A Experimental Study and Clinical Result of Prophylaxis aGVHD with Humanized Anti-CD25 Monoclonal Antibody in Haploidentical BMT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1251-1251
Author(s):  
Shu-Quan Ji ◽  
Hui-Ren Chen ◽  
Heng-Xiang Wang ◽  
Hong-Min Yan ◽  
Mei Xue ◽  
...  
Keyword(s):  
Median Time ◽  
Conditioning Regimen ◽  
Control Group ◽  
High Dose ◽  
Marrow Graft ◽  
Hla Antigen ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract Between February 1999 and March 2004, eighty-seven patients with high risk leukemia, age 3–50 (median 19 year), who needed urgent transplant but no HLA-matched or single HLA-antigen mismatched donors available, received unmanipulated HLA haploidentical BMT. The 87 patients were classified as follows AML 27 (CR1 in 7, CR2 in 15 and 5 in relapse), All 38 (CR1 in 4, CR2 in 30 and 4 in relapse) , CML 22 ( 4 in CP, 12 in AP and 6 in BP). All donors were HLA-haploidentical relatives who had at least two major histocompatibility complex antigen mismatched with the recipients. 87 patients underwent haplo-BMT with G-CSF primed BM as stem cells. All patients received a same conditioning regimen including high dose Ara-C, Cyclophosphamide, antithymocyte globulin and total body irradiation to provide both immunosuppression and myeloablation. GVHD prophylaxis consisted of anti-thymocyte globulin, cyclosporin A, methotrexate and mycofenolate mofitel. 72 patients underwent the transplants with the addition of CD25 mAb (Basiliximab Novartis) for GVHD prophylaxis designated as CD25 mAb group. Basiliximab 20mg each by 30min intravenous infusion on 2 hours before transplantion and day 4 after transplantaion. The other 15 patients without Basiliximab for GVHD prophylaxis were as the control group. The two group of patients were comparable in disease status, HLA-disparity and median age of patients. Immunophenotyping, limited dilution assay and colony forming assays were used to measure the effect of Basiliximab on the subsets of lymphocytes, cytotoxic T lymphocyte precursors (CTLp) and hematopoietic cells. All donors were primed with G-CSF at 3-5ug/kg/d for 7 days and the marrow cells were harvested on the eighth day. G-CSF donor priming significantly increased CD34+ and colony forming progenitors in the marrow grafts. More importantly, it significantly reduced lymphocytes and reversed CD4+/CD8+ lymphocyte ratio in the grafts. Both of group who were treated with and without Basiliximab had similar marrow graft contents. All patients established trilineage engraftments.The median time to achieve an absolute neutrophil count 0.5x109/L was 19 days (range, 13 to 24 days). The median time to achieve platelets above 20x109/L was 22 days (range, 16 to 32 days). Between the two groups were no differences in engraftment. Incidence of grades II–IV acute GVHD were 13.9% with GVHD-related deaths 6.9% in Basiliximab group and 33.3% with 20% GVHD-related deaths in control group. There were a significant difference between the anti-CD25 mAb treated Vs non-treated group.Forty-nine patients who survived over 12 months were eligible for the evaluation of cGVHD. 12 patients developed extensive cGVHD, one in control group and eleven in Basiliximab group. 49 were alive in CR during a median follow-up of 30 months (range3–64 months), 42 in Basiliximab group and 7 in control group. Basiliximab significantly decreased alloreactive CTLp by 10–100 fold in limiting dilution assays. It had no effect on hematopoietic stem and progenitor cells as determined by in vitro colony-forming assays.The addition of basiliximab as aGVHD prophylaxis effectively reduced severe lethal aGVHD in haplo-BMT. It is possible to selectively eliminate or reduce the number of alloreactive T cells with anti CD25 antibody, which results in prevention of or a reduction in the severity of GVHD.

