SNP12 and SNP13 Variants of NOD2/CARD15 Gene of Donor and Recipient as Independent Risk Factors for Severe Intestinal and Pulmonary GVHD after Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract Background: Presence of any of single nucleotide polymorphism (SNPs) of the NOD2/CARD15 gene have been recently proven to correlate with higher rate of GvHD after allogeneic hematopoietic stem cell transplantation - alloHSCT (Holler E et al; Blood2006,107,4189). Mutated variants lead to impaired antibacterial response. As NOD2/CARD15 is expressed not only in monocytets/macrophages but also in both intestinal and bronchial epithelial cells these organs seem to be a major target for developing advanced GvHD. Patients and methods: The impact of each single donor (D) and recipient (R) SNPs (8,12,13) of NOD2/CARD15 gene on the incidence of acute GvHD (grade II-IV, grade III-IV, intestinal), chronic GvHD (overall, extensive, pulmonary), survival, and non-relapse mortality was evaluated in a setting of 72 patients treated with alloHSCT in single BMT center in Katowice between Jan 2000 and Jun 2005. Median patient age was 33 (11–52) years. In 70/72 cases hematological malignancies were indication for alloHSCT. Conditioning regimen was myeloablative in all cases, bone marrow was used as the only source of stem cells in 74% of patients. GVHD prophylaxis consisted of CsA, Mtx and, in case of URD-HSCT - antithymocyte globulin. Results: In univariate and multivariate analysis, including other potential risk factors, the presence of SNP12 in the recipient was associated with increased incidence of intestinal acute GVHD (75% vs. 29%; RR 4,37, p=0,03), overall chronic GVHD (100% vs. 50%, RR 4,72; p=0,003), extensive chronic GVHD (80% vs. 24%; RR 5,12; p=0,02), and pulmonary chronic GVHD (47% vs. 9%; RR 5,97; p=0,02). SNP13 in the recipient resulted in increased incidence of grade III–IV acute GVHD (45% vs. 12%; RR 4,66; p=0,01), intestinal acute GVHD (64% vs. 24%; RR 4,21, p=0,005), and extensive chronic GVHD (55% vs. 25%; RR 3,59; p=0,03). SNP13D in the donor contributed to increased risk of pulmonary chronic GVHD (36% vs. 8%; RR 6,58; p=0,01). In this single centre analysis we were not able to demonstrate the impact of NOD2/CARD15 SNPs on survival. Conclusion: The presence of particular mutations of NOD2/CARD15 in the recipient and/or the donor is associated with increased risk of severe acute and chronic GVHD. In particular, intestines and lungs appear to be target organs of these complications. Our findings may contribute to optimization of immunosuppressive and gastrointestinal decontamination regimens based on individual risk assessment for GVHD.

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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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Association of recipient and donor interleukin 6 polymorphisms 174 and 597 with outcome after allogeneic hematopoietic stem cell transplantation in children

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03677-5 ◽

2021 ◽

Author(s):

Laura Wetzel ◽

Susan Wittig ◽

Bernd Gruhn

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Interleukin 6 ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Significant Risk ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Purpose The success of allogeneic hematopoietic stem cell transplantation (HSCT) is compromised by complications such as infection, relapse, and graft-versus-host disease (GVHD). The investigation of non-HLA immunogenetics, particularly of cytokines, could identify predictors of an unfavorable outcome after allogeneic HSCT. In this study, we examined the impact of single nucleotide polymorphisms (SNPs) within the promoter region of interleukin 6 (IL6) on the development of GVHD after pediatric allogeneic HSCT. Methods In this retrospective analysis, we included 320 pediatric patients with a median age of 10 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL6-174 (G/C) and IL6-597 (G/A). The IL6-174 polymorphism was examined in 300 recipients and 295 donors. The IL6-597 polymorphism was analyzed in 299 recipients and 296 donors. We investigated the influence of the IL6-174 and IL6-597 polymorphisms on overall survival, event-free survival, relapse incidence, transplant-related mortality, and the occurrence of GVHD. Results G polymorphism at position 174 of the recipient IL6 gene was associated with a higher incidence of acute GVHD (GG vs. GC/CC; P = 0.024). Patients with IL6-597 GG genotype developed acute GVHD more frequently than individuals with an A allele (GG vs. GA vs. AA; P = 0.013). IL6-174 GG homozygous recipients had a more frequent occurrence of chronic GVHD (GG vs. GC/CC; P = 0.049). We observed a significant increased risk of chronic GVHD in recipients with IL6-597 GG genotype (GG vs. GA vs. AA; P = 0.043). Polymorphisms of donors did not affect the incidence of acute GVHD and chronic GVHD. In multivariate analysis, the IL6-174 and IL6-597 SNPs were independent significant risk factors for acute GVHD (P = 0.030; P = 0.007, respectively) as well as for chronic GVHD (P = 0.045; P = 0.015, respectively). In addition, older age at time of transplantation turned out to be a significant risk factor for chronic GVHD (P = 0.003). Conclusion Our study identified the IL6-174 and IL6-597 GG genotypes of pediatric allogeneic HSCT recipients as genetic risk factors for the development of acute GVHD and chronic GVHD. After evaluations in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the occurrence of acute GVHD and chronic GVHD.

