IL10-592 CC Genotype In the Donor Is Associated with a Significant Decrease of Relapse Rate and a Significant Increase of Event-Free Survival and Overall Survival After Allogeneic Hematopoietic Stem Cell Transplantation In Children with Hematological Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4459-4459
Author(s):  
Bernd Gruhn ◽  
Janine Voigt ◽  
Nadine Pfaffendorf-Regler ◽  
Ilona Wolff ◽  
Felix Zintl ◽  
...  

Abstract Abstract 4459 IL10 is a pivotal immunomodulatory cytokine and is usually regarded as a suppressor of the immune responses. However, IL10 has been shown to have some immunostimulatory effects. The IL10-592 CC genotype is associated wit higher production of IL10. Because IL10 may promote the development of alloimmunity we hypothesized that the IL10-592 CC genotype in the donor reduces the risk of relapse after hematopoietic stem cell transplantation (HSCT). A cohort of 211 children (median age, 12 years) with acute lymphoblastic leukemia (n=100), acute myeloid leukemia (n=62), myelodysplastic syndrome (n=30) or chronic myeloid leukemia (n=19) who underwent allogeneic bone marrow (n=153) or peripheral blood stem cell transplantation (n=58; T-cell depleted: n=26) in a single center and/or their respective donors was genotyped of IL10 gene for rs1800872 using TaqMan real-time polymerase chain reaction. The donor was HLA-matched unrelated in 48% of transplants and HLA-identical related in 42% of transplants. Conditioning regimen was myeloablative in all cases. Two forms of post-transplant immunosuppression predominated, cyclosporine A and methotrexate in 69% of transplants and cyclosporine A alone in 17% of transplants. Cell samples from the donor were available in 174 cases and from the patient in 197 cases. The IL10-592 CC genotype was present in 82 of the 174 donors (47.1%) and in 104 of the 197 patients (52.8%). Interestingly, we found a significantly reduced incidence of relapse in patients who were transplanted from a donor with the IL10-592 CC genotype (15.9% versus 30.4%; p=0.016). In addition, we observed a significant increase of event-free survival (52.4% versus 33.7%; p=0.019) and a significant increase of overall survival (54.9% versus 37.0%; p=0.040) if the IL10-592 CC genotype was present in the donor. The occurrence of the IL10-592 CC genotype, in either donors or recipients, had no significant impact on treatment related mortality, acute and chronic graft-versus host disease. In conclusion, IL10-592 CC genotype in the donor is associated with a significant decrease of relapse rate and a significant increase of event-free survival and overall survival after HSCT in children with hematological malignancies. This is the first study to describe an association of IL10 gene polymorphism with relapse rate after HSCT. Selecting a donor with the IL10-592 CC genotype could be a useful therapeutic strategy for improving the final outcome after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

2021 ◽  
Author(s):  
Laura Schwenk ◽  
Susan Wittig ◽  
Bernd Gruhn

Abstract Purpose Interleukin-10 (IL-10) potentially can promote the development of alloimmunity. The aim of this study was to investigate if the IL-10-592 CC genotype in the donor reduces the risk of relapse after hematopoietic stem cell transplantation (HSCT) and if that has an impact on event-free survival (EFS) and overall survival (OS).Methods A cohort of 211 children with acute lymphoblastic leukemia (n=99), acute myeloid leukemia (n=69), myelodysplastic syndrome (n=31) or chronic myeloid leukemia (n=12) who underwent hematopoietic stem cell transplantation (HSCT) in a single center and their respective donors were genotyped of IL-10 gene for rs1800872 using TaqMan real-time polymerase chain reaction.Results The IL-10-592 CC genotype was detected in 107 of the 211 donors (50.7%) and in 98 of the 197 patients (49.7%). Genotype AC was found in 95 donors (45%) and in 84 patients (42.6%). 9 donors (4.3%) and 15 patients (7.6%) were homozygous for AA. Ultimately, we observed a significantly reduced incidence of relapse rate (RR) in patients who were transplanted from a donor with the IL-10-592 CC genotype (19% versus 43% (AC) versus 49% (AA); p=0.0007). In addition, a significant increase of event-free survival (p=0.004) and overall survival (p=0.006) was detected if the IL-10-592 CC genotype is present in the donor. The occurrence of the IL-10-592 CC genotype, in either donors or recipients, had no significant impact on acute and chronic graft-versus-host disease.Conclusion The IL-10-592 CC genotype in the donor was associated with a significant decrease of RR which led to a significant increase of EFS and OS after HSCT. This is the first study to describe an association of the IL-10 gene polymorphism with RR, EFS, and OS after HSCT. Selecting a donor with the IL-10-592 CC genotype could be a useful therapeutic strategy for improving the outcome after allogeneic HSCT.


