Acute GvHD after HLA-Haploidentical Hematopoietic Cell Transplantation with Regulatory and Conventional T Cell Immunotherapy Does Not Adversely Affect Transplantation Outcomes

Abstract Introduction Adoptive immunotherapy with CD4+CD25+FOXP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) has been employed after allogeneic hematopoietic stem cell transplantation (HSCT) to prevent Graft-versus-Host Disease (GvHD) while mantaining Graft-versus-Leukemia effect in the absence of any further immune suppressive GvHD prophylaxis (Di Ianni, Blood 2011; Martelli, Blood 2014). A recent study of age-adapted haploidentical HSCT with Treg/Tcon adoptive immunotherapy (Treg/Tcon haplo-HSCT) resulted in an unprecedented 75% chronic GvHD (cGvHD)/leukemia-free survival (CRFS) in acute myeloid leukemia patients. Acute GvHD (aGvHD) occured in 33% of patients and was the most frequent complication of the procedure (Pierini, Blood Advances 2021). Here, we analyzed clinical and histological characteristics of aGvHD and evaluated its impact on outcomes in patients who received Treg/Tcon haplo-HSCT. Methods We retrieved data of patients who underwent Treg/Tcon haplo-HSCT at Perugia University Hospital and who were evaluable for aGvHD from January 2015 until June 2021 (clinicaltrials.gov: NCT03977103). Histological features and lymphoid infiltration by immunohistochemistry were analyzed in gut samples of patients who received diagnostic colonscopy and biopsy for gastrointestinal symptoms. Results A total of 105 patients engrafted after Treg/Tcon haplo-HSCT. Mean age at transplant was 48 years (range 18-70). Acute leukemia was the most frequent diagnosis (78/105 myeloid, 23/105 lymphoblastic), 4 patients had myelodisplastic syndrome and 2 multiple myeloma. Twenty-seven (26%) patients had active disease at the time of HSCT. Fourteen (13%) patients received Treg/Tcon haplo-HSCT as a second HSCT procedure. Thirty-one (29%) patients developed grade II-IV aGvHD. Four patients had grade II aGvHD, 23 grade III, and 4 grade IV. Almost all patients (90%) presented gut involvement, while skin was involved in 64% of them and liver in 35%. To explain why gut symptoms such as diarrhea and abdominal pain were more frequently present than symptoms of skin or liver involvement, we evaluated 40 histological samples from 34 patients who received colonoscopy for suspected aGvHD. Twenty-two of them (65%) received a clinical diagnosis of aGvHD and pharmacological immune suppression was promptly started. Clinical diagnosis did not always match histological findings: biopsies were suggestive of aGvHD in 20/22 patients who required treatment, but also in 8/12 patients who did not. We found no difference in median CD3+ cell infiltration among patients who did not need immune suppressive treatments and patients with aGvHD (460 cells/mmq vs 446 cells/mmq). However, FOXP3+ Tregs preferentially infiltrated gut mucosa of patients who resolved clinical symptoms with no need of immune suppressive treatments (120 cells/mmq vs 59 cells/mmq, p = 0.008; FOXP3/CD3 ratio: 0.27 vs 0.18, p = 0.004). This observation suggested Treg defective homing to gut mucosa of aGvHD patients. Indeed, we found infused Tregs expressed lower levels of gut homing receptor α4β7 in comparison with Tcons (p< .001). Despite severe presentation at diagnosis, aGvHD resolved in the majority of patients (71%), and immune suppressive therapy could be completely withdrawn after a relatively short-course (median: 98 days, range 48-404). Sixteen/31 patients (52%) were steroid refractory and required further treatments after first-line (e.g. Ruxolitinib). Only two of them developed moderate/severe cGvHD and one is alive and off-therapy. Indeed, aGvHD diagnosis did not result in higher incidence of non-relapse mortality (cumulative incidence of 29% in aGvHD patients vs 27% in controls; p=non significant, ns, Fig.1A), relapse (13% vs 20%; p=ns, Fig.1B), or cGvHD (6.5% vs 3%; p=ns, Fig.1C). In fact, CRFS of aGvHD patients was similar to CRFS of patients that did not develop aGvHD (Fig. 1D, p=ns, median follow up of live patients: 1246 days). Conclusions Treg/Tcon haplo-HSCT is followed by low rates of relapse and cGvHD and results in good CRFS in high risk leukemia patients. aGvHD after Treg/Tcon haplo-HSCT preferentially involves the gut where Treg homing is defective. Strategies that enhance Treg homing in the gut (e.g. low-dose IL-2) may help reduce aGvHD after Treg/Tcon haplo-HSCT. In conclusion, despite aGvHD occurred in 29% of patients, it was responsive to treatments and it did not result in disease relapse or cGvHD. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation.

