Engraftment Syndrome after Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Graft-Versus-Host Disease Prophylaxis and T Cell Dose.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5052-5052
Author(s):  
Robert M. Dean ◽  
Kyle M. Donley ◽  
Juan Gea-Banacloche ◽  
Seth M. Steinberg ◽  
Jeanne Odom ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Engraftment Syndrome ◽  
Reduced Intensity

Abstract Engraftment syndrome (ES), defined as noninfectious fever, rash, and noncardiogenic pulmonary edema occurring at the time of hematopoietic recovery after stem cell transplantation, may cause significant morbidity in the peri-transplant period. However, its association with GVHD is unclear, and it remains controversial whether T-cell alloreactivity, nonspecific neutrophil activation, or other factors contribute to the pathogenesis of this syndrome. To study this question, we retrospectively analyzed patients enrolled in 3 separate protocols of reduced-intensity allogeneic hematopoietic stem cell transplantation (RIST). Group A included patients with relapsed/refractory hematologic malignancies undergoing RIST with T-cell replete allografts and cyclosporine for GVHD prophylaxis (n=49). Group B consisted of patients with hematologic malignancies receiving T-cell replete allografts and cyclosporine/methotrexate for GVHD prophylaxis (n=20). Group C included patients with metastatic breast cancer undergoing RIST with T-cell depleted allografts (1 x 105 CD3+ cells/kg) and cyclosporine for GVHD prophylaxis (n=17). All patients received an identical reduced-intensity conditioning regimen with fludarabine and cyclophosphamide, followed by infusion of filgrastim-mobilized peripheral blood stem cells and post-transplantation filgrastim until neutrophil recovery. The incidences of ES and acute GVHD varied according to treatment group (ES: chi-squared test, p=0.066; acute GVHD: chi-squared test, p=NS): Incidence of Engraftment Syndrome and Acute GVHD by Treatment Group Group Graft Composition GVHD Prophylaxis Engraftment Syndrome Acute GVHD, Grades 2–4 A T-cell replete Cyclosporine 24/49 (49%) 32/49 (65%) B T-cell replete Cyclosporine/Methotrexate 5/20 (25%) 9/20 (45%) C T-cell depleted Cyclosporine 4/17 (24%) 8/17 (47%) Logistic regression analysis identified hypoxemia requiring oxygen (OR 38.46, 95% CI 6.51 to 227.1; p=0.002), fever greater than 37 degrees C (OR 6.97, 95% CI 2.47 to 19.7; p<0.0001), and the maximum neutrophil count after engraftment (OR 1.07, 95% CI 1.02 to 1.125; p=0.0093) as factors strongly associated with steroid administration for ES. Subjects with acute GVHD displayed a modest trend toward increased frequency of ES (exact Cochran-Armitage trend test, p=0.103). The association of the intensity of GVHD prophylaxis and the maximum neutrophil count with the incidence of ES implies that both alloreactive T cells and donor granulocytes may play a role in the development of this complication after RIST. These results suggest that additional studies are warranted to explore the contribution of alloreactivity to the pathogenesis, prevention, and treatment of ES.

Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4771-4779 ◽  
Author(s):  
Anna Dodero ◽  
Cristiana Carniti ◽  
Anna Raganato ◽  
Antonio Vendramin ◽  
Lucia Farina ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity ◽  
Donor Lymphocyte Infusions

Abstract Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34+ cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

Ex-Vivo Reduction of Allograft T Cell Dose Does Not Prevent Acute Graft-vs-Host Disease after Reduced-Intensity Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2871-2871
Author(s):  
Nancy M. Hardy ◽  
Frances Hakim ◽  
Seth Steinberg ◽  
Michael Krumlauf ◽  
Rebecca Babb ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cell ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Cell Engraftment ◽  
Graft Vs Host Disease ◽  
Reduced Intensity