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Hematopoietic Stem Cell Transplantation for Patients with Refractory Cytopenia of Childhood

Blood ◽

10.1182/blood.v124.21.4646.4646 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4646-4646

Author(s):

Daisuke Hasegawa ◽

Shinsuke Hirabayashi ◽

Shizuka Watanabe ◽

Yuji Zaike ◽

Masahiro Tsuchida ◽

...

Keyword(s):

Stem Cell ◽

Brain Tumor ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Grade Iii

Abstract Introduction: Refractory cytopenia of childhood (RCC) is an entity of the pediatric myelodysplastic syndrome (MDS) proposed in the World Health Organization (WHO) 2008 classification and is characterized by persistent cytopenia with dysplasia and <5% blasts in the bone marrow (BM). Although the efficacy of immunosuppressive therapy (IST) has been reported in RCC with response rate of 40-60%, hematopoietic stem cell transplantation (HSCT) is still thought as the only curative therapy for children with MDS. However, appropriate setting of HSCT for patients with RCC has not been established. Recently, we described clinical characteristics and treatment outcome in 65 cases with RCC who were prospectively registered through the Japanese Society of Pediatric Hematology/Oncology (JSPHO) (Hasegawa et al, BJH 2014). In this analysis, we focused on a subgroup that underwent HSCT in order to identify the factors that can predict the outcome of patients with RCC after HSCT. Patients and Methods: From July 1999 to February 2008, 618 children who were suspected of having MDS were prospectively registered into the JSPHO database and 65 were diagnosed based on the central review of morphology as having primary MDS without excess blasts, which was compatible with criteria of RCC. Therapeutic strategy was determined by each physician based on the recommendations provided by the Japanese Childhood MDS Study Group MDS99. As a first-line therapy, 25 patients received IST, 12 patients received HSCT, and one patient received intensive chemotherapy. The remaining 27 patients were followed without treatment for more than 2 years. Eventually, 28 (11 male and 17 female) children ended up undergoing HSCT. Results: Median age at HSCT was 10.3 years (range, 1.5 - 17.2 years). Median duration between diagnosis and HSCT was 481 days (range, 123 – 2674 days). Twelve patients had a history of receiving IST. As a stem cell source, 15 patients received BM from an unrelated donor, 5 received BM from matched-sibling donor, 4 received BM from family donor, and 4 received unrelated cord blood. As a conditioning regimen, myeloablative conditioning (MAC) with total-body irradiation regimen was given to 8 patients, MAC with busulfan regimen was given to 7, and 13 patients received reduced intensity conditioning (RIC). As a GVHD prophylaxis, 22 patients received tacrolimus and 6 received cyclosporine (CyA). Engraftment was confirmed in all patients. Grade III-IV acute GVHD was observed in 3 patients. Of 23 evaluable patients, 7 patients had chronic GVHD. Seventeen patients remained in remission after HSCT. Secondary graft failure was observed in 2 patients who received RIC after failure of IST. Nine patients died due to the following causes: transplantation-related mortality (TRM; n=7), relapse (n=1), and secondary brain tumor (n=1). Seven patients died of TRM at a median time of 103 days after HSCT (range, 44-926 days) and 5-year cumulative incidence of TRM was 28±9%. Grade III-IV acute GVHD and the presence of chronic GVHD were associated with a higher probability of TRM (p=0.03 and 0.02, respectively). Five-year event-free survival (EFS) and overall survival (OS) was 58±10% and 66±9%, respectively. No patient characteristics or transplantation-related variables showed statistically significant difference in EFS or OS. Of 13 children receiving RIC, 7 remained in remission, whereas 3 succumbed to TRM, 2 experienced secondary graft failure, and one developed brain tumor. Discussion: TRM was the main cause of treatment failure in patients with RCC receiving HSCT. This analysis suggested appropriate prevention of GVHD might be important to succeed in HSCT for patients with RCC. Disclosures No relevant conflicts of interest to declare.