Allogeneic Stem Cell Transplantation (SCT) with Non Myeloablative Conditioning Regimen (NST) Following Intensive Consolidation May Be Equivalent to Conventional alloSCT and Superior to autoSCT for Patients over 50 with Acute Myeloid Leukemia (AML) in 1stCR: First Results of the AML 2001 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 319-319 ◽  
Author(s):  
B. Lioure ◽  
J. Delaunay ◽  
D. Blaise ◽  
N. Milpied ◽  
P. Guardiola ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Phase Iii ◽  
Late Relapse ◽  
Marrow Graft ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Significant Difference ◽  
First Results ◽  
Alternative Sources

Abstract From 11/01 until 04/05, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were included in prospective phase III AML 2001 trial. After achieving CR, research to identify an HLA-identical sibling was performed for all patients as they received low dose consolidation (Daunorubicin (D): 60 mg/m2 × 2d OR Idarubicin (I): 12 mg/m2 × 2d plus SC ARAC 100 mg/m2 ×7d). 33 % patients had a donor then could proceed to a T-replete alloSCT: either conventional if age ≤ 50 (bone marrow graft; conditioning regimen: TBI (12 Gy 6 fractions over 3d) - cyclophosphamide (60 mg/kg × 2d); GvHD prophylaxis: ciclosporin-methotrexate d1+3+6) = arm M; or NST if age 51–60 (peripheral blood; Busulfan (oral Bu 4–8 mg/kg over 2d) - Fludarabin (30 mg/m2 × 4d) – Thymoglobulin® (2,5 mg/kg × 2d); ciclosporin alone), AFTER intensive consolidation (D: 60 mg/m2 × 2d OR I: 12 mg/m2 × 2d plus ARAC 3 g/m2 × 8 doses over 4d) = arm m. A small group of patients with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction = 3% CR1 patients) didn’t receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered at relapse = arm C. Patients without donor proceed to intensive consolidation then 1 or 2 autoSCT (1st after HDM 200 mg/m2 according to randomization, then Bu 16 mg/kg over 4d + HDM 140 mg/m2 for all patients) = arms A + B; they were combined for analysis as no difference was observed for DFS and OS. Actual results concern 532 patients with 15 months follow-up (A + B = 367; M = 111; m = 54). Median age was different between 3 groups (A + B = 46; M = 40; m = 54) as no difference was observed regarding leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: A + B = 15%; M = 11%; m = 11%), intermediate (A + B = 72%; M = 78%; m = 67%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; A + B = 13%; M = 11%; m = 22%). Conventional alloSCT results in better 2y DFS than autoSCT arms (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06) as toxic death rate is higher (36% all deaths in arm M vs 14 % in arms A + B). No significant difference was observed between conventional alloSCT and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50: 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). After NST, toxicity accounts for 25% deaths, as relapse rate is 40% at 2y with no late relapse thereafter (vs 48 % at 2y and 61 % at 4y in arms A + B). In conclusion: 1) conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1 despite higher toxicity; 2) NST after intensive consolidation seems promising: for older patients as toxicity is lower than conventional alloSCT, as few late relapse are observed in comparison with chemotherapy or autoSCT approaches; 3) NST may extend use of alternative sources of allogeneic hematopoietic stem cells to propose alloSCT approach for the majority of patients ≤ 60 with AML in CR1. Data with more than 2 years follow-up will be presented.

