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1.  Risk factors for acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation with umbilical cord blood and matched related donors 
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.
doi:10.1016/j.bbmt.2015.09.008
PMCID: PMC4787268  PMID: 26365153
2.  Phase 1 study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies 
Background
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 1 dose escalation study to assess the safety, maximum tolerated dose (MTD), and preliminary efficacy of DT2219 in patients with relapsed/refractory B cell lymphoma or leukemia.
Methods
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.
Results
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 (AE) including, weight gain, low albumin, transaminitis and fevers 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 neutralizating antibody (30%).
Conclusions
We have determined the safety of a novel immunotoxin DT2219 and established it's biologically active dose between 40-80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned.
doi:10.1158/1078-0432.CCR-14-2877
PMCID: PMC4360883  PMID: 25770294
diphtheria toxin; refractory lymphoma; ALL; phase 1 trial; immunotherapy
3.  Higher Dose of Mycophenolate Mofetil Reduces Acute Graft-Versus-Host Disease in Reduced Intensity Conditioning Double Umbilical Cord Blood Transplantation 
Mycophenolate mofetil (MMF) is frequently used in hematopoietic cell transplantation (HCT) for graft-versus-host disease (GVHD) prophylaxis and to facilitate engraftment. We previously reported that a higher level of mycophenolic acid can be achieved with an MMF dose of 3 g/day as compared to 2g/day. Here, we retrospectively compared clinical outcomes of reduced intensity conditioning (RIC) double umbilical cord blood (dUCB) HCT recipients receiving cyclosporine A with MMF 2g (n=93) vs. 3g (n=175) daily. Multiple regression analysis adjusted for ATG in the conditioning revealed that MMF 3g/day led to a 49% relative risk reduction in grade II–IV acute GVHD rate (RR=0.51, 95%CI 0.36–0.72; p<0.01). However, the higher MMF dose was not protective for chronic GVHD. Additionally, MMF dose was not an independent predictor of neutrophil engraftment, treatment-related mortality at 6 months, or 2-year post-transplant disease relapse, disease-free survival, or overall survival. Higher MMF dose did not increase risk of infectious complications and infection-related mortality was similar for both MMF doses. Our data indicate that MMF 3g/day reduces the risk of acute GVHD without affecting other clinical outcomes and should be used for GVHD prophylaxis after RIC dUCBT.
doi:10.1016/j.bbmt.2015.01.023
PMCID: PMC4768800  PMID: 25655791
Transplantation; MMF; GVHD; RIC; UCB
4.  THE INFLUENCE OF HLA CLASS I ALLELES AND THEIR POPULATION FREQUENCIES ON HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 CONTROL AMONG AFRICAN AMERICANS 
Human immunology  2011;72(4):312-318.
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
doi:10.1016/j.humimm.2011.01.003
PMCID: PMC3778654  PMID: 21262311
HLA class I; Allele frequency; HIV-1 control; African American
5.  Human Leukocyte Antigen Class I Supertypes and HIV-1 Control in African Americans▿  
Journal of Virology  2009;84(5):2610-2617.
The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in African Americans has not been established. We examined the effects of the HLA-A and HLA-B alleles and supertypes on the outcomes of HIV-1 clade B infection among 338 African American women and adolescents. HLA-B58 and -B62 supertypes (B58s and B62s) were associated with favorable HIV-1 disease control (proportional odds ratio [POR] of 0.33 and 95% confidence interval [95% CI] of 0.21 to 0.52 for the former and POR of 0.26 and 95% CI of 0.09 to 0.73 for the latter); B7s and B44s were associated with unfavorable disease control (POR of 2.39 and 95% CI of 1.54 to 3.73 for the former and POR of 1.63 and 95% CI of 1.08 to 2.47 for the latter). In general, individual alleles within specific B supertypes exerted relatively homogeneous effects. A notable exception was B27s, whose protective influence (POR, 0.58; 95% CI, 0.35 to 0.94) was masked by the opposing effect of its member allele B*1510. The associations of most B supertypes (e.g., B58s and B7s) were largely explained either by well-known effects of constituent B alleles or by effects of previously unimplicated B alleles aggregated into a particular supertype (e.g., B44s and B62s). A higher frequency of HLA-B genotypic supertypes correlated with a higher mean viral load (VL) and lower mean CD4 count (Pearson's r = 0.63 and 0.62, respectively; P = 0.03). Among the genotypic supertypes, B58s and its member allele B*57 contributed disproportionately to the explainable VL variation. The study demonstrated the dominant role of HLA-B supertypes in HIV-1 clade B-infected African Americans and further dissected the contributions of individual class I alleles and their population frequencies to the supertype effects.
doi:10.1128/JVI.01962-09
PMCID: PMC2820922  PMID: 20032191
6.  Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency Virus Type 1 Infection in Native Africans 
Journal of Virology  2006;80(12):6056-6060.
Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every population.
doi:10.1128/JVI.02119-05
PMCID: PMC1472610  PMID: 16731944

Results 1-6 (6)