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Association of Recipient and Donor Interleukin 6 Polymorphisms 174 and 597 With Outcome After Allogeneic Hematopoietic Stem Cell Transplantation in Children

10.21203/rs.3.rs-397618/v1 ◽

2021 ◽

Author(s):

Laura Wetzel ◽

Susan Wittig ◽

Bernd Gruhn

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Interleukin 6 ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Significant Risk ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Purpose The success of allogeneic hematopoietic stem cell transplantation (HSCT) is compromised by complications such as infection, relapse, and graft-versus-host disease (GVHD). The investigation of non-HLA immunogenetics, particularly of cytokines, could identify predictors of an unfavorable outcome after allogeneic HSCT. In this study, we examined the impact of single nucleotide polymorphisms (SNPs) within the promotor region of interleukin 6 (IL6) on the development of GVHD after pediatric allogeneic HSCT. Methods In this retrospective analysis, we included 320 pediatric patients with a median age of 10 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL6-174 (G/C) and IL6-597 (G/A). The IL6-174 polymorphism was examined in 300 recipients and 295 donors. The IL6-597 polymorphism was analyzed in 299 recipients and 296 donors. We investigated the influence of the IL6-174 and IL6-597 polymorphisms on overall survival, event-free survival, relapse incidence, transplant-related mortality, and the occurrence of GVHD. Results GG polymorphism at position 174 of the recipient IL6 gene was associated with a higher incidence of acute GVHD (GG vs. GC/CC; P = 0.024). Patients with IL6-597 GG genotype developed acute GVHD more frequently than individuals with an A allele (GG vs. GA vs. AA; P = 0.013). IL6-174 GG homozygous recipients had a more frequent occurrence of chronic GVHD (GG vs. GC/CC; P = 0.049). We observed a significant increased risk of chronic GVHD in recipients with IL6-597 GG genotype (GG vs. GA vs. AA; P = 0.043). Polymorphisms of donors did not affect the incidence of acute GVHD and chronic GVHD. In multivariate analysis, the IL6-174 and IL6-597 SNPs were independent significant risk factors for acute GVHD (P = 0.030; P = 0.007, respectively) as well as for chronic GVHD (P = 0.045; P = 0.015, respectively). In addition, older age at time of transplantation turned out to be a significant risk factor for chronic GVHD (P = 0.003). Conclusion Our study identified the IL6-174 and IL6-597 GG genotypes of pediatric allogeneic HSCT recipients as genetic risk factors for the development of acute GVHD and chronic GVHD. After evaluations in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the occurrence of acute GVHD and chronic GVHD.

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Risk Factors for Late Infections after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Related Donor.

Blood ◽

10.1182/blood.v108.11.2848.2848 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2848-2848

Author(s):

Marie Robin ◽

Raphaël Porcher ◽

Renato De Castro Araujo ◽

Régis Peffault de Latour ◽

Agnès Devergie ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Viral Infection ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

