Abstract 5377: Low donor thymic output predicts increased incidence of extensive chronic GVHD and worse overall survival after TCD-matched sibling SCT

Abstract Abstract 328 Low CD4+ T cell counts early post-SCT are associated with a greater risk of developing chronic GVHD (cGVHD). However, the factors affecting post graft CD4+ T cell recovery are not known. Furthermore, the CD4 T cell subset correlating best with protection from cGvHD is not defined. We hypothesized that the donor immune repertoire determines CD4+ reconstitution after SCT. We studied 220 donor-recipient pairs undergoing a myeloablative matched-sibling T-cell depleted SCT for a variety of hematological malignancies including AML, ALL, CML, and MDS. Median donor and patient age was 36 years (range, 9 – 70). Median CD34+ cell dose was 5.56 ×106/kg (range, 2.3–14.5), with a fixed T cell dose per protocol of 1–5 ×104/kg. Ninety-four patients (43%) developed chronic GvHD (32 limited, 64 extensive). Prior to SCT a cryopreserved mononuclear fraction (PBMC) was obtained by leukopheresis on all donors. PBMC from 139 donors were stained with fluorescently conjugated antibodies against CD3, CD4, CD8, CD27, CD45RA, CD31, CD25, CD14, CD19, FOXP3, and Helios and acquired on a custom-built LSR Fortessa (BD) flow cytometer. The following T cell subsets were examined: naive, CD27+CD45RA+; central memory, CD27+CD45RA-; effector memory, CD27-CD45RA-; and effector T cells, CD27-CD45RA+. Regulatory T cells (Tregs) and Treg subsets were identified within the CD4+ T cell population using a combination of FOXP3 and Helios The combination of FOXP3 with Helios has recently been shown to identify natural, thymus-derived Tregs (nTregs), whereas CD4+FOXP3+ T cells lacking Helios represent a pool of induced Tregs (Thornton et al., 2010, J Immunol. 184:3433–3441). Combined expression of CD31 and CD45RA in the CD4+ and nTreg populations was used to identify recent thymic emigrants (RTE). Data were analyzed by FlowJo (Treestar, Ashland, OH, version 8.6.6), and both univariate and multivariate analysis analyses using the Cox regression models with right censored time-to-event variables were performed on the readouts (SPSS 15.0, S-Plus 8 and Prism 4 Software). All p-values were computed based on the log-rank test statistics. Absolute lymphocyte counts in 220 donors were 2.11/μl (range 0.89 – 4.12). A low absolute lymphocyte count was significantly correlated with a higher cumulative probability for time to incidence of extensive cGVHD (HR 2.38, p = 0.0008). This relationship between lymphocytes and cGVHD was retained in CD4+ T cell subsets: CD3+CD4+ (HR 2.48, p = 0.005); CD3+CD4+CD25+ < 30 cells/μL (HR 2.1, p = 0.02); nTregs < 8 cells/μL (HR 1.97, p = 0.043). RTE of total CD4 did not correlate with RTE nTregs, indicating that nTreg production varies among donors with similar levels of thymic activity. Furthermore recipients of donors with low RTE nTregs relative to overall thymic output had a significantly higher likelihood of developing extensive chronic GvHD (HR 2.78, p=0.0014). In multivariate analysis including patient age, acute GvHD (grade II – IV), graft direction (female donor to male recipient vs. other combinations), disease and status at transplant, and administration of post SCT donor lymphocyte infusion, only thymic output of nTregs (HR = 0.8, p = 0.037) and graft direction (HR = 2.1, p = 0.023) remained significant risk factors for extensive cGvHD. These data show that the thymic output of nTreg varies inherently among donors. Donors with low thymic output of nTreg may recreate a less tolerant immune system in the recipient leading to cGVHD of greater severity. (ZAM and JJM contributed equally to this work). Disclosures: No relevant conflicts of interest to declare.

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Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2015.66.3476 ◽

2016 ◽

Vol 34 (26) ◽

pp. 3141-3149 ◽

Cited By ~ 145

Author(s):

Nilanjan Ghosh ◽

Reem Karmali ◽

Vanderson Rocha ◽

Kwang Woo Ahn ◽

Alyssa DiGilio ◽

...

Keyword(s):

Overall Survival ◽

Calcineurin Inhibitor ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Marrow Transplant ◽

Free Survival ◽

Blood And Marrow Transplant ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Reduced Intensity

Purpose Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry. Materials and Methods We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor–based GVHD prophylaxis. Results Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34). Conclusion Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD.

