scholarly journals Post-Transplantation Cyclophosphamide after Allogeneic Hematopoietic Stem Cell Transplantation: Results of the Prospective Randomized HOVON-96 Trial in Recipients of Matched Related and Unrelated Donors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1-1 ◽  
Author(s):  
Cornelis N. De Jong ◽  
Ellen Meijer ◽  
Katerina Bakunina ◽  
Erfan Nur ◽  
Marinus van Marwijk Kooij ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Financial Support ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Skin Involvement ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality (TRM). Several strategies are applied in order to prevent GVHD following T-cell replete alloHSCT including conventional immunosuppression (CIS) with post-transplant administration of cyclosporine A (CyA) and mycophenolic acid (MA), or post-transplant cyclophosphamide (PT-Cy) either or not combined with CIS. Studies in haplo- and HLA matched donor transplantation have shown that PT-Cy is well tolerated and associated with low rates of severe GVHD and TRM. However, evidence from randomized clinical trials on the efficacy of PT-Cy as compared to CIS in the setting of HLA matched alloHSCT is scarce. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare a PT-Cy based immunosuppressive regimen with CIS and address the question whether PT-Cy would be associated with improved GVHD-free/relapse-free survival (GRFS). Endpoints included time to acute and chronic GVHD, progression free survival (PFS), GRFS, overall survival (OS), and adverse events. Methods Hematological patients (pts) with a matched related donor or at least an 8 out of 8 matched unrelated donor were included. Pts randomized for the CIS regimen received CyA twice daily until day +120 followed by tapering until day +180 and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day until day 84 post-transplant. Pts randomized for PT-Cy received 50 mg/kg of cyclophosphamide on day +3 and +4 combined with CyA from day +5 until day +70. Results A total of 160 pts was randomized 1:2 between CIS and PT-Cy, of whom 94% proceeded to transplant (52 versus 99 pts). Median age was 58 years (range: 20-70), 66% were male. Two pts received myeloablative conditioning. The donor type was matched related in 31% and matched unrelated in 69% of pts. Transplants were derived from peripheral blood in 97% of pts and consisted of median 6.14x106/kg CD34+ cells/kg (range: 1.36-19.4) and median 230x106/kg CD3+ T cells (range: 0-519). Baseline patient and transplantation characteristics were equally distributed between the two treatment arms. The cumulative incidence (CI) at six months of grade II-IV acute GVHD was 48% in recipients of CIS versus 32% following PT-Cy (SHR 0.52, 95%CI 0.31-0.87, p=0.014), and grade III-IV 12% versus 6%. In recipients of PT-Cy, acute GVHD was generally limited to stage 1 skin involvement, whereas more severe skin involvement and bowel involvement were observed following CIS. The two-year CI of chronic extensive GVHD was 50% in recipients of CIS versus 19% following PT-Cy (SHR 0.38, 95%CI 0.21-0.67, p=0.001). The three-year estimate of PFS was 60% (44%-73%) and 58% (46%-67%). The three-year CI of progression/relapse was 26% in the CIS arm versus 32% in the PT-Cy arm. The three-year estimate of OS was 69% (53%-80%) and 63% (52%-73%). The one-year estimate (95% confidence interval) of GRFS was 22% (12%-34%) and 45% (35%-55%), respectively. Conclusion Use of high-dose PT-Cy results in a significant reduction in severe acute and chronic GVHD without affecting relapse, thereby resulting in improved GRFS. Hence, a more intensified immunosuppression regimen with PT-Cy might be preferred as GVHD prophylaxis in the setting of RIC alloHSCT. Figure Disclosures Nur: Novartis Pharmaceuticals: Consultancy. Maertens:Cidara: Other: Personal fees and non-financial support; Gilead Sciences: Other: Grants, personal fees and non-financial support; Amplyx: Other: Personal fees and non-financial support; Merck: Other: Personal fees and non-financial support; Pfizer: Other: Grant and personal fees; Astellas Pharma: Other: Personal fees and non-financial support; F2G: Other: Personal fees and non-financial support. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Time-Restricted Versus Standard Duration Immunosuppression after Allogeneic Hematopoietic Stem Cell Transplantation: Results from the Prospective Randomized Phase III HOVON-96 Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 371-371
Author(s):  
Cornelis N. De Jong ◽  
Ellen Meijer ◽  
Katerina Bakunina ◽  
Erfan Nur ◽  
Marinus van Marwijk Kooij ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Phase Iii ◽  
Standard Regimen ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Grade Ii