First Year ◽

Hematopoietic Stem ◽

Cmv Status

Abstract After allogeneic hematopoietic stem cell transplantation (HSCT), late infections represent a major cause of morbidity and mortality but little has been previously reported. In a retrospective cohort study, late infections incidence was determined in 196 long-term survivors after matched related HSCT. Only patients transplanted for aplastic anemia, chronic myeloid leukemia (CML) and acute myeloblastic leukemia (AML) were included in this study. Median follow-up was 8 years. Among 30 patients who died beyond the first year, 9 patients died from graft-versus-host disease (GVHD) and 10 from infections. Bacterial late severe infections occurred in 30 patients, yielding an 8-year cumulative incidence of 15%. Late invasive fungal infection occurred in 8 patients corresponding to a cumulative incidence of 3.6%. Most viral infections were hepatitis C and VZV and overall late viral infection incidence was 35%. We identified 3 risk factors for bacterial infections in multiple analysis: CMV status (positive recipient and negative donor), irradiation based conditioning regimen and extensive chronic GVHD within the first year. Extensive chronic GVHD was the only risk factor of non-HCV viral infection in patients transplanted for AML or CML. Thus, late life threatening infections may occur in nearly a fourth of late survivors even after matched related transplantation and are associated not only with chronic GVHD but also with irradiation and to CMV status prior to transplantation.

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The Impact of Center Experience on Results of Reduced Intensity – Allogeneic Hematopoietic Stem Cell Transplantation. A Survey From the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v116.21.3517.3517 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3517-3517

Author(s):

Sebastian Giebel ◽

Myriam Labopin ◽

Mohamad Mohty ◽

Didier Blaise ◽

Charles Craddock ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem ◽

Therapeutic Decisions ◽

Increased Risk ◽

The Impact ◽

Reduced Intensity

Abstract Abstract 3517 Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC-HSCT) is increasingly applied for the treatment of patients with acute myeloid leukemia. However, the procedure is heterogeneous with no standards based on randomized trials being elaborated so far. Hence, particular therapeutic decisions are in major part based on individual experience. The goal of this study was to evaluate the impact of center experience on outcome of RIC-HSCT. Based on the registry of ALWP of the EBMT, we analyzed results of 1413 HLA-matched related (n=1058) or unrelated (n=355) transplantations performed in 203 European centers between 2001 and 2007. Only patients with AML in first complete remission were included. Median recipient age was 55 years (range, 18–77 y.). Centers were categorized by quintiles according to the number of RIC-HSCT procedures in a study period. The 2 years probability of leukemia-free survival (LFS) after RIC-HSCT performed in centers with the lowest activity (1st quintile, ≤ 15 procedures/7 years) equaled 43% compared to 55% in the remaining ones (p<0.001). The incidence of non-relapse mortality (NRM) was 24% and 15%, respectively (p=0.004). In a multivariate model adjusted for other potential prognostic factors low RIC-HSCT activity was associated with decreased chance of LFS (HR=0.69, p<0.001) as well as increased risk of NRM (HR=1.69, p=0.001) and relapse (HR=1.37, p=0.01). No significant differences were found between centers belonging to the 2nd -5th quintile. We conclude that center experience is a strong predictor of outcome and should be considered for future analyses evaluating results of RIC-HSCT. Disclosures: Off Label Use: Dasatinib as first line therapy in Ph ALL.

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Important Prognostic Impact of Early Monocytes Recovery after Reduced Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults

Blood ◽

10.1182/blood.v124.21.5923.5923 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5923-5923

Author(s):

Amandine Le Bourgeois ◽

Thierry Guillaume ◽

Jacques Delaunay ◽

Pierre Peterlin ◽

Viviane Dubruille ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Older Age ◽