Age-Adjusted Recipient Pre-Transplant Telomere Length and Treatment Related Mortality After Hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 490-490
Author(s):  
Régis Peffault de Latour ◽  
Rodrigo T. Calado ◽  
Marc Busson ◽  
Jeffrey Abrams ◽  
Marie Robin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Telomere Length ◽  
Hematopoietic Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Control Group ◽  
Transplant Recipients ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Related Mortality

Abstract Abstract 490 Telomeres are highly conserved protective terminal chromosomal structures consisting of hundreds of repeated TTAGGG hexamers and associated shelterin proteins. Telomeres shorten with every cell cycle, and telomere attrition has a fundamental role in cell senescence. Telomeres of leukocytes are shorter in transplant recipients than in their donors. Dyskeratosis congenita, a congenital aplastic anemia caused by mutations in the telomerase complex genes, is associated with treatment related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). We hypothesized that age-adjusted pre-transplant telomere length might generally predict TRM after HSCT. Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donor after myeloablative conditioning regimen (including TBI in 57 patients), mainly for hematological malignancies (n= 153) in our center. The stem cell source was bone marrow (BM) in 128 cases and peripheral blood (PB) in 50 cases. Median age at transplant was 32 years (range 3–65). Graft-versus-host disease (GvHD) prophylaxis mostly consisted of cyclosporine and methotrexate (n=149, 84%). Before HSCT, blood lymphocytes were obtained from each of the donor-recipient pair. Telomere length was assessed by real time quantitative PCR. We first determined the normal age distribution of telomere length using a group of 173 healthy French hematopoietic stem cell donors (f=-0.00833*age+1.522) as a control group. We then calculated the pre-transplant recipient age-adjusted telomere length in comparison to controls. After age adjustment, we categorized the population in quartiles (shortest telomeres for quartile 1) and analyzed the outcome post HSCT using competing risk in univariate and multivariate analyses (Fine and Gray). The mean telomere length in transplant recipients (1.05) was shorter than in the control group (1.23, p= 0.0001). After age-adjustment, patients' distribution was similar among all four quartiles except for disease severity (more high risk disease was present among patients with the shortest telomeres). The median follow-up was 51 months (range, 1 – 121 months). All patients engrafted. The median time to achieve absolute neutrophils count >500/ul was 18 days (range 4–45) and median time to platelet count >20.000/ul was 17 days (range 7–58). Cumulative incidence (CI) of acute GvHD grade II-IV was 45% (95% confidence interval [95CI] 37%–53%) and of chronic GvHD was 41% at 36 months (95CI 33%–49%). Thirty-four patients relapsed: CI: 22% at 5 years (95CI 16%–28%). There was no correlation between telomere length and engraftment, acute or chronic GvHD or relapse. The overall survival was 62% at 5 years (95CI 54%–70%). During the study, 37 patients died due to TRM. TRM rate inversely correlated with telomere length. In the first quartile, the 5-year CI of TRM was 33% (95CI 2%–22%), 20% (95CI, 8%–32%) in the second quartile; 20% (95CI, 8%–32%) in the third quartile; and 12% in the fourth quartile (95CI, 2%–22%) (p=0.06). When quartiles 2, 3 and 4 were pooled, the increased TRM in first quartile was statistically significant (p = 0.017) (Figure 1). In multivariate analysis using competing risk regression, (including age-adjusted telomeres length, disease stage, age, TBI and source of stem cells), age of the recipients (HR: 1.1, 95% CI [.0–1.1, p=0.0001] and age-adjusted telomeres [HR: 0.4, 95% CI [0.2–0.8, p=0.01]) were independently associated with TRM. The same two factors remained significant in subset analysis of patients with malignant diseases (n=154) (p= 0.0004, HR: 1.1 and p=0.018, HR: 0.43, respectively). No association was found between donor telomere length and outcome post HSCT. In conclusion, age-adjusted recipient pre-transplant telomere length is an independent biological marker of TRM after HSCT from related donors using a myeloablative conditioning regimen and cyclosporine-based GvHD prophylaxis. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

