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ABSTRACT: HA22 is a recombinant immunotoxin that kills CD22 expressing cells by ADP-ribosylating and inactivating elongation factor-2 (EF2). HA22 is composed of an Fv that binds to CD22 that is fused to a potion of Pseudomonas exotoxin A. HA22 is very active in drug resistant Hairy Cell Leukemia, but less active in children with acute lymphoblastic leukemia. To understand why some patients don't respond to HA22, we isolated a HA22 resistant lymphoma cell line and showed that resistance is due to the inability of HA22 to ADP-ribosylate and inactivate EF2. We analyzed the diphthamide synthesis genes and found that WDR85 gene was deleted. We showed that WDR85 knockdown confers HA22 resistance to sensitive cells and sensitivity is restored by introduction of a WDR85 cDNA into resistant cells. Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevents ADP-ribosylation and inactivation of EF2. The abnormal methylation appears to be catalyzed by DPH5. Inactivation of the WDR85 gene could be a mechanism of immunotoxin resistance in patients undergoing immunotoxin therapy.
Journal of Biological Chemistry 03/2013; · 4.77 Impact Factor
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Waleed Haso,
Damiel W Lee,
Nirali N Shah,
Maryalice Stetler-Stevenson,
Constance M Yuan,
Ira H Pastan,
Dimiter S Dimitrov,
Richard A Morgan,
David J Fitzgerald,
David M Barrett, Alan S Wayne,
Crystal L Mackall,
Rimas J Orentas
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ABSTRACT: Immune targeting of B cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22 positive, with median CD22 expression levels of 3,500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 moAb, which targets a proximal CD22 epitope demonstrated superior anti-leukemic activity compared to those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3ζ constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that 2nd generation m971 derived anti-CD22-CARs are promising novel therapeutics that should be tested in BCP-ALL.
Blood 12/2012; · 9.90 Impact Factor
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Fabio Candotti,
Kit L Shaw,
Linda Muul,
Denise Carbonaro,
Robert Sokolic,
Christopher Choi,
Shepherd H Schurman,
Elizabeth Garabedian,
Chimene Kesserwan,
G Jayashree Jagadeesh, [......],
Otto O Yang,
Arumugam Balamurugan,
Gerhard Bauer,
Joanna A Ireland,
Barbara C Engel,
Gregory M Podsakoff,
Michael S Hershfield,
R Michael Blaese,
Robertson Parkman,
Donald B Kohn
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ABSTRACT: We conducted a gene therapy trial in 10 patients with adenosine deaminase-deficient severe combined immunodeficiency (ADA-deficient SCID) using two slightly different retroviral vectors for the transduction of patients' bone marrow CD34+ cells. Four subjects were treated without pre-transplant cytoreduction and remained on ADA enzyme replacement therapy (ERT) throughout the procedure. Only transient (months), low level (<0.01%) gene marking was seen in peripheral blood mononuclear cells (PBMC) of two older subjects (15 and 20 years old), whereas some gene marking of PBMC has persisted for the past nine years in two younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years post-procedure), with gene marking in PBMC of 1-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT due to poor gene marking and immune recovery and one had a subsequent allogeneic hematopoietic stem cell transplant. These studies directly demonstrate the importance of providing non-myeloablative pre-transplant conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient SCID.
Blood 09/2012; · 9.90 Impact Factor
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ABSTRACT: HA22 is a recombinant immunotoxin composed of an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A. HA22 produced a high rate of complete remissions in drug-resistant hairy cell leukemia and has a lower response rate in pediatric acute lymphoblastic leukemia (ALL). To understand why patients with ALL have poorer responses, we isolated an ALL cell line that is resistant to killing by HA22. The resistance is unstable; without HA22 the cells revert to HA22 sensitivity in 4 mo. We showed that in the resistant cell line, HA22 is unable to ADP ribosylate and inactivate elongation factor-2 (EF2), owing to a low level of DPH4 mRNA and protein, which prevents diphthamide biosynthesis and renders EF2 refractory to HA22. Analysis of the promoter region of the DPH4 gene shows that the CpG island was hypomethylated in the HA22-sensitive cells, heavily methylated in the resistant cells, and reverted to low methylation in the revertant cells. Our data show that immunotoxin resistance is associated with reversible CpG island methylation and silencing of DPH4 gene transcription. Incubation of sensitive cells with the methylation inhibitor 5-azacytidine prevented the emergence of resistant cells, suggesting that this agent in combination with HA22 may be useful in the treatment of some cases of ALL.
