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.

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.

scholarly journals Evaluation of abatacept for GVHD prophylaxis in patients with non-malignant diseases after hematopoietic stem cell transplantation

2019 ◽  
Vol 18 (2) ◽  
pp. 22-29
Author(s):  
S. A. Radygina ◽  
A. P. Vasilieva ◽  
S. N. Kozlovskaya ◽  
I. P. Shipitsyna ◽  
A. M. Livshits ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hemopoietic Stem Cell ◽  
Control Group ◽  
Malignant Diseases ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Additional Agent

Graft-versus-host diseases (GVHD) is one of most significant complication after allogeneic hematopoietic stem cells transplantation (HSCT). T-cell activation is a major stage in the GVHD pathogenesis. T-cells require 2 signals for activation: cognate antigen/MHC binding T-cell receptors and positive costimulatory signals from antigen-presenting cells (APC). The predominant positive costimulatory signal to human CD4 T0-cells comes through the CD28 receptor. This signal can be blocked by fusion proteins (such as CTLA4-Ig). Abatacept is a soluble fusion protein, which links the extracellular domain of human CTLA-4 to the modified Fc portion of human IgG1. We present results of single-center prospective randomized study to evaluate the efficacy of adding abatacept to the GVHD prophylaxis protocol after hemopoietic stem cell transplantation in patients with non-malignant diseases. Study was approved by Ethics Committee and Scientific Council of the Institute (protocol # 9/2013 from 01.10.2013). During 4 years we included 62 patients, 30 of them received abatacept as additional agent. Cumulative incidence of acute GVHD was significantly lower in this group in compare with control group (p = 0,018). When we stratified patients in dependents of graft processing technology, we did not see any advantages of abatacept in patients after transplantation with TCRαβ+/СD19+ graft depletion. However, after HSCT with non-manipulated graft the abatacept showed significant efficacy in aGVHD prophylaxis compared with control group (p = 0,024). Abatacept can be recommended as effective additional agent for GVHD prophylaxis after allogeneic HSCT in patients with non-malignant diseases.

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.

Preliminary Experience with Haploidentical Stem Cell Transplantation for Children with Sickle Cell Disease and Stroke.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5434-5434
Author(s):  
Joseph Woodard ◽  
Winfred Wang ◽  
Raymond Barfield ◽  
Gregory Hale ◽  
Edwin Horwitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Sickle Cell Disease ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Sickle Cell ◽  
Chronic Gvhd ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Cell Counts

Abstract Hematopoietic stem cell transplantation has been shown to be curative for approximately 83% of symptomatic children with sickle cell disease who have undergone the procedure. Despite these encouraging results, only 15% of children with symptoms that might merit consideration for transplantation have an available, unaffected HLA-matched sibling donor, severely limiting this therapeutic option. To address this problem, we developed a protocol for children with SCD and stroke using reduced-intensity conditioning and CD34-selected peripheral blood stem cells from haploidentical parental donors. We now report our preliminary experience using this approach in three children with SCD and stroke. After a chemotherapy-only conditioning regimen of fludarabine 150–200 mg/m2, thiotepa 10 mg/kg, i.v. busulfan targeted to a steady state concentration of 900 ng/ml, and OKT3, patients received an average of 27.2 x 106 CD34+cells/kg and 1.1 x 104 CD3+ cells/kg. Two patients required additional immunosuppression with methylprednisolone and OKT3 followed by a CD34 boost after graft rejection. One of these two had durable long-term engraftment, while one had a second rejection. Two of three patients have durable donor engraftment 20 and 24 months after transplantation, respectively. Donor T-cell chimerism evolved from predominantly host-derived to donor-derived over a number of months. One patient developed grade I acute GVHD and none developed chronic GVHD. Two engrafted patients have had no further SCD events. Both have recovery of immune function with normal CD4+ T-cell counts and normal thymic function. This preliminary experience demonstrates the feasibility of using mismatched parental donors for children with sickle cell disease. Future studies will focus on achieving reliable donor engraftment through additional graft manipulation strategies.

