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1.  Health-related QoL of Bone Marrow versus PBSC Donors: A Pre-specified Subgroup Analysis from a Phase III RCT—BMTCTN protocol 0201 
Hematopoietic stem cells can be procured from unrelated donors via either the bone marrow (BM) aspiration or peripheral blood stem cell (PBSC) collection methods. There is no evidence from prospective randomized trials in the unrelated donor setting about the relative health-related quality-of-life (HRQoL) benefits/costs to donors. The goals of this prospective longitudinal investigation were to describe and compare the donation-related HRQoL experiences of 332 BM and PBSC donors.
Donors were interviewed at pre-donation, 48 hours after donation, weekly until fully recovered and at 6 and 12 months post-donation.
Pre-donation, BM donors had lower confusion, fewer concerns, and were more prepared for donation. Shortly post-donation BM donors reported more physical side effects. BM donors also reported more donation-related impact on their social activities. However, BM donors reported somewhat better psychological status and were more likely to indicate that the donation made their lives more meaningful. There were virtually no longer-term differences in the experiences of the two donor groups including no recovery time difference beginning 3 weeks after donation.
Although BM donors may experience the process as more physically stressful and more psychologically beneficial in the short-term, the longer-term HRQoL consequences of BM and PBSC donors are similar.
doi:10.1016/j.bbmt.2013.10.024
PMCID: PMC3978600  PMID: 24184336
2.  C-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice 
European journal of immunology  2013;43(9):2327-2337.
Transcription factor of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and GVHD remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel-/- T cells had reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients. c-Rel-/- T cells were defective in the differentiation into Th1 cells after encountering alloantigens, but were enhanced in the differentiation towards Foxp3+ regulatory T cells (Tregs). Furthermore, c-Rel-/- T cells had largely preserved activity to mediate graft-versus leukemia (GVL) response. Taken together, our findings indicate that c-Rel plays an essential role in T cells in the induction of acute GVHD, and suggest that c-Rel can be a potential target for therapeutic intervention in allogeneic HCT in clinic.
doi:10.1002/eji.201243282
PMCID: PMC3940138  PMID: 23716202
c-Rel; BMT; GVHD
3.  Bortezomib salvage followed by a phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma 
British journal of haematology  2012;157(5):553-563.
Summary
We conducted a phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received 2 cycles of salvage bortezomib followed by stem cell mobilization with G-CSF and harvest. Melphalan 100 mg/m2/day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4.35 mg/L (range: 1.8 - 11.4); albumin was 3.7 g/dL (range: 3.1 - 4.9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1.3 mg/m2 was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥PR) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 (95% CI: 11 - 21) months and the median overall survival was 35 (95% CI: 22 - 43) months. Correlative studies demonstrated decreased expression of FANCD1 (P=0.0072) and FANCF (P=0.0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well tolerated conditioning with some activity in patients with resistant myeloma.
doi:10.1111/j.1365-2141.2012.09099.x
PMCID: PMC4030553  PMID: 22449149
Bortezomib; autologous transplantation; multiple myeloma; Fanconi anemia; DNA repair pathway
4.  Dynamic Change and Impact of Myeloid Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice 
Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells comprised of hematopoietic progenitor cells, immature macrophages, dendritic cells and granulocytes, which accumulate in inflammatory diseases and various cancers. Here, we investigated the dynamic changes and effects of MDSCs in graft-versus-host disease (GVHD) development and/or tumor relapse after syngeneic and allogeneic bone marrow transplantation (BMT). We found that adding functional MDSCs in donor graft alleviated GVHD, whereas removal of MDSCs in vivo exacerbated GVHD. Following T cell-deplete BMT, MDSCs transiently accumulated in the blood and spleen of recipients without GVHD; In contrast, after T cell-replete BMT, the levels of blood MDSCs were constantly elevated in recipients with GVHD. MDSC accumulation positively correlated with the severity of GVHD. Additionally, MDSC accumulation was further increased upon tumor relapse. Although MDSCs isolated from both syngeneic and allogeneic BMT recipients inhibited T-cell proliferation in response to alloantigen stimulation ex vivo, MDSCs from the recipients with GVHD showed much higher suppressive potency compared to those from recipients without GVHD. These results indicate that MDSCs can regulate the immune response in acute GVHD, and possibly tumor relapse, subsequent to allogeneic BMT.