Proceedings of the National Academy of Sciences 04/2012; 109(18):6898-903. · 9.68 Impact Factor
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Nirali N Shah,
Ulrike Bacher,
Terry Fry,
Katherine R Calvo,
Maryalice Stetler-Stevenson,
Diane C Arthur,
Roger Kurlander,
Kristin Baird,
Barbara Wise,
Sergio Giralt,
Michael Bishop,
Nancy M Hardy, Alan S Wayne
American Journal of Hematology 03/2012; 87(9):916-22. · 4.67 Impact Factor
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Chimene Kesserwan,
Robert Sokolic,
Edward W Cowen,
Elizabeth Garabedian,
Kerstin Heselmeyer-Haddad,
Chyi-Chia Richard Lee,
Stefania Pittaluga,
Clarymar Ortiz,
Kristin Baird,
Dolores Lopez-Terrada,
Julia Bridge, Alan S Wayne,
Fabio Candotti
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ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) is a rare malignant skin tumor associated with a characteristic chromosomal translocation (t[17;22][q22;q13]) resulting in the COL1A1-platelet-derived growth factor β(PDGFB) fusion gene. This malignancy is rarely diagnosed in childhood.
We observed an unexpected high incidence of this DFSP in children affected with adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) and set out to evaluate the association of these 2 clinical entities.
Twelve patients with ADA-SCID were evaluated with a complete dermatologic examination and skin biopsy when indicated. Conventional cytogenetic and molecular analyses (fluorescence in situ hybridization, RT-PCR, or both) were performed when possible.
Eight patients were found to have DFSP. Six patients had multicentric involvement (4-15 lesions), primarily of the trunk and extremities. Most lesions presented as 2- to 15-mm, round atrophic plaques. Nodular lesions were present in 3 patients. In all cases CD34 expression was diffusely positive, and diagnosis was confirmed either by means of cytogenetic analysis, molecular testing, or both. The characteristic DFSP-associated translocation, t(17;22)(q22;q13), was identified in 6 patients; results of fluorescence in situ hybridization were positive for fusion of the COL1A1 and PDGFB loci in 7 patients; and RT-PCR showed the COL1A1-PDGFB fusion transcript in 6 patients.
We describe a previously unrecognized association between ADA-SCID and DFSP with unique features, such as multicentricity and occurrence in early age. We hypothesize that the t(17;22)(q22;q13) translocation that results in dermal overexpression of PDGFB and favors the development of fibrotic tumors might arise because of the known DNA repair defect in patients with ADA-SCID. Although the natural course of DFSP in the setting of ADA-SCID is unknown, this observation should prompt regular screening for DFSP in patients with ADA-SCID.
The Journal of allergy and clinical immunology 12/2011; 129(3):762-769.e1. · 9.17 Impact Factor
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ABSTRACT: To enable antibodies to function as cytotoxic anticancer agents, they are modified either via attachment to protein toxins or highly potent, low-molecular-weight drugs. Such molecules, termed immunotoxins and antibody-drug conjugates, respectively, represent a second revolution in antibody-mediated cancer therapy. Thus, highly toxic compounds are delivered to the interior of cancer cells based on antibody specificity for cell-surface target antigens.