2015 ◽  
Vol 33 (11) ◽  
pp. 1265-1274 ◽  
Author(s):  
Christina Peters ◽  
Martin Schrappe ◽  
Arend von Stackelberg ◽  
André Schrauder ◽  
Peter Bader ◽  
...  

Purpose Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia). Patients and Methods After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci. Results Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications. Conclusion Outcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5849-5849
Author(s):  
Haiwen Huang ◽  
Xiaofang Xiao ◽  
Jia Chen ◽  
Zhengming Jin ◽  
Xiaowen Tang ◽  
...  

Abstract Purpose: The role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) therapy for refractory or relapsed (R/R) aggressive non-Hodgkin lymphoma (NHL) patients was still unknown. In this study, we aimed to explore the clinical outcome of R/R aggressive NHL patients received haplo-HSCT treatment. Patients and Methods: 23 R/R aggressive NHL patients who had undergone haplo-HSCT in our center between February 2006 and October 2015 were retrospectively analyzed, and 25 R/R aggressive NHL patients who received HLA-matched HSCT at the same period were also involved in this study. All patients received myeloablative conditioning (MAC) regimen, and antithymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. 12 patients had experienced autologous HSCT prior to allo-HSCT. Results: The median age of the total 48 patients was 33 (16-58) years old, and there were 33 males and 15 females in the total cohorts. The diagonosis were as following: 16 (33%) diffuse large B cell lymphoma and 22 (46%) peripheral T cell lymphoma. There were no difference in sex, age at transplantation, histologic diagnosis, aaIPI score, previous ASCT and conditioning regime between HLA-matched HSCT and Haplo-hsct groups. 44 patients had achieved engrafment, and the median times to neutrophil and platelet recovery were 12 and 15 days, respectively. Incidences of grade 3-4 acute GVHD were 18.3% in haplo-HSCT group and 16.7% in HLA-matched HSCT groups(p=0.87), while 2 years cumulative incidences of chronic GVHD in these two groups were 43.5% and 36.7% (P=0.68). For 16 patients who had chemoresistant disease at transplantation in haplo-HSCT group, four patients achieved complete remission, and ten patients achieved partial remission, while the other two patients experienced disease progression at 21 days and 37 days, respectively. With a median follow-up of 25 months, 12 patients experienced disease recurrence or progression in haplo-HSCT. And four patients died of transplantation related mortality: infection (n=2); acute GVHD (n=1) and multi-organ failure (n=1). There were no differences in overall survival (OS) rate at 2 years (52.8% vs 57.0%, P=0.85) and 2 years progress free survival (PFS) rate (52.7% vs 56.9%, p=0.73) between the haplo-SCT and HLA-matched SCT groups. Multivariate analyses suggested that old age (>45 years)(p=0.02), primarychemorefractory (p=0.04)and occurrence of grade3-4 aGVHD (p=0.01) may contribute to poor prognosis. Conclusion: Haploidentical hematopoietic stem cell transplantation withmyeloablative conditioning regimenachieved satisfactory outcome with acceptable side-effects. This approachcan be a feasible and acceptabletherapy for young patients withR/R NHLwho have no access to a HLA-matched donor. Figure Comparison of outcomes after haplo-SCT and HLA-matched SCT. (a) Overall survival, (b) Progression-free survival, (c) Cumulative incidences of grade3-4 acute GVHD, (d) cumulative incidences of chronic GVHD, (e) cumulative incidences of relapse, (f) cumulative incidences of non-relapse mortality. Figure. Comparison of outcomes after haplo-SCT and HLA-matched SCT. (a) Overall survival, (b) Progression-free survival, (c) Cumulative incidences of grade3-4 acute GVHD, (d) cumulative incidences of chronic GVHD, (e) cumulative incidences of relapse, (f) cumulative incidences of non-relapse mortality. Disclosures No relevant conflicts of interest to declare.


