Celalettin Ustun

University of Minnesota Duluth, Duluth, Minnesota, United States

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Publications (80)323.09 Total impact

  • Thorax 05/2015; DOI:10.1136/thoraxjnl-2015-206841 · 8.56 Impact Factor
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    ABSTRACT: The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase I dose-escalation study to assess the safety, maximum tolerated dose, and preliminary efficacy of DT2219 in patients with relapsed/refractory B-cell lymphoma or leukemia. DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose-limiting toxicity (DLT) was observed. Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events, including weight gain, low albumin, transaminitis, and fever were transient grade 1-2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizing antibody (30%). We have determined the safety of a novel immunotoxin DT2219 and established its biologically active dose between 40 and 80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned. Clin Cancer Res; 21(6); 1267-72. ©2015 AACR. ©2015 American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(6):1267-1272. DOI:10.1158/1078-0432.CCR-14-2877 · 8.19 Impact Factor
  • Celalettin Ustun, Guido Marcucci
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    ABSTRACT: In acute myeloid leukaemia (AML), the presence of t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22) and/or the corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 [collectively referred to as core binding factor (CBF) AML] predict for a more favourable outcome in patients receiving cytarabine-anthracycline based induction and upon achievement of complete remission, high-dose cytarabine consolidation chemotherapy. However, 40-45% of these patients eventually relapse and die of their disease. Here, we review emerging molecular and therapeutic results that may be used to guide the clinical management of this subset of patients. Integration of cytogenetic results with molecular genetic and epigenetic data refines the diagnosis, classification and risk-stratification of CBF AML. Clinical studies with targeting compounds (e.g. gemtuzumab ozogamicin, dasatinib) added to intensive chemotherapy appear beneficial both in younger and older patients, albeit the latter continue to have a significantly worse outcome than the former. Regularly molecular monitoring of disease during remission may provide a strategy for early therapeutic intervention before overt relapse. Emerging evidence supports that novel diagnostic, treatment and molecular disease monitoring approaches may improve the prognosis of CBF AML.
    Current Opinion in Hematology 01/2015; DOI:10.1097/MOH.0000000000000124 · 4.05 Impact Factor
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    ABSTRACT: Various cytogenetic risk scoring systems may determine prognosis for patients with myelodysplastic syndromes (MDS). We evaluated four different risk scoring systems in predicting outcome after allogeneic hematopoietic cell transplantation (alloHCT). We classified 124 patients with MDS using the International prognostic scoring system (IPSS), the revised international prognostic scoring system (R-IPSS), Armand's transplantation-specific cytogenetic grouping (TSCG), and monosomal karyotype (MK) both at the time of diagnosis and alloHCT. After adjusting for other important factors, MK at diagnosis (compared to no MK) was associated with poor 3-year disease-free survival (DFS) (27% (95% CI, 12-42%) versus 39% (95% CI, 28-50%), p=0.02) and overall survival (OS) (29% (95% CI, 14-44%) versus 47% (95% CI, 36-59%), p=0.02). OS but not DFS was affected by MK at HCT. MK frequency was uncommon in low score R-IPPS and IPSS. Although IPSS and R-IPSS discriminated good/very good groups from poor/very poor groups, patients with intermediate risk scores had the worst outcomes and therefore these scores did not show a progressive linear discriminating trend. Cytogenetic risk score change between diagnosis and alloHCT was uncommon and did not influence OS. MK cytogenetics in MDS are associated with poor survival suggesting the need for alternative or intensified approaches to their treatment. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2015; 21(5). DOI:10.1016/j.bbmt.2015.01.017 · 3.35 Impact Factor