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality. The current standard Dutch regimen for prevention of GVHD in T-cell replete (TCR) alloHSCT following reduced intensity conditioning (RIC) consists of mycophenolic acid (MA) and cyclosporine A (CyA) for three and six months post-transplant, respectively. However, as approximately 30% of patients will never develop GVHD, immunosuppressive overtreatment is of concern and might impair outcome. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare time-restricted immunosuppression versus a standard immunosuppressive regimen. The primary objective was to increase the proportion of patients with non-severe GVHD (either acute GVHD grades I-II without gut involvement or chronic GVHD not requiring systemic treatment) within 180 days after transplantation and to reduce the relapse rate, without increasing severe GVHD. Secondary endpoints included time to acute and chronic GVHD, progression-free survival (PFS), GVHD-free/relapse-free survival (GRFS), overall survival (OS), and adverse events. Methods Hematological patients planned to undergo TCR alloHSCT with a related or unrelated 8/8 HLA matched donor were included. The trial randomized patients between three treatment arms. The current analysis includes all patients randomized between arms A and B. Immunosuppression consisted of CyA twice daily aiming for serum trough levels of 250-350 µg/L and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day. The standard regimen (arm A) prescribed to discontinue MA at day 84 post-transplant and CyA was continued until day +120 followed by tapering until day +180. In those randomized for the time-restricted regimen (arm B) MA was discontinued at day 28 post-transplant and CyA was continued until day +84 followed by tapering. Results A total of 389 patients were randomized 1:1 between arms A and B, of whom 95% (184 in arm A versus 185 in arm B) proceeded to transplant. The median age was 55 (range: 18-71), 57% were male. Fifty-one patients received myeloablative conditioning and 318 (86%) patients RIC. Donors were matched siblings for 135 patients and matched unrelated donor (MUD) for 233 patients. The majority of patients received peripheral blood stem cells, consisting of median 6.46x106/kg CD34+ cells/kg (range: 0.94-26.3) and median 230x106/kg CD3+ T cells (range: 0-936). Baseline patient and transplantation characteristics were equally distributed between the treatment arms. The proportion of patients developing non-severe GVHD within 180 days post-alloHSCT was 24% in both treatment arms, with an odds ratio (OR) of 1.01 (95% confidence interval 0.61-1.67, p 0.98). The cumulative incidence (CI) of grade II-IV and grade III-IV acute GVHD at 6 months post-alloHSCT was not significantly different between the two arms (47% and 15% versus 52% and 18%), nor was the maximum grade or organ involvement of acute GVHD. In addition, no difference was seen in the two-year CI of chronic extensive GVHD between the two treatment arms (51% versus 49%). The three-year estimate of PFS was 51% (44-59%) versus 52% (44-59%), respectively. The three-year CI of progression/relapse was 28% in arm A versus 27% in arm B. OS at three years was 59% (0.51-0.66%) versus 57% (0.50-0.64%). The one-year estimate of the composite endpoint GRFS was 14% (9-19%) in arm A, and 17% (12-22%) in arm B. Incidences and nature of adverse events were comparable in both arms. Conclusion A time-restricted combination of MA and CyA did not increase the proportion of patients with non-severe GVHD within 180 days after transplantation and resulted in similar outcome as compared to standard immunosuppression following alloHSCT using sibling and well-matched unrelated donors. Given the observed high CI of acute grade II-IV and chronic extensive GVHD and low GRFS for both the time-restricted and standard regimen, recipients of TCR RIC alloHSCT should be considered for more intensive immunosuppression. Figure Disclosures Nur: Novartis: Consultancy. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Long-Term Follow-up of Hematopoietic Stem Cell Transplantation with the Modified Peking Regimen for the Treatment of Acute Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2034-2034
Author(s):  
Xi Yang ◽  
Chenglong Li ◽  
Rong Zhang ◽  
Hong Zheng ◽  
Qing Wei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment strategy for patients with acute leukemia. The ATG-based transplantation system initiated by Peking University people's hospital, known as the Peking regimen, has become a mainstream transplant system worldwide. Here, based on the Peking regimen, we report a modified protocol:(1)add Fludarabine and replace ATG with ATG-F in the conditioning regimen; (2)transfuse higher-dose cell collections from granulocyte-colony stimulating factor(G-CSF) primed bone marrow and peripheral blood samples; (3) add Basiliximab (a CD25-antibody) on day +3 for acute GVHD prophylaxis. In this study, 265 patients (158 patients with haplo-SCT and 107 patients with sibling-SCT) underwent allo-HSCT with our modified protocols. All patients achieved sustained full-donor chimerism. The incidence of grade II-IV and III-IV acute GVHD in haplo-SCT comparing with sibling-SCT was 36.1%(57/158) vs 17.8%(19/107)(P=0.001) and 13.3% (21/158) vs 9.3%(10/107)(P>0.05) respectively. The 2-year cumulative incidence of total chronic GVHD and extensive chronic GVHD in haplo-SCT was 41% (65/158) and 15% (24/158) respectively. The 3-year cumulative incidence of non-relapse mortality (NRM) in haplo-SCT and sibling-SCT was 6.3% (10/158) and 4.7%(5/107) respectively(P>0.05). The 100-day cumulative incidence of CMV viremia in haplo-SCT and sibling-SCT was 35.5% (56/158) and 23.4%(25/107) respectively(P=0.036). A total of 36 patients in haplo-SCT group and 24 patients in haplo-SCT group had recurrent disease, reaching a cumulative incidence of relapse of 20.8% in haplo-SCT and 23.4% in sibling-SCT at 3 years respectively(P>0.05). The relapse ratio of haplo-SCT and sibing-SCT in the 1st year, between the 1st and the 2nd year and after 2 years was 21.5% vs 14.1%(P>0.05), 1.3%(2/158) vs 0%(P>0.05) and 0% vs 6.5%(P=0.009) respectively. The 3-year overall survival(OS) and leukemia-free survival(LFS) rates in haplo-SCT and sibling-SCT was 78.8% vs 74.2% and 76.8% vs 75.04% respectively(P>0.05) by the Kaplan-Meier estimate. The 3-year GVHD-free and leukemia-free survival rates (GRFS) in haplo-SCT and sibling-SCT were 43.4% vs 69.5%(P=0.045) respectively. Lower OS in haplo-SCT was associated with III-IV aucte GVHD and lower MNC(<19×10^8/L) in grafts by Cox regression analysis. In a word, the results from our experience showed that the modified protocol based on the Peking Regimen is safe and reliable for acute leukemia patients and brings on a long-stage survival post transplantation. Disclosures Zheng: Pfizer: Research Funding.