Mycophenolate Mofetil (MMF) with or without Tracolimus (FK506) as a Second Line Treatment for Steroid-Resistant Acute Graft-Versus-Host Disease. The Experience of Saint Louis Hospital.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2892-2892
Author(s):  
Gustavo Fisher ◽  
Vanderson Rocha ◽  
Moema dos Santos ◽  
Agnes Devergie ◽  
Marie Robin ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Acute Gvhd ◽  
Phase Ii Trial ◽  
Conditioning Regimen ◽  
High Dose ◽  
Line Treatment ◽  
Second Line ◽  
Steroid Resistant ◽  
Gvhd Prophylaxis

Abstract Acute GVHD remains a major problem following allogeneic HSCT. Use of steroids is the first line to treat aGVHD, with an overall improvement of 55%, but durable responses of 35%. Recently, results of a randomized trial testing ATG in patients non-responding to steroids have been disappointing. Drugs such as MMF or FK506 have been used as GVHD prophylaxis, but few data is available as a second line treatment of steroid-resistant aGVHD. We conducted a prospective phase II trial in our unit to test the role of MMF associated or not to FK506 in steroid-resistant aGVHD in 53 patients. Four criteria of steroid-resistant aGVHD were defined: A) no improvement of signs of skin GVHD after 1 week of treatment with prednisolone 2mg/kg; B) signs of skin progression or no response of visceral (gut or liver) GVHD 3 days after treatment; C) visceral signs of progression 2 days after treatment; D) progression to organ stage 4 (Gluksberg classification) 1 day after treatment. Response of signs of aGVHD to MMF (30 mg/kg day) or FK506 (0.05mg/kg/day) was defined as complete remission (CR) (all organs); partial remission (PR) or failure (progression even in one organ). HSCT were performed from 1999 to 2004 for patients with hematological malignancies (73%) or aplastic syndromes (27%). The median age was 29 y (5–58) (34% of children) and the median follow-up time was 24 mo (1–54). The donor was HLA identical in 23 (43%) and unrelated in 30 (57%) (including 18 cases of HLA mismatched). Myeloablative conditioning regimen was used in 77%. As GVHD prophylaxis CsA+MTX was used in 26 patients (68%), CsA alone in 14 (26%) and in 3 patients CsA+ steroids. Bone Marrow cells were used in 62% of the cases, PB in 25% and CB in 13%. Treatment of aGVHD consisted in prednisolone 2mg/kg IV in all patients associated to CsA. Once criteria of resistance were established, CsA was stopped and replaced by MMF and/or FK506. FK was not added if renal insufficiency was observed. Criteria of steroid-resistant aGVHD were A in 7 patients; B in 26; C in 19, and D in 1 patient. Steroid resistant acute GVHD grade I was observed in 9 patients (17%); II in 26 (49%); III in 19 (36%) and IV in 3 (6%). MMF was used in 15 patients (28%) and associated to FK506 in 38 (72%). Median time to start second line treatment was 16 days (7 to 100). Complete response in skin was observed in 74% of the patients, 66% in gut and 75% in liver. However, overall CR was observed in 21 patients (40%), partial response in 5 (9%) and failure in 27 (51%). Median time to obtain CR or PR was 8 days (2–20) after starting second line treatment. Cumulative incidence of CR at one year was 39%. Recipient’s age, CMV serology, source of stem cells, conditioning regimen, HLA incompatibility were not associated with CR; there was not statistical difference of CR if MMF was used alone or associated to FK. For those patients with aGVHD in progression, third line treatment consisted most frequently in the use of high dose steroids or ATG/ALG. Overall survival at 1y was 35±7%; it was 74±10% for patients achieving CR (n=21), 5±4% for non-responders (n=27) and 4 out of 5 patients with PR died. Cause of death was commonly associated to infections. In conclusion, in this phase II trial, use of MMF and/or FK506 is an option to treat steroid resistant GVHD but did not result in 1-y survival rate that would justify to set-up a larger randomized study.