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Comparison of Cyclosporine and Methotrexate with Cyclosporine and Mycophenolate Mofetil for Gvhd Prophylaxis in Myeloablative Allogeneic Bone Marrow Transplantation.

Blood ◽

10.1182/blood.v112.11.2240.2240 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2240-2240 ◽

Cited By ~ 2

Author(s):

Robert Dean ◽

Lisa Rybicki ◽

Ronald Sobecks ◽

Edward Copelan ◽

Matt Kalaycio ◽

...

Keyword(s):

Overall Survival ◽

Chronic Gvhd ◽

Mucosal Injury ◽

Post Transplantation ◽

Myeloablative Conditioning ◽

Sibling Donor ◽

Allogeneic Bmt ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Neutrophil Engraftment

Abstract Cyclosporine (CSA) and methotrexate (MTX) is a standard, effective regimen for prophylaxis of GVHD following allogeneic BMT. However, MTX increases mucosal injury and delays hematopoietic recovery in myeloablative allografts. We demonstrated in a prospective, randomized trial that CSA and mycophenolate mofetil (MMF) decreased mucositis and permitted more rapid neutrophil engraftment versus CSA/MTX in 40 patients undergoing myeloablative allogeneic BMT from matched sibling donors, with similar rates of acute and chronic GVHD, relapse, and 6-month survival. We subsequently adopted CSA/MMF as our preferred regimen for GVHD prophylaxis in matched sibling donor allografts. The objective of this analysis is to describe peri-transplant and long-term outcomes in an expanded cohort, comparing CSA/MMF with CSA/MTX. Inclusion criteria: adult patients (18 years or older) who underwent allogeneic BMT with myeloablative conditioning from a matched sibling donor with either CSA/MTX (n=76) or CSA/MMF (n=89) for GVHD prophylaxis. Median age was 45 years (range, 18–65). Diagnoses: AML (50%), CML (15%), ALL (15%), MDS (9%), NHL (6%), other (8%). Only 21% of patients had more than 2 prior regimens, and 9% had prior radiotherapy. Preparative regimens included busulfan (Bu) and cyclophosphamide (Cy) (64%), Bu/Cy + etoposide (19%), TBI-based (13%), or other (4%). All but 1 patient who received Bu/Cy + etoposide also received CSA/MTX. No other baseline characteristic differed between the groups. Median CD34+ cell dose: 1.78 x 10E6/kg overall, no difference between groups; CD3+ cell doses were incomplete for most patients who received CSA/MTX, but median values were equal between CSA/MMF and CSA/MTX patients with available data. Compared with CSA/MMF patients, those who received CSA/MTX had worse mucositis (median score 0.17 versus 1.0, P<0.001) and longer length of hospital stay for transplantation (27 versus 34 days, P<0.001). The risk of mucositis remained elevated for patients who received CSA/MTX versus CSA/MMF after adjusting for the influence of etoposide in the preparative regimens (P<0.001). Patients who received CSA/MMF had more rapid neutrophil engraftment (ANC > 500, median 11 versus 19 days, P<0.001) and platelet engraftment (platelets > 20,000, median 19 versus 24 days, P<0.001) post-transplantation. Median follow-up post allogeneic BMT was shorter for CSA/MMF patients (36 vs. 82 months, P<0.001). The probabilities of acute GVHD (all grades, grades II-IV, grades III-IV) were similar for CSA/MMF (58%, 36%, 18%) and CSA/MTX (66%, 42%, 15%) (P=NS). CSA/MMF patients experienced a lower likelihood of chronic GVHD than CSA/MTX patients (overall 42% vs. 53%, P=0.04; extensive 20% versus 37%, P=0.01). Overall infection rates were similar (P=NS), although CMV reactivation or infection was somewhat more frequent in CSA/MMF patients (58% versus 43% at 1 year, P=0.08). Five-year rates of relapse (36% versus 39%), non-relapse mortality (39% versus 39%), and overall survival (39% versus 37%) also did not differ between CSA/MMF and CSA/MTX patients. In multivariable models, CSA/MTX prophylaxis was the only factor associated with a greater risk of chronic GVHD (overall, HR 1.79, 95%CI 1.06– 3.02, P=0.03; extensive, HR 2.27, 95%CI 1.16–4.44, P=0.02). CONCLUSION: GVHD prophylaxis with CSA/MMF in matched sibling donor allografts reduces mucositis, time to engraftment, length of stay, and the risk of chronic GVHD compared with CSA/MTX, without adversely influencing rates of relapse, non-relapse mortality, or overall survival. The protective effect of CSA/MMF against chronic GVHD may be related to the fact that MMF is administered for a longer period post-transplantation than MTX, or the reduction in peri-transplant mucosal injury with MMF could result in decreased activation of potentially alloreactive T-cells. CSA/MMF is a safe and effective regimen for prophylaxis against GVHD in matched sibling donor allogeneic BMT with myeloablative conditioning.