scholarly journals A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2107-2107
Author(s):  
Christopher R. D'Angelo ◽  
Aric C. Hall ◽  
Kyungmann Kim ◽  
Ryan J. Mattison ◽  
Walter L. Longo ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort. Methods In this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180. Results We enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index. All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft. Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%). Conclusions Decitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. Disclosures No relevant conflicts of interest to declare.

A Prospective Cost Analysis of Non-Myeloablative Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2239-2239
Author(s):  
Chris Skedgel ◽  
Jo-Ann Edwards ◽  
Jean Roy ◽  
Andrea McNeil ◽  
Yvonne Gulliver ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Hospital Admissions ◽  
Chronic Gvhd ◽  
Direct Costs ◽  
First Year ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Cost

Abstract Hematopoietic stem cell transplantation (HSCT) is an intensive medical therapy used to treat both malignant and non-malignant conditions. Non-myeloablative transplantation (NMT) is an emerging transplant modality often performed on an outpatient basis. While NMT is associated with fewer acute complications compared to myeloablative HSCT, long-term complications, particularly chronic graft vs host disease (GvHD), are of concern. To our knowledge, there have been few economic evaluations of NMT and none in a Canadian healthcare environment. We prospectively developed and validated a process for capturing the costs and outcomes of NMT in order to estimate the cost per patient of NMT at a Canadian transplant centre. Ten consecutive patients undergoing NMT were followed from the first day of conditioning (Day −11) until either 1 year post-transplant or death. Donor costs were also recorded. All patient encounters, procedures and interventions during the study period were prospectively recorded. Nursing and other non-physician human resource costs were calculated based on recorded contact times and salaries. Physician costs were derived from Nova Scotia fee codes. Costs of hospital admissions were derived from Ontario Case Costing Initiative (OCCI) data and were specific to the primary diagnosis. Drug costs were based on acquisition costs at hospital and community pharmacies. Materials and equipment costs were based on costs at the QEII Health Sciences Centre, Halifax NS. The proportion of administrative costs to direct costs was derived from OCCI data and applied to local direct costs. All costs are in 2005 Canadian dollars ($CAN). Ten patients were followed for a median of 12 months (range 3.6–12) from September 2003 to April 2005. Eight patients were male and the median age of the cohort was 60 years (19–73). Five patients had AML; 3 had lymphoma and 2 had multiple myeloma.Cyclophosphamide and fludarabine were used as conditioning and tacrolimus and mycophenolate mofetil were used as GvHD prophylaxis. There were 7 hospital admissions among the 10 patients: 3 before day 100 and 4 after day 100. Eight patients survived at least one year post-transplant. No patients developed acute GvHD, while all 8 patients surviving to 1 year post-transplant developed chronic GvHD. Three patients relapsed within 1 year. The average cost per NMT was $CAN 43,377 of which $CAN 31,761 were recipient costs, $CAN 2,562 were donor costs and $CAN 8,675 were equipment and overhead costs. The key cost driver was hospital admissions for complications and/or palliative care at $CAN 9,793 per recipient. Physician fees ($CAN 6,958) and chemotherapy ($CAN 6,485) were also significant. Compared to published estimates of the cost of myeloablative HSCT, NMT appears considerably less costly in the first year post-transplant. Our analysis suggests that the lower cost of NMT was largely attributable to the limited amount of inpatient care these patients received. Further follow-up will be informative since the major complications of NMT including chronic GvHD and relapse may impact per transplant cost after the first year post-transplant. Direct comparison with myeloablative HSCT using our prospective costing method is also planned.