Abstract Allograft T cell depletion (TCD) reduces acute graft-vs. host disease (aGVHD) after myeloablative hematopoietic stem cell transplantation (HSCT). Lower incidences of aGVHD reported after reduced-intensity stem cell transplantation (RIST) may reflect delayed donor T cell engraftment. We compared the incidence of aGVHD following RIST with TCD (19 patients (pts) vs. T cell replete (TCR) allografts (20 pts)(Table). There was no difference in the incidence aGVHD, occurring in 71% of TCD recipients (median onset Day 47) and 70% of TCR recipients (median onset Day 25). After TCD, 100% of those who engrafted prior to any DLI developed aGVHD compared with 56% of those who engrafted after DLI, including two pts who developed “late-acute” aGVHD after Day 100, upon completion of donor T cell engraftment. T cell engraftment after TCD was uneven: engraftment kinetics were associated with residual host circulating CD8+ T cell counts after immune depletion; and aGVHD did not occur in the setting of mixed T cell chimerism (Figure). These observations demonstrate that aGVHD can occur with very low doses (105/kg) of allograft T cells after RIST. Protection from aGVHD conferred by mixed T cell chimerism may be lost with full donor T cell engraftment. With limited donor T cell numbers, host T cells appear to determine kinetics of engraftment and of aGVHD after RIST. Figure: Post-induction circulating CD8+ T cell counts in TCD recipients with delayed donor T cell engraftment. After TCD, all subjects who developed aGVHD did so at or after the establishment of T cell full donor T cell chimerism, and occasionally prior to any DLI. Shaded triangle represents the theoretical area in which values would fall if subjects developed aGVHD prior to complete donor T cell engraftment. Arrows: DLI. Patient and Transplant Characteristics and Outcomes Protocol TCD TCR Flu/Cy: Fludarabine and cyclophosphamide; EPOCH-F: Etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and fludarabine; FDC: Full donor chimerism. Median (range) Median (range) Recipient Age 43 years (32 – 56) 44 (19 – 67) CMV Risk 14/19 16/20 Pretransplant Immune Depletion Flu/Cy EPOCH-F Conditioning Regimen Flu/Cy Flu/Cy Pre-conditioning Host Cell Counts: CD3 86 (1 – 701) 140 (21 – 441) CD4, p=0.017 44 (1 – 156) 71 (12 – 191) CD8 34 (0 – 555) 55 (2 – 309) NK 58 (0 – 376) 88 (3 – 467) Day 0 CD3 Cell Count 1 (1 – 6) 5 (0 – 42) Allograft CD34+ cells/kg 7.75 x 106 (5.1 – 12.9) 7.68 x 106 (4.6–18.4) Allograft CD3+ cells/kg 1.0 x 105 (preset) 3.63 x 108 (1.5 – 8.3) Donor T cell engraftment Day +70 (14 – 180) 14 (14 – 100) Figure Figure

Sustained Engraftment Using Fludarabine, Melphalan and Thiotepa Conditioning for Haploidentical Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5081-5081 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Suhail Qureshi ◽  
Gabriela Rondon ◽  
Susana Pesoa ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Platelet Recovery ◽  
Haploidentical Stem Cell Transplantation ◽  
Cd34 Cells ◽  
Reduced Intensity