Reduced Intensity Conditioning ◽

The Impact ◽

Reduced Intensity ◽

Grade Iii

Abstract Introduction: Little is known regarding the impact of hematopoietic and immune recoveries after double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT), especially after the TCF (low dose 2 Grays total body irradiation + cyclophosphamide 50 mg/Kg 1 day + fludarabine 200 mg/m² 5 days) reduced-intensity conditioning (RIC) regimen, which is considered as a standard RIC regimen for dUCB allo-SCT in adults Patients and Methods: Here we considered a homogeneous cohort of 47 patients (males: n=24; median age: 55.5 years (range: 17.5-69) who engrafted after a dUCB TCF allo-SCT performed between November 2006 and April 2013 in our department. Fifty-three percent of the patients had myeloid disease. The majority of cases were in complete remission at time of transplant (72.3%). GVHD prophylaxis consisted of cyclosporine + mycophenolate mofetyl in all cases. All patients received G-CSF from day 1 until neutrophils recovery. The median nucleated cells dose infused was 4.17 107/kg. The aim of the study was to investigate the impact on outcomes of the recovery of the following cellular subsets: leucocytes, monocytes, lymphocytes, neutrophils at day +30 and day +42, and CD4+, CD8+ T cells, B and NK cells at day+100. Results: Median times for neutrophils and platelets recoveries were 17 days (range: 6-59) and 37 days (range: 0-164), respectively. With a median follow-up of 30.4 months (range: 2.8-77.5), the 3-year overall and relapse-free survivals (OS, RFS), relapse incidence (RI), and non-relapse mortality (NRM) were 65.7%, 57.2%, 27.1% and 19%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 38.3% and 10.6%, respectively, while, 3-year incidence of chronic GVHD was 53.5% (limited 42%, extensive 11.5%). In univariate analysis, 3-year OS was significantly higher in case of lymphoid disease (80.9% vs 51.9%, p=0.05) or when achieving at day+30 or day +42 higher counts of leucocytes (> median: 2760/mm3; 79% vs 51%, p=0.05; median > 4250/mm3; 78.6% vs 55.4%, p=0.04) or monocytes (> median: 615/mm3; 87.5% vs 45.8 %, p=0.02; median > 830/mm3, 86.2% vs 54.1%, p=0.03). Older age (>median: 55 years) and higher monocytes count at day +42 (> median: 830/mm3) were significantly associated with higher 3-year RFS (63.6% vs 49.1 %, p=0.046; and 75.7 vs 44.4%, p=0.014). Higher leucocytes count at day +42 (>median: 4250/mm3) was the only factor associated with significant 3-year lower NRM (7.1% vs 31.7%, p=0.04), while younger age was associated with higher risk of grade 3-4 acute GVHD (16.7% vs 4.4 %, p=0.05). No factor was predictive of chronic GVHD in this series. In multivariate analysis, older age and early higher monocytes count after transplant were the two independent factors associated with a significantly higher OS (>55 years, HR: 0.21; 95%CI: 0.05-0.85, p=0.028; >615/mm3 at day +30, HR: 0.05; 95%CI: 0.01-0.43, p=0.006) while only older age remained independently associated with better RFS (>55 years, HR: 0.25, 95%CI: 0.08-0.78, p=0.017). No factor was predictive of NRM, grade 2-4 GVHD, grade III-IV acute or chronic GVHD. Conclusion: These results suggest that higher early monocytes recovery is predictive of outcome after dUCB TCF RIC allo-SCT in adults. Immune recovery seems to have no impact on survivals in this series while influence of age has to be confirmed by other studies. Our results pave the way for future studies aiming to closely and prospectively monitor the kinetics of hematopoietic and immune recoveries after this type of graft. As all patients received G-CSF after transplant, other immunostimulatory cytokines should be tested to ensure sufficient hematopoietic recovery in the setting of adult dUCB TCF RIC allo-SCT. Disclosures No relevant conflicts of interest to declare.

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The Addition of Sirolimus to GVHD Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Efficacy and Safety

Frontiers in Oncology ◽

10.3389/fonc.2021.683263 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoli Chen ◽

Hengrui Sun ◽

Kaniel Cassady ◽

Shijie Yang ◽

Ting Chen ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Acute Gvhd ◽

Meta Analysis ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Safety And Efficacy

