Calcineurin Inhibitor-Free GVHD Prophylaxis with Post-Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 923-923
Author(s):  
Melissa Sanacore ◽  
Asad Bashey ◽  
Connie A. Sizemore ◽  
H. Kent Holland ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Platelet Recovery ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Allogeneic Pbsct

Abstract Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. Although advances in immunosuppressive regimens have had a significant impact on the incidence and severity of acute GVHD, it is noteworthy that CNIs have had little impact on chronic GVHD. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. Twenty-seven patients with high risk hematologic malignancies were enrolled in the study: median age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD. Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). Transplant-related toxicity included BK virus-associated cystitis in 33% of patients and a non-fatal hepatotoxicity syndrome in three patients consisting of transaminase elevation and ascites, with resolution following discontinuation of sirolimus. CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT. Disclosures: Off Label Use:fludarabine, cyclophosphamide, and sirolimus are not FDA-labeled for stem cell transplantation.

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.

scholarly journals HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia

2021 ◽  
Vol 5 (5) ◽  
pp. 1333-1339
Author(s):  
Luisa Strocchio ◽  
Daria Pagliara ◽  
Mattia Algeri ◽  
Giuseppina Li Pira ◽  
Francesca Rossi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Fanconi Anemia ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Platelet Recovery

Abstract We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell–depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

Prevention of Acute GVHD with Sirolimus Does Not Abrogate the Risk of Chronic GVHD.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3317-3317
Author(s):  
Corey Cutler ◽  
Shuli Li ◽  
Haesook T. Kim ◽  
Edwin Alyea ◽  
Vincent Ho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Serum Level ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Tissue Injury ◽  
Chronic Gvhd ◽  
Effective Prevention ◽  
Gvhd Prophylaxis

Abstract Chronic graft-vs.-host-disease (cGVHD) is a major cause of morbidity and mortality after allogeneic stem cell transplantation. The pathophysiology of cGVHD is poorly understood, but allogeneic T and B cells are thought to be important mediators of tissue injury. Risk factors for cGVHD include mismatched or unrelated transplantation, the use of peripheral blood stem cells, increased age and sex mismatching. Prior acute GVHD (aGVHD) is the most important risk factor and therefore strategies that reduce aGVHD are expected to reduce cGVHD as well. We have described a novel GVHD prophylaxis regimen comprised of sirolimus and tacrolimus that is effective in reducing aGVHD. Here, we report cGVHD outcomes with this novel regimen. Methods: 53 patients underwent HLA-matched sibling peripheral blood stem cell transplantation using cyclophosphamide and TBI conditioning. The GVHD prophylaxis regimen was comprised of sirolimus (target serum level 3–12 ng/ml) and tacrolimus (target serum level 5–10 ng/ml) without methotrexate. Median follow-up is 11 months from transplantation. Results: The incidence of grade II-IV aGVHD was 19%. Of the 10 patients with aGVHD, only 3 developed cGVHD. In these three patients, aGVHD had resolved entirely. In total, 21 patients developed cGVHD at a median of 231 days from transplantation, 18 of whom had no prior aGVHD. The cumulative incidence of cGVHD was 63% when relapse and death were considered as competing risks. At the time of cGVHD diagnosis, 10 patients were off all immunosuppressive medications, 6 patients were on sirolimus, either alone(2) or in combination with tacrolimus(4). 3 patients were on tacrolimus, either alone (2) or with prednisone(1), 1 patient was on prednisone alone and information was unavailable for 1 patient. cGVHD end-organ involvement included liver(13), skin(12), oral mucosa(12), eye(6), musculoskeletal(5), hematologic(1), lung(1) and serosa(1). 3 patients had isolated, limited hepatic cGVHD. Therapy included the re-institution of prednisone alone(5) or with mycophenolate(6), sirolimus(4), tacrolimus(2), rituximab(1) or multiple agents(1). One patient began on mycophenolate alone and 1 patient required no therapy. 4 patients had a complete response to immunosuppressive therapy. Only 1 patient died after the diagnosis of cGVHD while still on immunosuppression. No patient with cGVHD had malignant disease relapse. Conclusions: Despite effective prevention of aGVHD with sirolimus and tacrolimus, cGVHD was not prevented in this patient cohort. This argues that the pathophysiologic mechanisms involved in tissue injury in aGVHD and cGVHD may be different, or that methotrexate may be important in the prevention of cGVHD. Since the development of antibodies directed against minor histocompatibility antigens has been correlated with the development of cGVHD, novel strategies designed to interfere with B cell immunity after transplantation may be required to prevent cGVHD.