Cancer Research 10/2011; 71(20):6300-9. · 7.86 Impact Factor
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Kristin Baird,
Terry J Fry,
Seth M Steinberg,
Michael R Bishop,
Daniel H Fowler,
Cynthia P Delbrook,
Jennifer L Humphrey,
Alison Rager,
Kelly Richards, Alan S Wayne,
Crystal L Mackall
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ABSTRACT: Some subsets of pediatric sarcoma patients have very poor survival rates. We sought to determine the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric sarcoma populations with <25% predicted overall survival (OS). Patients with ultrahigh-risk Ewing's sarcoma family of tumors (ESFT), alveolar rhabdomyosarcoma, or desmoplastic small round cell tumors received EPOCH-fludarabine induction, a cyclophosphamide/fludarabine/melphalan preparative regimen, and HLA matched related peripheral blood stem cells. Thirty patients enrolled; 7 did not undergo alloHSCT because of progressive disease with diminishing performance status during induction. All 23 alloHSCT recipients experienced rapid full-donor engraftment, with no peritransplantation mortality. Five of 23 alloHSCT recipients (22%) remain alive (OS of 30% by Kaplan-Meier analysis at 3 years), including 3 of 7 (42%) transplanted without overt disease (median survival 14.5 versus 29.0 months from alloHSCT for patients transplanted with versus without overt disease, respectively). Among the 28 patients who progressed on the study, the median survival from date of progression was 1.9 months for the 7 who did not receive a transplant compared with 11.4 months for the 21 transplanted (P = .0003). We found prolonged survival after posttransplantation progression with several patients exhibiting indolent tumor growth. We also saw several patients with enhanced antitumor effects from posttransplantation chemotherapy (objective response to pretransplantation EPOCH-F was 24% versus 67% to posttransplantation EOCH); however, this was associated with increased toxicity. This largest reported series of alloHSCT in sarcomas demonstrates that alloHSCT is safe in this population, and that patients undergoing alloHSCT without overt disease show higher survival rates than reported using standard therapies. Enhanced chemo- and radiosensitivity of tumors and normal tissues was observed posttransplantation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2011; 18(5):698-707. · 3.15 Impact Factor
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Robert Sokolic,
Irina Maric,
Chimene Kesserwan,
Elizabeth Garabedian,
I Celine Hanson,
Margaret Dodds,
Rebecca Buckley,
Andrew C Issekutz,
Naynesh Kamani,
Kit Shaw,
Ben Tan,
Pawan Bali,
Michael S Hershfield,
Donald B Kohn, Alan S Wayne,
Fabio Candotti
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ABSTRACT: Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319.
Blood 07/2011; 118(10):2688-94. · 9.90 Impact Factor
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ABSTRACT: Quantitative flow cytometry (QFCM) is being applied in the clinical flow cytometry laboratory for diagnosis, prognosis, and assessment of patients receiving antibody-based therapy. ABC values and the effect of technical variables on CD22 quantitation in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FCL), hairy cell leukemia (HCL) and normal B cells were studied.
The QuantiBrite System® was used to determine the level of CD22 expression (mean antibody bound per cell, ABC) by malignant and normal B cells. The intra-assay variability, number of cells required for precision, effect of delayed processing as well as shipment of peripheral blood specimens (delayed processing and exposure to noncontrolled environments), and the effect of paraformaldehyde fixation on assay results were studied.
The QuantiBRITE method of measuring CD22 ABC is precise (median CV 1.6%, 95% confidence interval, 1.2-2.3%) but a threshold of 250 malignant cells is required for reliable CD22 ABC values. Delayed processing and overnight shipment of specimens resulted in significantly different ABC values whereas fixation for up to 12 h had no significant effect. ABC measurements determined that CD22 expression is lower than normal in ALL, CLL, FCL, and MCL but higher than normal in HCL.
CD22 expression was atypical in the hematolymphoid malignancies studied and may have diagnostic utility. Technical variables such as cell number analyzed and delayed processing or overnight shipment of specimens impact significantly on the measurement of antigen expression by QFCM in the clinical laboratory.
Cytometry Part B Clinical Cytometry 03/2011; 80(2):83-90. · 2.53 Impact Factor
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ABSTRACT: Natural killer (NK) cells can mediate potent antitumor effects, but factors regulating the efficiency of tumor lysis remain unclear. Studies in allogeneic stem cell transplantation highlight an important role for killer cell immunoglobulin-like receptor (KIR) mismatch in overcoming human leukocyte antigen-mediated inhibitory signals. However, other activating and inhibitory signals also modulate tumor lysis by NK cells. We used rhIL15 and artificial antigen presenting cells expressing CD137L and IL15Rα to activate and expand peripheral blood NK cells (CD137L/IL15 NK) up to 1000-fold in 3 weeks. Compared with resting NK cells, CD137L/IL15 NK cells show modest increases in KIR expression and substantial increases in NKG2D, tumor necrosis factor-related apoptosis-inducing ligand, and natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46). Compared with resting NK cells, CD137L/IL15 NK cells mediate enhanced cytotoxicity against allogeneic and autologous tumors and KIR signaling did not substantially inhibit cytotoxicity. Rather, tumor lysis by CD137L/IL15 activated NK cells was predominantly driven by NCR signaling as blockade of NCRs dramatically diminished the lysis of a wide array of tumor targets. Furthermore, tumor lysis by CD137L/IL15 NK cells was tightly linked to NCR expression levels that peaked on day 8 to 10 after NK activation, and cytotoxicity diminished on subsequent days as NCR expression declined. We conclude that KIR mismatch is not a prerequisite for tumor killing by CD137L/IL15 NK cells and that NCR expression provides a biomarker for predicting potency of CD137L/IL15 NK cells in studies of NK cell-based immunotherapy.
