Genetic Associations with Immune-mediated Outcomes after Allogeneic Hematopoietic Cell Transplantation

Previous studies have identified more than 200 genetic variants associated with acute or chronic graft-versus-host disease (GVHD) or recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). We tested these candidate donor and recipient variants in a cohort of 4270 HCT recipients of European ancestry and in sub-cohorts of 1827 sibling and 1447 unrelated recipients who had 10/10 HLA-A, B, C, DRB1, DQB1-matched donors. We also carried out a genome-wide association study (GWAS) for these same outcomes. The discovery and replication analysis of candidate variants identified a group of closely linked recipient HLA-DPB1 single-nucleotide polymorphisms (SNPs) associated with an increased risk of acute GVHD and a corresponding decreased risk of recurrent malignancy after unrelated HCT. These results reflect correlation with the level of HLA-DPB1 expression previously shown to affect the risks of acute GVHD and relapse in unrelated recipients. Our GWAS identified an association of chronic GVHD with a locus of X-linked recipient intron variants in NHS, a gene that regulates actin remodeling and cell morphology. Evaluation of this association in a second replication cohort did not confirm the original replication results, and we did not reach any definitive conclusion regarding the validity of this discovery. The cohort used for our study is larger than those used in most previous HCT studies but is smaller than those typically used for other genotype-phenotype association studies. Genomic and disease data from our study are available for further analysis in combination with data from other cohorts.

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Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

Blood Advances ◽

10.1182/bloodadvances.2020001927 ◽

2020 ◽

Vol 4 (14) ◽

pp. 3224-3233

Author(s):

Paul J. Martin ◽

David M. Levine ◽

Barry E. Storer ◽

Sarah C. Nelson ◽

Xinyuan Dong ◽

...

Keyword(s):

Cell Transplantation ◽

Genetic Variants ◽

Hematopoietic Cell Transplantation ◽

Genome Wide Association Study ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

European Ancestry ◽

A Genome ◽

Grade 3 ◽

Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

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Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation

Blood ◽

10.1182/blood-2011-01-330217 ◽

2011 ◽

Vol 118 (2) ◽

pp. 456-463 ◽

Cited By ~ 57

Author(s):

Yoshihiro Inamoto ◽

Mary E. D. Flowers ◽

Stephanie J. Lee ◽

Paul A. Carpenter ◽

Edus H. Warren ◽

...

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Immunosuppressive Treatment ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Study Cohort ◽

Recurrent Malignancy ◽

Time Varying Covariates ◽

Risk Of Relapse

AbstractThis study was conducted to elucidate the influence of immunosuppressive treatment (IST) and GVHD on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). The study cohort included 2656 patients who received allogeneic HCT after high-intensity conditioning regimens for treatment of hematologic malignancies. Rates and hazard ratios of relapse and mortality were analyzed according to GVHD and IST as time-varying covariates. Adjusted Cox analyses showed that acute and chronic GVHD were both associated with statistically similar reductions in risk of relapse beyond 18 months after HCT but not during the first 18 months. In patients with GVHD, resolution of GVHD followed by withdrawal of IST was not associated with a subsequent increase in risk of relapse. In patients without GVHD, withdrawal of IST was associated with a reduced risk of relapse during the first 18 months, but the risk of subsequent relapse remained considerably higher than in patients with GVHD. In summary, the association of GVHD with risk of relapse changes over time after HCT. In patients without GVHD, early withdrawal of IST might help to prevent relapse during the first 18 months, but other interventions would be needed to prevent relapse at later time points.

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Causes and Effects of Methotrexate Dose Alterations in Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v124.21.2460.2460 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2460-2460 ◽

Cited By ~ 1

Author(s):

Radha Ramanan ◽

Andrew Boon Ming Lim ◽

Kate Mason ◽

Jeffrey Szer ◽

David Ritchie

Keyword(s):