Author(s):  
Laura Schwenk ◽  
Susan Wittig ◽  
Bernd Gruhn

Abstract Purpose Interleukin-10 (IL-10) potentially can promote the development of alloimmunity. The aim of this study was to investigate if the IL-10-592 CC genotype in the donor reduces the risk of relapse after hematopoietic stem cell transplantation (HSCT) and if that has an impact on event-free survival (EFS) and overall survival (OS). Methods A cohort of 211 children with acute lymphoblastic leukemia (n = 99), acute myeloid leukemia (n = 69), myelodysplastic syndrome (n = 31) or chronic myeloid leukemia (n = 12) who underwent hematopoietic stem cell transplantation (HSCT) in a single center and their respective donors were genotyped of IL-10 gene for rs1800872 using TaqMan real-time polymerase chain reaction. Results The IL-10-592 CC genotype was detected in 107 of the 211 donors (50.7%) and in 106 of the 211 patients (50.2%). Genotype AC was found in 95 donors (45.0%) and in 90 patients (42.7%). Nine donors (4.3%) and 15 patients (7.1%) were homozygous for AA. Ultimately, we observed a significantly reduced incidence of relapse rate (RR) in patients who were transplanted from a donor with the IL-10-592 CC genotype (19% versus 43% (AC) versus 49% (AA); P = 0.0007). In addition, a significant increase of EFS (P = 0.004) and OS (P = 0.006) was detected if the IL-10-592 CC genotype is present in the donor. The occurrence of the IL-10-592 CC genotype, in either donors or recipients, had no significant impact on acute and chronic graft-versus-host disease. In addition, the IL-10-592 genotype of the recipients was not relevant for the RR (P = 0.47434), the EFS (P = 0.840), and the OS (P = 0.535). Conclusion The IL-10-592 CC genotype in the donor was associated with a significant decrease of RR which led to a significant increase of EFS and OS after HSCT. This is the first study to describe an association of the IL-10 gene polymorphism with RR, EFS, and OS after HSCT. Selecting a donor with the IL-10-592 CC genotype could be a useful therapeutic strategy for improving the outcome after allogeneic HSCT.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4600-4600
Author(s):  
Magalie Joris ◽  
Delphine Lebon ◽  
Amandine Charbonnier ◽  
Pierre Morel ◽  
Berengere Gruson ◽  
...  