Journal of immunotherapy (Hagerstown, Md.: 1997) 03/2011; 34(2):187-95. · 3.20 Impact Factor
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Jeffrey I Cohen,
Elaine S Jaffe,
Janet K Dale,
Stefania Pittaluga,
Helen E Heslop,
Cliona M Rooney,
Stephen Gottschalk,
Catherine M Bollard,
V Koneti Rao,
Adriana Marques, [......],
Rachael Fulton, Alan S Wayne,
Richard F Little,
Mitchell S Cairo,
Nader K El-Mallawany,
Daniel Fowler,
Claude Sportes,
Michael R Bishop,
Wyndham Wilson,
Stephen E Straus
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ABSTRACT: Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.
Blood 03/2011; 117(22):5835-49. · 9.90 Impact Factor
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Michael R Bishop,
Edwin P Alyea,
Mitchell S Cairo,
J H Frederik Falkenburg,
Carl H June,
Nicolaus Kröger,
Richard F Little,
Jeffrey S Miller,
Steven Z Pavletic,
David L Porter,
Stanley R Riddell,
Koen van Besien, Alan S Wayne,
Daniel J Weisdorf,
Roy S Wu,
Sergio Giralt
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ABSTRACT: The National Cancer Institute's First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation was organized and convened to identify, prioritize, and coordinate future research activities related to relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Each of the Workshop's 6 Working Committees has published individual reports of ongoing basic, translational, and clinical research and recommended areas for future research related to the areas of relapse biology, epidemiology, prevention, and treatment. This document summarizes each committee's recommendations and suggests 3 major initiatives for a coordinated research effort to address the problem of relapse after allo-HSCT: (1) to establish multicenter correlative and clinical trial networks for basic/translational, epidemiologic, and clinical research; (2) to establish a network of biorepositories for the collection of samples before and after allo-HSCT to aid in laboratory and clinical studies; and (3) to further refine, implement, and study the Workshop-proposed definitions for disease-specific response and relapse and recommendations for monitoring of minimal residual disease. These recommendations, in coordination with ongoing research initiatives and transplantation organizations, provide a research framework to rapidly and efficiently address the significant problem of relapse after allo-HSCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(4):443-54. · 3.15 Impact Factor
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ABSTRACT: Blastic plasmacytoid dendritic cell neoplasm is a rare malignancy that typically follows a highly aggressive clinical course in adults, whereas experience in children with this disease is very limited.
This retrospective study analyzed the pathological and clinical findings of nine cases of blastic plasmacytoid dendritic cell neoplasm presenting in patients under the age of 18 years who were reviewed at our institution. We also identified 20 well-documented additional pediatric cases in the literature.
In the combined analysis, the overall survival rate among the 25 patients with available follow-up, all having received chemotherapy, was 72% (follow-up ranging from 9 months to 13 years, with a median of 30 months). The event-free survival rate was 64%. Nine patients were alive 5 years after the original diagnosis, although only three of them had undergone hematopoietic stem cell transplantation--one in first complete remission and two in second remission. Of the seven patients who lacked cutaneous disease at presentation, 100% survived, including five who were alive more than 5 years after diagnosis, although only two had undergone stem cell transplantation. Among the 18 patients who presented with cutaneous disease and for whom follow-up data were available, only 11 survived (61%). Detailed immunophenotypic characterization and clinical features of all cases are presented. Unexpectedly, three of four cases of blastic plasmacytoid dendritic cell neoplasm tested showed focal positivity for S-100. S-100 was negative in 28 cases of acute myeloid leukemia evaluated for this marker.