Overall Survival ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

World Health ◽

Gvhd Prophylaxis ◽

Increased Risk ◽

Grade 3

Abstract Aim To identify the causes and consequences of omission and/or reduction of methotrexate (MTX) doses in graft-versus-host disease (GVHD) prophylaxis used during allogeneic hematopoietic cell transplantation (alloHCT). Method We conducted a retrospective medical record review of 125 alloHCTs performed between the years 2011 and 2013 at our hospital where MTX (15, 10, 10, 10 mg/m2 intravenously on day [D] +1, D+3, D+6, D+11 respectively) is used with cyclosporine as GVHD prophylaxis. The association of MTX dose omission with overall survival (OS), non-relapse mortality (NRM) and acute GVHD, measured from a landmark of D+12, was evaluated with univariate and multivariate analysis. Results 116 patients (median age 48, range 17-67, 59% male) were eligible for analysis. Commonest indications for alloHCT were acute leukemia (47%) and chronic lymphoproliferative disorders (28%). Conditioning was myeloablative in 54%, donors were siblings in 53%, and grafts were peripheral blood in 87%. 85 patients (73%) received all four full doses of MTX. 22 patients had a dose omission at D+11, and two at both D+6 and D+11. 43 patients were given folinic acid rescue. Documented reasons for MTX alteration were mucositis (n = 22; World Health Organisation mucositis grade 4 in 16 patients, grade 3 in 4 patients and grade 2 in 2 patients), fluid overload (n = 10), liver impairment (n = 8, median bilirubin 83 micromol/L, range 19-204 micromol/L, normal < 21 micromol/L), renal impairment (n = 8, median creatinine 138 micromol/L, range 67-276 micromol/L, normal 45-90 micromol/L) and sepsis (1). MTX omission was associated with poorer OS (48% vs 90%; hazard ratio [HR] for mortality 5.4, 95% CI 2.5-11.7, P < 0.001, Figure 1) and higher NRM (39% vs 5%, HR 10.2, 95% CI 3.4-30.8, P < 0.001, Figure 2) at 12 months post landmark. A pattern of ongoing NRM was observed beyond day 100. Strikingly, those patients who received all four full doses of MTX had NRM of 0% at 100 days post landmark. There was no difference in rates of grade 2-4 (24% vs 22%, P = .950) or grade 3-4 (9% vs 11%, P = .662) acute GVHD, or relapse (20% vs 17%, P = .514), at day 100 post landmark. Conclusion MTX dose reduction has no significant impact on GVHD development, suggesting that MTX omissions or other adjustments of GVHD prophylaxis did not lead to enhanced T cell activation. However, it seems that the need to reduce MTX indicates an increased risk of NRM, likely reflecting ongoing organ dysfunction. Older patients or those with pre-transplant co-morbidities may be better served by strategies that lower the likelihood of organ toxicity, including reduced intensity conditioning and lower initial doses of MTX. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Disclosures No relevant conflicts of interest to declare.

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HLA-mismatched donor and high ferritin level showed poor clinical outcomes after allogeneic hematopoietic cell transplantation in patients with advanced myelofibrosis

Therapeutic Advances in Hematology ◽

10.1177/2040620720936935 ◽

2020 ◽

Vol 11 ◽

pp. 204062072093693

Author(s):

Jae-Ho Yoon ◽

Gi June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Ferritin Level ◽

Chronic Gvhd ◽

Human Leukocyte ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Mismatched Donor ◽

Grade Iii

Background: Preconditioning intensity, donor choice and graft- versus-host disease (GVHD) prophylaxis of allogeneic hematopoietic cell transplantation (allo-HCT) for advanced myelofibrosis (MF) have not been fully elucidated. Methods: Thirty-five patients with advanced MF were treated with reduced-intensity conditioning (RIC) allo-HCT. We searched for matched sibling donors first, followed by matched or mismatched unrelated donors and familial mismatched donors. Preconditioning regimen consisted of fludarabine (total 150 mg/m2) and busulfan (total 6.4 mg/kg) with total body irradiation ⩽400cGy. Results: All showed engraftments, but four showed either leukemic relapse or delayed graft failure. Two-year overall survival (OS) and non-relapse mortality (NRM) was 60.0% and 29.9%, respectively. Acute GVHD was observed in 19 patients, and grade III–IV acute GVHD (eight grade III and four grade IV) was higher in human leukocyte antigen (HLA)-mismatched donor HCT compared with HLA-matched HCT (70% versus 20%). Chronic GVHD was observed in 16 patients, and a cumulative incidence of severe chronic GVHD was 33% in HLA-mismatched donor HCT and 7.7% in HLA-matched HCT. Significant hepatic GVHD was observed in nine patients (five acute, four chronic) and six of them died. Multivariate analysis revealed inferior OS in HLA-mismatched donor HCT (hazard ratio (HR) = 6.40, 95% confidence interval (CI) 1.6–25.7, p = 0.009) and in patients with high ferritin level at the time of pre-conditioning period (HR = 7.22, 95% CI 1.9–27.5, p = 0.004), which were related to higher incidence of hepatic GVHD with high NRM rate. Conclusion: RIC allo-HCT can be a valid choice providing graft- versus-fibrosis effect for advanced MF patients. However, HLA-mismatched donor and high pre-HCT ferritin level related to fatal hepatic GVHD should be regarded as poor-risk parameters.