doi:10.1016/j.bbmt.2013.01.008
PMCID: PMC4011929  PMID: 23376089
5.  Adoptive transfer of Tc1 or Tc17 cells elicits anti-tumor immunity against established melanoma through distinct mechanisms1 
Adoptive cell transfer (ACT) of ex vivo activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that Th17/Tc17 cells may exhibit potent anti-tumor activity, but the specific mechanisms have not been completely defined. In the present study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized Tc1 or Tc17 cells combined with autologous BMT after total TBI. BMT combined with ACT of anti-tumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFNγ but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFNγ or both IFNγ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT the Tc17 cells had a long-lived effector T cell phenotype (CD127hi/KLRG-1low) as compared to Tc1 cells. Mechanistically, Tc1 cells mediated anti-tumor immunity primarily through the direct effect of IFNγ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFNγ, Tc17-mediated anti-tumor immunity was independent of the direct effects of IFNγ on the tumor. Nevertheless, IFNγ played a critical role by creating a microenvironment that promoted Tc17-mediated anti-tumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective anti-tumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression.
doi:10.4049/jimmunol.1201989
PMCID: PMC3563723  PMID: 23315072
6.  Hematopoietic Cell Transplantation in 2020: Summary of Year 2 Recommendations of the National Marrow Donor Program’s System Capacity Initiative 
The National Marrow Donor Program, in partnership with the American Society for Blood and Marrow Transplantation, sponsored and organized a series of symposia to identify complex issues affecting the delivery of hematopoietic cell transplantation (HCT) and to collaboratively develop options for solutions. “Hematopoietic Cell Transplantation in 2020: A System Capacity Initiative” used a deliberative process model to engage professional organizations, experts, transplant centers, and stakeholders in a national collaborative effort. Year 2 efforts emphasized data analysis and identification of innovative ideas to increase HCT system efficiency, address future capacity requirements, and ensure adequate reimbursement for HCT programs to meet the projected need for HCT. This report highlights the deliberations and recommendations of Year 2 and the associated symposium held in September 2011.
doi:10.1016/j.bbmt.2012.10.005
PMCID: PMC3617925  PMID: 23078785
Allogeneic transplant; Care delivery model; Reimbursement; Healthcare disparities; Workforce
7.  T helper17 Cells Are Sufficient But Not Necessary to Induce Acute Graft-Versus-Host Disease 
T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-γ after being transplanted into allogeneic recipients; however, IFN-γ was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4 T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORγt (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.
doi:10.1016/j.bbmt.2009.09.023
PMCID: PMC3876952  PMID: 19804837
Th1; Th17; BMT; GVHD
8.  Human CMV-induced Memory-like NKG2C+ NK cells are Transplantable and Expand in vivo in Response to Recipient CMV Antigen1 
We have previously shown that NKG2C+ NK cells from CMV naïve umbilical cord blood (UCB) grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation (HCT). In this study, recipients of adult donor HCT were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C+ NK cells in order to determine responses to secondary CMV events. Expansion of NKG2C+ NK cells was seen following clinical CMV reactivation. However, they also expanded in the absence of detectable CMV viremia when both the donor and recipient were CMV seropositive. Upregulation of NKG2C was observed in NK cells from CMV positive recipients receiving grafts from CMV seropositive or seronegative donors. These in vivo expanded NKG2C+ NK cells had an increased capacity for target cell induced cytokine production, expressed an inhibitory KIR for self HLA and preferentially acquired CD57. Most importantly, NKG2C+ NK cells transplanted from seropositive donors exhibit heightened function in response to a secondary CMV event compared to NKG2C+ NK cells from seronegative donors. We conclude that NKG2C+ memory-like NK cells are transplantable and require active or latent (subclinical) expression of CMV antigen in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.
doi:10.4049/jimmunol.1201964
PMCID: PMC3490031  PMID: 23077239
9.  Stemness of B cell progenitors in multiple myeloma bone marrow 
Purpose
In myeloma, B cells and plasma cells show a clonal relationship. Clonotypic B cells may represent a tumor-initiating compartment or cancer stem cell responsible for minimal residual disease in myeloma.
