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

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

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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 ◽

10.1182/blood.v118.21.839.839 ◽

2011 ◽

Vol 118 (21) ◽

pp. 839-839 ◽

Cited By ~ 1

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

Frontiers in Oncology ◽

10.3389/fonc.2021.683263 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoli Chen ◽

Hengrui Sun ◽

Kaniel Cassady ◽

Shijie Yang ◽

Ting Chen ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Acute Gvhd ◽

Meta Analysis ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Safety And Efficacy

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

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Prospective Validation of a Chronic GvHD-Specific Proteome Pattern (cGvHD-MS14) Post Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v118.21.1970.1970 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1970-1970

Author(s):

Eva M. Weissinger ◽

Daniel Wolff ◽

Jochen Metzger ◽

Christiane E Dobbelstein ◽

Stefanie Buchholz ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Urine Samples ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Abstract 1970 Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many hematologic malignancies and non-malignant hematopoietic disorders, but is associated with significant morbidity and mortality with focus on acute and chronic graft-versus-host disease (GvHD). Chronic GvHD (cGvHD) occurs with increasing frequency, hampering quality of life of patients post-allogeneic HSCT and leading to increased morbidity and mortality even years after allogeneic HSCT. Diagnosis of chronic GvHD is based on clinical features and histology. Here we present the generation of cGvHD-specific proteomic pattern (cGvHD-MS14) using capillary electrophoreses and mass spectrometry to analyze urine sample collected prospectively after allogeneic HSCT. Methods: A proteomic pattern (cGvHD-MS14) was developed in order to diagnose cGvHD, to differentiate acute versus cGvHD, and to predict onset and severity of cGvHD prior to clinical diagnosis of cGVHD as a non-invasive, unbiased laboratory test for diagnosis of cGvHD. This pattern was prospectively evaluated on 329 patients (1034 urine samples) after allogeneic HSCT at MHH and 3 collaborating transplant centers. The majority of the patients had acute leukemias prior to transplantation (n=210) and were transplanted from matched unrelated or related donors (MUD n=134; MRD n=125). Reduced intensity conditioning regimens were used in about 75% of all patients and the majority (80%) received ATG (anti-thymocyte globulin) as GVHD-prophylaxis prior to transplantation and a calcineurin-inhibitor based prophylaxis afterwards. Results: Prospective and blinded evaluation revealed the correct classification of patients developing cGvHD with a sensitivity 78% and specificity of about 71% at time of diagnosis. Differentiation between late onset acute GvHD and chronic GvHD was achieved in 3 patients in this validation set. Acute GvHD prior to day 100 is not recognized by cGvHD-MS14, since aGvHD-specific peptides had been excluded during cGvHD-pattern generation. The pattern consists of 14 differentially excreted peptides, differentiating chronic GvHD from tolerant patients. Four of 14 peptides have been sequenced to date, 2 are fragments from collagen 1, 1 is from inter-alpha trypsin inhibitor heavy chain 4 and 1 is a fragment from the fibrinogen ß-chain. Conclusions: The proteomic pattern of urine proteomics enables diagnosis of cGvHD as well as differentiation of acute versus chronic GvHD. Further prospective evaluation of the cGvHD-specific pattern cGvHD-MS14 for organ specificity as well as severity prediction is currently ongoing. Taken together our results indicate that diagnosis of cGvHD is possible using CE/MS analysis of prospectively collected urine samples with high sensitivity and specificity. Disclosures: Metzger: mosaiques-diagnostics GmbH: Employment. Krons:mosaiques-diagnostics GmbH: Employment.

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

Blood ◽

10.1182/blood.v112.11.4421.4421 ◽

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.

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