Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy with proven efficacy in the management of hematologic malignancies. However, it is complicated by the syndromes ...of acute and chronic graft-vs-host disease (GVHD).
A narrative review is provided to summarize major biologic insights into the pathogenesis of these immune-mediated disorders, as well as advances in diagnosis, classification, prevention, management, and allied supportive care with the aim of providing essential understanding for clinicians with or without subspecialty experience in the field of blood and marrow transplantation.
Major scientific advances have contributed to enhanced understanding of the pathogenesis of these disorders, and clinical investigation has provided more effective preventive and therapeutic strategies for GVHD. However, since acute GVHD and chronic GVHD remain leading sources of transplantation-related morbidity and mortality, ongoing investigation is needed to develop new approaches to addressing these syndromes.
The major challenge for future investigation will be to capitalize on biologic insights in order to develop novel strategies for the prevention and therapy of acute and chronic GVHD that will address the current shortcomings in existing therapeutic approaches.
High-dose therapy with allogeneic hematopoietic cell transplantation (HCT) offers effective control and potential cure of hematopoietic malignancies, but with the cost of associated morbidity that ...includes adverse effects on quality of life (QOL). A growing body of literature has characterized this impact. Longitudinal studies suggest early moderate impairments that largely return to pretransplantation levels by day 100; the majority of studies suggest that greater than 60% of patients report good to excellent QOL in years 1 to 4 after HCT. Comparisons of allogeneic HCT with autologous HCT and standard-dose chemotherapy suggest impairments in QOL and a different trajectory of recovery in allogeneic HCT, but these conclusions are limited by confounding variables. Cross-sectional studies suggest larger and more persistent decrements in QOL in comparison with matched noncancer controls and population normative data. Acute and chronic graft-versus-host disease (GVHD) are significant threats to QOL. Behavioral interventions show promise to maintain or improve quality of life after allogeneic HCT. The review concludes with recommendations to investigators and clinicians as the state of this research advances.
Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor–recipient ...HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.
Background: Regulatory CD4 T cells (Treg) are potent to suppress the responses of conventional CD4+ (Tcon) and CD8+ T cells to alloantigens and prevent graft-vs.-host diseases (GVHD). Since the ...mechanisms for thymic selection of Treg and Tcon are distinct, we hypothesized that the two cells types use distinct TCR repertoires in the response to same alloantigen. We have used high throughput deep sequencing to study the T cell receptor (TCR) Vbeta CDR3 repertoire of CD4 Treg and CD4 Tcon at baseline and again after expansion with alloantigen.
Methods: CD4+CD25+CD127- Treg and CD4+CD25-CD127- Tcon were FACS-sorted from healthy donor PBMCs or umblical cord blood mononuclear cells. Aliquots of sorted Treg and Tcon were expanded separately by DC from the same Major Histocompatibility (MHC)-mismatched donor. Treg were cultured with DCs, IL-2, IL-15 and rapamycin, while Tcon were cultured with DCs and IL-2. Genomic DNA from baseline or expanded purified Treg and Tcon was sequenced, at least 10^6 deep, by Adaptive Biotechnologies multiplex kit to detect unique T cell receptor (TCR) Vbeta CDR3 sequences. Data was analyzed by the algorithm established for the Adaptive Biotechnologies software and characterized according to the IMGT (International ImmunoGeneTics information system) nomenclature.
Results: The TCR Vbeta CDR3 sequences of baseline natural Treg and Tcon T cell have minimal overlap, indicating that the thymus shapes distinct TCR repertoires in these two cell types. However, the CDR3 length and the frequency of nucleotide deletion or insertion at the Vbeta-Dbeta and Dbeta-Jbeta junction were similar. By employing the "robust regression model", we identified expanded TCR Vbeta CDR3 sequences among both Treg and Tcon after in vitro culture with the same alloantigens. These expanded Treg and Tcon used unique TCR Vbeta CDR3 sequences that are not shared by the other cell type. Expanded Treg and Tcon displayed fewer nucleotide deletions and insertions at the Vbeta-Dbeta and Dbeta-Jbeta junction than at baseline. The frequency of the expanded sequences, insertions and deletions were of the same magnitude in Treg and Tcon suggesting that both undergo similar processes of antigen-driven TCR selection and magnitude of cell expansion in vitro.