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Effect of Race on Outcomes After Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia

Blood ◽

10.1182/blood.v118.21.1020.1020 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1020-1020

Author(s):

Michael J Eckrich ◽

Kwang W Ahn ◽

Zhiwei Wang ◽

H. Joachim Deeg ◽

Mary M. Horowitz ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

African Americans ◽

Aplastic Anemia ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Survival Rates ◽

Unrelated Donor ◽

Matched Sibling ◽

Overall Mortality

Abstract Abstract 1020 Severe aplastic anemia (SAA) is the most common non-malignant indication for hematopoietic cell transplantation (HCT). Although survival after HCT for SAA has improved in recent years, it is not known whether the observed higher survival rates are uniform across racial groups or whether there are differences similar to those seen with HCT for hematologic malignancies. Our primary objective was to compare overall survival after HCT for SAA in patients of African American and Caucasian races. The study population included patients who received HCT in the U.S. between 1990 and 2008. Eighty-four African Americans (cases) and 215 Caucasians (controls) were matched on factors known to be associated with survival after HCT for SAA, including age at HCT (±3 years), donor type (HLA-matched sibling, matched unrelated donor, mismatched unrelated donor), graft type (bone marrow or peripheral blood progenitor cells) and transplant year (±1 year). For 39 cases the match ratio for controls was 1:4, for 14 cases, 1:3, for 22 cases, 1:2 and the remaining 9 cases, 1:1. The median age of cases and controls was 17 years and the median interval from diagnosis to HCT was 3.4 months. Forty-five percent of transplants were from unrelated and 55% from HLA-matched sibling donors. A third of unrelated donor-recipient pairs were HLA-mismatched. Bone marrow was the predominant source of stem cells. The median follow-up of cases and controls was 5 years. In multivariate analysis, risk of overall mortality was higher for African Americans compared to Caucasians, relative risk [RR] 1.75, 95% CI 1.14–2.69, p=0.01. Risks of overall mortality were also higher during the early post-transplant period; odds ratio (OR) 2.42, 95% CI 1.09–5.37, p=0.03) and OR 2.61, 95% CI 1.33–5.47, p=0.005) at 3-months and 1-year post-transplantation, respectively. The 5-year probability of overall survival adjusted for interval from diagnosis to HCT, performance score and conditioning regimen, the other significant variables associated with higher mortality was 58% for African Americans and 73% for Caucasians. The likelihood of neutrophil recovery was similar in both groups (OR 1.03, 95% CI 0.46–2.33, p=0.94). Acute grades II–IV graft-versus-host disease (GVHD) risks did not differ between African Americans and Caucasians (RR 0.81, 95% CI 0.56–1.17, p=0.26). However, chronic GVHD risk was higher for African Americans, although the difference did not reach statistical significance (RR 1.55, 95% CI 0.98–2.44, p=0.06). Thirty-seven (45%) of 82 African Americans died compared to 56 (27%) of 207 Caucasians. The proportion of patients dying with GVHD was higher in African Americans (12 of 37; 32%) than among Caucasians (9 of 56; 16%). Death secondary to organ failure was higher in Caucasians (12 of 56; 26%) compared to African Americans (4 of 37; 11%). There were no differences between African Americans and Caucasian in regards to deaths from graft failure, infection or hemorrhage. These data suggest recent improvements in overall survival rates after HCT for SAA are largely limited to Caucasians. Higher mortality in African Americans may be explained by greater genetic diversity, which renders the identification of donors by high-resolution HLA-typing more challenging, genetic polymorphisms impacting drug metabolism and unmeasured co-morbidities. Novel strategies aimed at lowering acute and chronic GVHD rates are needed to lower GVHD-related deaths. Disclosures: No relevant conflicts of interest to declare.