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

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 &lt; 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 &lt; 0.00001) and VOD (p &lt; 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.

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.

Impact of the Inhibitory KIR-HLA Receptor-Ligand Model on Unrelated Hematopoietic Stem Cell Transplantation in Patients with Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5063-5063
Author(s):  
Jun He ◽  
Zi-xing Chen ◽  
Xiao-jing Bao ◽  
De-pei Wu ◽  
Xiao-ni Yuan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Receptor Ligand ◽  
Hematopoietic Stem ◽  
Ligand Model

Abstract The interaction between killer cell immunoglobin-like receptor (KIR) and HLA molecule has particular relevance to the unrelated hematopoietic stem cell transplantation (HSCT). The presence of KIR on donor’s NK cells and the absence of the corresponding KIR ligand in the recipient’s HLA repertoire as a receptor-ligand model can be used to predict the outcome of HSCT. To investigate the effect of KIR-HLA receptor-ligand mismatching and the expression of inhibitory KIR (iKIR) on the unrelated Allo-HSCT of leukemia, the following study has been carried out. The KIR genotypes of 36 patients of ALL (n=18), AML (n=10), and CML (n=8) as well as their unrelated donors were obtained from the Database of China Marrow Donor Program. KIR genotyping was performed with PCR-SSP. The KIR and HLA mismatching status (receptor-ligand mismatch model) between recipients and donors was analyzed thereafter. The expression of iKIR was determined by flow cytometry on recipients after HSCT. All cases were followed up closely until July, 2007. Among all the donor/recipient pairs analyzed, 15 pairs displayed the matched pattern with respect to the KIR genotyping though, graft-versus-host (GVH) KIR ligand-mismatched in 13 pairs, and host-versus-graft (HVG) KIR ligand-mismatched in 8 pairs. 26 recipients were lack of HLA-Cw2,4,5,6,15 ligands although iKIR/2DL1 was expressed on their corresponding donors. Similarly, 35 donors with iKIR/2DL2/L3 on their NK cells could recognized HLA- Cw1,3,7,8,12,14 ligands in their recipients. iKIR/3DL1 was expressed on 9 donors although the correlated HLA-Bw4 ligand was absent on the recipients. iKIR/3DL2 was expressed on 24 donors although the correlated HLA-A11 ligand was absent on the recipients. Except for one case, 35 patients were successfully transplanted, in which seven patients were dead, giving the survival rate of 80.0%. The cause of death was either acute/chronic GVHD or relapse. The frequency of acute GVHD (60.0%, 9/15), leading to death (26.7%, 4/15), was the highest in KIR receptor-ligand matched model. The incidence of acute GVHD and death was 30.8% (4/13) and 23.1% (3/13) in the GVH KIR ligand-mismatching, respectively; while the incidence of chronic GVHD was 37.5% (3/8) and no death happened in HVG KIR ligand-mismatching pattern. The expression of iKIR/2DL1 could be detected on ALL (13.0%∼16.6%) and CML (1.8∼6.2%) patients four month after HSCT. The expression of both iKIR/2DL1 (4%) and iKIR/2DL2 (12%) was found only in one patient with CML three month after HSCT, increased to 33.4% and 32.6% accompanied by cGVHD, and dropped to 7.6% and 10.3% one year after HSCT. These results suggested that the deficiency in iKIR/2DL1 based on the KIR-HLA receptor-ligand mismatching model together with the expression of a number of activating KIR in recipients increases the occurrence of GVHD, relapse, and death in unrelated HSCT. Analysis on KIR-HLA gene expression profiling could be useful in predicting the clinical outcome of unrelated Allo-HSCT in leukemia patients. The overall and disease-free survival after HSCT could be improved by preventing the development of GVHD.

