Daniel J Weisdorf

Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States

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Publications (590)3677.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The maximum age of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has been moving up over time. However, the availability of a suitable HLA-matched sibling donor may limit access of this patient population to alloHCT. We retrospectively investigated the outcomes of umbilical cord blood (UCB) transplantation after reduced intensity conditioning regimen (RIC) in patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) ≥ 70 years between 2010 and 2014. During this period, 70 patients with AML/MDS were referred to our center for alloHCT consideration. Twenty-two patients (33%) received alloHCT, including 10 UCB transplantation, 9 HLA full-matched sibling donor transplantation, 2 haploidentical alloHCT, and 1 unrelated donor (URD) alloHCT. In UCB transplantation, cumulative incidence of non-relapse mortality and relapse was 20% and 30% at 2 years, respectively. The cumulative incidence of acute graft versus host disease (GVHD) at day +100 and chronic GVHD at 2 years was 10%. Seven patients had viral reactivation/infections. Overall survival and disease-free survival were 60% and 50% at 2 years, respectively. Moreover, these outcomes seem similar to that of patients 60-69 years of age receiving UCB transplantation (n=60) and patients ≥ 70 years receiving HLA full-matched sibling donor transplantation (n=9). These results suggest that UCB transplantation is feasible in selected AML/MDS patients ≥ 70 years. In fact, UCB shortens required time for URD search and thus increases the chance of proceeding with alloHCT, which might contribute to higher rates of alloHCT in the referral group. Outcomes of UCB transplantation are promising; however, larger studies with a longer follow-up are needed.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2015; DOI:10.1016/j.bbmt.2015.09.020 · 3.40 Impact Factor
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    ABSTRACT: We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% [17-35%], p=0.05) and superior disease-free survival (DFS) (55% [45-65%] p=0.04) 1 year after reduced intensity conditioning (RIC) compared to CMV seronegative recipients who experienced higher relapse rates (35% [27-43%]) and lower DFS (46% [38-54%]). This protective effect was independent of age and graft-versus-host disease (GvHD) and was not observed in recipients who received myeloablative (MA) regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months post-transplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on post-transplant relapse is in part driven by adaptive NK cell responses.Leukemia accepted article preview online, 29 September 2015. doi:10.1038/leu.2015.260.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2015; DOI:10.1038/leu.2015.260 · 10.43 Impact Factor
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    ABSTRACT: Infection is a major complication of hematopoietic cell transplantation. Prolonged neutropenia and graft versus host disease are the two major complications with an associated risk for infection, and these complications differ according to the graft source. A phase 3, multicenter, randomized trial (BMT CTN 0201) of transplantation of bone marrow (BM) versus peripheral-blood stem cells (PBSC) from unrelated donors (URD) showed no significant differences in two-year survival between these graft sources. In an effort to provide data regarding whether bone marrow or peripheral-blood stem cells could be used as a preferential graft source for transplantation, we report a detailed analysis of the infectious complications for 2 years following transplantation from the BMT CTN 0201 trial. A total of 499 patients in this study had full audits of infection data. A total of 1347 infection episodes of moderate or greater severity were documented in 384 (77%) patients; 201/249 (81%) of the evaluable patients had received a BM graft and 183/250 (73%) had received a PBSC graft. Of 1347 infection episodes, 373 were severe and 123 were life-threatening and/or fatal; 710 (53%) of these episodes occurred on the BM arm and 637 (47%) on the PBSC arm, resulting in a two-year cumulative incidence 84.7% (95% confidence interval [CI]: 79.6-89.8) for BM vs. 79.7% (95%CI, 73.9-85.5) for PBSC, P = .013. The majority of these episodes, 810 (60%), were due to bacteria, with a two-year cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bloodstream bacterial infections during the first 100 days was 44.8% (95%CI, 38.5-51.1) for BM vs. 35.0% (95%CI, 28.9-41.1) for PBSC (P = .027). The total infection density (# infection events / 100 patient days at risk) was .67 for BM and .60 for PBSC. The overall infection density for bacterial infections was .4 in both arms; for viral infections was .2 in both arms; and for fungal/parasitic infections was .04 and .05 for BM and PBSC, respectively. The cumulative incidence of infection prior to engraftment was 47.9% (95%CI, 41.5-53.9) for BM vs. 32.8% (95%CI, 27.1-38.7) for PBSC (P = .002), possibly related to quicker neutrophil engraftment using PBSC. Infections remain frequent following URD HCT, particularly following BM grafts.