Rapid Immune Reconstitution Following Unmanipulated Haploidentical BMT with Post-Transplant High Dose Cyclophosphamide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3050-3050 ◽  
Author(s):  
Alida Dominietto ◽  
Anna Maria Raiola ◽  
Barbara Bruno ◽  
Maria Teresa van Lint ◽  
Francesco Frassoni ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd4 Counts ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Donor Type ◽  
Unrelated Cord Blood

Abstract Abstract 3050 Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for the majority of hematological malignancies. Early and successful immunologic reconstitution after HSCT reduces morbidity and mortality due to infection complications and improves survival. Aim of the study. We analyzed immune recovery after HSCT in 444 patients according to donor source. Patients and Methods. From January 2005 to June 2011 176 patients were grafted from HLA identical siblings (MSD), 125 from alternative donors (1 antigen mismatched family or unrelated donors) (ALT), 103 from unrelated cord blood grafted intra bone (CBIB) and 40 from haplo-identical mismatched family donors (HAPLO). All patients received unmanipulated bone marrow: 283 after a myeloablative (MA) conditioning regimen (CY-TBI or BU-CY) and 161 after a fludarabine based reduced intensity regimen (RIC). Graft versus host disease (GvHD) prophylaxis was cyclosporin methotrexate (CyA+MTX) for all patients except for CBIB (CyA and mycophenolate, MMF) and for HAPLO transplants which consisted of CyA+MMF and post-transplant high dose cyclophosphamide (HDCY) according to the Baltimore protocol (Lutznik et al BBMT 2008). Anti-thymocyte globulin (ATG) was used only for ALT transplants. Results. We compared immune reconstitution in MA and RIC transplants according to donor type at different time points post BMT. CD3+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 477, 565, 700; in ALT donors were 146, 404, 470; in CBIB were 30, 57, 196; for HAPLO transplants they were 195, 182, 499. CD3+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 301, 660, 700; in ALT donors were 506, 186, 721; in CBIB 234, 399, 522; in HAPLO were 178, 276, 1300. CD4+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 166, 170, 198; in ALT donors were 36, 86, 111; in CBIB 7, 36, 106; for HAPLO transplants they were 45, 127, 211. CD4+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 89, 189, 274; in ALT donors were 131, 210, 220; in CBIB 52, 110, 130; for HAPLO transplants they were 41, 205, 385. CD8+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 280, 389, 500; in ALT donors were 102, 278, 413; in CBIB 42, 16, 51; in HAPLO transplants were 73, 424, 408. CD8+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 196, 432, 300; in ALT donors were 366, 65, 494; in CBIB 71, 167, 199; for HAPLO transplants they were 137, 129, 900. CD3, CD8, and CD4 counts in HAPLO transplants were not statistically different from MSD with the only exception of day +30, both for MA and RIC conditioning. Platelet median counts/μl on day+30, +90, +180 in MA conditioning were in MSD 142, 129, 180, in ALT 75, 101, 147, in CBIB were 19, 77, 128 and for HAPLO transplants were 67, 126, 128; in RIC conditioning platelets counts were in MSD 137, 156, 168, in ALT 33, 134, 142, in HAPLO were 77, 95, 188. Acute GvHD II-IV developed in 29% (MSD) 38% (ALT) 16% (CBIB) and 12% (HAPLO) (p=0.004) in MA conditioning and 40% (MSD) 18% (ALT) 25% (CBIB) and 10% (HAPLO) (p=0.07). Overall Cumulative Incidence of Non-Relapse Mortality (CI-NRM) was respectively 18% (MSD), 35% (ALT), 34% (CBIB), 22% (HAPLO) (p=0.02) in MA conditioning (p=0.02) and was 30% (MSD), 33% (ALT), 45% (CBIB), 0% (HAPLO) (p=0.02) in RIC conditioning (p=0.02). Day+100 CI-NRM was respectively 10% (MSD), 21% (ALT), 