Conclusion: CD4 Treg and Tcon utilize largely distinct TCR Vbeta CDR3 repertoires at baseline and after expansion against the same alloantigens. Questions remain whether Treg and Tcon recognize the same or distinct peptides from the same antigen, and whether they bind peptide with different avidity. TCR Vbeta CDR3 deep sequencing ought to be used to track single Treg and Tcon after adoptive cell therapy.
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No relevant conflicts of interest to declare.
Background: Innovative means to risk-stratify HSCT patients are needed. Previous studies in cancer patients suggest association between body composition and survival. However, this has not been ...previously described is allogeneic HSCT recipients. Furthermore, the correlation of body composition with pre- and post-HSCT physical activity in cancer patients remains undefined. We postulated that body composition prior to HSCT is associated with post-HSCT outcomes.
Methods: Patients who had completed pre-HSCT physical function assessment as part of ongoing prospective clinical trial were identified. Analysis of self-reported and measured physical activity and their association with outcomes after transplantation is currently ongoing. Regional CT at the 4th thoracic vertebra (T4) was obtained for post-hoc analysis of body composition within this cohort. Using Slice-O-Matic software V4.3 (Tomovision, Magog, Quebec, Canada), both adipose and muscle tissue were quantified to obtain the respective cross sectional area (cm2). Fat and skeletal muscle were identified and quantified within the following CT Hounsfield unit thresholds: -29 to +150 for skeletal muscle and -190 to -30 for adipose tissue. Tissue boundaries were manually corrected as necessary. Cross sectional areas were subsequently normalized for stature (height2) to obtain a tissue index for both fat and muscle (cm2/m2). For this analysis, fat index (FI) and muscle index (MI) were divided into quartiles (group 0: ≤25%, group 1: 26-50%, group 2: 51=75%, group 3: ≥75%). Statistical significance was defined as p < 0.05 and all analyses were done on SAS 9.3.
Results: All patients (n=50) enrolled on the pre-HSCT functionality trial between 02/2014 and 02/2015 were identified for this analysis. 3 patients were excluded for analysis: 2 subjects ultimately did not proceed to HSCT and 1 subject had a CT scan that was not evaluable. Thus, 47 subjects had evaluable data; baseline characteristics are summarized (Table 1). Median follow-up for survivors is 298 days (interquartile range (IQR): 272-368 days). Overall survival (OS) significantly differs between FI strata (log rank p value =0.0013) (Figure 1). MI is not associated with OS (p=NS). FI is inversely correlated with distance walked during 6-minute walk test pre-HSCT (r = -0.33, p = 0.027). FI and MI are not significantly associated with self-reported physical activity using the International Physical Activity Questionnaire (IPAQ) post-HSCT (day 1, 30, 90), or patient-reported quality of life (QOL).
Conclusions: These data provide the first evidence supporting an association between CT-defined cross sectional adipose tissue index and survival following HSCT. This non-invasive, routinely employed imaging modality may provide a new avenue for enhanced risk-assessment for HSCT patients. Subsequent studies will examine this effect in larger populations, with specific attention to other established prognostic variables.
Table 1Baseline CharacteristicsVariablesN (%)Age, yrs (median, range)60 (24-75)Gender, male30 (63.8%)KPS ≥9042 (89.3%)HCT-CI≥329 (61.7)Diagnosis § AML § ALL § CLL § CML § MDS § HD § MM § MPS § NHL12 (25.5%) 5 (10.6%) 3 (6.4%) 2 (4.3%) 9 (19.1%) 2 (4.3%) 3 (6.4%) 2 (4.3%) 9 (19.1%)Conditioning Intensity, Myeloablative24 (51.1%)Armand Disease Risk at HSCT § Low § Intermediate § High/Very High2 (4.3%) 26 (55.3%) 19 (40.4%)Donor Type § Matched Related Donor § Matched Unrelated Donor § Mismatched Unrelated Donor § Double Umbilical Cord Blood13 (27.7%) 27 (57.4%) 6 (12.8%) 1 (2.1%)
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No relevant conflicts of interest to declare.