Experimental Design
We report a study of 58 patients with myeloma at time of diagnosis or relapse. B cells in bone marrow were evaluated by multicolor flow cytometry and sorting. Clonality was determined by light chain and/or immunoglobulin chain gene rearrangement PCR. We also determined aldehyde dehydrogenase activity and colony formation growth. Drug sensitivity was tested with conventional and novel agents.
Results
Marrow CD19+ cells express a light chain identical to plasma cells and are therefore termed light chain restricted (LCR). The LCR B cell mass is small in both newly diagnosed and relapsed patients (≤1%). Few marrow LCR B cells (~10%) are CD19+/CD34+, with the rest being more differentiated CD19+/CD34− B cells. Marrow LCR CD19+ B cells exhibit enhanced aldehyde dehydrogenase activity versus healthy controls. Both CD19+/CD34+ and CD19+/CD34− cells showed colony formation activity, with colony growth efficiency optimized when stroma-conditioned medium was used. B cell progenitors showed resistance to melphalan, lenalidomide, and bortezomib. Panobinostat, a histone deacetylase inhibitor, induced apoptosis of LCR B cells and CD138+ cells. LCR B cells are CD117, survivin, and Notch positive.
Conclusions
We propose that antigen-independent B cell differentiation stages are involved in disease origination and progression in myeloma. Further investigations of myeloma putative stem cell progenitors may lead to novel treatments to eradicate the potential reservoir of minimal residual disease.
doi:10.1158/1078-0432.CCR-12-0531
PMCID: PMC3500436  PMID: 22988056
multiple myeloma; B cell progenitors; bone marrow; stemness
10.  Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors 
The New England journal of medicine  2012;367(16):10.1056/NEJMoa1203517.
BACKGROUND
Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.
METHODS
We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37).
RESULTS
The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P = 0.29), with an absolute difference of 5 percentage points (95% CI, −3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P = 0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P = 0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse.
CONCLUSIONS
We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute–National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.)
doi:10.1056/NEJMoa1203517
PMCID: PMC3816375  PMID: 23075175
11.  Time to consider HPV vaccination after allogeneic stem cell transplantation 
Squamous cell carcinoma (SCC) is among the most common secondary cancers after allogeneic stem cell transplantation (allo-SCT). Several types of human papillomavirus (HPV) are causally linked with SCC of the genital tract and head & neck, and the incidence of these cancers is higher among immunosuppressed patients compared to immunocompetent patients. In June 2006, a quadrivalent HPV vaccine was approved by the Food and Drug Administration (FDA) for females aged 9–26 to prevent cervical warts and vulvar, vaginal, and cervical cancer. FDA approval was granted in October 2009 for males aged 9–26 to prevent genital warts. The quadrivalent HPV vaccine is now available for off-label use and may be beneficial to patients after allo-SCT. It is time to evaluate the immunogenicity and efficacy in preventing HPV-related squamous cell carcinoma in this population.
doi:10.1016/j.bbmt.2010.03.007
PMCID: PMC3750708  PMID: 20302962
HPV; vaccination; secondary cancer; squamous cell carcinoma; transplantation
12.  LBH589 enhances T-cell activation in vivo and accelerates graft-versus-host disease in mice 
Histone deacetylase inhibitors (HDACi) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The FDA approved HDACi, Vorinostat or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of pro-inflammatory cytokines. In preclinical allogeneic transplantation models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia (GVL). LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplantation (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T-cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT, and alerts that LBH589 (Panobinostat) could have adverse effect on GVHD, and possibly on other inflammatory diseases.
doi:10.1016/j.bbmt.2012.06.002
PMCID: PMC3417119  PMID: 22698484
13.  T-Cell Depleted Partial Matched Unrelated Donor Transplant for Advanced Myeloid Malignancy: KIR Ligand Mismatch and Outcome 
To evaluate the applicability of high-dose conditioning, CD34 selection and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplant conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M2/day × 5) and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg day × 2) and a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 (range 22–61)) were mismatched at 1–3/10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with one primary graft failure and two early deaths. The cumulative incidence of Grade II–IV acute GVHD (34%, 95% confidence interval (CI), 14–54%), chronic GVHD (20%, 95% CI, 2–38%) and relapse (26%, 95% CI, 8–84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) vs. KIR ligand match (n = 19). Only three (12%) had Grade III–IV GVHD. Non-relapse occurred in 17% (95% CI, 30–31%) by 100 days and 35% (95% CI, 15–55%) by 1 year. Two year survival and leukemia-free survival were each 40% (95% CI, 21–59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first two months, were frequent, and were the cause of death in five patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high risk, unstable leukemia limited accrual. Improvements in peritransplant disease control and additional measures to augment the allogeneic graft vs. leukemia effect are still required.
doi:10.1016/j.bbmt.2011.11.024
PMCID: PMC3319849  PMID: 22155505
Transplantation; Unrelated donor; Leukemia; Mismatch
14.  Have we improved in preventing and treating acute GVHD? 
Current opinion in hematology  2011;18(6):408-413.