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HLA DR15 Antigen Status Does Not Impact Graft-Versus-Host Disease or Disease-Free Survival in HLA-Matched Sibling Transplantation for Hematologic Malignancies

Blood ◽

10.1182/blood.v118.21.3094.3094 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3094-3094

Author(s):

Minoo Battiwalla ◽

Kristin Ellis ◽

Steven Z. Pavletic ◽

Gorgun Akpek ◽

Peiman Hematti ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Disease Free Survival ◽

Free Survival ◽

Graft Versus Host ◽

Matched Sibling ◽

Disease Free

Abstract Abstract 3094 The HLA class II DRB1 antigen DR15 is an important immunobiologic marker in immune mediated marrow failure states. DR15 has also been reported in small studies to be associated with favorable outcomes (reduction in acute GVHD and reduced relapse resulting in improved overall survival) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on major transplant outcomes, we conducted a retrospective study of 2, 891 recipients of first marrow or mobilized peripheral blood stem cell transplantation for the treatment of acute myeloid leukemia (n=1038), acute lymphoblastic leukemia (n=700), chronic myeloid leukemia (n=948), or myelodysplastic syndrome (n=205) between 1990–2008 and reported to the CIBMTR registry. Selection was confined to HLA-identical sibling transplantation to avoid HLA-disparity as a driving force for observed differences. All patients received conventional myeloablative conditioning, T-replete grafts and cyclosporine plus methotrexate- based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 (25.3%) patients as positive and 2159 (74.7%) patients as negative for DRB1*15 :01 or *15 :02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and -negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, acute graft-versus-host disease (GvHD) II-IV or III-IV, chronic GVHD, treatment related mortality, relapse, disease-free survival or overall survival. Confining the univariate analysis to myeloid malignancies did not alter these findings. Multivariate analysis models were constructed with DR15 status forced into the models in all steps of model building and the final model regardless of its statistical significance. Other variables tested included: donor/recipient age, CMV status, disease, disease stage, graft source, Karnofsky score, race and year of transplant. Variables that attained a p-value ≤0.05 were held in the final multivariate models. In multivariate analysis, DR15 status showed no significant difference in the primary outcomes of acute GVHD II-IV or III-IV, chronic GVHD, overall survival, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplantation outcomes in this large and homogenous cohort of leukemia and MDS patients. Disclosures: No relevant conflicts of interest to declare.

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Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2017.72.6869 ◽

2017 ◽

Vol 35 (30) ◽

pp. 3425-3432 ◽

Cited By ~ 72

Author(s):

Carmen Martínez ◽

Jorge Gayoso ◽

Carmen Canals ◽

Hervé Finel ◽

Karl Peggs ◽

...

Keyword(s):

Overall Survival ◽

Hodgkin Lymphoma ◽

Lower Risk ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Unrelated Donor ◽

Post Transplantation ◽

Free Survival ◽

Blood And Marrow Transplantation ◽

Matched Sibling

Purpose To compare the outcome of patients with Hodgkin lymphoma who received post-transplantation cyclophosphamide–based haploidentical (HAPLO) allogeneic hematopoietic cell transplantation with the outcome of patients who received conventional HLA-matched sibling donor (SIB) and HLA-matched unrelated donor (MUD). Patients and Methods We retrospectively evaluated 709 adult patients with Hodgkin lymphoma who were registered in the European Society for Blood and Marrow Transplantation database who received HAPLO (n = 98), SIB (n = 338), or MUD (n = 273) transplantation. Results Median follow-up of survivors was 29 months. No differences were observed between groups in the incidence of acute graft-versus-host disease (GVHD). HAPLO was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%; P = .04). Cumulative incidence of nonrelapse mortality at 1 year was 17%, 13%, and 21% in HAPLO, SIB, and MUD, respectively, and corresponding 2-year cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. On multivariable analysis, relative to SIB, nonrelapse mortality was similar in HAPLO ( P = .26) and higher in MUD ( P = .003), and risk of relapse was lower in both HAPLO ( P = .047) and MUD ( P < .001). Two-year overall survival and progression-free survival were 67% and 43% for HAPLO, 71% and 38% for SIB, and 62% and 45% for MUD, respectively. There were no significant differences in overall survival or progression-free survival between HAPLO and SIB or MUD. The rate of the composite end point of extensive chronic GVHD and relapse-free survival was significantly better for HAPLO (40%) compared with SIB (28%; P = .049) and similar to MUD (38%; P = .59). Conclusion Post-transplantation cyclophosphamide–based HAPLO transplantation results in similar survival outcomes compared with SIB and MUD, which confirms its suitability when no conventional donor is available. Our results also suggest that HAPLO results in a lower risk of chronic GVHD than MUD transplantation.

