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.
HPV; vaccination; secondary cancer; squamous cell carcinoma; transplantation
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.
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.
Transplantation; Unrelated donor; Leukemia; Mismatch
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.
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.
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.
Graft-versus-Host Disease (GVHD); Hematopoietic Cell Transplantation (HCT); regulatory T cells (Tregs)
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.
transplant; acute leukemia; patient; recipient; donor; risk factors; HLA mismatch; comorbidity; related; unrelated
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
Bim; T cells; proliferation; apoptosis; alloantigen; GVHD; GVL; and BMT
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.
Unrelated donor transplantation; TBI conditioning regimens; Busulfan
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.
Quality of Life; BMT; Cancer; Stem Cell Transplantation
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.
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.
voriconazole; hematopoietic cell transplant; invasive fungal infections; graft-versus-host disease
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.
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).
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.
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.
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.
Fludarabine; nucleoside analogs; population pharmacokinetics; limited sampling schedule; hematopoietic cell transplant
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.
graft-versus-host disease; tacrolimus; cyclosporine
Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for patients with myelodysplastic syndromes (MDS). Most patients with MDS are older than 60 years and age-associated morbidities limit the patients’ options for curative transplant therapy. Since the development of conditioning regimens with reduced toxicity, the age limitations for HCT have waned for those patients with good performance status. This review will discuss the role of HCT for MDS based on prognostic features, the optimal timing of HCT, and outcomes based on patient age.
Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved.
Patients and Methods
Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk.
Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL.
This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may facilitate individualized risk estimates and raise several interesting biologic questions.
CD28 is required for the development of regulatory T cells (Tregs; CD4+CD25+Foxp3+) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using wild-type, CD28-, ICOS-, or CD28/ICOS-double knockout mice on C57BL/6 background as T cell sources, we found that CD28 is essential, whereas ICOS is dispensable, for the development and homeostasis of Tregs. Furthermore, the differentiation of Tregs from naive CD4+CD25− T cells in vivo also depends on CD28. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb-blocked Treg differentiation from wild-type CD4+CD25− T cells and addition of IL-2 restored Treg differentiation from CD28−/− T cells. Other common γ-chain cytokines, IL-4, IL-7, or IL-15, do not share such a role with IL-2. Although CD28 is required for the differentiation of Tregs from naive T cells, already generated Tregs do not depend on CD28 to exert their suppressive function. Our study reveals a new aspect of CD28 function in regulating T cell response.
The best unrelated donor (URD) for hematopoietic cell transplantation (HCT) is allele-matched at HLA-A,B,C and DRB1. Earlier studies mostly used incomplete or lower resolution HLA typing for analysis of transplant outcome. To understand the impact of incomplete HLA characterization, we analyzed 14,797 URD HCT (1995-2006) using multivariable regression modeling adjusting for factors affecting survival. Of 21 matching cohorts, we identified 3 groups with significantly different outcomes. Well-matched cases had either no identified HLA mismatch and informative data at 4 loci or allele matching at HLA-A,B & DRB1 (n=7,477, 50% of the population). Partially matched pairs had a defined, single locus mismatch and/or missing HLA data (n=4,962, 34%). Mismatched cases had ≥2 allele or antigen mismatches (n=2,358, 16%). Multivariate adjusted five-year survival estimates were: Well-matched: 54.1 (95% confidence interval), 52.9-55.4); Partially matched: 43.7 (42.3-45.2) and Mismatched: 33.4 (32.5-36.5), p<0.001. A better matched donor yielded 10-11% better 5 year survival. Importantly, intermediate resolution A,B and DRB1 allele matched “6/6 antigen matched” HCT had survival outcomes within the partially matched cohort. We suggest that these proposed HLA subgroupings be used when complete HLA typing is not available. This improved categorization of HLA matching status allows adjustment for donor-recipient HLA compatibility and can standardize interpretations of prior URD HCT experience.
Few studies have tested the benefits of using peripheral blood stem cell (PBSC) grafts versus bone marrow (BM) grafts for unrelated donor transplantation. Yet there has been a substantial change in clinical practice, with increasing numbers of adults receiving unrelated donor PBSC grafts. We compared outcomes after 331 PBSC and 586 BM transplants in adults with leukemia and myelodysplastic syndrome who were followed for a median of 3 years after transplantation. PBSC recipients were less likely to have chronic myeloid leukemia and more likely to have myelodysplastic syndrome, to have poor performance scores and to be transplanted more recently. Outcomes were analyzed using Cox regression models. Rates of grades 2–4 acute graft-versus-host disease (GVHD) (58% vs. 45%, p<0.001) and chronic GVHD (56% vs. 42%, p<0.001) were significantly higher with PBSC than with BM transplants. Rates of grade 3–4 acute GVHD were similar with PBSC and BM transplants. The 3-year probabilities of treatment-related mortality, leukemia recurrence, leukemia-free and overall survival were similar in the two groups with 3-year leukemia-free survival rates of 30% and 32% after transplantation of PBSC and BM, respectively. Unlike results after HLA-matched sibling donor PBSC transplants, we did not identify a survival advantage with PBSC grafts in patients receiving unrelated donor transplants for advanced leukemia. The higher rate of chronic GVHD after PBSC transplants and, consequently, more frequent late adverse events warrant extended follow up of PBSC recipients.
peripheral blood graft; graft-versus-host disease; unrelated donor transplant
The combination of the induction of lymphopenia and vaccination and/or T cell transfer is garnering much attention for cancer treatment. Preclinical studies have shown that the induction of lymphopenia by chemotherapy or radiation can enhance the antitumor efficacy of several distinct, cell-based immunotherapeutic approaches. The mechanism(s) by which such enhancement is achieved are being intensively studied, yet there is much opportunity for improvement. The animal studies reported by Wrzesinski and colleagues in this issue of the JCI are a promising and timely step in this direction (see the related article beginning on page 492). The authors have evaluated both the effect of increasing the intensity of lymphodepletion and the influence of HSC transfer on the in vivo function of adoptively transferred CD8+ T cells. We discuss their results in light of the evolving field and their implications for advancing cell-based immunotherapies for cancer.
Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined the mechanism of anti-CD28–mediated immunosuppression and found that anti-CD28 mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28 treatment prevented GVHD by selectively depleting alloantigen-activated donor T cells through apoptosis but spared the T cells that did not recognize recipient alloantigens. Overexpression of Bcl-xL did not protect T cells from depletion and did not affect GVHD prevention after anti-CD28 treatment. Depletion of activated T cells mediated through CD28 did not depend on the expression of death receptors Fas and TNF receptors type I and II, but both the depletion of activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality required donor-derived IFN-γ production. This study demonstrates that agonistic Ab’s specific for the CD28 costimulatory molecule may be used as novel therapeutic agents to abrogate pathogenic T cell responses by selective depletion of activated T cells.