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

Blood ◽  
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.

Pulmonary Complications after T-Cell Depleted Allogeneic Stem Cell Transplantation: Low Incidence and Strong Association with Acute GVHD.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1821-1821
Author(s):  
Cynthia Huisman ◽  
Hanneke M. van der Straaten ◽  
Marijke R. Canninga-van Dijk ◽  
Rob Fijnheer ◽  
Leo F. Verdonck
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Pulmonary Complications ◽  
Hematopoietic Stem ◽  
Control Subjects ◽  
Significant Difference

Abstract Lung injury limits the success of hematopoietic stem cell transplantation (HSCT). The overall incidence varies from 30–50% and noninfectious causes occur in one third to one half of these. We reviewed pulmonary complications in 369 patients who received either allo-BMT or allo-PBSCT at our institution between 1993 and 2003. Control subjects were selected from the same database and matched on sex, underlying diagnosis, age, type of transplantation and cytomegalovirus-serostatus. For all patients the conditioning myeloablative regimen consisted of cyclophosphamide (60 mg/kg/day for 2 days) followed by total body irradiation (total lung dose 850 cGy). The graft was partially T-cell depleted (1–2 x 105 T cells/kg). Sixty-one patients (16.5%) developed pulmonary complications, which were diagnosed at a median of 22 weeks after transplantation (range 2–263). Twenty-one patients (5.7%) developed infectious pneumonia. Non-infectious complications were further subclassified as BO (3.5%), BOOP (0.5%), DAH (0.8%), IPS (5.4%) or mixed etiology (0.5%). Acute GVHD ≥ grade II was significantly more common in patients with pulmonary complications than in the controls (36/61 versus 24/61 patients, P=0.02). There was no significant difference in the incidence of chronic GVHD (in 26/48 pulmonary patients versus 20/55 controls, P=0.1). Median survival was 41 weeks (range 4–583) for the pulmonary patients and 173 weeks (range 8–582) for the control subjects. These data illustrate that the incidence of pulmonary complications is low after T-cell depleted HSCT and demonstrate a clear association with acute GVHD. Improvement of the poor outcome of pulmonary complications is of utmost importance. Current studies at our institution are focused at the detection of early markers so that possible pre-emptive-like therapy can be initiated before symptomatic lung damage arises.

Oligoclonal T Cells Associated with Gvhd Following Allogeneic Stem Cell Transplantation Conditioned with Thymoglobulin and Reduced Intensity Total Body Irradiation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4662-4662
Author(s):  
Masoud Manjili ◽  
Catherine H Roberts ◽  
Maciej Kmieciak ◽  
Madhu S Gowda ◽  
Andrea Ferreira-Gonzalez ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Count ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Recovery ◽  
Reduced Intensity