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Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors

Blood ◽

10.1182/blood-2010-01-261958 ◽

2010 ◽

Vol 116 (19) ◽

pp. 4007-4015 ◽

Cited By ~ 78

Author(s):

Peter J. Shaw ◽

Fangyu Kan ◽

Kwang Woo Ahn ◽

Stephen R. Spellman ◽

Mahmoud Aljurf ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Myeloid Leukemia ◽

Chronic Gvhd ◽

Unrelated Donors ◽

Matched Sibling ◽

Disease Free ◽

Related Mortality

AbstractAlthough some trials have allowed matched or single human leukocyte antigen (HLA)–mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.

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Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

Blood ◽

10.1182/blood-2010-12-327536 ◽

2011 ◽

Vol 118 (8) ◽

pp. 2351-2357 ◽

Cited By ~ 115

Author(s):

Judith C. Marsh ◽

Vikas Gupta ◽

ZiYi Lim ◽

Aloysius Y. Ho ◽

Robin M. Ireland ◽

...

Keyword(s):

Overall Survival ◽

Aplastic Anemia ◽

Viral Infections ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Median Total Dose ◽

Unrelated Donors ◽

Matched Sibling ◽

Low Incidence ◽

Acquired Severe Aplastic Anemia

Abstract We evaluated a novel alemtuzumab-based conditioning regimen in HSCT for acquired severe aplastic anemia (SAA). In a multicenter retrospective study, 50 patients received transplants from matched sibling donors (MSD; n = 21) and unrelated donors (UD; n = 29), using fludarabine 30 mg/m2 for 4 days, cyclophosphamide 300 mg/m2 for 4 days, and alemtuzumab median total dose of 60 mg (range:40-100 mg). Median age was 35 years (range 8-62). Overall survival at 2 years was 95% ± 5% for MSD and 83% for UD HSCT (p 0.34). Cumulative incidence of graft failure was 9.5% for MSD and 14.5% for UD HSCT. Full-donor chimerism (FDC) in unfractionated peripheral blood was 42%; no patient achieved CD3 FDC. Acute GVHD was observed in only 13.5% patients (all grade I-II) and only 2 patients (4%) developed chronic GVHD. A low incidence of viral infections was seen. Factors influencing overall survival were HSCT comorbidity 2-year index (92% with score 0-1 vs 42% with score ≥ 2, P < .001) and age (92% for age < 50 years vs 71% ≥ 50 years, P < .001). Our data suggest that the use of an alemtuzumab-based HSCT regimen for SAA results in durable engraftment with a low incidence of chronic GVHD.

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Selecting between HLA-Matched Siblings and HLA- Haploidentical Related Donors for Acute Leukemia in the Era of Post-Transplant Cyclophosphamide: The Center for International Blood and Marrow Transplant Registry and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplant

Blood ◽

10.1182/blood.v130.suppl_1.851.851 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 851-851

Author(s):

Tara M. Robinson ◽

Ephraim J. Fuchs ◽

Mei-Jie Zhang ◽

Myriam Labopin ◽

Andrew St. Martin ◽

...

Keyword(s):

Overall Survival ◽

Treatment Failure ◽

Cox Regression ◽

Chronic Gvhd ◽

Matched Pair ◽

Patient Age ◽

Patient Âgé ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Overall Mortality