Non-T-Cell-Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation for Children with Hematological Malignancies: Single-Center Pilot Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4421-4421
Author(s):  
Kazuhiro Mochizuki ◽  
Atsushi Kikuta ◽  
Masaki Ito ◽  
Hideki Sano ◽  
Shogo Kobayashi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematological Malignancies ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Number Of Patients

Abstract Allogeneic hematopoietic stem cell transplantation is the only curative approach for a number of patients with hematological malignancies. For patients who do not have an HLA-identical related or unrelated donor, a related haploidentical transplantation is an alternative option. Recent advances in effective T-cell depletion of stem cells have significantly decreased graft-versus-host disease (GVHD) and early transplantationrelated mortality (TRM). However, the problems related to delayed immune reconstitution causing infectious complications and relapse remain, limiting the efficacy of haploidentical transplantation. Here, we report the results of ten children with hematological malignancies who received non-T-cell-depleted haploidentical hematopoietic stem cell transplantation. Malignancies included acute lymphoblastic leukemia (ALL, n = 6), acute myeloid leukemia (n = 2), chronic myeloid leukemia (n = 1) and Epstein Barr virus (EBV)-associated peripheral T cell lymphoma (n = 1). Median patient age was 5 years, and all patients presented with clinical and biologic features that indicated a very high risk of relapse with conventional chemotherapy. At the time of transplantation, seven patients were in remission, and two of these were urgent cases with primary graft failure of the first cord blood transplantation. The remaining three patients were not in remission. HLA disparity was two loci mismatches in one case and three loci mismatches in nine cases. The conditioning regimen consisted of the myeloablative method in five cases and reduced intensity conditioning in five cases. GVHD prophylaxis was conducted with tacrolimus and short-term methotrexate (sMTX) in the initial two cases and the remaining eight cases were given a combination of tacrolimus, sMTX and prednisolone (PSL). The stem cell source for the initial two cases was peripheral blood stem cells mobilized with G-CSF, and that for the remaining eight cases was bone marrow. Nine (90%) of the ten patients engrafted showed myeloid and platelet recovery on days +15 and +31 (median), respectively. All of these patients achieved full donor chimerism by day +30, and it persisted, except in one patient who relapsed. Acute GVHD of Grades II–IV and III–IV occurred in six (66.7%) and two (22.2%) patients, respectively, all of which responded to temporary augmentation of PSL. Chronic GVHD occurred in five (62.5%) patients, three of whom had extensive GVHD. Although one of these developed steroid refractory chronic GVHD, it was not difficult to control the symptoms of GVHD of the remaining patients. Infectious complications, including cytomegalovirus (CMV) antigenemia (n = 2), interstitial pneumonia associated with CMV (n = 1), temporary elevation of EBVDNA (n = 1), zoster (n = 1), invasive aspergillus infection (n = 1) and sepsis (n = 1), were observed. TRM occurred in two patients, and one patient with ALL relapsed on day +472 after transplantation. The Karnofsky performance scales of six of the eight survivors were 100%, and more than half of the evaluable patients were expected to discontinue immunosuppressive therapy within 2 years after transplantation. Because only one patient had relapsed by the time of the last follow-up, we believe that our GVHD prophylactic regimen suppresses the incidence of both acute and chronic GVHD to an acceptable level, while preserving the graft-versus-leukemia effect. Median follow-up of the eight patients who survived event-free was 34 months (range, 3 to 95 months). The 5-year probability of overall survival and event-free survival (EFS) were 77.6% and 66.6%, respectively. In the analysis of disease status at transplantation, encouraging results were obtained in patients who received the transplantation while in remission, with the rate of engraftment and 5-year probability of EFS at 100% and 80%, respectively. Although the number of patients in this series was small, the results described here indicate the feasibility of non-T-cell-depleted haploidentical stem cell transplantation for children with hematological malignancies who do not have an HLA-identical donor.