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2015; DOI:10.1016/j.bbmt.2015.09.013 · 3.40 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic cell transplantation is often complicated by graft-versus-host disease (GVHD). We analyzed the incidence and risk factors for acute and chronic graft-versus-host disease (GVHD), and their impact on disease relapse and survival, among recipients of single umbilical cord blood (sUCB, n=295), double umbilical cord blood (dUCB, n=416), and matched sibling donor (MSD, n=469) allografts. The incidence of grade II-IV aGVHD and chronic GVHD among dUCB, sUCB, and MSD was 56%, 26% and 37% and 26%, 7%, and 40%, respectively. Development of acute GVHD had no effect on relapse, non-relapse mortality, or overall survival among UCB recipients, but was associated with worse non-relapse mortality and survival in MSD recipients. Development of cGVHD was only associated with lower relapse in dUCBT. In multivariate analysis of GVHD incidence, age > 18 years was associated with higher incidence of aGVHD and cGVHD across all cohorts, while worse HLA match and prior aGVHD were associated with higher risks of aGVHD in both UCB cohorts. Non-myeloablative conditioning limited the risk of aGVHD compared to myeloablative conditioning in dUCB recipients. Cyclosporine A and mycophenolate mofetil as GVHD prophylaxis lowered the risk of cGVHD compared to steroids with cyclosporine A among sUCB recipients. This large contemporary analysis suggests similarity of risks and consequences of GVHD for UCB and MSD recipients. Limiting the severity of aGVHD remains important in all groups. Increasing the UCB inventory or developing strategies that reduce the cell-dose threshold and thereby increase the chance of identifying an adequately dosed, better HLA-matched single UCB unit may further limit risks of acute GVHD after UCB transplantation.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2015; DOI:10.1016/j.bbmt.2015.09.008 · 3.40 Impact Factor
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    ABSTRACT: The number of allogeneic hematopoietic stem cell (HSC) transplants performed globally each year continues to increase. Advances in HLA typing, better supportive care and administration of reduced-intensity conditioning regimens allow treatment of older patients with older sibling donors. Pre-transplant donor assessment and testing are very important processes affecting the quality and safety of donation. For unrelated HSC donors detailed recommendations for health assessment have been published allowing donation only if they are unrestrictedly healthy. Eligibility criteria for related donors are less strict and vary significantly between centers. In situations where a family donor does not meet the suitability criteria for unrelated donors, involved physicians often struggle with the decision whether the matched relative is suitable for donation or not. On behalf of the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues we intended to develop a consensus document with recommendations for donor work-up and final clearance of family donors who would not be able to serve as unrelated donors due to their age or pre-existing diseases. This manuscript covers different topics intending to support decision-making, with the goal of minimizing medical risk to the donor and protection of the recipient from transmissible diseases. 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 08/2015; DOI:10.1016/j.bbmt.2015.08.009 · 3.40 Impact Factor
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    ABSTRACT: The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, N=240) and in myelodysplastic syndrome (MK+MDS, N=221) on hematopoietic cell transplantation (HCT) outcomes compared to other cytogenetically defined groups (AML, N=3,360; MDS, N=1,373) as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1998 to 2011. MK+AML was associated with higher disease relapse (hazard ratio [HR] 1.98, p<0.01), similar transplant related mortality (TRM, HR 1.01, p=0.9) and worse survival (HR 1.67, p<0.01) compared to other cytogenetically defined AML. Among patients with MDS, MK+MDS was associated with higher disease relapse (HR 2.39, p<0.01), higher TRM (HR 1.80, p<0.01) and worse survival (HR 2.02, p<0.01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (HR 1.72, p<0.01) and MDS (HR1.79, p<0.01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. 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 08/2015; DOI:10.1016/j.bbmt.2015.08.024 · 3.40 Impact Factor
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    ABSTRACT: Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in a large cohort (n=1321, 2003-2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III-IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.Bone Marrow Transplantation advance online publication, 13 July 2015; doi:10.1038/bmt.2015.162.