Abstract BACKGROUND: Haploidentical stem cell transplantation (HaploSCT) using mega-doses of CD34 cells and a T-cell depleted allograft has generally been performed in advanced hematologic malignancies using a fractionated TBI-based conditioning regimen (CR) with very high toxicity. Here we evaluated the results of a reduced intensity chemotherapy-only conditioning regimen (RIC) with fludarabine (F), melphalan (M) and thiotepa (T) for HaploSCT. METHODS: 24 patients (pts) with advanced hematologic malignancies (18 with AML/MDS, 3 with ALL, 2 with CML and 1 with T-cell lymphoma underwent HaploSCT from related donors at MDACC between 10/2001 and 04/2007. The median age was 36 years. At the time of transplantation 15/24 pts (63%) had relapsed or primary refractory disease and 37% were in remission. Pts received a median of 10.8x10e6 CD34 cells. The median number of CD3 cells infused was 1x10e4/kg. The number of allele mismatch was 3/10 in 4 pts, 4/10 in 10 pts, 5/10 in 9 pts and 6/10 in 1 pt. HLA antibody (AB) specificity was determined using fluorescent beads coated with single antigens and detected in a Luminex platform. The CR consisted of M 140 mg/m2 on day −8, T 10 mg/m2 on day −7, F 160 mg/m2 over 4 days on days −6, −5, −4, −3, and 1.5 mg/kg of rabbit ATG a day x 4 on days −6, −5, −4, and −3 (FMT). No GVHD prophylaxis and no growth factors were administered. The pts were evaluated for engraftment and 100-day transplant-related mortality (TRM). RESULTS: 23 pts were evaluable for engraftment. 1 pt died on day 27 due to respiratory failure. 19/23 pts (83%) engrafted with hematopoietic recovery with donor-derived cells. 18 pts achieved a full donor chimerism while 1 had progressive leukemia. Neutrophil recovery to ANC >0.5 x 10e9/l occurred after a median of 13 days and platelet recovery to >20 x 10e9/l occurred after a median of 13.5 days. 4 pts failed to achieve primary engraftment, presumably due to rejection. No statistically significant correlation was found between graft failure (GF) and KIR-ligand mismatch (KIR-LM). In fact KIR-LM were more common in the group of pts who engrafted (7/19) than in pts with GF (1/4). After 09/2005 when anti HLA AB were started to be done, 3/14 pts had GF, 2 of which had donor directed AB. The regimen was relatively well tolerated; 4 pts experienced grade 4 nonhematologic, organ toxicities. Cumulative day 100 TRM was 25%. 19/24 pts (79%) were in CR after transplant with 6 surviving at the last follow-up (OS 25%). Only 1 pt developed aGVHD (4.1%) and 5 pts developed cGVHD (20.8%) with 3 experiencing extensive GVHD. 9 pts (37.5%) relapsed after a median of 71.5 days post transplant. The distribution of KIR-LM in the GVH direction was similar in pts with and without relapse (3/9 pts with relapse and 5/15 pts without relapse). Causes of death were disease relapse in 9 pts, infections in 3 pts, pulmonary failure/MOF in 4 pts and cGVHD in 1 pt. CONCLUSIONS: The reduced intensity FMT regimen was sufficiently immunosuppressive to support rapid engraftment after HaploSCT in 83% of pts with advanced hematologic malignancies. In this small series, KIR-LM in the HVG or GVH direction were not associated with graft rejection or malignancy relapse. The role of anti-HLA AB need further evaluation. The rate of toxicity and 100-day TRM appears lower as compared with published studies of TBI-based CR. The FMT RIC merits further evaluation in studies of HaploSCT.

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

Blood ◽  
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.

WT1-Specific Immune Responses in Patients with High-Risk Multiple Myeloma Undergoing Allogeneic T Cell-Depleted Hematopoietic Stem Cell Transplantation Followed by Donor Lymphocyte Infusions

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1993-1993 ◽  
Author(s):  
Eleanor Tyler ◽  
Achim A Jungbluth ◽  
Richard J. O'Reilly ◽  
Guenther Koehne
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Immune Responses ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Cell Responses