Purpose of review
Acute graft vs. host disease (GVHD) is a considerable source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Accordingly, progress in the prevention and primary therapy of this complication is needed to improve patient outcomes.
Recent findings
Guided by insights into acute GVHD pathogenesis, investigators have explored novel cellular and pharmacologic approaches to acute GVHD prevention that demonstrates promise. While pan-T cell depletion has reduced GVHD, novel strategies that selectively deplete alloreactive T cells or modulate the balance of effector T cells and regulatory T cells offer promise to selectively abrogate acute GVHD while retaining protection from primary disease relapse and infectious complications.
Summary
Divergent approaches in the primary therapy of acute GVHD have explored both combination approaches with standard dose glucocorticoids and additional immunosuppressive agents and conversely steroid-sparing approaches including topical agents such as beclomethasone or sirolimus as a steroid-free approach to acute GVHD therapy. Mature results of high quality clinical trials are needed to determine the optimal therapy that results in effective control of the syndrome and limited toxicity. These complementary outcomes represent the therapeutic goal for future investigation in acute GVHD therapy.
doi:10.1097/MOH.0b013e32834b6196
PMCID: PMC3432261  PMID: 21912253
Graft-versus-Host Disease (GVHD); Hematopoietic Cell Transplantation (HCT); regulatory T cells (Tregs)
15.  What are the most important donor and recipient factors affecting the outcome of related and unrelated allogeneic transplantation? 
Several recipient and donor risk factors affect outcome after transplantation with allogeneic hematopoietic stem cells. The most important recipient risk factors are patient age, comorbidity, performance status, cytomegalovirus (CMV) status, and disease considerations, such as diagnosis, stage, and cytogenetic risk. Prior chemotherapy regimens, patient race, and IL10 promoter polymorphism also appear to have some impact, but to a lesser extent. The most important donor factor is the level of HLA mismatch. Donor gender, relation, age, and KIR genotype also affect outcome. Donor CMV serology, parity, and race do not appear to affect outcome. These factors must all be considered in relation to one another when selecting whether to recommend patients for transplant.
doi:10.1016/j.beha.2008.10.002
PMCID: PMC3470825  PMID: 19041609
transplant; acute leukemia; patient; recipient; donor; risk factors; HLA mismatch; comorbidity; related; unrelated
16.  Impact of donor-recipient HLA-matching at HLA-A, -B, -C and –DRB1 on outcomes after umbilical cord blood transplantation for leukemia and myelodysplastic syndrome: a retrospective analysis 
The lancet oncology  2011;12(13):1214-1221.
Background
The importance of matching at the human leukocyte antigen (HLA) C locus has not been well defined for unrelated umbilical cord blood transplantation. The selection algorithm for umbilical cord blood units generally considers intermediate resolution HLA typing at A and B, and allele-level at DRB1. We aimed to determine the relative importance of matching at HLA-C in addition to current selection criteria.
Methods
We used Cox regression to retrospectively examine for the effect of donor-recipient HLA matching on outcomes of 803 single umbilical cord blood transplantations for leukemia (N=727) and myelodysplastic syndrome (N=76). The primary endpoint was transplant-related mortality. HLA typing was performed using molecular techniques with a minimum of intermediate resolution for HLA-A, -B and -C and allele-level for DRB1.
Findings
Compared to transplantations matched at HLA-A, -B, -C, -DRB1 (N=69; HR 1.00), transplant-related mortality risks were higher after transplantations matched at HLA-A, -B, -DRB1 and mismatched at HLA-C (N=23;HR 3.97, 95% CI 1.27 – 12.40, p=0.018). Transplant-related mortality risk were also higher after transplantations with a single mismatch at HLA-A or -B, or -DRB1 and mismatched at HLA-C (N=234; HR 1.70 95% CI 1.06 – 2.74, p=0.029) compared to transplantations matched at HLA-C with a single mismatch at HLA-A, -B, or -DRB1 (N=127; HR 1.00). Examining for an overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (N=259; HR 3.27 95% CI 1.42 – 7.54, p=0.006), three (N=253; HR 3.34 95% CI 1.45 – 7.71, p=0.005) or four (N=75; HR 3.51 95% CI 1.44 – 8.58, p=0.006) loci compared to matched units (N=69; HR 1.00).