ObjectiveThe objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft-versus-host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).MethodsRandomized controlled trials (RCTs) evaluating the safety and efficacy of SRL-based prophylaxis regimens in patients receiving allo-HSCT were obtained from PubMed, Embase, and the Cochrane database. Following specific inclusion and exclusion criteria, studies were selected and screened by two independent reviewers who subsequently extracted the study data. The Cochrane risk bias evaluation tool was used for quality evaluation, and RevMan 5.3 software was used for statistical analysis comparing the effects of SRL-based and non–SRL-based regimens on acute GVHD, chronic GVHD, overall survival (OS), relapse rate, non-relapse mortality (NRM), thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD).ResultsSeven studies were included in this meta-analysis, with a total sample size of 1,673 cases, including 778 cases of patients receiving SRL-based regimens and 895 cases in which patients received non-SRL-based regimens. Our data revealed that SRL containing prophylaxis can effectively reduce the incidence of grade II–IV acute GVHD (RR = 0.75, 95% CI: 0.68∼0.82, p < 0.0001). SRL-based prophylaxis was not associated with an improvement of grade III–IV acute GVHD (RR = 0.78, 95% CI: 0.59∼1.03, p = 0.08), chronic GVHD (p = 0.89), OS (p = 0.98), and relapse rate (p = 0.16). Despite its immunosuppressant effects, SRL-based regimens did not increase bacterial (p = 0.68), fungal (p = 0.70), or CMV (p = 0.10) infections. However, patients receiving SRL-based regimens had increased TMA (p < 0.00001) and VOD (p < 0.00001).ConclusionsThis meta-analysis indicates that addition of sirolimus is an effective alternative prophylaxis strategy for II–IV aGVHD but may cause endothelial cell injury and result in secondary TMA or VOD events.

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Outcome of Non-T-Cell-Depleted Hematopoietic Stem Cell Transplantation between HLA-Haploidentical Non-Inherited Maternal Antigen (NIMA)-Mismatched Family Members in Childhood.

Blood ◽

10.1182/blood.v106.11.2913.2913 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2913-2913

Author(s):

Takao Yoshihara ◽

Keiko Okada ◽

Hiromasa Yabe ◽

Michihiro Kobayashi ◽

Atsushi Kikuta ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Family Members ◽

Hematopoietic Stem

Abstract Sporadic cases of successful non-T-cell-depleted (TCD) hematopoietic stem cell transplantation (SCT) from HLA-haploidentical family members mismatched for noninherited maternal antigens (NIMAs) have been reported over the last few years. This kind of SCT is based on the hypothesis that long-term feto-maternal microchimerism is associated with acquired immunologic hyporesponsiveness to NIMA or inherited paternal antigens (IPAs). To confirm the effectiveness and safety of NIMA-mismatched SCT in a large cohort, we retrospectively surveyed the outcomes of 76 children (44 boys, 32 girls; median age 7 years, range, 0–18) with either advanced non-malignant disorders (n=10), hematological malignancies (n=62) or solid tumors (n=4) who underwent T-cell-replete HLA-2-loci- or HLA-3-loci incompatible SCT from NIMA-mismatched donors (mother, n=53; NIMA-mismatched sibling, n=12) or other family donors (father/NIPA-mismatched sibling) (n=11) between 01/2000 and 12/2004. Disease status of malignant disease at SCT was as follows: CR1/CR2/CP in 19 and chemorefractory in 47. Types of grafts were bone marrow in 40 and peripheral blood stem cells in 35. Feto-maternal michrochimerism was detected in 32 out of 35 mothers tested and 8 out of 8 NIMA-mismatched sibling donors. GVHD prophylaxis consisted of tacrolimus-based regimen in 73. All but two patients achieved sustained neutrophil engraftment at median of 16.5 days (range, 10–29). Grade II to IV acute GVHD occurred in 36 of 73 evaluable patients (49%) between days 7 and 36 (median, 17). In non-malignant disorders, no severe (grade III/IV) acute GVHD was observed, while in malignant disorders, severe acute GVHD occurred in 21 (32%) of 65 evaluable patients. Twenty-two out of 41 evaluable patients (54%) who survived more than 6 months had extensive chronic GVHD. As of 04/2005, in non-malignant disorders, all 9 patients who obtained engraftment were alive. In malignant disorders, twenty-nine out of 66 patients (44%) were alive and 25 of them were disease-free with median follow-up of 25 (range, 4 to 57) months. Death were due to disease progression (n=22), infection (n=6), GVHD (n=4) and others (n=4). These results suggest that pediatric patients who lack immediate access to a conventional stem cell source can obtain successful results with non-TCD transplants from an HLA-haploidentical NIMA-mismatched donor.

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A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v110.11.46.46 ◽

2007 ◽

Vol 110 (11) ◽

pp. 46-46

Author(s):

B.E. Shaw ◽

Nigel H. Russell ◽

A. Pagliuca ◽

J. Apperley ◽

G. Cook ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Increased Risk ◽

Significant Difference ◽

Cell Source ◽

The Impact

Abstract The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

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