    Bone marrow transplantation 07/2015; DOI:10.1038/bmt.2015.162 · 3.57 Impact Factor
  • Celalettin Ustun · Richard Stone · Daniel Weisdorf
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2015; 21(10). DOI:10.1016/j.bbmt.2015.07.011 · 3.40 Impact Factor
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    ABSTRACT: We studied adults with acute myeloid leukemia (AML) after haploidentical (n=192) and 8/8 HLA-matched unrelated donor (n=1982), transplantation. Data were obtained from the Center for International Blood and Marrow Transplant Research. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88, reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737, reduced intensity conditioning regimens. In the myeloablative setting, day-30 neutrophil recovery was lower after haploidentical compared to matched unrelated donor transplants (90% versus 97%, p=0.02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96%, (p=0.25). In the myeloablative setting, 3-month acute grade 2-4 (16% versus 33%, p<0.0001) and 3-year chronic GVHD (30% versus 53%, p<0.0001) were lower after haploidentical compared to matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% versus 28%, (p=0.05) and 34% versus 52%, (p=0.002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI 36-54) and 50% (95% CI 47-53) after haploidentical and matched unrelated donor transplants (p=0.38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI 35-56) and 44% (95% CI 0.40-47) (p=0.71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. Copyright © 2015 American Society of Hematology.
    Blood 06/2015; 126(8). DOI:10.1182/blood-2015-04-639831 · 10.45 Impact Factor
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    ABSTRACT: Cytomegalovirus (CMV) reactivates in >30% of CMV seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of NK cells expressing NKG2C, CD57 and inhibitory killer-cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation post-HCT. These NK cells persist after the resolution of infection and display 'adaptive' or memory properties. Despite these findings, the differential impact of persistent/inactive vs. reactivated CMV on NK vs. T cell maturation following HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pre-transplant CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an 'adaptive' phenotype (NKG2C(+)CD57(+)). Compared to CMV seronegative recipients, those who reactivated CMV (React(+)) had the highest adaptive cell frequencies, while intermediate frequencies were observed in CMV seropositive recipients harboring persistent/non-replicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV seropositive recipients of sibling, but not UCB grafts, and correlated with lower rates of CMV reactivation (sibling 33% vs. UCB 51%; p<0.01). These data suggest that persistent/non-replicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling, but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. 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 06/2015; 21(9). DOI:10.1016/j.bbmt.2015.05.025 · 3.40 Impact Factor
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    ABSTRACT: Hematopoietic cell transplantation (HCT) has been used as a part of cancer therapy for over half a decade. Beyond the necessity for donor-derived cells to reconstitute hematopoiesis after radiation and chemotherapy, immunologic reconstitution from allogeneic cells is important for the elimination of residual tumor cells. Natural killer (NK) cells are first among lymphocytes to reconstitute post-transplant and protect against cancer relapse. In this review, we provide a historical perspective on the role of NK cells in cancer control in the transplant setting and focus on current research aimed at improving NK cell responses for therapeutic benefit.