Interpretation
These data suggest that we re-evaluate the current strategy for umbilical cord blood unit selection, by considering matching at HLA-C for units that are matched at HLA-A, -B, -DRB1 or in the presence of a single locus mismatch at HLA-A, -B or DRB1 to minimize mortality risks.
Funding
National Cancer Institute, National Heart Lung and Blood Institute and National Institute for Allergy and Infectious Diseases; Scholar in Clinical Research Award, the Leukemia and Lymphoma Society; Heath Resources and Services Administration; Office of Naval Research, United States Department of Navy; Children’s Leukemia Research Association; INSERM grant TGIR.
doi:10.1016/S1470-2045(11)70260-1
PMCID: PMC3245836  PMID: 21982422
17.  HLA-C Antigen mismatches are associated with worse outcomes in unrelated donor peripheral blood stem cell transplantation 
Purpose
The association between human leukocyte antigen (HLA) matching and outcome in unrelated donor, peripheral blood stem cell (PBSC) transplantation has not been established.
Patients and Methods
1933 unrelated donor-recipient pairs transplanted between 1999-2006 for AML, ALL, MDS or CML and who had high resolution HLA typing for HLA-A, B, C, DRB1, DQA1 and DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics.
Results
Matching for HLA-A, -B, -C and DRB1 alleles [8/8 match] was associated with better survival at one year compared with 7/8 HLA-matched pairs (56% vs. 47%). Using 8/8 HLA-matched patients as the baseline (n=1243), HLA-C antigen mismatches (n=189) were statistically significantly associated with lower LFS (RR 1.36 [95% CI 1.13-1.64] p=0.0010), and increased risk for mortality (RR=1.41 [1.16-1.70], p=0.0005), treatment-related mortality (RR=1.61 [1.25-2.08], p=0.0002), and grades III-IV graft-versus-host disease (RR=1.98 [1.50-2.62], p<0.0001). HLA-B antigen or allele mismatching was associated with a higher risk for acute GVHD grades III-IV. No statistically significant differences in outcome were observed for HLA-C allele mismatch (n=61), nor for mismatches at HLA-A antigen/allele (n=136), HLA-DRB1 allele (n=39) or HLA-DQ antigen/allele (n=114) compared to 8/8 HLA-matched pairs. HLA mismatching was not associated with relapse or chronic GVHD.
Conclusion
HLA-C antigen mismatched unrelated PBSC donors are associated with worse outcomes compared with 8/8 HLA-matched donors. Limited power due to small sample sized prevents comment about other mismatches.
doi:10.1016/j.bbmt.2010.09.012
PMCID: PMC3071866  PMID: 20870028
18.  Efficient and Selective Prevention of GVHD by Antigen-Specific Induced Tregs via Linked-Suppression in Mice 
Naturally occurring regulatory T cells (nTregs) suppress the development of GVHD and may spare graft-versus-leukemia (GVL) effect. Because nTreg is a rare population in a healthy individual, the limited source and the non-selective suppression are major hurdles towards the application of nTregs in the control of clinical GVHD after allogeneic HCT. An alternative approach is to generate induced Tregs (iTregs) from naïve CD4 precursors, but the effectiveness of iTregs in the control of GVHD is highly controversial and requires further investigation. The other critical but unsolved issue on Treg therapy is how to achieve antigen (Ag)-specific tolerance that distinguishes GVHD and GVL effect. To address the important issues on the effectiveness of iTregs and Ag-specificity of Tregs, we generated Ag-specific iTregs and tested their potential in the prevention of GVHD in pre-clinical BMT model. CD4+CD25+Foxp3+ iTregs generated from OT-II TCR transgenic T cells specific for OVA target Ag efficiently prevented GVHD induced by polyclonal T effector cells (Teffs) only in the allogeneic recipients that express OVA protein but not in OVA− recipients. The efficacy of these Ag-specific iTregs was significantly higher than polyclonal iTregs. As controls, OT-II CD4+Foxp3− cells had no effect on GVHD development in OVA− recipients and exacerbated GVHD in OVA+ recipients when transplanted together with polyclonal Teffs. Because the iTregs recognize OVA whereas Teffs recognize alloAg bm12, our data reveal for the first time that Tregs prevent GVHD through a linked suppression. Mechanistically, OT-II iTregs expanded extensively, and significantly suppressed expansion and infiltration of Teffs in OVA+ but not in OVA− recipients. These results demonstrate that Ag-specific iTregs can prevent GVHD efficiently and selectively, providing a proof of principle that Ag-specific iTregs may represent a promising cell therapy for their specificity and higher efficacy in allogeneic HCT.