Blood ◽

10.1182/blood.v110.11.2167.2167 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2167-2167

Author(s):

Sebastian Giebel ◽

Aleksandra Holowecka-Goral ◽

Izabela Nowak ◽

Tomasz Czerw ◽

Jerzy Wojnar ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Kir Genes ◽

Increased Risk ◽

Grade Ii ◽

Card15 Gene ◽

Grade Iii

Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.

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Use Of Unrelated Donors In Elderly Patients (age >60 years) Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation For Hematologic Malignancies

Blood ◽

10.1182/blood.v122.21.5544.5544 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5544-5544

Author(s):

El-Cheikh Jean ◽

Devillier Raynier ◽

Fürst Sabine ◽

Crocchiolo Roberto ◽

Granata Angela ◽

...

Keyword(s):

Elderly Patients ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity

Abstract Objectives The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. However, there are only limited data on the feasibility and outcomes of URD HCT in elderly patients.The aim of the study was to compare the outcome in OS and PFS for patients transplanted using unrelated donor (URD) in patients age 60 or older. Patients and methods We retrospectively analyzed outcomes in 62 consecutive hematologic malignancy patients aged > or =60 years (median, 62 years; range: 60-70 years) undergoing reduced intensity conditioning regimens (RIC) from URD. In this study, URD was used only when a MRD was not available. Then we compared the outcome of 17 elderly patients (age >65 years) with 44 younger patients aged between 60 and 65 years. Patient, disease and transplant characteristics are shown in Table 1. Results No patients experienced graft rejection. The median HCT comorbidity index score was 2 (range, 0 to 6). With a median follow up of 36 months (range, 5-74), the cumulative incidence of grades II to IV acute GVHD was 28% and of grades III to IV acute GVHD, 13%. At 2 years, the cumulative incidence of chronic GVHD was 27%, progression-free survival (PFS) was 62%, overall survival (OS) was 63%, and relapse was 14%. Non relapse mortality (NRM) was 24% at 2 years. The cumulative incidence of grade II–IV Acute GVHD was 43% for the younger group and 17% for the older group (P = 0.056). The cumulative incidence of chronic GVHD was not different between the two groups (23% vs. 45% (p=0.3), respectively). Two-year OS and PFS was 57% versus 86% (P = 0.059) and 55% versus 86% (P = 0.03), in the younger and the older group respectively. The 2-year NRM and relapse was 26% versus 14% (P = 0.4) and 19% versus 0% (P = 0.04), in the younger and older group respectively. Conclusions This retrospective study suggest that RIC HCT from URD is a safe and effective option for patients aged > or =60 years or older, and in the absence of suitable related donors, well-matched URD may offer a very reasonable alternative, and that does not appear to be associated with a detrimental outcome. However these results are encouraging showing once again that with an adequate selection, age is not a definitive limitation. Disclosures: No relevant conflicts of interest to declare.

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HLA-Haploidentical Hematopoietic Cell Transplantation of Ex Vivo Tcrαβ-Depleted Grafts with CD45RA-Depleted Memory T Cell Add-Back in Adults and Children with Hematological Malignancies: 4-Year Follow-up of Multicenter Study in Singapore

Blood ◽

10.1182/blood-2021-152372 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 555-555

Author(s):

Ian Q Wu ◽

Yeh Ching Linn ◽

Yang Liang Boo ◽

Rajat Bhattacharyya ◽

Zi Yi Lim ◽

...