Abstract Abstract 4662 Patients undergoing unrelated donor stem cell transplantation following reduced intensity regimens are prone to acute graft vs host disease (GVHD). In vivo T cell depletion with rabbit anti-thymocyte globulin (r-ATG, Thymoglobulin, Genzyme inc. Cambridge MA) is consistently associated with reduced risk of acute GVHD however poor T cell reconstitution seen with current schedules results in a high incidence of opportunistic infections and relapse. We report data on immune reconstitution in patients participating in an ongoing clinical trial testing a novel conditioning regimen for allogeneic GCSF-mobilized blood stem cell transplantation. Patients were randomized to receive conditioning with either 7.5 or 5.1 mg/kg of r-ATG in divided doses between days -9 and -7, followed by 450 cGy total body irrradiation (TBI) in 3 fractions on day -1 and 0. GVHD prophylaxis was with tacrolimus (day -3 to 120) and mycophenolate mofetil (day 0-30). So far 10 heavily pre-treated (median number of prior therapies 4, prior autologous SCT n=5) patients have been transplanted; 6 from unrelated donors (1 bone marrow), 3 from matched related donors and 1 from an HLA-A mismatched sibling. Diagnosis includes MM (4), NHL (3), and CLL/PLL (3). Median patient age is 57 years. No patients have developed acute GVHD in the first 90 days. All patients achieved prompt engraftment of neutrophils and have demonstrated sustained complete myeloid donor chimerism (median <1% recipient DNA) at 3-6 months post transplant. NK cell recovery is prompt (mean±SD absolute CD56+ cell count 177±85/μL at day 30) and sustained (184±116 at day 90). T cell subset recovery is modest (absolute CD3+ cell count 861±934/μL at day 90) with predominantly cytotoxic T cells (CD3+/4+ cell count 143±116 and CD3+/8+ cell count 708±837). T cell chimerism at day 90 is mixed with either donor ('10% recipient DNA, n=5) or recipient dominance (>10% recipient DNA, n=3). Patients demonstrating dominant donor T cell chimerism at day 90 went on to develop either delayed onset acute GVHD (n=2/8 evaluable) or chronic GVHD (n=2/8) after withdrawal of immunosuppression. Patients demonstrating mixed T cell chimerism with recipient dominance did not develop chronic GVHD; one of these patients has relapsed, following an HLA-A mismatched SCT from his brother, and though he had predominantly recipient derived T cells, his granulocytes were completely donor derived indicating graft tolerance. T cell receptor beta locus was examined by RT-PCR for oligoclonality in all the donor-recipient pairs at baseline, day 90 and at onset of GVHD. Patients with GVHD demonstrated high level of expression of TCR V beta 23 and 24 (n=1/4), 11 (n= 1/4), 18 (n= 1/4), or 11 and 18 (n= 1/4) exclusively, in addition to TCR V beta 14, 16, 17, 22. The latter loci were also expressed in patients who had no GVHD with mixed T cell chimerism; this group of patients also expressed TCR V beta 4 (n=2/2), 13 and 19 (n=1/2) exclusively. All but one of the patients expressed the majority of TCR V beta loci at day 90 (with the exceptions noted above) indicating early polyclonal T cell recovery following transplantation. Asymptomatic CMV and EBV reactivation requiring therapy developed in one patient each. No patients have developed invasive fungal infections. In conclusion conditioning with Thymoglobulin and reduced intensity TBI results in stable myeloid engraftment in patients receiving unrelated and alternative donor transplants. In this small group of patients, GVHD appears to be associated with emergence of oligoclonal T cell populations which in the future may be selectively depleted ex vivo to allow engraftment without risk of chronic GVHD. Disclosures: McCarty: Celgene: Honoraria; Genzyme: Honoraria. Toor:Genzyme: Research Funding.

Haploidentical Stem Cell Transplantation: High Doses of Alloreactive-T Cell Depleted Donor Lymphocytes Administered Post-Transplant Decrease Infections and Improve Survival without Causing Severe Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 512-512 ◽  
Author(s):  
Denis-Claude Roy ◽  
Silvy Lachance ◽  
Thomas Kiss ◽  
Sandra Cohen ◽  
Lambert Busque ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
T Cell Depletion ◽  
Post Transplant