doi:10.1016/j.bbmt.2010.12.710
PMCID: PMC3039088  PMID: 21224010
19.  Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo  
Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim-/- T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation.
PMCID: PMC3301434  PMID: 22432091
Bim; T cells; proliferation; apoptosis; alloantigen; GVHD; GVL; and BMT
20.  Comparative Analysis of Busulfan and Cyclophosphamide versus Cyclophosphamide and Total Body Irradiation in Full Intensity Unrelated Marrow Donor Transplantation for Acute Myelogenous Leukemia, Chronic Myelogenous Leukemia and Myelodysplasia 
Bone marrow transplantation  2010;46(1):34-43.
We retrospectively compared clinical outcomes in 1593 T-repleted URD marrow transplant recipients with AML, MDS and CML who received myeloablative conditioning regimens of either busulfan and cyclophosphamide (BuCy), standard-dose Cy/TBI (1,000-1,260 cGy) or high-dose Cy/TBI (1,320-1,500 cGy). Subjects were drawn from patients transplanted between 1991 and 1999 facilitated by the National Marrow Donor Program (NMDP). Patients who received high-dose Cy/TBI regimens were slightly younger, more likely to receive a mismatched transplant and to have intermediate or advanced disease compared to patients in the BuCy or standard-dose TBI group. Neutrophil recovery was significantly higher in the standard dose CY/TBI group compared to the high-dose Cy/TBI or BuCy group. Patients who received the high-dose Cy/TBI regimen had an increased risk of developing grade III-IV aGVHD when compared to the control group who received BuCy (p=0.011). Overall survival (OS), disease free survival (DFS), transplant-related mortality (TRM) and relapse were not significantly different between any of the regimens. We conclude that BuCy, standard-dose and high dose Cy/TBI regimens have equivalent efficacy profiles for OS, DFS, TRM and relapse risk in patients undergoing T-replete URD marrow transplantation for AML, CML and MDS.
doi:10.1038/bmt.2010.81
PMCID: PMC3169009  PMID: 20400989
Unrelated donor transplantation; TBI conditioning regimens; Busulfan
21.  Health-related quality of life following hematopoietic cell transplantation: Patient education, evaluation, and intervention 
British journal of haematology  2009;148(3):373-385.
Summary
Health-related quality of life (QOL) is a vital concern in the pre-treatment consent process and post-treatment care of recipients of hematopoietic cell transplantation (HCT). We propose that comprehensive care of such patients requires an integration of knowledge of the impact of HCT on QOL, assessment of QOL, as well as resources available for intervention. This knowledge may significantly improve patient care when incorporated into daily clinical practice in the transplant setting. As a framework for this approach, this article reviews the literature on QOL after allogeneic and autologous HCT for adults with hematological malignancies. We then discuss evidence in support of the beneficial impact of clinical QOL assessment, and finally evaluate behavioral interventions that show promise to maintain or improve QOL after HCT.
doi:10.1111/j.1365-2141.2009.07992.x
PMCID: PMC2810350  PMID: 19919651
Quality of Life; BMT; Cancer; Stem Cell Transplantation
22.  Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia 
Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days) and cyclophosphamide (60 mg/kg IV × 2 days) - (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000 μM/L*min per day × 4 days) and fludarabine (40 mg/m2 × 4 days) - (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered.
doi:10.1186/1756-8722-3-36
PMCID: PMC2958877  PMID: 20925957
23.  Voriconazole Provides Effective Prophylaxis for Invasive Fungal Infection in Patients Receiving Glucocorticoid Therapy for Graft-Versus-Host Disease 
Bone marrow transplantation  2009;45(4):662-667.