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

Blood ◽  
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.

scholarly journals Efficacy of Hematopoietic Stem Cell Transplantation from Alternative Donors in Pediatric Severe Aplastic Anemia: A Single-Center Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1240-1240
Author(s):  
Jin Kyung Suh ◽  
Seong Wook Lee ◽  
Kyung-Nam Koh ◽  
Ho Joon Im ◽  
Eun Seok Choi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
The Other ◽  
Hematopoietic Stem ◽  
Alternative Donor ◽  
Cmv Reactivation

Abstract Background: Hematopoietic Stem Cell Transplantation (HSCT) from a matched sibling donor (MSD) is the treatment of choice for pediatric patients with severe aplastic anemia (SAA). On the other hand, HSCT from alternative donor (AD-HSCT) is indicated as salvage therapy for patients who failed immunosuppressive therapy (IST) without MSD. However, the outcomes of alternative donor HSCT have been improved with recent advances in HSCT techniques. Therefore the indication of alternative donor HSCT in SAA needs to be reevaluated. Methods: We retrospectively reviewed the medical records of 45 pediatric patients with SAA who received HSCT at Asan Medical Center Children’s Hospital from February 2001 to January 2014. To analyze the efficacy of HSCT from alternative donors, we compared overall survival, incidence of acute and chronic GVHD, incidence of graft failure (GF), and incidence of post HSCT infections including CMV reactivation, PTLD, bacteria and fungi according to the type of donors. Results: Of the 45 patients, 32 were male and 13 were female. Median age at diagnosis was 8.0 years (range, 0.2-17.0). Median age at HSCT was 12.9 years (range, 0.7-21.7). Median CD34+ cell dose was 7.64 X 106 /kg (range, 2-33.8). Ten patients received HSCT from MSD (MSD-HSCT), 15 patients from URD (URD-HSCT) and 20 patients from haploidentical family donor (HFD-HSCT). Twenty-six patients (55.3%) had received IST prior to HSCT. Of 45 patients, eight patients experienced GF (one from MSD, one from URD, and six from HFD). Cumulative incidence (CI) of GF was higher in HFD-HSCT compared to the other type of HSCT (30% vs 8%, P=0.049). Among the 8 patients, 6 patients achieved engraftment after additional HSCT, one died of infection after GF and the remaining one patient was waiting for the second HSCT. The CIs of acute GVHD were 20% for MSD-HSCT, 60% for URD-HSCT and 40% for HFD-HSCT, respectively (P>0.05). The CIs of chronic GVHD were 10% for MSD-HSCT, 46% for URD-HSCT and 16% for HFD-HSCT, respectively (P>0.05). Twenty-two patients developed CMV reactivation, 7 had PTLD and 13 had bacterial infection after HSCT. CI of CMV reactivation was higher in AD-HSCT than that of in MSD (63% vs 0%, P=0.002). Three patients (one with MSD-HSCT, one with URD-HSCT and one with HFD-HSCT) died at 81 days, 405 days, and 456 days after transplantation. Of the three patients, one died of acute GVHD, one died of autoimmune hemolytic anemia and the remaining one died of infection after GF. At a median follow-up of 40.8 months (range, 6.5-162.8), 3 year-OS of all 45 patients was 92.9% (100% for MSD-HSCT, 92.3% URD-HSCT and 89.4% for HFD-HSCT, P>0.05). All survived 42 patients were transfusion-independent. Conclusions: In our study, we suggest that early alternative HSCT including HFD-HSCT could be beneficial to the children with SAA who do not have MSD. However, a larger multicenter study is needed to verify our results. Disclosures No relevant conflicts of interest to declare.

scholarly journals Haploidentical Stem Cell Transplantation after Myeloabaltive Conditioning Is a Valid and Safe Option for Young Patients with Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma: A Study Compared with HLA-Matched Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5849-5849
Author(s):  
Haiwen Huang ◽  
Xiaofang Xiao ◽  
Jia Chen ◽  
Zhengming Jin ◽  
Xiaowen Tang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Young Patients ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival

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

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