Abstract An HLA-matched sibling has been considered the optimal donor for allogeneic hematopoietic cell transplantation (HSCT). However, several potential transplant recipients may have a haploidentical sibling or an offspring who may also serve as donors. In this study, we sought to determine the optimal alternative related donor (haploidentical sibling or an offspring) as compared to an HLA-matched sibling. The primary objective was comparison of chronic graft-versus-host disease (GVHD). Secondary outcomes included acute GVHD, non-relapse mortality (NRM), relapse, treatment failure (relapse or death, inverse of relapse-free survival) and overall mortality. The study population included 4540 donor-recipient pairs (n=218 haploidentical sibling; n=218 offspring; n=4104 HLA-matched sibling) with acute myeloid (n=3617) and acute lymphoblastic (n=923) leukemia transplanted in 2008 to 2015. There were few offspring (n=87) who donated to patients aged 18-54 years and haploidentical siblings (n=61) who donated to patients aged 55-76 years and were excluded from the analysis. Post-transplant cyclophosphamide (PT-Cy) with calcineurin inhibitor (CNI) and mycophenolate was used for GVHD prophylaxis for all haploidentical HSCTs. HLA-matched siblings received CNI-containing GVHD prophylaxis; CNI with methotrexate was the predominant prophylaxis regimen. Patient age was correlated with donor age and donor-recipient relationship. Bone marrow was the predominant graft for haploidentical HSCTs (64%) and peripheral blood (89%) for HLA-matched sibling HSCTs. Younger patients (age 18-54 years) of were more likely to receive reduced intensity conditioning regimens for haploidentical HSCTs compared to HLA-matched sibling HSCTs (22%). Among older patients, conditioning regimen intensity did not differ by donor type. Exploratory analysis confirmed differences in survival by patient age. Therefore, based on differences in survival by patient age, two age groups were created: 18 - 54 years and 55 - 76 years and within each patient age group, donor-recipient relationship and its effect on transplant outcomes were tested using Cox regression models. In addition to the standard Cox regression model, we also performed a matched-pair analysis. Recipients of haploidentical HSCT (cases; n=436) were matched to HLA-matched siblings (controls; n=1707) on age, disease and disease risk index. 88% of patients aged 18-54 years were matched to 4 controls and 96% of patients aged 55-76 years were matched to 4 controls. The median difference in age between cases and controls were 0.08 (range 0-9.9) years for patients aged 18-54 years and 0.05 (0 - 9.5) years for patients aged 55-76 years. The results of multivariate Cox regression and matched-pair analysis are shown in Tables 1, 2. Among patients aged 18-54 years, chronic GVHD risks were lower after haploidentical sibling compared to HLA-matched sibling HSCT. There were no differences in acute GVHD, NRM, relapse, treatment failure or overall mortality. Among patients aged 55-76 years, acute and chronic GVHD risks were lower after offspring compared to HLA-matched sibling HSCT. But risks for NRM, treatment failure and overall mortality were higher after offspring compared to HLA-matched sibling HSCT. The 2-year probabilities of overall survival, adjusted for disease risk index and sex are shown in Figure 1. In summary, chronic GVHD rates were lower after haploidentical HSCT with PT-Cy containing GVHD prophylaxis regimens compared to HLA-matched sibling HSCT for all patients. Whether this can be attributed solely to the GVHD prophylaxis regimen or in part attributed to use of peripheral blood grafts for HLA-matched sibling HSCT must be studied further in a setting in which PT-Cy containing GVHD prophylaxis is used for HLA-matched sibling HSCT. Despite lower chronic GVHD with haploidentical sibling donor HSCT with PT-Cy, NRM and overall survival did not differ by donor type for patients aged 18-54 years. However, for patients aged 55 - 76 years, despite lower chronic GVHD with offspring donor HSCT with PT-Cy, NRM was higher and overall survival was lower compared to HLA-matched sibling HSCT. Definitive proof of these findings would require a prospective randomized trial. Disclosures Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty: Sanofi: Honoraria, Speakers Bureau.

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Occurrence and Impact of Minor Histocompatibility Antigens' Disparities on Outcomes of Hematopoietic Stem Cell Transplantation from HLA-Matched Sibling Donors

Bone Marrow Research ◽

10.1155/2012/257086 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Monika Dzierzak-Mietla ◽

M. Markiewicz ◽

Urszula Siekiera ◽

Sylwia Mizia ◽

Anna Koclega ◽

...

Keyword(s):

Overall Survival ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Histocompatibility Antigens ◽

Hematopoietic Stem ◽

Minor Histocompatibility Antigens ◽

Negative Effect ◽

Matched Sibling

We have examined the alleles of eleven minor histocompatibility antigens (MiHAs) and investigated the occurrence of immunogenic MiHA disparities in 62 recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning performed between 2000 and 2008 and in their HLA-matched sibling donors. Immunogenic MiHA mismatches were detected in 42 donor-recipient pairs: in 29% MiHA was mismatched in HVG direction, in another 29% in GVH direction; bidirectional MiHA disparity was detected in 10% and no MiHA mismatches in 32%. Patients with GVH-directed HY mismatches had lower both overall survival and disease-free survival at 3 years than patients with compatible HY; also higher incidence of both severe acute GvHD and extensive chronic GVHD was observed in patients with GVH-directed HY mismatch. On contrary, GVH-directed mismatches of autosomally encoded MiHAs had no negative effect on overall survival. Results of our study help to understand why posttransplant courses of allo-HCT from siblings may vary despite the complete high-resolution HLA matching of a donor and a recipient.

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