Patients on systemic glucocorticoids for graft-versus-host disease (GVHD) after hematopoietic cell transplant are susceptible to invasive fungal infections (IFI), which greatly contribute to morbidity and mortality. We evaluated the efficacy of prophylactic treatment options (voriconazole versus fluconazole or itraconazole) for IFI by performing a retrospective review of patients on glucocorticoids for GVHD given voriconazole (n = 97), fluconazole (n = 36), or itraconazole (n = 36). IFI developed in 7/72 (10%) patients on fluconazole/itraconazole versus 2/97 (2%) on voriconazole (P = 0.03) within the first 100 days of glucocorticoids. Five patients developed Aspergillus IFI on fluconazole/itraconazole (7%), compared to none on voriconazole (0%) (P = 0.008); Aspergillus IFI resulted in death in all 5 patients. We found that IFI occurred in patients who received an initial dose of at least 2 mg/kg/day of prednisone or equivalent; when the analysis was restricted to these patients, the hazard ratio (0.39; 95% confidence interval: 0.08–1.86) was consistent with a protective effect of voriconazole compared with fluconazole/itraconazole, although this subset analysis did not reach significance. Overall survival at 100 days after start of glucocorticoids was 77% in patients given fluconazole/itraconazole and 85% in those given voriconazole (P = 0.22). Our results suggest that voriconazole is more effective than fluconazole/itraconazole in preventing IFI, especially aspergillosis, in patients receiving glucocorticoids posttransplant.
doi:10.1038/bmt.2009.210
PMCID: PMC2850960  PMID: 19684623
voriconazole; hematopoietic cell transplant; invasive fungal infections; graft-versus-host disease
24.  A Limited Sampling Schedule to Estimate Individual Pharmacokinetic Parameters of Fludarabine in Hematopoietic Cell Transplant Patients 
Purpose
Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS.
Experimental Design
A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily IV fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve (AUC).
Results
A two compartment model best fit the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean square error (sMSE) for the AUC for each simulated individual. The LSS times chosen were: 0.583 hour (hr), 1.5 hr, 6.5 hr and 24 hr after the start of the 30 minute fludarabine infusion.
Conclusion
The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining 4 blood samples (using the LSS) and maximum a posteriori (MAP) Bayesian estimation.
Conclusions
These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving IV fludarabine in the ambulatory clinic.
doi:10.1158/1078-0432.CCR-09-0427
PMCID: PMC2763506  PMID: 19671874
Fludarabine; nucleoside analogs; population pharmacokinetics; limited sampling schedule; hematopoietic cell transplant
25.  Longitudinal Assessment of Morbidity and Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation: Retrospective Analysis of a Multicenter Phase III Study 
Since morbidity early after HCT results in large part from the development of acute GVHD, we previously proposed that a longitudinal assessment of morbidity involving the skin, liver, and gastrointestinal tract might provide a more complete, objective approach for comparing two arms of open-label randomized clinical trials for acute GVHD prevention. In the current study, we determined both morbidity-across-time and GVHD-across-time in a retrospective analysis of a database from an open-label randomized clinical trial comparing tacrolimus/methotrexate versus cyclosporine/methotrexate after myeloablative conditioning and marrow transplantation from HLA-matched unrelated donors. The results confirmed differences in overall morbidity across time among patients with peak grades II-IV GVHD as compared to those with grades 0-I GVHD, but no significant differences were found between morbidity associated with grade II GVHD as compared to grades 0-I GVHD. We observed less skin and a trend towards less liver morbidity across time in the tacrolimus group (p=0.04; p= 0.09, respectively) but not for gastrointestinal or overall morbidity, despite significantly decreased skin and liver stages and overall grades of GVHD-across-time in the tacrolimus arm. In conclusion, an objective assessment of differences in morbidity (regardless of cause) as a measure of acute GVHD in a randomized clinical tria of acute GVHD prevention had limited utility. The difficulty of demonstrating clinical benefits from objective parameters such as survival and morbidity and the subjectivity of grading acute GVHD emphasize that blinded assessments are required in clinical trials of GVHD prevention.
doi:10.1016/j.bbmt.2009.03.009
PMCID: PMC2684865  PMID: 19450760
graft-versus-host disease; tacrolimus; cyclosporine

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