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.

Donor Lymphocyte Infusion after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5863-5863 ◽  
Author(s):  
Clemence Roux ◽  
Samia Harbi ◽  
Raynier Devillier ◽  
Faezeh Legrand ◽  
Sabine Fürst ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract Background Although allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative option to treat hematologic malignancies, disease recurrence remains a concern in the setting of high risk diseases. Thus, post alloSCT therapeutic strategies are needed to treat and/or prevent disease progression. In this setting, donor lymphocytes infusion (DLI) is an option as post alloSCT immunotherapy aiming to enhance graft versus leukemia (GVL) effect. Although DLI may induce persistent remission, graft versus host disease (GVHD) is a potential complication following DLI. Because of the suspected higher incidence of GVHD in the presence of HLA mismatches, few series focused on DLI following haploidentical stem cell transplantation (HaploSCT) so far. We therefore report our experience of DLI following HaploSCT using post-transplantation cyclophosphamide (PT-Cy) platform. Methods: We included in this single center study all consecutive adult patients with hematological malignancies who received DLI after HaploSCT with PT-Cy as part of GVHD prophylaxis from 2013 to 2016 (n=21). Conditioning regimens were non-myeloablative (low dose TBI-based) or with reduced toxicity (various dose of busulfan according to disease and patient characteristics). Ciclosporine A and mycophenolate mofetil were given as additional GVHD prophylaxis in all cases. DLI were given at escalating doses, expressed as CD3+cells/kg, without GVHD prophylaxis, and ranged from 1x105 to 5x107 cells/kg. Results: Eleven patients (52%) were transplanted for high risk disease according to the disease risk index (DRI, Armand et al., blood 2015). Twelve patients (57 %) received haploSCT in complete remission,.18 patients received first transplant and 3 patients their second transplant. After HaploSCT, 21 patients (median age: 56 years [range: 23-73]) received either therapeutic (treatment of hematological post transplantation relapse, n=6) or prophylactic (n=15) DLI. The median interval from HaploSCT to the first DLI was 128 days (range: 79-1011). The average number of DLI per patient was 1.8 (range, 1-3). Clinical characteristics are outlined in Table 1. Patients with AML and MDS received DLI alone (n = 13) or in association with azacytidine (n = 2). Patients with MM received DLI in association with Revlimid (n=3). Chimerism before first DLI was complete in 19 patients. 6 patients (33%) developed post DLI GVHD in a median time of 42 days (range: 30-210) with exclusively chronic features. 2 patients (9 %) had severe forms of chronic GVHD. GVHD-related death occurred in 1 patient No response was achieved when DLI were given as therapeutic and 4 of 6 patients died from disease progression. Otherwise, only 3 of 16 patients who received prophylactic DLI experienced relapse. With a median follow up of 129 days, overall survival was 63%. Conclusion Our study suggests that DLI following HaploSCT with PT-Cy is feasible. GVHD is frequent but with a relatively low incidence of severe forms. No response rate was achieved in the context of hematological relapse, underlining that preemptive or prophylactic strategy might be preferred. Indeed, the overall good outcome in patients receiving prophylactic DLI is promising taking into account the poor prognostic of the diseases indicated for alternative donor transplantation. Further prospective studies are needed in specific disease settings to assess the benefit for using such post alloHSCT immune-intervention. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4576-4576
Author(s):  
Patricia Ferraz ◽  
Arturo Pereira ◽  
María Suárez-Lledó ◽  
Gonzalo Gutiérrez-García ◽  