  • American Journal of Hematology 01/2015; 90(4). DOI:10.1002/ajh.23942 · 3.48 Impact Factor
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    ABSTRACT: Cyclophosphamide in combination with busulfan (Bu) or total body irradiation (TBI) are the most commonly used myeloablative conditioning regimens in patients with Chronic Myeloid Leukemia (CML). We used data from the Center for International Bone Marrow Transplantation Research to compare outcomes in adults who underwent hematopoietic cell transplantation for CML in first chronic phase following myeloablative conditioning with cyclophosphamide (Cy) in combination with TBI, oral Bu or intravenous (IV) Bu. Four hundred thirty-eight adults received human leukocyte antigen (HLA)-matched sibling grafts and 235 received well-matched grafts from unrelated donors from 2000 through 2006. Important differences existed between the groups in distribution of donor relation, exposure to tyrosine kinase inhibitors and year of transplantation. In multivariate analysis, relapse occurred less frequently among patients receiving IV Bu compared to TBI (RR=0.36; P=0.022) or oral Bu (RR=0.39; P=0.028), but non-relapse mortality and survival were similar. A significant interaction was detected between donor relation and the main effect in leukemia-free survival (LFS). Among recipients of HLA-identical sibling grafts, but not URD grafts, LFS was better in patients receiving IV (RR=0.53; P=0.025) or oral Bu (RR=0.64; P=0.017) compared to TBI. In CML in first chronic phase, Cy in combination with IV Bu was associated with less relapse than TBI or oral Bu. LFS was better following IV or oral Bu compared to TBI. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2014; DOI:10.1016/j.bbmt.2014.12.010 · 3.35 Impact Factor
  • Leukemia and Lymphoma 12/2014; DOI:10.3109/10428194.2014.994179 · 2.61 Impact Factor
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    ABSTRACT: Core binding factor acute myelogenous leukemia (CBF AML) constitutes 15% of adult AML and carries an overall good prognosis. CBF AML encodes two recurrent cytogentic abnormalities referred to as t(8;21) and inv (16). The two CBF AML entities are usually grouped together but there is a considerable clinical, pathologic and molecular heterogeneity within this group of diseases. Recent and ongoing studies are addressing the molecular heterogeneity, minimal residual disease and targeted therapies to improve the outcome of CBF AML. In this article, we present a comprehensive review about CBF AML with emphasis on molecular heterogeneity and new therapeutic options.
    American Journal of Hematology 12/2014; 89(12). DOI:10.1002/ajh.23821 · 3.48 Impact Factor
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    ABSTRACT: The use of alternative donor transplants is increasing as the transplantation-eligible population ages and sibling donors are less available. We evaluated the impact of donor source on transplantation outcomes for adults with acute myeloid leukemia undergoing myeloablative (MA) or reduced-intensity conditioning (RIC) transplantation. Between January 2000 and December 2010, 414 consecutive adult patients with acute myeloid leukemia in remission received MA or RIC allogeneic transplantation from either a matched related donor (n = 187), unrelated donor (n = 76), or umbilical cord blood donor (n = 151) at the University of Minnesota or Hôpital St. Louis in Paris. We noted similar 6-year overall survival across donor types: matched related donor, 47% (95% confidence interval [CI], 39% to 54%); umbilical cord blood, 36% (95% CI, 28% to 44%); matched unrelated donor, 54% (95% CI, 40% to 66%); and mismatched unrelated donor, 51% (95% CI, 28% to 70%) (P < .11). Survival differed based on conditioning intensity and age, with 6-year survival of 57% (95% CI, 47% to 65%), 39% (95% CI, 28% to 49%), 23% (95% CI, 6% to 47%), 47% (95% CI, 36% to 57%), and 28% (95% CI, 17% to 41%) for MA age 18 to 39, MA age 40+, or RIC ages 18 to 39, 40 to 56, and 57 to 74, respectively (P < .01). Relapse was increased with RIC and lowest in younger patients receiving MA conditioning (hazard ratio, 1.0 versus 2.5 or above for all RIC age cohorts), P < .01. Transplantation-related mortality was similar across donor types. In summary, our data support the use of alternative donors as a graft source with MA or RIC for patients with acute myeloid leukemia when a sibling donor is unavailable.