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Introduction:
Optimal donor selection is critical to reduce morbidity and mortality from allogeneic hematopoietic cell transplant (HCT). HLA identical female parous sibling donors (pSIB) confer an ...increased risk of chronic graft vs. host disease (cGVHD) compared to male sibling donors, possibly from alloimmunization and exposure to fetal antigens during pregnancy. Unrelated donors (URD) also confer higher GVHD risk than sibling donors. While both pSIB and URD donors confer increased GVHD risk, they have never been directly compared. This study compares incidence of acute GVHD (aGVHD), cGVHD, survival, and treatment- related mortality in patients who received transplants from pSIB donors to male unrelated donors (mURD).
Methods:
A retrospective cohort study was completed using the Center for International Bone Marrow Transplant Registry (CIBMTR). We identified patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who underwent a non-T cell depleted HCT from an HLA identical pSIB or a matched mURD between 2000-2012. Recipients were at least 25 years at time of transplant to ensure female sibling donors had biological opportunity to become parous. Primary outcome was Grade II-IV aGVHD, cGVHD, and overall survival (OS). Secondary outcomes were relative risk (RR) of leukemia free survival (LFS), transplant related mortality (TRM) and relapse.
Results:
We identified 892 pSIB donors and 1921 mURD donors. Median recipient age at transplant was 49 (pSIB) and 50 (mURD), p=0.14. Median donor age was higher in pSIB than mURD (48 vs. 32, p<0.001). Cumulative incidence of aGVHD was higher in mURD than pSIB at 100 days, 46% vs. 35%, p<0.001. Incidence of cGVHD at 100 days was also higher in mURD (9% vs. 4%, p<0.001), but was not different at 1 year (mURD 50%, pSIB 50%, p=0.99) or 2 years (mURD 56%, pSIB 56%, p=0.77). In multivariate analysis adjusting for other risks of GVHD (prophylaxis, graft source, gender, and transplant year), mURD had a 1.6 times higher risk of grade II-IV aGVHD (p<0.0001) and 1.23 times higher risk of cGVHD (p=0.0003) than pSIB donors (Table 1).
A greater proportion of pSIB recipients were alive at 100 days (88% vs. 82%, p<.001), 1 year (62% vs. 57%, p=0.02), and 2 years (51% vs. 47%, p=0.02). However, in multivariate analysis donor type did not significantly affect OS (RR mURD 1.10, p=0.072), LFS (RR mURD 1.04, p=0.47), TRM (RR mURD 1.04, p=0.59), or relapse (RR mURD 1.03, p=0.62). Variables associated with OS included increasing recipient age (p<0.0001), Karnofsky performance status <90% (RR 1.37, p<0.0001), disease status at HCT (p<0.0001), and year of HCT (p<0.0001) (Table 2).
Conclusion:
Male URD confer a higher risk of grade II-IV acute and chronic GVHD compared to HLA-identical female parous sibling donors. Donor type does not significantly affect OS, LFS, TRM, or disease relapse. When available, female pSIB should be utilized rather than mURD donors to minimize toxicity of GVHD.
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No relevant conflicts of interest to declare.
Introduction: In adult HLA matched sibling donor (MSD) hematopoietic cell transplantation, both recipient and donor age have been shown to be a risk factors for graft versus host disease (GVHD). ...While it is widely recognized that pediatric patients are at lower risk for GVHD than adults, the importance of age within the pediatric age group in MSD transplantation has not been examined. We, therefore, assessed the impact of age on GVHD risk after MSD bone marrow transplantation (BMT) in 477 pediatric patients with acute leukemia.