19% (CBIB), 12% (HAPLO) in MA conditioning (p=0.01) and 11% (MSD), 19% (ALT), 26% (CBIB), 0% (HAPLO) in RIC conditioning (p=0.02). Death due to infections were respectively 6% (MSD), 26% (ALT), 30% (IBCB), 17% (HAPLO) in MA conditioning and for RIC were 15 (MSD), 36% (ALT), 32% (IBCB), 0% (HAPLO). Conclusions. HAPLO transplant with HDCY post transplant as proposed by the Baltimore group, is associated with (1) rapid immunologic (CD3, CD4, CD8) recovery (2) low infectious death rate, (3) low overall and Day+100 CI-NRM, (4) rapid hematologic recovery. These results are comparable with those achieved with MSD and warrant further studies with HDCY post transplant as a GvHD prophylaxis. Figure: absolute CD4+ counts/μl on day+30, +90, +180, according to donor type in MA conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

Human Leukocyte Antigen (HLA) DR15 Is Associated with Reduced Incidence of Acute GvHD in HLA-Matched Allogeneic HSCT but Does Not Impact Survival.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3319-3319
Author(s):  
Minoo Battiwalla ◽  
Theresa Hahn ◽  
Hilary N. Roy ◽  
Afrin Wahab ◽  
Eileen A. Duman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Bone Marrow Failure ◽  
Conditioning Regimen ◽  
Hla Antigens ◽  
Human Leukocyte ◽  
Hla Antigen ◽  
Positive Group ◽  
Allogeneic Hsct ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract HLA DR 15 is found more frequently in patients with bone marrow failure syndromes and is associated with response to immunosuppression. This suggests that HLA DR15 may preferentially present immunodominant myeloid antigens or that HLA DR15 positive cells may be more sensitive to immunosuppression. We investigated the role of HLA DR15 on graft-versus-leukemia effect and graft-versus-host disease (GVHD) in HLA-matched HSCTs performed for myeloid malignancies. We performed a retrospective review of 109 consecutive related and 42 consecutive unrelated allogeneic HSCT patients treated between 1991 and 2003 at Roswell Park Cancer Institute to investigate the influence of HLA DR15 on overall survival (OS), progression-free survival (PFS) and the incidence of grade 2–4 acute GVHD. HLA DR15 was determined by either molecular (n=92) or serologic (n=59) methods. The proportion of patients with one or two HLA DR15 alleles was 21% (32/151) which is similar to the general Caucasian population. Patient characteristics included: AML (n=74), CML (n=59), and MDS (n=18); median age 42 years (range 11–62); Males (n=93), Females (n=58); Caucasian (>95%); TBI-containing conditioning regimens (n=130); Busulfan + Cyclophosphamide (n=19), Busulfan + TBI (n=27), Cyclophosphamide + TBI (n=11), Etoposide + Cyclophosphamide + TBI (n=84), or other combinations (n=10). There was no difference in OS between the HLA DR15 positive versus negative groups in any disease or donor relation subgroups. There was no significant difference in PFS between the HLA DR15 positive and negative groups, however a trend toward late relapses after three years was observed in the HLA DR15 positive group. The HLA DR15 positive group experienced a significantly lower incidence of acute GVHD grade 2–4: 22% versus 41%, p=0.045. There was no difference between the HLA DR15 positive versus negative groups with respect to conditioning regimen, use of TBI or GVHD prophylaxis regimen. We are currently expanding this study to include a larger cohort from other centers. These results suggest that HLA DR15 may function as a surrogate for an altered response to the immunosuppression induced by GvHD prophylaxis. If these results are confirmed, this would be the first association between a specific HLA antigen and GvHD development, thus suggesting the need for studying GvHD prophylaxis modification based on specific HLA antigens.