In contrast to adult cases, in which long-term survival depends on stem cell transplantation in first complete remission, blastic plasmacytoid dendritic cell neoplasms in children are clinically less aggressive. Treatment with high-risk acute lymphoblastic leukemia-type chemotherapy appears to be effective, and stem cell transplantation may be reserved for children who relapse and achieve a second remission. Outcomes were more favorable in cases that lacked cutaneous disease at presentation, although a comparison of cutaneous and non-cutaneous cases might be confounded by differences in treatment regimens. Focal expression of S-100 may be seen in concert with other markers of plasmacytoid dendritic cells.
Haematologica 11/2010; 95(11):1873-9. · 6.42 Impact Factor
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David L Porter,
Edwin P Alyea,
Joseph H Antin,
Marcos DeLima,
Eli Estey,
J H Frederik Falkenburg,
Nancy Hardy,
Nicolaus Kroeger,
Jose Leis,
John Levine,
David G Maloney,
Karl Peggs,
Jacob M Rowe, Alan S Wayne,
Sergio Giralt,
Michael R Bishop,
Koen van Besien
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ABSTRACT: Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2010; 16(11):1467-503. · 3.15 Impact Factor
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Nicolaus Kröger,
Ulrike Bacher,
Peter Bader,
Sebastian Böttcher,
Michael J Borowitz,
Peter Dreger,
Issa Khouri,
Eduardo Olavarria,
Jerald Radich,
Wendy Stock,
Julie M Vose,
Daniel Weisdorf,
Andre Willasch,
Sergio Giralt,
Michael R Bishop, Alan S Wayne
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ABSTRACT: Relapse has become the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Outcome of patients with clinical relapse after transplantation generally remains poor, but intervention prior to florid relapse improves outcome for certain hematologic malignancies. To detect early relapse or minimal residual disease, sensitive methods such as molecular genetics, tumor-specific molecular primers, fluorescence in situ hybridization (FISH), and multiparameter flow cytometry (MFC) are commonly used after allogeneic stem cell transplantation to monitor patients, but not all of them are included in the commonly employed disease-specific response criteria. The highest sensitivity and specificity can be achieved by molecular monitoring of tumor- or patient-specific markers measured by polymerase chain reaction-based techniques, but not all diseases have such targets for monitoring. Similar high sensitivity can be achieved by determination of recipient-donor chimerism, but its specificity regarding detection of relapse is low and differs substantially among diseases. Here, we summarize the current knowledge about the utilization of such sensitive monitoring techniques in chronic leukemias, myeloproliferative neoplasms, and lymphoid malignancies based on tumor-specific markers and cell chimerism and how these methods might augment the standard definitions of posttransplant remission, persistence, progression, relapse, and the prediction of relapse. Critically important is the need for standardization of the different residual disease techniques and to assess the clinical relevance of minimal residual disease and chimerism surveillance in individual diseases, which in turn must be followed by studies to assess the potential impact of specific interventional strategies.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2010; 16(10):1325-46. · 3.15 Impact Factor
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Nicolaus Kröger,
Ulrike Bacher,
Peter Bader,
Sebastian Böttcher,
Michael J Borowitz,
Peter Dreger,
Issa Khouri,
Homer A Macapinlac,
Homer Macapintac,
Eduardo Olavarria,
Jerald Radich,
Wendy Stock,
Julie M Vose,
Daniel Weisdorf,
Andre Willasch,
Sergio Giralt,
Michael R Bishop, Alan S Wayne
[show abstract]
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ABSTRACT: Relapse has become the major cause of treatment failure after allogeneic stem cell transplantation. Outcome of patients with clinical relapse after transplantation generally remains poor, but intervention prior to florid relapse improves outcome for certain hematologic malignancies. To detect early relapse or minimal residual disease, sensitive methods such as molecular genetics, tumor-specific molecular primers, fluorescein in situ hybridization, and multiparameter flow cytometry (MFC) are commonly used after allogeneic stem cell transplantation to monitor patients, but not all of them are included in the commonly employed disease-specific response criteria. The highest sensitivity and specificity can be achieved by molecular monitoring of tumor- or patient-specific