    Biology of Blood and Marrow Transplantation 11/2014; 21(2). DOI:10.1016/j.bbmt.2014.10.030 · 3.35 Impact Factor
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    Article: Nasal GVHD
    Bone Marrow Transplantation 09/2014; 50(1). DOI:10.1038/bmt.2014.214 · 3.47 Impact Factor
  • Bone Marrow Transplantation 09/2014; 50(1). DOI:10.1038/bmt.2014.211 · 3.47 Impact Factor
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    ABSTRACT: Purpose Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown. Patients and Methods In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non-mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC). Results Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response. Conclusion AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial. (C) 2014 by American Society of Clinical Oncology
    Journal of Clinical Oncology 08/2014; 32(29). DOI:10.1200/JCO.2014.55.2018 · 17.88 Impact Factor
  • Leukemia and Lymphoma 07/2014; DOI:10.3109/10428194.2014.946029 · 2.61 Impact Factor
  • Haematologica 07/2014; DOI:10.3324/haematol.2014.109975 · 5.87 Impact Factor
  • Celalettin Ustun, Zuzan Cayci, Elizabeth Courville
    British Journal of Haematology 07/2014; 167(3). DOI:10.1111/bjh.13034 · 4.96 Impact Factor
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    ABSTRACT: AML relapse remains the leading cause of transplant failure among Allo-SCT recipients. A single institution study was conducted on 348 patients with AML who received an Allo-SCT from an umbilical cord blood (UCB, 222) or HLA-matched-related (RD, 126) donor between 2000-2011. Relapse after Allo-SCT occurred in 72 UCB and 32 RD transplant recipients. Three patients achieved CR after withdrawal of immune suppression with no further therapy. Fifty-two patients received intensive post-relapse therapy, defined as systemic chemotherapy (22 UCB, 7 RD), second Allo-SCT (nine UCB, two RD), or DLI±systemic chemotherapy (0 UCB, 12 RD); of these, 25% achieved CR (21% UCB vs 35% RD, P=0.16). Survival at 1 year after relapse was 22% for all patients (19% UCB vs 28% RD, P=0.36). In multivariable analysis, post-relapse mortality was lower in patients receiving intensive therapy for relapse (hazard ratio (HR)=0.4; 95% confidence interval (CI) 0.2-0.6, P<0.01) and higher in patients with peripheral blood blasts above the median (HR=3.8; 95% CI 2.2-6.6, P<0.01), active infection (HR=1.9; 95% CI 1.0-3.5, P=0.05) and non-infectious medical complications (HR=2.0; 95% CI 1.2-3.5, P=0.01). In conclusion, patients with AML relapsing after Allo-SCT who were in good-enough clinical condition to receive intensive therapy had superior short-term survival.Bone Marrow Transplantation advance online publication, 2 June 2014; doi:10.1038/bmt.2014.116.
    Bone Marrow Transplantation 06/2014; 49(8). DOI:10.1038/bmt.2014.116 · 3.47 Impact Factor
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    ABSTRACT: Status epilepticus after allogeneic hematopoietic cell transplantation (alloHCT) is rare. The authors report a case involving a 65-year-old man with nonconvulsive status epilepticus 34 days after umbilical cord blood transplantion for chronic lymphocytic leukemia. Cerebrospinal fluid and serum were positive for human herpesvirus 6 (HHV6). Magnetic resonance imaging of the brain showed symmetric T2 hyper-intensity bilaterally in the mesial temporal lobes, and T2 hyperintensi-ties and restricted diffusion of bilateral putamina. Despite aggressive anticonvulsive therapy, his seizures only abated with initiation of ganciclovir therapy. The patient completed six weeks of combination antiviral therapy (ganciclovir and foscarnet). His cognitive function gradually improved and, after prolonged rehabilitation, the patient was discharged home with residual intermittent memory loss but otherwise functional. HHV6 should be considered in the differential diagnosis of nonconvulsive status epilepticus after alloHCT, especially in patients with hyponatremia. Empirical antiviral therapy targeting HHV6 should be administered to these patients.
