E. Karp

There have been minimal therapeutic advancements in acute myeloid leukemia (AML) over the past 4 decades and outcomes remain unsatisfactory. Alvocidib (formerly flavopiridol) is a multi-serine threonine cyclin-dependent kinase inhibitor with demonstrable in vitro and clinical activity in AML when combined in a timed sequential chemotherapy regimen, FLAM (alvocidib followed by cytarabine continuous infusion and mitoxantrone). FLAM has been evaluated in sequential phase 1 and phase 2 studies in 149 and 256 relapsed/refractory and newly diagnosed non-favorable risk AML patients, respectively, with encouraging findings in both patient populations warranting further investigation. This review highlights the mechanism of action of alvocidib, pre-clinical studies of alvocidib in AML, and the clinical trials evaluating alvocidib alone and in combination with cytotoxic agents (FLAM) in AML.


Blood | 2018

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML

Ronan Swords; Steven Coutre; Michael B. Maris; Joshua F. Zeidner; James M. Foran; Jose Cruz; Harry P. Erba; Jesus G. Berdeja; Wayne Tam; Saran Vardhanabhuti; Iwona Pawlikowska-Dobler; Hélène M. Faessel; Ajeeta B. Dash; Farhad Sedarati; Bruce J. Dezube; Douglas V. Faller; Michael R. Savona

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.


Current Drug Targets | 2017

Immunomodulatory Drugs: IMiDs in Acute Myeloid Leukemia (AML)

Joshua F. Zeidner; Matthew C. Foster

AML patients have an aberrant and dysfunctional immune state, paving the way for novel agents targeting pathways that integrate with immune signaling, function, and response. Small molecule immunomodulatory drugs (IMiDs) represent a class of agents derived from the parent compound, thalidomide. There are currently 3 IMiDs approved for a variety of malignancies: thalidomide, lenalidomide, and the newest agent, pomalidomide. IMiDs lead to a multitude of immunobiologic effects such as cytokine modulation, co-stimulation of T cells, down-regulation of co-inhibitory molecules, enhancing natural killer cell activity, inhibition of regulatory T cells, and repairing perturbed synapse formation on T cells. IMiDs have been extensively studied in various AML settings with promising clinical activity. This review discusses the immunologic effects of IMiDs, the rationale for studying IMiDs in AML, and the published and ongoing clinical trials investigating IMiD activity in AML.


Haematologica | 2016

Association of acute myeloid leukemia’s most immature phenotype with risk groups and outcomes

Jonathan M. Gerber; Joshua F. Zeidner; Sarah J Morse; Amanda Blackford; Brandy Perkins; Breann Yanagisawa; Hao Zhang; Laura A. Morsberger; Judith E. Karp; Yi Ning; Christopher D. Gocke; Gary L. Rosner; B. Douglas Smith; Richard J. Jones

The precise phenotype and biology of acute myeloid leukemia stem cells remain controversial, in part because the “gold standard” immunodeficient mouse engraftment assay fails in a significant fraction of patients and identifies multiple cell-types in others. We sought to analyze the clinical utility of a novel assay for putative leukemia stem cells in a large prospective cohort. The leukemic clone’s most primitive hematopoietic cellular phenotype was prospectively identified in 109 newly-diagnosed acute myeloid leukemia patients, and analyzed against clinical risk groups and outcomes. Most (80/109) patients harbored CD34+CD38− leukemia cells. The CD34+CD38− leukemia cells in 47 of the 80 patients displayed intermediate aldehyde dehydrogenase expression, while normal CD34+CD38− hematopoietic stem cells expressed high levels of aldehyde dehydrogenase. In the other 33/80 patients, the CD34+CD38− leukemia cells exhibited high aldehyde dehydrogenase activity, and most (28/33, 85%) harbored poor-risk cytogenetics or FMS-like tyrosine kinase 3 internal tandem translocations. No CD34+ leukemia cells could be detected in 28/109 patients, including 14/21 patients with nucleophosmin-1 mutations and 6/7 acute promyelocytic leukemia patients. The patients with CD34+CD38− leukemia cells with high aldehyde dehydrogenase activity manifested a significantly lower complete remission rate, as well as poorer event-free and overall survivals. The leukemic clone’s most immature phenotype was heterogeneous with respect to CD34, CD38, and ALDH expression, but correlated with acute myeloid leukemia risk groups and outcomes. The strong clinical correlations suggest that the most immature phenotype detectable in the leukemia might serve as a biomarker for “clinically-relevant” leukemia stem cells. ClinicalTrials.gov: NCT01349972.


Journal of the National Cancer Institute | 2016

Phase I Clinical Trials in Acute Myeloid Leukemia: 23-Year Experience From Cancer Therapy Evaluation Program of the National Cancer Institute

Joshua F. Zeidner; Judith E. Karp; Amanda Blackford; Matthew C. Foster; E. Claire Dees; Gary K. Smith; S. Percy Ivy; Pamela Jo Harris