Keyword(s):

T Cells ◽

High Risk ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Grade Ii

Abstract Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donors. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications are main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells will permit hematopoietic engraftment while effectively reducing GVHD and providing donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC products were divided into two fractions in 9:1 ratio and depleted using CliniMACS device after labelling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany) respectively. All except 6 patients received the standard conditioning regimen of fludarabine 160mg/m 2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70 - 140mg/m 2 for 1 day, in combination with either total lymphoid irradiation 6Gy (n=53) or 7.5Gy (n=12) over 3 equal fractions, or total body irradiation of 2Gy (n=17), or thymoglobulin (n=2). Short term GVHD prophylaxis was given for 30 days to 1 patient using MMF, 73 using tacrolimus, and 2 using sirolimus. Results: Between January 2017 and July 2021, we transplanted 85 patients, including 78 adults (median age, 48 years; range 20 - 70) and 7 children (median age, 13 years, range 7 - 17), with high risk AML (n=44), ALL (n=19), MDS (n=9), plasma cell neoplasm (n=4), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), CMMoL (n=2), CML (n=1) and lymphoma (n=2). Patients were infused with TCRαβ and CD45RA depleted grafts containing median of 6.19 x 10 6 (range 3.54 - 20.78) CD34+ cells/kg, 0.00 x 10 4 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 1.10 x 10 6 (range 0.15 - 11.67) CD45RO+CD3+ cells/kg. TCRαβ depleted graft fraction contained a median of 0.42 x 10 4 (range 0 - 11.30) TCRαβ+ cells/kg, and 7.61 x 10 6 (range 0.62 - 31.84) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure with no secondary graft failures. All others had engraftment of ANC > 500 cells/µL at median of 12 days (range 8 - 22) and PLT > 20,000 cells/µL at median of 11 days (range 7 - 17). 6 patients with high donor-specific HLA antibodies (DSA) titres engrafted successfully after desensitisation with plasma exchange, rituximab, and immunoglobulin. 29 patients (34%) developed acute GVHD of grade II - IV (Gd II, n=20; Gd III, n=5; Gd IV, n=4), with a cumulative incidence (CI) of grade II-IV and grade III-IV of 31% (95% CI 21-42%) and 11% (95% CI 5-19%) respectively, at 100 days. Chronic GVHD was seen in only 4 patients at a 2-year CI of 6% (95% CI 2-13%). 1-year CI of non-relapse mortality (NRM) and relapse were 22.7% (95% CI 13.9 - 32.9%) and 15.7% (95% CI 8.3 - 25.3%) respectively. 4 of the 17 NRM were attributed to aGVHD. Viral reactivation included CMV (n=32), HHV-6 (n=22), EBV (n=15), and adenovirus (n=8). 15 patients (17.6%) died of infection within 180 days, including 6 patients with fatal bacteraemia (bacteria, n=4; candidemia, n=2) and 1 patient from disseminated adenovirus infection. At a median follow up of 448 days (range 16- 1648) in surviving patients, 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 64.2 %, 54.0 %, and 49.0%, respectively (Figure 1). In multivariate analysis, only HCT-comorbidity index (HCT-CI) showed significant impact on OS (HR 3.38; 95% CI 1.42 - 8.02; p=0.0059), EFS (HR 2.62; 95% CI 1.18 - 5.76; p=0.0017), and NRM (HR 4.92; 95% CI 1.79 - 13.58; p=0.0021). Disease risk index (DRI) showed a trend in higher risk of relapse (HR 2.83; 95% CI 0.96 - 8.33; p=0.059). 2-year OS, EFS, and GRFS for the subset of 58 patients (adults, n=52; children, n=6) with HCT-CI score of 0 were 76.6 %, 63.4%, and 57.5 %, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allow successful allograft in high-risk patients lacking suitable matched donors, including patients with high levels of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD. Best outcomes are seen in patients with favourable HCT-CI. Further efforts are needed to reduce the risk of infection-related death in patients with high risk HCT-CI, and relapse in patients with high risk DRI, through optimization of anti-microbial prophylaxis or prophylactic infusion of memory-cell DLI. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Impact of Immune Reconstitution (IR) and Graft-Versus-Host Disease (GvHD) on Clinical Outcomes after Treatment with Donor T Cells Transduced to Express the Herpes Simplex Virus Thymidine-Kinase Suicide Gene (TK cells) in Acute Leukemia Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽

10.1182/blood.v128.22.4599.4599 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4599-4599 ◽

Cited By ~ 1

Author(s):

Fabio Ciceri ◽

Chiara Bonini ◽

Arnon Nagler ◽

Evangelia Yannaki ◽

Maria Teresa Lupo Stanghellini ◽

...