Abstract Abstract 512 Delayed immune reconstitution following intensive T cell depletion of the stem cell graft is the main complication limiting broad utilization of haplo-mismatched donors for stem cell transplantion (SCT). Indeed, it results in frequent and rapidly lethal infectious events. The ability to accelerate immune reconstitution following haplo-SCT would provide a unique opportunity to transplant the large number of patients who cannot find an HLA-matched donor. We present results of our Phase I clinical trial of haploidentical allogeneic SCT followed by an “add-back of donor T cells to accelerate immune reconstitution” (ATIR). This donor lymphocyte infusion (DLI) underwent photodynamic depletion (PD) of host-reactive T cells using dibromorhodamine as photosensitizer (Kiadis Pharma). Nineteen patients (11 M, 8 F) with very high-risk hematologic malignancies (mostly refractory or relapsed acute myeloid leukemia (10) and myelodysplastic syndromes (4), and refractory ALL (1), CLL (2), CML (1) and NHL (1)) entered the trial. Median age at SCT was 54 years (range: 19-62). HLA compatibility was 3/6 in 6 pts, 4/6 in 12 pts and 5/6 (DR mismatch) in 1 pt. Increasing doses of PD-treated donor cells (ATIR: 1×104 to 5.0 ×106 CD3+ cells/kg) were administered on day 34±6 after transplant. In the ATIR, greater than 95% of CD4+CD25+ and CD8+CD25+ T cells as well as anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection (Miltenyi). The myeloablative regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (200 mg/m2). No GVHD prophylaxis was administered. All patients showed complete donor chimerism and durable hematologic engraftment. Five patients developed grade II GVHD affecting skin (n = 5 pts), liver (2 pts) and gastrointestinal tract (1 pt) at a median of 101 days post-SCT. No patient developed grade III-IV acute GVHD. Chronic GVHD developed in 9 pts, mostly in those receiving higher T cell doses. Treatment of acute and chronic GVHD involved steroids, tacrolimus and mycophenolate mofetil in 3 patients, steroids and tacrolimus in 3 pts, and steroids only in 3 pts. GVHD responded rapidly to treatment since the median duration of total immunosuppressive therapy in each patient was 187 days (range: 61-319 d). All 7 patients in cohorts 1-3, who received 1.3×105 or less CD3+ cells/kg, developed infectious complications (100% of pts), with 5 lethal episodes in these 7 pts. In sharp contrast, only 6 (50%) of the following 12 patients (cohorts 4-7) receiving ATIR with the highest CD3+ cell doses (3.2×105 to 5.0×106 CD3+ cells/kg) developed infections (p <0.05), none resulting in a fatal event (p<0.001). Interestingly, CD3 lymphocytes recovered earlier in the last 2 cohorts (6 and 7) receiving 2-5×106 CD3+ cells/kg than in the first 5 cohorts (7.9×105 or less CD3+ cells/kg) (p<0.01). Eight patients died: 4 of relapsed leukemia (3 AML; 1 ALL) and 4 of infections. Overall treatment related mortality (TRM) is 27% at 2 years post-SCT, with a TRM of 0% in patients receiving the highest CD3+ cell doses (cohorts 4-7). The overall survival is 60% at 2 years (median f-up: 12.1 mo; 95% confidence interval at 2 years: 37-83%). The 12 patients in cohorts 4-7 receiving the higher CD3+ cell doses had an improved survival (82% at 2 yrs) over the 7 patients in cohorts 1-3 administered a lower CD3+ cell dose (14% at 2 yrs) (p<0.05). Our results indicate that the post-transplant infusion of an ATIR-PD treated DLI is feasible, results in accelerated T cell reconstitution, and decreases the incidence and severity of infections without inducing severe GVHD. These results suggest a clinical benefit for patients receiving the highest ATIR doses and form the basis of an international pivotal clinical trial to decrease TRM in patients undergoing haploidentical stem cell transplantation. Disclosures: Roy: Kiadis Pharma: Research Funding. Egeler:Kiadis Pharma: Employment.

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1695-1700 ◽  
Author(s):  
Donna Przepiorka ◽  
Paolo Anderlini ◽  
Rima Saliba ◽  
Karen Cleary ◽  
Rakesh Mehra ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Blood Stem Cell ◽  
Gvhd Prophylaxis ◽  
Blood Stem Cell Transplantation

Abstract The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P = .001), whereas the risk was increased with prior acute GVHD (HR, 1.67;P = .046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P &lt; .001) and treatment failure (HR, 5.2; P &lt; .001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.

Non-T-Cell Depleted HLA Haploidentical Hematopoietc Stem Cell Transplantation for Refractory or Relapsed Pediatric Solid Tumor

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4470-4470 ◽  
Author(s):  
Hideki Sano ◽  
Shogo Kobayashi ◽  
Mitsuko Akaihata ◽  
Masaki Ito ◽  
Atsushi Kikuta
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Tumor Progression ◽  
Cell Transplantation ◽  
Solid Tumor ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Pediatric Solid Tumor