BACKGROUND Therapy for acute myeloid leukemia (AML) has largely remained unchanged, and outcomes are unsatisfactory. We sought to analyze outcomes of AML patients enrolled in phase I studies to determine whether overall response rates (ORR) and mortality rates have changed over time. METHODS A retrospective analysis was performed on 711 adult AML patients enrolling in 45 phase I clinical trials supported by the Cancer Therapy Evaluation Program of the National Cancer Institute from 1986 to 2009. Changes in ORR and mortality rates for patients enrolled in 1986 to 1990, 1991 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009 were estimated with multivariable logistic regression models. All statistical tests were two-sided. RESULTS There was a statistically significant increase in AML patients enrolling in phase I clinical trials over time (1986 to 1990: n = 61; 2006 to 2009: n = 256; P = .03). The ORR for the entire cohort was 15.4% (1986 to 1990: 8.9%, 1991 to 1995: 21.1%; 1996 to 2000: 7.0%; 2001 to 2005: 10.0%; 2006 to 2009: 22.6%), and it statistically significantly improved over time (P < .001). There was a statistically significant improvement in ORRs with novel agents in combination vs single agents (ORR = 22.8% vs 4.7%, respectively, odds ratio = 5.95, 95% confidence interval = 3.22 to 11.9, P < .001). The 60-day mortality rate for the entire cohort was 22.6%, but it statistically significantly improved over time (P = .009). CONCLUSIONS There has been an encouraging increase in AML patients enrolling in phase I clinical studies over time. The improvement in ORRs appears to be partly because of the increase in combination trials and the inclusion of previously untreated poor-risk AML. Continued enrollment of AML patients in early phase clinical trials is vital for drug development and improvement in therapeutic outcomes.


Clinical Lymphoma, Myeloma & Leukemia | 2018

A Comparison of Clofarabine-based (GCLAC) and Cladribine-based (CLAG) Salvage Chemotherapy for Relapsed/Refractory AML

Benyam Muluneh; Kaitlyn M. Buhlinger; Allison M. Deal; Joshua F. Zeidner; Matthew C. Foster; Katarzyna Jamieson; Jill S. Bates; Hendrik W. van Deventer

Background Salvage regimens for patients with relapsed/refractory acute myeloid leukemia (rrAML) lack comparative data for superiority. Thus, we conducted a retrospective analysis of clofarabine‐based (GCLAC; granulocyte colony‐stimulating factor [filgrastim], clofarabine, high‐dose cytarabine) versus cladribine‐based (CLAG; cladribine, cytarabine, granulocyte colony‐stimulating factor [filgrastim]) regimens in rrAML. Patients and Methods We identified 41 consecutive patients with rrAML who had received either GCLAC or CLAG from 2011 to 2014. The primary outcome measure was the complete remission (CR) rate defined according to the International Working Group criteria. The secondary outcomes included the proportion of patients who underwent allogenic stem cell transplantation and the rate of relapse‐free survival and overall survival. Results We found no significant differences in the baseline characteristics of the patients treated with GCLAC (n = 22) or CLAG (n = 19). The outcomes with these 2 regimens were not significantly different. Patients treated with GCLAC had a CR/CR with incomplete blood count recovery rate of 64% compared with 47% for the patients treated with CLAG (P = .36). Of the GCLAC patients, 45% underwent allogeneic stem cell transplantation compared with 26% of the CLAG patients (P = .32). The median relapse‐free survival after GCLAC and CLAG was 1.59 years and 1.03 years, respectively (P = .75). The median overall survival after GCLAG and CLAG was 1.03 years and 0.70 years, respectively (P = .08). The drug costs were significantly different for GCLAC versus CLAG. Using an average wholesale price, the cost per patient per cycle was


Clinical Cancer Research | 2018

A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure

Amer M. Zeidan; Hanna A. Knaus; Tara M. Robinson; Andrea M. H. Towlerton; Edus H. Warren; Joshua F. Zeidner; Amanda Blackford; Amy S. Duffield; David A. Rizzieri; Mark G. Frattini; Yair M. Levy; Mark A. Schroeder; Anna Ferguson; Katherine Sheldon; Amy E. DeZern; Ivana Gojo; Steven D. Gore; Howard Streicher; Leo Luznik; B. Douglas Smith

60,821.60 for GCLAC and


Leukemia & Lymphoma | 2018

Clonal evolution of Philadelphia chromosome in acute myeloid leukemia after azacitidine treatment

Meera Yogarajah; Nathan D. Montgomery; Melissa Matson; Laura Blanchard; Cassiopeia Frank; Sean Gallagher; Katherine Pepin; Lori Vaught; Benyam Muluneh; Matthew C. Foster; Joshua F. Zeidner

4910.60 for CLAG. Conclusion A single‐institutional retrospective analysis found no significant differences in the outcomes between GCLAC and CLAG for rrAML patients, although formal comparisons should be performed in a randomized clinical trial. The cost of GCLAC was greater than that of CLAG, which should be considered when evaluating the choice for the salvage chemotherapy options. Micro‐Abstract The data for savage regimens in relapsed/refractory AML is largely based on phase 2, single arm studies and comparative data is scarce. The purpose of this retrospective study was to compare two salvage AML chemotherapy regimens, GCLAC (clofarabine‐based) and CLAG (cladribine based) in 41 patients (22 and 19 in each arm, respectively). There were no statistically significant differences in complete response rates (GCLAC = 64%; CLAG = 47%, P = .36) as well as other endpoints including safety endpoints. GCLAC was associated with significantly higher costs compared with CLAG (


Leukemia & Lymphoma | 2015

Optimizing the management of relapsed chronic myeloid leukemia post-allogeneic bone marrow transplant

Joshua F. Zeidner; B. Douglas Smith

60,821.60 vs

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Matthew C. Foster

University of North Carolina at Chapel Hill

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Leo Luznik

Johns Hopkins University School of Medicine

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Ivana Gojo

Johns Hopkins University

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Judith E. Karp

Johns Hopkins University

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Howard Streicher

National Institutes of Health

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Amy E. DeZern

Johns Hopkins University

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Benyam Muluneh

University of North Carolina at Chapel Hill

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