Abstract Abstract 1993 Wilm's tumor protein-1 (WT1) is over-expressed in a number of solid and hematologic malignancies including multiple myeloma (MM). The emergence of WT1-specific T cells has been shown to correlate with better relapse-free survival after allogeneic stem cell transplantation in patients (pts) with hematologic malignancies, such as leukemia. In MM, the expression of WT1 in the bone marrow has been shown to correlate with numerous negative prognostic factors, including disease stage and M protein ratio. Taken together, these findings suggest that immunotherapeutic augmentation of WT1-specific immune responses, such as adoptive transfer of WT1-specific T cells, may be capable of eradicating minimal residual disease and preventing relapse in MM. Thus, we examined the significance of WT1-specific cellular immune responses in pts with relapsed MM and high-risk cytogenetics who are undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation (TCD HSCT). In this study, pts were eligible to receive low doses of donor lymphocyte infusions (DLI, 5×105-1×106 CD3+/kg) no earlier than 5 months post TCD HSCT. WT1-specific T-cell frequencies were measured in freshly isolated peripheral blood and bone marrow specimens. Frequencies were detected by staining for intracellular IFN-γ production in response to WT1 peptides, and/or by tetramer analysis, where available. Of 17 pts evaluated, all pts exhibited low frequencies of WT1-specific T-cell responses pre TCD HSCT. Ten of these pts received DLI post TCD HSCT. All 10 pts developed WT1-specific T cell responses post DLI. These increments in WT1-specific T-cell frequencies were associated with reduction in circulating myeloma proteins in all pts. Long-term evaluation demonstrated fluctuations in persisting WT1-specific T-cell frequencies following DLI. In one representative patient, a peak of 3.5% (72/ml) WT1-specific CD8+ T cells were detected in the peripheral blood by staining with the tetramer HLA-A*0201 RMF. This peak T-cell response occurred post TCD HSCT and DLI, and coincided with disease regression. This patient has remained in complete remission for more than 3 years post transplant, with fluctuating levels of WT1-specific CD8+ T cells ranging from 0.3–1.5% still persisting. Findings from concurrent molecular chimerism studies conducted on isolated T cells post TCD HSCT suggest that the WT1-specific T cells are of donor origin. Immunohistochemical analyses of WT1 and CD138 staining in MM bone marrow specimens demonstrated consistent co-expression within malignant plasma cells. WT1 expression in the bone marrow of all 6 pts tested correlated with the extent of malignant plasma cell infiltration. In contrast, no WT1 expression was observed when disease was low or absent. Taken together, our findings suggest a correlation between the emergence of WT1-specific T cells post DLI, and disease regression in pts being treated for relapsed MM. The present data support the development of adoptive immunotherapeutic approaches utilizing WT1-specific T cells for pts with MM. Disclosures: No relevant conflicts of interest to declare.

Long Term Follow-up of Haploidentical Hematopoietic Stem Cell Transplantation without in Vitro T Cell Depletion for the Treatment of Hematological Malignancies: 9-Year Experience of a Single Center

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 839-839 ◽  
Author(s):  
Xiao Jun Huang
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Acute Gvhd ◽  
Disease Stage ◽  
Hematopoietic Stem

Abstract 839FN2 Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Recently, we developed a new strategy named GIAC protocol for HLA-mismatched/haploidentical transplantation from family donors that combines granulocyte-colony stimulating factor (G-CSF) primed bone marrow (G-BM) and peripheral blood stem cells (PBSC) without in vitro T-cell depletion (TCD). For the past nine years, promising results for HLA-mismatched allo-HSCT without in vitro TCD have been achieved at our institute using this protocol. From May 2002 to December 2010, 820 patients, including 206 in high-risk group, underwent transplantation from haploidentical family donors. Eight-hundred and eleven patients (99%) achieved sustained, full donor chimerism. The incidence of grade 2–4 acute graft-versus-host disease (GVHD) was 42.9%, and that of grades 3 and 4 was 14.0% which was not associated with the extent of HLA disparity.Figure 1Cumulative incidence of acute GVHD grade 2–4 according to HLA disparity.Figure 1. Cumulative incidence of acute GVHD grade 2–4 according to HLA disparity.Figure 2Probability of LFS after haploidentical HSCT according to disease stage (p =.001).Figure 2. Probability of LFS after haploidentical HSCT according to disease stage (p =.001). Disclosures: No relevant conflicts of interest to declare.

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