    Current topics in microbiology and immunology 06/2015; DOI:10.1007/82_2015_445 · 4.10 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are regulated killer immunoglobulin-like receptor (KIR) interactions with HLA class I ligands. Several models of NK reactivity have been associated with improved outcomes following myeloablative allogeneic hematopoietic cell transplantation (HCT), but this issue has not been rigorously addressed in reduced-intensity conditioning (RIC) unrelated donor (URD) HCT. We studied 909 patients undergoing RIC-URD HCT. Patients with acute myeloid leukemia (AML, n=612) lacking >1 KIR ligands experienced higher grade III-IV acute graft-vs.-host disease (GvHD) (HR 1.6, 95%CI 1.16-2.28, p=0.005) compared to those with all ligands present. Absence of HLA-C2 for donor KIR2DL1 was associated with higher grade II-IV (HR 1.4, p=0.002) and III-IV acute GvHD (HR 1.5, p=0.01) compared to HLA-C2+patients. AML patients with KIR2DS1+, HLA-C2 homozygous donors had greater treatment-related mortality compared to others (HR 2.4, 95%CI 1.4-4.2, p=0.002), but did not experience lower relapse. There were no significant associations with outcomes for AML when assessing donor activating KIRs or centromeric KIR content, nor for any donor-recipient KIR-HLA assessments in patients with myelodysplastic syndrome (n=297). KIR-HLA combinations in RIC-URD HCT recapitulate some but not all KIR-HLA effects observed in myeloablative HCT. 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 05/2015; 21(9). DOI:10.1016/j.bbmt.2015.05.002 · 3.40 Impact Factor
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    ABSTRACT: The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature.Bone Marrow Transplantation advance online publication, 27 April 2015; doi:10.1038/bmt.2015.82.
    Bone marrow transplantation 04/2015; 50(8). DOI:10.1038/bmt.2015.82 · 3.57 Impact Factor
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    ABSTRACT: Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. One-hundred-and-thirty FA patients (median age 9.0 years, range 1-48) underwent alternative donor HCT at the University of Minnesota between 1995-2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell depleted bone marrow (BM) or unmanipulated umbilical cord blood (UCB) transplantation. The addition of FLU enhanced engraftment three-fold. The incidence of grades II-IV acute and chronic graft-versus-host disease (GVHD) was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age, or with a history of opportunistic infections or transfusions prior to HCT. Mortality was lowest in patients without a prior history of opportunistic infection or transfusions, and who received conditioning with TBI 300 cGy, CY, FLU and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(24). DOI:10.1182/blood-2015-02-626002 · 10.45 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 · 8.72 Impact Factor
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    ABSTRACT: Circulating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration vs. those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding-EGF-like growth factor, vascular endothelial growth factor-A, -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, placental growth factor [PlGF]) were measured in a discovery set of HCT recipients with grade III/IV aGVHD versus controls, then validated in two aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (N=105, serum) and 0802 (N=158, plasma) versus controls without aGVHD (N=53, serum). Levels of EGF and VEGF-A were lower than controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio 9.3 in CTN 0302, 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and thus may contribute to both pathogenesis and recovery. 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 03/2015; 21(6). DOI:10.1016/j.bbmt.2015.02.018 · 3.40 Impact Factor
  • Journal of the American College of Cardiology 03/2015; 65(10):A1100. DOI:10.1016/S0735-1097(15)61100-7 · 16.50 Impact Factor
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    ABSTRACT: Failure-free survival, defined as absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but it has only been reported for single center studies. We measured failure free survival in a prospective observational cohort of patients with both newly diagnosed and existing chronic graft-versus-host disease (n=575) from nine centers. Failure was observed in 389 (68%) during the observation period. Median follow up of all patients was 30.9 months, and median failure free survival was 9.8 months (63% at 6 months, 45% at one year, and 29% at two years). Of the variables measured at enrollment, ten were associated with shorter failure free survival: higher NIH 0-3 skin score, higher NIH 0-3 GI score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor into male patient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (HR=2.06, 95%CI: 1.29-3.32, p<0.003) and decreased survival (HR=1.51, 95%CI: 1.04-2.18, p<0.03). These results show fewer than half of patients on systemic treatment will be failure-free survivors at one year, and fewer than a third will reach two years without experiencing failure. Better treatments are needed for chronic graft-versus-host disease. Clinicaltrials.gov identifier: NCT00637689. Copyright © 2015, Ferrata Storti Foundation.