Abstract Abstract 4470 Background: Despite intensive multi-modal therapies, prognosis of refractory or relapsed pediatric solid tumor is dismal because majority of those tumors already get acquired chemo-resistance. Therefore new break through approaches are expected in order to improve their survival. The efficacy of allogeneic hematopoietic stem celltransplantation(SCT) is primarily attributed to a T/NK- cell-mediated response to HLA disparity between donor and tumor cell. Non–T-cell depleted (non TCD) haploidentical hematopoietc stem cell transplantation as immunothrapy is attractive challenge for refractory tumor, however, there are several reports describing graft-versus-tumor (GVT) effects in patients with solid tumors. The major problems of non-TCD haplo-SCT are lethal graft-versus-host disease (GVHD), graft failure (GF) and high-risk of early death. Previously we reported the safety profile from the retrospective study assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone in non-TCD haplo-SCT (Mochizuki, Kikuta, Clin Transplant,2010 DOI:10.1111/j.1399-0012.2010.01352.x). We started clinical study of non-TCD HLA haploidentical hematopoietc stem cell transplantation for refractory or relapsed pediatric solid tumor as cell-mediated immune therapy since July, 2007. Objectives/Methods: This study presents a series of transplant experiments aiming to evaluate the efficacy and feasibility of non-TCD HLA haploidentical hematopoietc stem cell transplantation for refractory or relapsed pediatric solid tumor. Seven cases (3males, 4females) with refractory or relapsed pediatric solid tumor were enrolled on this study between July 2007 to December 2010. One patient had second transplantation due to tumor progression 1year after transplantation. Among 7 patients, there are 3 cases of relapsed neuroblastoma, 1 case of relapsed Mesenchymal Chondrosarcoma, 1 case of relapsed Ewing sarcoma family tumor, 1 case of refractory alveolar soft part sarcoma with multiple lung metastasis, and 1 case of refractory primitive neuroectodermal tumor. Conditioning regimens consisted with fludarabine30mg/m2 at day-9 to -5+Melphalan70mg/m2 at day-4 to-3+rabbit ATG 1. 25mg/kg at day-2 to -1. The GVHD prophylaxis was conducted with tacrolimus (0.03mg/kg/day, start on day-1), methotrexate (10mg/m2, 7mg/m2, 7mg/m2 on day+1, +3, +6) and predonisolone (1mg/kg/day, day 0–29, taper on day30 without GVHD). HLA disparities were 3/8 in 3, 4/8 in 5. Donors included father(1), mothers(5), siblings(1), mother’s younger brother(1). Four pts received peripheral blood stem cells and 4 pts received bone marrow. Result: All of seven patients achieved primary engraftment but secondary graft rejection was observed in one patients. Median follow up period after transplantation were 14 months (range 11–40 months). Incidence of acute GvHD was 3/7 cases (grade±:1, gradeII:1, grade III:1), chronic GvHD was observed in 5(83%) of 6 evaluable patients. Three cases were underwent DLI for tumor progression. Treatment-related mortality(TRM) was not observed and reactivation of VZV, interstitial pneumonia, and HHV6 related limbic system encephalitis were recognized as major complication within 100 days after transplantation. Five cases of patients had tumor progression after transplantation, and two children were dead by tumor progression, other 3 cases had additional treatment. Two cases are alive and well, with no evidence of disease 13 and 14 months after transplantation. Graft versus Tumor effect was clearly observed in three cases. Conclusion: The survival rate of relapsed or refractory pediatric solid tumor is under 20%, however, the two-year probability of overall survival was 71.4% with no TRM in this study. These results indicated the feasibility and the possibility of efficacy of non-TCD HLA haploidentical hematopoietc stem cell transplantation for relapsed or refractory pediatric solid tumor. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Recovery of Specific Subsets of Natural Killer and T Cells Highly Associated with Graft-Versus-Host Disease after Haploidentical Stem Cell Transplantation in Acute Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4581-4581
Author(s):  
Jieun Jang ◽  
Haerim Chung ◽  
Yu Ri Kim ◽  
Hoi-kyung Jeung ◽  
Ju-In Eom ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Chronic Gvhd ◽  
Cd4 T Cell ◽  
High Dose