Francesc Fernández-Avilés ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Detrimental Effect ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) from unrelated donors mismatched (MMUD) at a single HLA-A, -B, -C, or -DRB1 locus (7/8) were previously reported to be associated with lower overall survival (OS) and disease-free survival (DFS), higher treatment-related mortality (TRM), and more acute graft-versus-host disease (GVHD) compared to 8/8 matched unrelated (MUD) allografts. Despite these risks, 7/8 MMUD grafts remain a viable option for alloSCT, particularly in patients who lack suitable donors or in those with aggressive hematologic malignancies for whom the risks of disease progression due to delays in identifying optimal donors is offset in part by the benefits of earlier transplantation with a 7/8 MMUD alloHCT. According to the published experience of post-transplant cyclophophamide (PTCy) in the context of haploidentical alloSCT, this GVHD prophylaxis strategy could potentialy overcome the detrimental effect of a single-locus HLA MMUD. Methods: We retrospectively analyzed 72 consecutive adult patients (median age 53y, range 18-69) who received 7/8 MMUD (n=44) or 8/8 MUD (N=28) alloSCT with PTCy in our institution. Unrelated donor selection was performed according to standard criteria, including high resolution typing for alleles at HLA-A, -B, -Cw, DRB1 and DQB1. For those patients in whom an 8/8 HLA-matched related or unrelated donor was not available, a search was performed based on a single HLA-mismatch. Results: Acute myeloid or lymphoblastic leukemia accounted for 51% of all hematologic diseases, myelodisplastic syndrome for 17%, chronic lymphoproliferative or myeloproliferative disorders for 28%, and severe aplastic anemia for 4%. Disease Risk Index (DRI) was intermediate in 51%, high 16% and very high 6%. Forty-four percent of patients had a HCT-CI ≥3. All patients, except 6 have received peripheral blood stem cells (PBSC). Fludarabine-based conditioning regimens were used in all patients (fludarabine-busulphan in 61%); of them, myeloablative (MAC) in 34 patients (47%) and RIC in 38 (53%). GVHD prophylaxis consisted on PTCy 50mg/kg IV on days 3 and 4 after transplant followed by one (tacrolimus or mycophenolate mofetil, MMF) (n=62, 86%) or 2 (n=10, 14%) immunossuppresor drugs. All but two patients engrafted and the median time to neutrophil (>500/mL) and platelet (>20,000/mL) recovery were 18 days (range 11-30) and 18 days (10-47), respectively. Thirteen patients (18%) developed an invasive pulmonary Aspergillosis, 20 (27%) had severe bacterial infection, 40 (56%) CMV reactivation, 5 (7%) cytomegalic disease and 3 EBV reactivation. The cumulative incidences of 1-year TRM, 100-days acute grade II-IV, 100-days grade III-IV GHVD, and 1-year moderate-severe chronic GHVD were 19%, 24%, 13%, and 11%, respectively. The cumulative incidence of relapse at 1-year was 16%. After a median follow-up for surviving patients of 12 months (2-60), 2-year OS, DFS, and survival free of moderate/severe chronic GVHD and relapse (cGRFS) were 64%, 61%, and 49%, respectively. Univariate analysis of variables that could influence OS, PFS, and cGRFS, including age, donor/patient sex, comorbidity, DRI, conditioning type, 1 vs. 2 immunosuppressors, and HLA 7/8 vs. 8/8 did not show any statistical differences. At 6 and 12 months after alloSCT, 42% and 73% of patients alive and without relapse were free of immunosuppressor drugs and prednisone. Conclusions: This study suggests that PTCy after unrelated PBSC alloSCT results in a low incidence of acute and chronic GVHD with encouraging survival outcomes even in the context of 7/8 HLA-mismatched transplant. An immunosuppressive schema of intermediate intensity such as PTCy followed by single-agent tacrolimus may provide an adequate GVHD prophylaxis and could be a good alternative to ATG in both MMUD and MUD transplants. Confirmatory and comparative studies are warranted to examine the effect of this approach on alloSCT outcomes. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Martinez:BMS: Research Funding; Takeda: Consultancy.

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