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A Retrospective Comparison of Tacrolimus Vs. Cyclosporine for Immunosuppression After Allogeneic Hematopoietic Cell Transplantation with G-CSF-Mobilized Blood Cells

Blood ◽

10.1182/blood.v116.21.2319.2319 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2319-2319

Author(s):

Yoshihiro Inamoto ◽

Mary E.D. Flowers ◽

Frederick R. Appelbaum ◽

Paul A. Carpenter ◽

H. Joachim Deeg ◽

...

Keyword(s):

Cell Transplantation ◽

Blood Cells ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Unrelated Donors ◽

Total Body

Abstract Abstract 2319 Background: Graft-versus-host disease (GVHD) is a common immunologic complication after allogeneic hematopoietic cell transplantation (HCT). Cyclosporine or tacrolimus in combination with other agents represent widely accepted standards of care as immunosuppressive regimens after HCT. Results of open-label randomized prospective phase III studies have indicated that the risk of grades II-IV acute GVHD after bone marrow transplantation with related or unrelated donors is lower with the use of tacrolimus as compared to cyclosporine, in combination with methotrexate. The current study was carried out to compare results with tacrolimus versus cyclosporine after HCT with G-CSF-mobilized blood cells. Patients and methods: The study cohort included 510 consecutive patients who received a first G-CSF-mobilized blood cell graft from related or unrelated donors after high-intensity conditioning for treatment of hematological malignancies between 7/1/2003 and 2009 at our center. All patients received ursodeoxycholic acid from 2 weeks before conditioning until 90 days after HCT to prevent hepatic complications, and all patients received immunosuppression with either tacrolimus or cyclosporine in combination with methotrexate after HCT. Endpoints included grades II-IV acute GVHD, grades III-IV acute GVHD, chronic GVHD, end of treatment for chronic GVHD, overall survival, disease-free survival, recurrent malignancy and nonrelapse mortality. Multivariate Cox regression models were used to evaluate hazard ratios for these endpoints with tacrolimus as compared to cyclosporine. The models were adjusted for patient age, donor type, recipient and donor gender combination, disease type, disease risk category, use of total body irradiation in the conditioning regimen, and year of HCT. The analysis was carried out as of July, 2010. Results: The median age of patients was 47 (range, 1 to 66) years. Diagnosis at HCT was acute myeloid leukemia in 200 (39%) patients, acute lymphoblastic leukemia in 73 (14%), chronic myeloid leukemia in 49 (10%), myelodysplastic syndrome or myeloproliferative disorders in 160 (31%) and other lymphoid malignancies in 28 (5%). Total body irradiation was used for conditioning in 168 (33%) patients. Of the 510 patients, 277 (54%) had HLA-matched related donors, 203 (40%) had HLA-matched unrelated donors, and 30 (6%) had HLA-mismatched related or unrelated donors. Outcomes according to immunosuppression with tacrolimus or cyclosporine are shown in Table 1. Multivariate analysis showed no statistically significant differences between tacrolimus and cyclosporine for any of the endpoints tested (Table 2), although the results showed a trend suggesting that the risk of non-relapse mortality might be lower with tacrolimus as compared to cyclosporine. Conclusion: In this retrospective analysis, tacrolimus offered no statistically significant advantage over cyclosporine for preventing grades II-IV acute GVHD after HCT with G-CSF-mobilized blood cells, and results for other outcomes also showed no statistically significant differences. Although our data support the hypothesis that either regimen could be an acceptable standard of care for immunosuppression, the number of patients analyzed in this study is not sufficient to completely exclude clinically meaningful differences in outcomes with the two regimens. Disclosures: Off Label Use: Tacrolimus and cyclosporine for immunosuppression after allogeneic hematopoietic cell transplantation.