Background : Patients with acute myeloid leukemia in relapse or refractory to induction therapy have dismal prognosis. Response rates to common salvage regimens are low and allogenic hematopoietic stem cell transplantation is the only curative option. Several studies have demonstrated that salvage chemotherapy with sequential conditioning could reduce leukemia relapse risk with an acceptable toxicity profile for unfavorable acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). [1] Therefore, we decided to assess this procedure in our center at Amiens University Hospital. Methods We conducted a monocentric retrospective study, including 53 patients aged over 18 years undergoing a hematopoietic stem cell transplant (HSCT) with sequential conditioning between January 2012 and December 2018, for relapse/refractory AML or high risk MDS. 44 (83%) patients received sequential conditioning containing clofarabine (SET-RIC) or Amsacrine (FLAMSA) and 9 (17%) thiotepa based (TEC-RIC) with post-transplant cyclophosphamide for mismatched donors. Patients who were GVHD free after immunosuppressors withdrawal received immunomodulation as relapse prevention with azacytidine 37.5mg/m²/day 5 days every 4 weeks for 12 cycles with 3 donor lymphocyte infusions (DLI) alterned between azacytidine cycles. Results The median age was 52 years (range 18-70). Before conditioning, 48 patients had unfavorable AML with ELN intermediate score refractory to at least one course of induction therapy or in relapse, or unfavorable ELN score; 5 patients had high risk MDS with complex karyotype. 32 patients (60,5%) had active disease and 21 (39,5%) were in complete remission (CR) including 12 with positive MRD. 13 (24,5%) patients had HLA-identical sibling donors, 27 (51%) match unrelated donors (MUD), 4 (7,5%) mismatch unrelated donors (MMD) and 9 (17%) haploidentical donors. Majority of patients (90,5%) received peripheral blood stem cell (PBSC) PBSC with median CD34+ count of 7,94.106/kg (1,84-8,44). Acute GvHD prophylaxis with Ciclosporin A, in combination with Mycophenolate mofetil for MUD/MMR/Haplo, was withdrawal with a median time of 90 days. With a median follow-up of 40 months, overall survival (OS) at 1 and 2 years was 68% and 52%. Median OS was 18,7 months (0-72,4 months) and median disease free survival (DFS) was 14,9 months (0-72,4 months). 17 patients (32%) experienced relapse after HSCT with a median time from HSCT to relapse of 6 months (1-35 months). 22 (41,5%) of patients presented with grade I-II acute graft versus host disease (GVHD) and 6 (11,3%) with grade III IV aGVHD . GVHD free relapse free survival (GRFS) at 1 and 2 years was 53% and 34,2%. One-year cumulative incidence of disease related death and non-relapse mortality was 12,6% and 17% respectively. 19 patients received immunomodulation with 5 Azacitidine and DLI if no GVHD occurred within day 120. OS was 79 % in the 19 patients receiving DLI. In univariate analysis immunomodulation post HSCT (Figure 1) was significantly associated with overall survival and leukemia free survival (p=0,0164 and p=0,0359 respectively) but not the disease status before HSCT (p=0,7). Immunomodulation administration with azacytidine and DLI was not significantly associated with cGVHD occurrence (p=0.31). Benefit of immunomodulation OS persisted in multivariate analysis (p=0.0284). Conclusion: Sequential conditioning regimen on refractory AML with secondary immunomodulation with azacytidine and DLI shows very good results with an acceptable toxicity profile in unfavorable AML. We achieve very good OS and DFS whatever disease status before HSCT. GRFS is also encouraging comparing to previously report datas [1]. Reference: [1] Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Decroocq et al. Am J Hematol 2018 ;93 :416-423. Figure 1 Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 964-964 ◽  
Author(s):  
Farge Dominique ◽  
Jaap Van Laar ◽  
Jacob K Sont ◽  
Kamran Naraghi ◽  
Zora Marjanovic ◽  
...  