Keyword(s):

Risk Factors ◽

T Cells ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Suicide Gene ◽

Baseline Risk ◽

Hematopoietic Stem ◽

Cell Dose ◽

Grade Ii

Abstract Background: Haploidentical HSCT is a readily available platform for most patients lacking an HLA-matched donor, but the T-cell depleted (TCD) approach without any post-transplant donor cell therapy is impaired by high non-relapse mortality (NRM) due to slow IR, while the T-cell replete (TCR) approach followed by cyclophosphamide and immunosuppressive therapy is hampered by high chronic GvHD and relapse incidence (RI) Methods: The impactof IR and TK-cell dose on outcomes was assessed in 45 patients with several hematological malignancies treated with 1 to 4 monthly TK infusions (0.1-1.0x107/Kg, 21-49 days after haploidentical HSCT) in a phase 2 trial (n=30; Lancet Oncol 2009; 10: 489) and in the experimental arm of an ongoing phase 3 trial (n=15; NCT00914628). Median follow-up time for TK-treated patients was 3.7 years (interquartile range [IQR], 1.5-8.5). Outcome measures included 1-year NRM, overall survival (OS), leukemia-free survival (LFS), RI and GvHD. Hazard ratios (HR) and odds ratios (OR) were derived by regression models adjusted for baseline risk factors. IR (T cells ≥ 100/µL) was modelled as a time-dependent covariate. These pooled data were the basis for the positive opinion for conditional marketing authorization recently granted for TK cells (www.ema.europe.eu/EPAR/Zalmoxis) Results: IR was achieved by 34 patients (76%) after a median of two TK infusions (IQR, 1-2), a median cumulative cell dose of 1.3x107/kg (1.0-2.4) and a median time from HSCT of 83 days (65-108). IR was not influenced by baseline risk factors or TK-cell doses and was associated with decreased NRM (12% vs 75%; p<0.0001) and improved LFS (HR=0.20; p=0.005) and OS (HR=0.08; p<0.0001). Grade II-IV acute GvHD (35%; grade III-IV: 7%) was unrelated to TK-cell dose and occurred nearly exclusively in IR (OR=7.0; p=0.07) and female patients (OR=9.7; p=0.007). Only one patient had de novo chronic GvHD. All GvHD events fully resolved (median, 14 days; 10-27) after suicide-gene induction with ganciclovir (median, 15 days; 13-16). Cumulative RI (31%) did not differ according to IR, while it was inversely related to TK-cell dose, with decreased relapse rates (60%, 33% and 0%) observed with increasing cell doses (<1.0, 1.0-2.4 and >2.4x107, respectively; p=0.004). TK patients had significant outcomes in OS (51%), NRM (20%) and chronic GvHD (6%). Importantly, TK patients with grade II-IV acute GvHD treated with ganciclovir experienced high OS rates (67%), thus confirming the ability of TK machinery to selectively targeting GvHD effector cells, while sparing a wide repertoire protective against infections and leukemia recurrence Conclusions: TK-cell treatment is characterized by early IR and full GvHD control that translate in improved NRM and OS and by dose-related antileukemic effects, with overall outcomes comparing very favorably with those of current approaches to haploidentical HSCT Disclosures Ciceri: MolMed SpA: Consultancy. Bonini:TxCell: Membership on an entity's Board of Directors or advisory committees; Molmed SpA: Consultancy. Colombi:MolMed: Employment. Lambiase:MolMed: Employment. Bordignon:MolMed SpA: Employment.

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The Effect of Costimulatory Moleculars on Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.4875.4875 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4875-4875

Author(s):