Abstract Background In the allogeneic hematopoietic stem cell transplantation, recent studies showed that T cell and natural killer (NK) cells recovery are implicated in the graft-versus-host disease (GVHD) and graft versus leukemia (GVL) effects. However, the significance of specific subsets of NK and T cell recovery in relation to transplantation outcomes remains to be elucidated in the haploidentical stem cell transplantation (haploSCT). Methods Clinical data of patients with acute myeloid leukemia (n = 21) and acute lymphoblastic leukemia (n = 24) who underwent their first haploSCT between September 2009 and December 2017 were analyzed. Peripheral blood mononuclear cells obtained from 27 patients were examined by multiparametric flow cytometric analysis. PD-1 and Tim-3 expression were examined in CD4+ and CD8+ T-cells and NK cell receptor (NKG2D, NKG2A, NKG2C, DNAM1 and NKp46) expression were analyzed in NK cells, respectively, at the 3 determined times (immediate prior to conditioning therapy, 28 and 90 days after haploSCT). Results Median age at haploSCT was 38 years (range, 21-62) and median follow-up duration was 31.6 months. Myeloablative conditioning was used for 32% and reduced intensity regimen for 68% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide for 8 (18%) or on anti-thymocyte-globulin for 36 (82%) plus standard prophylaxis. Incidence of grade II-IV acute GVHD was 50%, gastrointestinal tract (GIT) GVHD was 55.6%, non-GIT acute GVHD 35.7%, and chronic GVHD was 52.4%. Longitudinal analysis of immune reconstitution after haploSCT showed that the incidence of acute GVHD was associated with a delayed expansion of the NK cell population and incidence of chronic GVHD was associated with the extent of CD4+ T cell reconstitution. The incidence of acute GVHD was significantly higher in patients with lower counts of CD56bright CD16neg cell (100% for patients with less than 30 cells/uL at day 28 vs 50% for patients with higher counts, P = 0.026), particularly in NKG2A (P = 0.002) and DNAM1 (P = 0.027)-positive NK cell subsets. In univariate analysis, early CMV replication (P < 0.001), chronic GVHD (P = 0.001), donor age ≥ 28years (P = 0.018), CD4/CD8 ratio of product ≥ 2.4 (P = 0.033), and dose of infused T cells ≥ 3.91 x 108 /kg (P = 0.022) were significantly associated with lower 3-year cumulative incidence of relapse after haploSCT. Donor age ≥ 28years was significantly associated with high incidence of chronic GVHD (P = 0.002). Dose of infused T cells ≥ 3.91 x 108 /kg (HR, 0.088; CI, 0.009 to 0.823; P = 0.033) were independent factors for reducing leukemia relapse after adjustment in multivariate analysis. Chronic GVHD was an independent prognostic factor for higher leukemia-free survival rate (72.7% versus 20.1%, P = 0.008). Longitudinal analysis of T cell reconstitution after haploSCT showed that the high dose of infused T cells was associated with the increased expansion of CD4+PD-1- T cells (P = 0.031 at day 28 and P = 0.017 at day 90). Of note, The incidence of chronic GVHD was significantly higher in patients with higher counts of CD4+ T cell at day 28 (100% for patients with over than 150 cells/uL at day 28 vs 38.8% for patients with lower counts, P = 0.008), particularly in CD4+PD-1- subsets (P = 0.008). Among CD4+ T cell, PD-1-/PD-1+ ratio over than 4.5 was significantly associated with increased chronic GVHD (P = 0.005). In 22 patients with chronic GVHD, GIT GVHD was adverse prognostic factor for overall survival (59.5 % in GIT GHVD vs 100% in patients without GIT GVHD, P = 0.063). The incidence of GIT GVHD was significantly higher in patients with lower CD4/CD8 ratio at day 28 (77.8% for patients with less than 1.5 vs 0% for patients with higher ratio, P = 0.045). Conclusions Our findings suggest that high CD56brightCD16neg NK cell count at day 28 after hasploSCT was significantly associated with decreased incidence of acute GVHD. High dose of infused T cells was associated with increased reconstitution of CD4+ PD-1- T cells and high CD4+ T cell counts, particularly in PD-1- subset, are associated with increased development of chronic GVHD. These findings should be further validated for elucidating the roles of these immune effectors cells in the development of GVHD and GVL effect in haploSCT for acute leukemia. Disclosures Kim: Novartis Korea: Honoraria.

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