    Haematologica 02/2015; 100(5). DOI:10.3324/haematol.2014.117283 · 5.81 Impact Factor
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    ABSTRACT: Cyclophosphamide (Cy) is a prodrug that depends on bioactivation by hepatic cytochrome P450 (CYP) enzymes for its cytotoxicity. We evaluated the influence of single nucleotide polymorphisms (SNPs) of CYP enzymes on the efficacy of autologous hematopoietic cell transplantation (HCT) for lymphoma. SNPs of 22 genes were analyzed in 93 patients with Hodgkin (n=52) and non-Hodgkin lymphoma (n=41) treated with high-dose Cy followed by autologous HCT between 2004-2012. Preparative regimens contained Cy (120mg/kg) combined with carmustine/etoposide (n=61) or Cy (6000mg/m2) with total body irradiation (n=32). Lack of complete remission as measured by pre-transplant positron emission tomography was the sole clinical factor associated with increased risk of relapse (HR 2.1). In genomic analysis, we identified a single SNP (rs3211371) in exon 9 (C >T) of the CYP2B6 gene (allele designation 2B6*5) that significantly impacted patient outcomes. After adjusting for disease status and conditioning regimen, patients with CYP2B6*1/*5 genotype had a higher 2-year relapse rate (HR 3.3; 95%CI 1.6-6.5; p=0.041) and decreased overall survival (HR 13.5; 95%CI 3.5-51.9; p=0.008) than patients with wild-type allele. Two-year progression-free survival for patients with two hypo-functional CYP2B6 variant genotypes (*5 and *6) was only 11% (95%CI 1-39%) compared to 67% (95% CI 55-77%) for patients with the wild-type CYP2B6*1 allele in exon 9. Our results suggest that CYP2B6 SNPs influence the efficacy of high-dose Cy and significantly reduce the success of autologous HCT for lymphoma patients with the CYP2B6*5 variant.
    Biology of Blood and Marrow Transplantation 02/2015; 21(5). DOI:10.1016/j.bbmt.2015.02.001 · 3.40 Impact Factor

Publication Stats

28k Citations
3,677.11 Total Impact Points


  • 2007–2015
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
    • Northwestern University
      Evanston, Illinois, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1991–2015
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 1982–2015
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States
    • University of Connecticut
      • Department of Nutritional Sciences
      Storrs, Connecticut, United States
  • 2014
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2013
    • Carolinas HealthCare System
      Charlotte, North Carolina, United States
    • American Cancer Society
      Atlanta, Georgia, United States
  • 2011–2012
    • Moffitt Cancer Center
      • Program in Blood and Marrow Transplantation
      Tampa, FL, United States
    • Emory University
      Atlanta, Georgia, United States
  • 2002–2012
    • University of Toronto
      Toronto, Ontario, Canada
  • 2002–2011
    • Roswell Park Cancer Institute
      • Department of Medicine
      Buffalo, New York, United States
  • 2010
    • University Hospitals Bristol NHS Foundation Trust
      Bristol, England, United Kingdom
  • 2007–2010
    • City of Hope National Medical Center
      • Department of Population Sciences
      Duarte, CA, United States
  • 2002–2010
    • University of Minnesota Twin Cities
      • • Division of Pediatric Blood and Marrow Transplantation (BMT)
      • • Division of Hematology, Oncology and Transplantation
      Minneapolis, Minnesota, United States
  • 1995–2009
    • Fred Hutchinson Cancer Research Center
      • Division of Clinical Research
      Seattle, Washington, United States
  • 2008
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
    • British Society of Blood and Marrow Transplantation
      Bristol, England, United Kingdom
  • 2000–2008
    • Medical College of Wisconsin
      • Center for International Blood & Marrow Transplant Research
      Milwaukee, Wisconsin, United States
    • The Rockefeller University
      New York, New York, United States
  • 2006
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, Michigan, United States
  • 1995–2006
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2005
    • Columbia University
      New York, New York, United States
  • 1999–2005
    • National Cancer Institute (USA)
      • • Experimental Transplantation and Immunology Branch
      • • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
  • 2003
    • National Marrow Donor Program
      Minneapolis, Minnesota, United States
  • 2001–2002
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 1998
    • Children's Hospitals and Clinics of Minnesota
      Minneapolis, Minnesota, United States
  • 1990
    • Children's Hospital Los Angeles
      • Division of Hematology-Oncology
      Los Ángeles, California, United States
  • 1988
    • Minnesota Department of Health
      Saint Paul, Minnesota, United States
  • 1981
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States