Zhenhua Qiao ◽

Fang Ye ◽

Lei Zu

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Group A ◽

Group B

Abstract Objective: To explore the effect of costimulatory molecular and CD25 expressed on peripheral CD4+ T lymphocytes on graft-versus-host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods: 1. The 21 patients who suffered of hematology diseases or malignant solid tumors and were underwent allo-HSCT and 10 normal individuals were enrolled in the study.2. For the sake of difference conditioning regimens we divided the 21 patients into two groups: patients undergoing non-myeloablative stem cell transplantation(NST) belonged to group A, others undergoing traditional myeloablative stem cell transplantation belonged to group B; we divided them into five groups for with GVHD or without GVHD and types of GVHD: group 1(group A with acute GVHD), group 2(group A with chronic GVHD), group 3(group B with acute GVHD), group 4(group B without GVHD), group 5(group A without GVHD).3. The levels of CD28, CD80, CD152 and CD25 expressions on peripheral CD4+ T lymphocytes were detected by three colors flow cytometry (FCM)in different time(before allo-HSCT,7days,14days,21days,30days after allo-HSCT, the time of GVHD and the time after GVHD treated).4.STR-PCR for detecting micro-satellites chimeras forming. Results: 1. All 21 patients achieved engraftment. By STR-PCR assay,12 cases formed complete chimeras(CC) and 9 cases formed mixed chimeras(MC). In group A,3 cases developed acute GVHD and 4 cases developed chronic GVHD; in group B,4 cases developed aGVHD. The incidence of GVHD and infection rates between group A and B has no difference(X2=3.711, P=0.144).2. Among these 21 cases,5 cases died:2 cases died of multiple organs function failure due to primary disease relapse,1 case died of bleeding in brain and 2 cases died of liver function failure for the sake of complicated with acute GVHD; others survive with disease free till present.3. The results of multivariate logistic regression models and Kaplan-Meier survival curves analyses showed: age, sex, infection, HLA-type, blood type, conditioning regiment and the times of absolute neutrophil counts and platelets recovering to normal, had no association with the incidence of GVHD;A multivariate COX survival function model analysis showed CD4CD152 and CD4CD25 are independent prognostic factors for GVHD(X2=13.128, P<0.0001).4. Patients with GVHD demonstrated higher CD4+CD28+ and CD4+CD80+ T cell levels than those without GVHD(P<0.01);patients with aGVHD demonstrated higher than those with cGVHD(P<0.05) and without GVHD(P<0.05); Patients with GVHD demonstrated lower CD4+CD152+ and CD4+CD25+ T cell levels than those without GVHD(P<0.01); the same result occurs between aGVHD and cGVHD and without GVHD. After effective treatment, unnormal CD4+CD28+, CD4+CD80+, CD4+CD152+ and CD4+CD25+ T cell levels recovered to the levels before transplantation. Conclusions: The incidences of GVHD between NST and traditional myeloablative stem cell transplantation had no difference. B7-CD28/CD152 costimulatory pathway plays a critical role in developing of GVHD. Peripheral CD4+CD28+, CD4+CD80+, CD4+CD152+ and CD4+CD25+ T cell levels were relative to recipient GVHD, especially CD4+CD152+ and CD4+CD25+ T cell levels. Down-grade CD4+CD28+ and CD4+CD80+ T cell levels and up-grade CD4+CD152+ and CD4+CD25+T cell levels could reduce the incidence of GVHD.

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Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.

Blood ◽

10.1182/blood.v114.22.661.661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 661-661

Author(s):

Jon J van Rood ◽

Cladd E Stevens ◽

Jacqueline Smits ◽

Carmelita Carrier ◽

Carol Carpenter ◽

...

Keyword(s):

Conflicts Of Interest ◽

Chronic Gvhd ◽

Hla Antigens ◽

Human Leukocyte ◽

Hematologic Malignancies ◽

Hematopoietic Stem ◽

Leukocyte Antigens ◽

Grade Ii ◽

The Impact ◽

Related Mortality

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

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The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽

10.1182/blood.v114.22.873.873 ◽

2009 ◽

Vol 114 (22) ◽

pp. 873-873

Author(s):

Andrea Toma ◽

Marie-Lorraine Balère-Appert ◽

Jean-Michel Boiron ◽

Pierre Bordigoni ◽

Gerard Socie ◽

...

Keyword(s):

Stem Cells ◽

Multivariate Analysis ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity Conditioning Regimen ◽

Unrelated Donors ◽

Grade Ii

Abstract Abstract 873 The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures: No relevant conflicts of interest to declare.

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Regulatory Role of Host IL-17 Via Control of Host Macrophage Activation Contributes to Less Acute Gvhd

Blood ◽

10.1182/blood.v120.21.4669.4669 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4669-4669

Author(s):

Rie Kuroda ◽

Katsuaki Sato ◽

Hideaki Maeba ◽

Toshihiro Fujiki ◽

Shintaro Mase ◽

...