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    ABSTRACT: Mast cell leukemia (MCL), the leukemic manifestation of systemic mastocytosis (SM), is characterized by leukemic expansion of immature mast cells (MCs) in the bone marrow (BM) and other internal organs; and a poor prognosis. In a subset of patients, circulating MCs are detectable. A major differential diagnosis to MCL is myelomastocytic leukemia (MML). Although criteria for both MCL and MML have been published, several questions remain concerning terminologies and subvariants. To discuss open issues, the EU/US-consensus group and the European Competence Network on Mastocytosis (ECNM) launched a series of meetings and workshops in 2011-2013. Resulting discussions and outcomes are provided in this article. The group recommends that MML be recognized as a distinct condition defined by mastocytic differentiation in advanced myeloid neoplasms without evidence of SM. The group also proposes that MCL be divided into acute MCL and chronic MCL, based on the presence or absence of C-Findings. In addition, a primary (de novo) form of MCL should be separated from secondary MCL that typically develops in the presence of a known antecedent MC neoplasm, usually aggressive SM (ASM) or MC sarcoma. For MCL, an imminent prephase is also proposed. This prephase represents ASM with rapid progression and 5%-19% MCs in BM smears, which is generally accepted to be of prognostic significance. We recommend that this condition be termed ASM in transformation to MCL (ASM-t). The refined classification of MCL fits within and extends the current WHO classification; and should improve prognostication and patient selection in practice as well as in clinical trials.
    Annals of Oncology 03/2014; 25(9). DOI:10.1093/annonc/mdu047 · 6.58 Impact Factor
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    ABSTRACT: We studied AML patients over age 50 in CR1 after adult unrelated donor (URD; n = 441, 8/8 and n = 94 7/8 HLA-matched) or umbilical cord blood (UCB; n = 205) transplantations. UCB recipients less often achieved CR1 within 8 weeks, more often received reduced-intensity conditioning, and cyclosporin-based graft-versus-host disease (GVHD) prophylaxis. Neutrophil recovery was slower in UCB (69% by day 28) vs. 8/8 URD (97%); 7/8 (91%) (p<0.001). Three-year transplant-related mortality (TRM) was higher and leukemia-free survival (LFS) lower with UCB (35% and 28%, respectively) vs. 8/8 URD (27% and 39%). TRM was higher in 7/8 URD (41%, p=0.01), but LFS similar 34% (p=0.39). Three-year chronic GVHD was least in UCB (28%) vs. 53% and 59% in 8/8 and 7/8 URD recipients. Three-year survival was 8/8 URD 43% (95% CI 38-48), UCB 30% (95% CI 23-37) (p=0.002) and 7/8 URD 37% (95% CI 27-46). Allotransplantation for AML in CR1 with any of these grafts extends LFS for over a third of older patients. In the absence of an 8/8 HLA-matched URD or when transplantation is needed urgently, UCB can provide extended survival. Less frequent chronic GVHD with UCB transplantation may be of particular value for older patients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2014; 20(6). DOI:10.1016/j.bbmt.2014.02.020 · 3.35 Impact Factor
  • Cancer Genetics 02/2014; DOI:10.1016/j.cancergen.2014.02.006 · 2.42 Impact Factor

Publication Stats

790 Citations
323.09 Total Impact Points

Institutions

  • 2010–2015
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States
  • 2014
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 2013
    • University of Toronto
      Toronto, Ontario, Canada
    • Carolinas HealthCare System
      Charlotte, North Carolina, United States
  • 2012
    • Saint Mary's University of Minnesota
      Minneapolis, Minnesota, United States
  • 2002–2010
    • Georgia Health Sciences University
      • • Department of Medicine
      • • Section of Hematology/Oncology
      Augusta, Georgia, United States
  • 2005
    • Temple University
      Philadelphia, Pennsylvania, United States