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Pre-transplant Marital status and Hematopoietic Cell Transplantation Outcomes

Current Oncology ◽

10.3747/co.27.6327 ◽

2020 ◽

Vol 27 (6) ◽

Author(s):

J. Tay ◽

S. Beattie ◽

C. Bredeson ◽

R. Brazauskas ◽

N. He ◽

...

Keyword(s):

Social Support ◽

Marital Status ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Hematopoietic Cell ◽

Increased Risk ◽

The Impact

Background Evidence regarding the impact of pre-hematopoietic cell transplantation (HCT) marital status on post-HCT outcomes is conflicting. Methods We identified patients, ≥40-years within the Center for International Blood and Marrow Transplant Research registry who received a HCT between January 2008 and December 2015. Pre-HCT marital status was declared as either 1) Married/living with a partner, 2) Single/never married, 3) Separated/divorced, and 4) Widowed. We performed multivariable analysis to determine the association of marital stsatus with post-HCT outcomes. Results We identified 10,226 allogeneic and 5,714 autologous HCT patients with a median follow-up of 37 months (range 1-102) and 40 months (range 1-106) respectively. There was no association between marital status and OS in both allogeneic (p=0.58) and autologous (p=0.17) settings. However, marital status was associated with grade 2-4 acute GVHD (p<0.001) and chronic GVHD (p=0.04). There was an increased risk of grade 2-4 acute GVHD in separated patients compared with married patients [HR 1.13, 95%CI (1.03-1.24)], while single patients had a reduced risk of grade 2-4 acute GVHD [HR 0.87, 95%CI (0.77-0.98)]. The risk of chronic GVHD was lower in widowed patients [HR 0.82, 95%CI (0.67-0.99)] compared with married patients. Conclusions OS post-HCT is not influenced by marital status, but there are associations between marital status and grade 2-4 acute and chronic GVHD. Future research should consider measuring social support using validated scales, patient and caregiver reports of caregiver commitment, and assess health-related quality of life together with health-care utilization to better appreciate the impact of marital status and social support.

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Comparable Survival and Transplant-Related Mortality Following Allogeneic Hematopoietic Cell Transplantation from HLA Allele-Matched Unrelated and HLA-Identical Sibling Donors.

Blood ◽

10.1182/blood.v108.11.3146.3146 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3146-3146 ◽

Cited By ~ 2

Author(s):

Thai M. Cao ◽

Schickwann Tsai ◽

Linda Kelley ◽

Stephen C. Alder ◽

Thomas C. Fuller ◽

...

Keyword(s):

Overall Survival ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

P Value ◽

Unrelated Donor ◽

Related Mortality

Abstract Comprehensive analyses of unrelated donor (URD) and recipient HLA-matching for allogeneic hematopoietic cell transplantation (AHCT) have demonstrated better outcomes when allele typing is performed using high-resolution nucleotide sequence-based techniques. To evaluate survival following myeloablative AHCT using allele-level HLA-matched URD as compared with HLA-identical sibling donors, we analyzed outcomes for 430 patients treated at our center between March 1991 and April 2005. Sequence-based allele typing was retrospectively performed for HLA-A, B, C, DR and DQ when not done at time of AHCT for URD (n = 124; 29%) and non-sibling related donors (n = 19; 4%). Donors were HLA-identical siblings (n = 276; 64%), HLA allele-matched URD (n = 52; 12%), single HLA-locus mismatched donors (n = 52; 12%), or > 1 locus mismatched donors (n = 50; 12%). The median age at transplant was 23.4 years (range: 0.2 – 61). The most common diagnoses were AML (n = 107; 25%), CML (n = 90; 21%), ALL (n = 86; 20%) and MDS (n = 50; 12%). Total body irradiation-based preparative regimens were used for 283 patients (66%). Bone marrow (BM) was the graft for 388 patients (90%) and GCSF-mobilized peripheral blood stem cells (PBSC) for the remaining 42 (10%). Graft-versus-host disease (GVHD) prophylaxes were cyclosporine and methotrexate (n = 327; 76%), long methotrexate (n = 42; 10%), T-cell depletion (n = 19; 4%), or other regimens (n = 42; 10%). With a median follow-up of 4.8 years (range: 0.2 – 12.1), the 5-year estimate of overall survival (OS) for the entire group was 48.2% (95% CI: 45.7 – 50.7) and transplant-related mortality (TRM) was 31.4% (95% CI: 28.8 – 34). As shown in the Table, OS and TRM were indistinguishable between AHCT performed with HLA-identical siblings compared with HLA allele-matched URD. There was also no difference in grade III – IV acute GVHD (P = .46) between these two groups whereas there was a trend towards more extensive chronic GVHD (HR 1.8; 95% CI: 0.9 – 3.6; P = 0.12) for the URD recipients. Using a multivariate analysis to adjust for advanced disease, age (> vs ≤ 30 years), graft (BM vs PBSC) and female-to-male gender mismatch, there remained no difference in OS between HLA-identical siblings and HLA allele-matched URD (P = 0.67). These results demonstrate that key outcomes (OS, TRM, and severe acute GVHD) are equivalent in recipients of grafts from either allele-level 10/10 HLA-matched URD or HLA-identical siblings. Overall Survival TRM Number Hazard Ratio 95% CI P value Hazard Ratio95% CI P value HLA-ID Sibling 276 1 - - 1 - - HLA-ID URD 52 1.1 0.7 – 1.7 0.67 0.8 0.4 – 1.6 0.58 1 Locus MM 52 1.3 0.9 – 2.0 0.19 1.4 0.8 – 2.4 0.25 > 1 Locus MM 50 2.0 1.4 – 2.9 < 0.001 2.6 1.7 – 4.1 < 0.001