Abstract Abstract 964 Background: High dose immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) has shown efficacy in severe or rapidly progressive systemic sclerosis (SSc) in phase 1 and 2 trials with durable responses in two thirds of patients (pts), while a recent phase 2 randomised trial in 19 SSc pts showed superior benefit of HSCT over iv pulse cyclophosphamide (Cy) on skin score and lung function. Methods: The ASTIS-trial (Autologous Stem cell Transplantation International Scleroderma trial) is a multinational prospective randomized controlled phase 3 trial, comparing safety and efficacy of HSCT versus Cy in early progressive dcSSc pts with disease duration of a) 4 years or less and evidence of organ involvement or b) of 2 years or less and evidence of systemic inflammation with or without major organ involvement. Major exclusion criteria were: concomitant severe SSc disease (mean PAP > 50 mmHg, DLCO < 40% predicted, creatinine clearance (CCl) <40 ml/min, LVEF <45%, uncontrolled arythmia, infection, previous Cy (>5gr iv or >3months oral) treatment), liver failure. Pts randomized to the transplant arm underwent mobilization with Cy 2×2 g/m2 + G-CSF 10mcg/kg/d, conditioning with Cy 200 mg/kg, rbATG 7.5 mg/kg, followed by reinfusion of CD34+ autologous HSCT. Controls were treated with 12× monthly iv pulse Cy 750 mg/m2. Crossing over was allowed after 2 years. The primary endpoint was event-free survival (EFS), defined as survival until death or development of major organ failure at 2 yrs. Toxicity according to WHO criteria and progression free survival (defined as worsening of modified Rodnan skin score, functional ability, major organ function) were the main secondary endpoints. The effects of treatment were analyzed on an ITT basis and by comparing EFS using the KM survival curves (using log-rank test) and Cox models. Results: 156 pts (female 59%), from 27 centers were enrolled in 10 countries from March 2001 until October 2009 and randomized to HSCT (n=79) or iv pulse Cy (n=77). Seventy-five pts in each arm started treatment, 70 pts in HSCT and 58 pts in control groups completed treatment. The median time (Interquartile Range (IR)) from randomization to completion of treatment was 93 (43.0) days in the HSCT and 338 (41.75) days in the control groups respectively. Baseline characteristics (mean (SD)) of the pts were: age 44 (11.2) yrs, SSc duration 1.4 (1.3) yrs, BMI 24 (14.4), Rodnan skin score 25 (8), HAQ 1.35 (0.8), prior Cy therapy 22%, creat cl 116 (39.5) ml/min, LVEF 65% (8.5), DLCO 59% (14), with no significant differences between the 2 arms. With data cut at 1 May 2012, median follow-up (IR) are 33 (42.0) and 27 (34.0) months in the HSCT and control groups respectively. Forty two events occurred : 18 in the HSCT group (16 deaths and 2 irreversible renal failures) and 24 in the control group (24 deaths). Event-free survival was time-dependent with a hazard ratio at 84 months of 0.22 (95% CI 0.08–0.58, P= 0.002). Eight deaths (including 1 during mobilization and 1 after conditioning) in the HSCT group were deemed treatment-related by the independent data monitoring committee with heart failure (3), ARDS (2), multiple organ failure (2) and pulmonary oedema (1) as the causes of death. In the control group, none died from treatment causes and most deaths were due to progressive disease. Eight pts in the control arm received rescue HSCT treatment, one of whom later died from secondary acute myeloid leukaemia. Two HSCT pts received rescue iv Cy therapy. Conclusions: The ASTIS-trial is the first international, investigator-initiated, phase 3 HSCT trial in early diffuse cutaneous systemic sclerosis. The data show that despite 10% treatment-related mortality, long term event-free survival and overall survival were better in the HSCT group than in the group treated with iv pulse cyclophosphamide. (Funded by the European Group for Blood and Marrow Transplantation, European League Against Rheumatism, AP-HP, NIHR, DIGR, Imtix-Sangstat, Miltenyi-Biotec, Amgen Europe; Current Controlled Trials number, ISRCTN 54371254). Disclosures: No relevant conflicts of interest to declare.


2020 ◽  
Vol 33 (2) ◽  
pp. 116
Author(s):  
Manuel Abecasis ◽  
Nuno Miranda ◽  
Isabelina Ferreira ◽  
Gilda Teixeira ◽  
Filipa Moita ◽  
...  

Introduction: Allogeneic stem cell transplantation is an established procedure for a variety of diseases of the hematopoietic system. Our transplant program started in 1987 and since then advances have been made in the care of patients undergoing transplantation. We conducted a study to evaluate whether the changes implemented over time have improved the outcomes of transplantation.Material and Methods: We analyzed changes in patients, cell source, transplantation and outcome among 682 consecutive patients receiving their first transplant between 1987 and 2016. We compared overall survival, progression-free survival, the incidence of nonrelapse mortality and relapse in 10-year cohorts over the three decades of the study.Results: The median age of transplanted patients, the use of peripheral blood and unrelated donors all increased very significantly. There was an increase in the number of high-risk patients when comparing the first decade with the two subsequent ones. The 3-year non-relapse mortality decreased significantly from 29% to 20% (p = 0.045), while the overall survival, progression free survival and cumulative incidence of relapse remained stable.Discussion: Allogeneic hematopoietic stem cell transplantation has evolved considerably since its introduction in clinical practice. In the present study, we evaluated how these changes affected our practice along 30 years of activity and compared the results with those published in the literature.Conclusion: Despite increasing age, higher risk patients and the increasing use of unrelated donors our results show a continuous significantly reduced non-relapse mortality, with stable overall survival, progression free survival and relapse rate.


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