Methods: This is a Center for International Blood and Marrow Transplantation registry study. Patients younger than 18 years with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in 1st or 2nd complete remission (CR), who received myeloablative conditioining, T cell-replete HLA MSD BMT and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 were included. Patients who received a lymphocyte depleting antibody were excluded. Because donor and recipient ages were highly correlated, their effects could not be independently assessed. We, therefore, assessed only recipient age.
Results: The transplants were drawn from 101 centers. The median age of the recipients was 10.1 years. 21% had ALL in 1st CR, 24% ALL in 2nd CR, 47% AML in 1st CR and 8% AML in 2nd CR. 73% received cyclosporine and Methotrexate for GVHD prophylaxis. In a preliminary model, using grade 3-4 acute GVHD as the endpoint, we identified two cut points, 2 years and 13 years using the likelihood ratio test. In all final models, three age groups were used to define recipient age: < 2 years (n=60), 2 to 12.99 (n=255) years and 13-17.99 years (n=162). The cumulative incidence of grade 2-4 acute GVHD at 100 days post-transplant was 19% (95% confidence interval, CI, 16-23%); 24% (95% CI 14-35%), 13% (95% CI 9-18%) and 28% (95% CI 21-35%) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (p-value=0.001). For grade 3-4 acute GVHD, the cumulative incidence estimate at 100 days was 8% (95% CI 3-17%), 3% (95% CI 1-6%) and 14% (95% CI 9-20%) (p <0.001) and the cumulative incidence estimate for chronic GVHD at 1 year was 15% (95% CI 7-25%), 10% (95% CI 7-14%) and 27% (95% CI 20-34%) (p <0.001) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (Figures 1-3). In the multivariate analyses, using age 13-17.99 as the baseline and .01 as the threshold for significance, age 2-12.99 years (HR 0.43, 95% CI 0.26-0.71, p=0.001), but not age < 2 years (HR 0.59, 95% CI 0.3-1.18, p=0.14), was associated with a lower risk for grade 2-4 acute GVHD (after adjustment for GVHD prophylaxis, performance score and year of transplant). For grade 3-4 acute GVHD, again age 2-12.99 years (HR 0.24, 95% CI 0.1-0.56, p=0.001), but not age < 2 years (HR 0.75, 95% CI 0.29-1.94, p=0.55), was associated with a lower risk, after adjustment for year of transplant. For chronic GVHD (after adjustment for donor-recipient birth order, and GVHD prophylaxis), age 2-12.99 years (HR 0.32, 95% CI 0.19-0.54, p<0.001) was associated with lower risk; the effect was similar in age < 2 years, but did not reach significance (HR 0.36, 95% CI 0.16-0.82, p=0.016). Year of transplant had a strong effect on acute, but not chronic GVHD. Its effect did not appear to be mediated by changes in GVHD prophylaxis. Using 2000-2004 as the baseline, the HR for grade 2-4 acute GVHD was 0.38 (95% CI 0.20-0.64, p=0.0006) and 0.28 (95% CI 0.13-0.59, p=0.0008) for 2005-2008 and 2009-2013, respectively. For grade 3-4 acute GVHD, they were 0.23 (95% CI 0.08-0.65, p=0.0057) and 0.23 (95% CI 0.07-0.78, p=0.0183) for these periods, respectively. There was no difference in overall survival, leukemia-free survival or transplant related mortality between the age groups.
Conclusion:
Our results indicate that children 2-12.99 years have a lower risk for acute and chronic GVHD than those 13 years and older. Children less than 2 years may also have a reduced risk for chronic GVHD, but this possibility needs to be re-examined in a larger sample. It is plausible that pubertal changes underlie the rise in risk for GVHD during adolescence. An important limitation of our study was that we were unable to examine the impact of donor age because of the strong correlation between donor and recipient age. A study with a larger sample is also needed to further investigate this matter.
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No relevant conflicts of interest to declare.
Abstract We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or ...myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplantation morbidity in this population.
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