Keyword(s):

Protective Effect ◽

Inflammatory Cytokine ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Paneth Cell ◽

Peritoneal Macrophages ◽

Regulatory Role ◽

Hematopoietic Stem ◽

Anti Inflammatory

Abstract Abstract 4669 IL-17 has emerged as a key pro-inflammatory cytokine, however, recent studies demonstrated that IL-17 has also anti-inflammatory effects. In addition, a wide variety of IL-17 producing cells are identified not only in T-cells but also in subpopulation of monocytes and macrophages, mast cells, Paneth cell in the gut so on. Therefore, IL-17 mediated immune responses are becoming much more complicated. In hematopoietic stem cell transplantation, we have reported that host-derived IL-17 has a protective effect against acute graft-versus-host disease (GVHD) using rodent models, in contrast, donor-BM-derived IL-17 exacerbates chronic GVHD. In acute GVHD model, lethally irradiated IL-17 knockout (KO) recipient mice receiving allogeneic BM with low dose splenocytes developed more severe acute gut GVHD compared to wild type (WT) host mice and finally half of them died (p<0.05). Much higher number of infiltrated monocyte/macrophage cluster was observed in spleen and gut in IL-17 KO host mice. Furthermore, residual host-typed peritoneal macrophages in IL-17 KO host mice were highly activated with the expression of TNF-α, while activation of donor-typed macrophages was much less with the production of anti-inflammatory cytokine IL-10. It suggested that these activated and increased macrophages might deeply involve in the pathogenesis of lethal GVHD. To test this, IL-17 KO recipient mice were given lipoCL2MDP intraperitoneally on day -7 before BMT to deplete host macrophages. As shown in the figure below, the macrophages depleted IL-17 KO host mice given splenocytes to induce lethal GVHD showed a significant survival benefit compared with IL-17 KO mice without depletion of macrophages. In conclusion, host IL-17 has a protective effect against acute GVHD with suppression of the activated macrophages. This is the first report that IL-17 has the immuno-regulatory role via control of activated host macrophages in acute GVHD. Disclosures: No relevant conflicts of interest to declare.

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Influence of Ceacams Expression in Graft-Versus-Host Disease After Allogeneic Transplantation

Blood ◽

10.1182/blood.v120.21.4490.4490 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4490-4490

Author(s):

Michael Koldehoff ◽

Janine D. Dreesen ◽

Ahmet H. Elmaagacli ◽

Dietrich W. Beelen ◽

Bernhard B. Singer

Keyword(s):

Whole Blood ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Cellular Growth ◽

Urine Samples ◽

Serum Samples ◽

Peripheral Blood Stem Cells ◽

Hematopoietic Stem

Abstract Abstract 4490 Background: The carcinoembryonic antigen (CEA) family is involved in intercellular binding interactions that affect various normal and pathogenic processes associated with cellular growth and differentiation. In human, the CEA family are subdivided into the CEA-related cell-adhesion molecules (CEACAMs) and the pregnancy-specific glycoproteins (PSGs). Never before the influence of CEACAMs on patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) was evaluated. Methods: Here we analyzed in a retrospective study 33 patients (pts) for CEACAMs expression that underwent allogeneic HSCT for various diseases and analyzed their outcome. CEACAMs expressions were performed by flow cytometry and ELISA in whole blood, serum and urine samples. Results: We report the analysis of 19 pts with acute leukemia (58%), 5 pts with chronic leukemia (15%), 4 pts with MDS (12%) and 5 pts with advanced NHL (15%). The median age at transplant was 50.5 (range, 18–69) years. In this cohort 12 pts received grafts from HLA-identical siblings (36%), 16 pts from matched (49%) and 5 pts from mismatched (15%) unrelated donors. Transplantat consisted of unmanipulated peripheral blood stem cells (n=26, 79%) or bone marrow (n=7, 21%). Of all pts, 7 (21%) had relapsed after transplant. Among these pts, 31 (94%) developed acute GVHD (21 pts had an acute GvHD of grade ≥2). There was no significant correlation between CEACAMs expression after transplant between the variant leukemic disorders in the whole blood and the urine samples. Analysis of each CEACAMs for relapse showed no statistically differences. For CEACAM-6, we found a moderate up-regulation in pts with acute GvHD ≥2 versus acute GvHD <2 (p<0.1). In pts with severe acute GVHD (grade >3) comparing all other pts, we found significant induction of CEACAM-1 (118.5 ng/ml vs. 198.3 ng/ml, p<0.05) in urine samples and CEACAM-1 (109.2 vs. 157.5 ng/ml, p<0.04) in serum samples. However, no statistic differences were found in the CEACAM-1 in regards to chronic GVHD. Conclusions: These results suggest that pts with high levels of CEACAM-1 confirms a relevant association of the development of acute GVHD and CEACAM profiling could be an early indicator of severe acute GvHD. Disclosures: No relevant conflicts of interest to declare.