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Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning

Journal of Clinical Oncology ◽

10.1200/jco.2005.08.136 ◽

2005 ◽

Vol 23 (9) ◽

pp. 1993-2003 ◽

Cited By ~ 254

Author(s):

Frédéric Baron ◽

Michael B. Maris ◽

Brenda M. Sandmaier ◽

Barry E. Storer ◽

Mohamed Sorror ◽

...

Keyword(s):

Multivariate Analysis ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

High Dose ◽

Increased Risk ◽

Risk Of Relapse

Purpose We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m2/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. Patients and Methods We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130). Results Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). Conclusion New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

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Comparable Allogeneic Hematopoietic Cell Transplantation Outcome of a Haplo-Identical Family Donor with an Alternative Donor in Adult Aplastic Anemia

Acta Haematologica ◽

10.1159/000445820 ◽

2016 ◽

Vol 136 (3) ◽

pp. 129-139 ◽

Cited By ~ 3

Author(s):

Hawk Kim ◽

Je-Hwan Lee ◽

Young-Don Joo ◽

Sung-Hwa Bae ◽

Sang Min Lee ◽

...

Keyword(s):

Aplastic Anemia ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Engraftment Failure ◽

Alternative Donor ◽

Neutrophil Engraftment

We performed a study on allogeneic hematopoietic cell transplantation (alloHCT) from an HLA-haplo-identical familial donor (haploFD) using a busulfan-fludarabine-antithymocyte globulin conditioning regimen for severe aplastic anemia (sAA) and hypoplastic myelodysplastic syndrome. For the comparison between a haploFD and an alternative donor (AD; matched unrelated or partially matched donor) for sAA in adults, we collected haploFD data retrospectively and prospectively. Forty-eight AD cases were selected for the comparison with 16 haploFD cases. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoidal obstruction syndrome (p = 1.000), acute GvHD (p = 0.769), grade 3/4 acute GvHD (p = 0.258), chronic GvHD (p = 0.173), extensive chronic GvHD (p = 0.099), primary neutrophil engraftment failure (p = 1.000), secondary graft failure (p = 1.000) and platelet engraftment failure (p = 0.505) were similar. Time to neutrophil engraftment was faster in haploFD (p = 0.003), while the cumulative incidence of platelet engraftment was similar (p = 0.505). Overall survival was also similar between AD and haploFD (p = 0.730). In conclusion, alloHCT from haploFD in sAA was comparable with alloHCT from AD, but extensive chronic GvHD seemed frequent in haploFD. Therefore alloHCT from haploFD could be an alternative approach for alloHCT from AD in adult sAA.

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Patterns of Acute and Chronic Graft-Versus-Host Disease Following ATG-Based Conditioning for Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v120.21.4479.4479 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4479-4479

Author(s):

Nandita Khera ◽

Amylou C. Dueck ◽

Veena Devi Salem Fauble ◽

Lisa Sproat ◽

Pierre Noel ◽

...

Keyword(s):

Cell Transplantation ◽

Median Time ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Median Number ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Grade Ii

Abstract Abstract 4479 Background: In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods: We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results: The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion: These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures: No relevant conflicts of interest to declare.

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