markers measured by polymerase chain reaction-based techniques, but not all diseases have such targets for monitoring. Similar high sensitivity can be achieved by determination of donor chimerism, but its specificity regarding detection of relapse is low and differs substantially among diseases. Here, we summarize the current knowledge about the utilization of such sensitive monitoring techniques based on tumor-specific markers and donor cell chimerism and how these methods might augment the standard definitions of posttransplant remission, persistence, progression, relapse, and the prediction of relapse. Critically important is the need for standardization of the different residual disease techniques and to assess the clinical relevance of minimal residual disease and chimerism surveillance in individual diseases, which in turn, must be followed by studies to assess the potential impact of specific interventional strategies.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2010; 16(9):1187-211. · 3.15 Impact Factor
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ABSTRACT: Acute lymphoblastic leukaemia (ALL) remains the most frequent cause of cancer-related mortality in paediatrics and outcome is poor for patients who have high-risk ALL or relapse. HA22 (CAT-8015) is an immunotoxin composed of an anti-CD22 variable fragment linked to a 38 kDa truncated protein derived from Pseudomonas exotoxin A. Using a bone marrow mesenchymal cell culture assay to support ALL cell viability, we investigated the in vitro cytotoxicity of HA22 against ALL blasts from newly diagnosed (n = 13) and relapsed patients (n = 22). There was interpatient variability in sensitivity to HA22. Twenty-four of 35 patient samples tested were sensitive (median 50% lethal concentration 3 ng/ml, range 1-80 ng/ml). Blasts from the other 11 patients were not killed by 500 ng/ml HA22. The median 50% lethal concentration was 20 ng/ml for all patients. There was no significant difference in HA22 sensitivity between diagnosis and relapse samples but peripheral blood ALL blasts were more sensitive to HA22 than those from bone marrow (P = 0.008). Thus, HA22, at concentrations achievable in patients, is highly cytotoxic to B-lineage ALL cells. These results provide a strong rationale for clinical testing of this agent in children with drug-resistant ALL and offers the potential to reduce morbidities of treatment while improving outcome.
British Journal of Haematology 08/2010; 150(3):352-8. · 4.94 Impact Factor
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ABSTRACT: This is a phase 2 study to assess the role of tumor histogenesis (subtype), fluorodeoxyglucose positron emission tomography (FDG-PET), and short-course etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with dose-dense rituximab (SC-EPOCH-RR) in newly diagnosed HIV-associated CD20(+) diffuse large B-cell lymphoma. Patients received a minimum of 3 and a maximum of 6 cycles with 1 cycle beyond stable radiographic and FDG-PET scans. Overall, 79% of patients received 3 cycles. Combination antiretroviral therapy was suspended before and resumed after therapy. Thirty-three enrolled patients had a median age of 42 years (range, 9-61 years), and 76% had a high-intermediate or high age-adjusted international prognostic index. At 5 years median follow-up, progression-free and overall survival were 84% and 68%, respectively. There were no treatment-related deaths or new opportunistic infections during treatment, and patients had sustained CD4 cell count recovery and HIV viral control after treatment. FDG-PET after 2 cycles had an excellent negative but poor positive predictive value. Tumor histogenesis was the only characteristic associated with lymphoma-specific outcome with 95% of germinal center B-cell (GCB) versus 44% of non-GCB diffuse large B-cell lymphoma (DLBCL) progression-free at 5 years. SC-EPOCH-RR is highly effective and less immunosuppressive with shorter duration therapy compared with standard strategies. However, new therapeutic advances are needed for non-GCB DLBCL, which remains the important cause of lymphoma-specific death. This trial was registered at www.clinicaltrials.gov as NCT000019253.
Blood 04/2010; 115(15):3017-24. · 9.90 Impact Factor
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Michael R Bishop,
Edwin P Alyea,
Mitchell S Cairo,
J H Frederik Falkenburg,
Carl H June,
Nicolaus Kröger,
Richard F Little,
Jeffrey S Miller,
Steven Z Pavletic,
David Porter,
Stanley R Riddell,
Koen van Besien, Alan S Wayne,
Daniel J Weisdorf,
Roy Wu,
Sergio Giralt
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2010; 16(5):563-4. · 3.15 Impact Factor