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Development and Preliminary Testing Of The Post-Transplant Multimorbidity Index (PTMI)

Blood ◽

10.1182/blood.v122.21.2076.2076 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2076-2076 ◽

Cited By ~ 1

Author(s):

Sandra A. Mitchell ◽

Steven Z. Pavletic ◽

Ernst Holler ◽

Philipp Y. Herzberg ◽

Pia Heussner ◽

...

Keyword(s):

Peptic Ulcer ◽

Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Measurement Properties ◽

Comorbid Conditions ◽

Hematopoietic Stem ◽

Post Transplant ◽

Comorbidity Index

Abstract Background Comorbid health conditions, both those present before transplant and those acquired as late effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) and the treatment of chronic graft-versus-host disease (cGVHD), represent an important covariate. While the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror et al. Cancer, 2008; 112(9):1992-2001) has been developed to predict non-relapse mortality and overall survival in allo-HSCT recipients, many of the chronic comorbid conditions that develop in the allogeneic post-transplant setting are not represented in the HCT-CI, and its predictive validity has had limited study in long-term transplant survivors. The objectives of this study were to: (i) establish a new measure of multimorbidity for the post-transplant setting (Post-Transplant Multimorbidity Index [PTMI]), and (ii) explore its content validity. Methods Based on a review of the literature and the most commonly used comorbidity measures, the PTMI was developed to reflect a broad and inclusive list of comorbid conditions that may arise in the post-transplant setting. Preliminary definitions to establish the presence of each of these conditions were developed. To enhance longitudinal comparisons, the conditions and definitions from the HCT-CI were nested within the PTMI. The conditions and definitions were iteratively refined (SM and DW) through application in a cohort of 30 post-transplant patients. Subsequently, the PTMI, HCT-CI, Charlson Comorbidity Scale (CCS), and the Functional Comorbidity Index (FCI) were comparatively evaluated in a cohort of 50 alloHSCT survivors referred for comprehensive cGVHD consultation. The evaluation cohort was a mean age of 42 (range 23-68) years and a median of 33.5 (range 13-208) months post-transplant. All but two (late acute GVHD n=1; no cGVHD n=1) had active cGVHD that had been present for a median of 27 (range 3-197) months. A majority had severe cGVHD (NIH global severity score 1 n=4; 2 n=8; 3 n=36) and 90% were currently receiving systemic immunosuppression. Results Applying the PTMI, HCT-CI, CCS and FCI to our evaluation cohort yielded a mean of 5 (SD±2.5), 1.5 (SD±1.23), 1.39 (SD±0.78), and 2.18 (SD±1.16) co-occurring conditions, respectively. On average the HCT-CI, CCS, and FCI missed the identification of one or more comorbidities 71%, 75%, and 43% of the time. Conditions that were prevalent in the cohort but missed by the other comorbidity measures included osteoporosis, avascular necrosis, hypertriglyceridemia, hypothyroidism, BMI<22, and secondary solid malignancy (excluding nonmelanoma skin cancer) after transplant. Using the PTMI, the two most prevalent comorbid conditions were osteoporosis (64%) and underweight/sarcopenia (BMI<22) (46%), whereas the FCI identified osteoporosis and depression as most prevalent, and the HCT-CI psychiatric disturbance and peptic ulcer, and the CCS history of malignancy and peptic ulcer disease, as the two most prevalent comorbidities, respectively. Conclusions Our results offer preliminary evidence that the PTMI improves the identification of chronic comorbid conditions in long-term transplant survivors with cGVHD, and demonstrate that the choice of a measure is an important methodologic issue in the design of epidemiologic studies of comorbidity in post-transplant survivors with cGVHD. Prospective studies evaluating the measurement properties of the PTMI are ongoing in post-transplant survivors with and without active chronic GVHD. With continued testing and refinement, we anticipate that this new measure will have utility for risk-adjustment and stratification in both observational studies and clinical trials in the post-transplant setting. Disclosures: No relevant conflicts of interest to declare.

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