Successful Peripheral Haematopoitic Autologous Stem Cells Transplants After More Than 5 Days of without Cryopreservation In Non Hodgkin Lymphoma: Asian Scenario

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4447-4447
Author(s):  
Sandeep Jasuja ◽  
Hemant Malhota ◽  
Neetu Kukar(Jasuja) ◽  
Dinesh Gautam ◽  
Shrikant Sharma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Developing Countries ◽  
Stem Cell ◽  
Median Time ◽  
Eligible Patient ◽  
Conditioning Regimen ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Abstract 4447 Background: Methods to simplify the stem cell transplantation procedure are the need of the hour in developing countries due to constraints of affordability and the large number of eligible patient for transplantation. Unprocessed leukapheresed material is useful to restore hemopoiesis after high dose chemotherapy and, in addition to being significantly less expensive, it also avoids the toxicity of cryopreservation (DMSO). Method: Over a period of 18 months (January 2009 to June 2010) in a hospital setting, we prospectively performed auto transplants in 5 relapsed/resistant non-Hodgkin's lymphoma patients using non-cryopreserved (stored for 5–8 days at 4°C) and un-manipulated peripheral blood stem cells mobilized by GCSF (10mg/kg/day) and GMCSF (5mg/kg/day) using a 5–7 day conditioning regimen. Viability of stem cells was checked daily by trypen blue and the cell were reinfused cells when viability comes down to less then 80% (minimum 5 days) or on day 8 which ever was earlier. The median collection of CD34+ stem cells was 2.8 × 106/cu mm (range 2–4.8 × 10 6/cumm) Result: The median time to achieve > 0.5 × 109/l granulocytes was 14 days. The median time to achieve > 20 × 109/l platelets was 16 days. CR was achieved in 4 cases. A very good partial response was achieved in 1 case. The 100-day mortality was zero. One patient, who was not in CR, died from relapse of the lymphoma, 9 months post transplant. The overall median post-transplant survival for other patients has not been reached. The approximate cost of the each graft was US$6,000. Conclusion: From this small series, we conclude that a simplified method to autograft patients avoiding purging procedures and cryopreservation of the cells is feasible. This technique helps avoid toxicity of DMSO and significantly decreases the cost of autologous hematopoietic stem cell transplant, perhaps in the world, an important issue in developing countries. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improved Control of GvHD with Rabbit ATG, Rituximab and Bortezomib Among Pediatric Leukemia Patients after Tcrαβ/CD19-Depletion of Transplant from Matched Unrelated and Haploidentical Family Donors: A Single-Center Retrospective Analysis of Two Gvhd-Prophylaxis Regimens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3427-3427
Author(s):  
Zhanna Shekhovtsova ◽  
Larisa Shelikhova ◽  
Dmitry Balashov ◽  
Elena Kurnikova ◽  
Iakov Muzalevskyi ◽  
...  
Keyword(s):  
Median Time ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Single Center ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Donor Type

Abstract Introduction: Graft-versus-host disease (GvHD) remains to be a factor associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Bortezomib was shown in vitro to induce selective depletion of alloreactive T-lymphocytes, decrease the production of Th1 cytokines (Blanco et al. 2006), and to suppress the maturation and cytokine production by dendritic cells (Naujokat et al. 2007). Bortezomib was successfully used to prevent and treat GVHD in different settings (Al-Homsi et al. 2015; Koreth et al. 2015). As GvHD-prophylaxis agent Bortezomib was implemented since 2014 in aim to improve the results in a cohort of pediatric patients with acute leukemia who underwent HSCT from HLA-matched unrelated and haploidentical family donors after TCRαβ/CD19-depletion. Here we present the results of a retrospective comparison of two GvHD-prophylaxis regimens. Patients and methods: Between May 2012 and July 2016 eighty-one transplantation from 40 HLA-matched unrelated and 41 haploidentical donors were performed for children (56 boys and 25 girls with median age 9 years, range 0,6-23 years) with acute lymphoblastic (n=31) and acute myeloblastic (n=50) leukemia in complete remission. TCRαβ/CD19-depletion of HSC with CliniMACS technology was implemented in all cases. For all patients it was first allogeneic HSCT. The majority (93%) of the patients received Treosulfan-based condition regimen. Remaining 7% of patients received TBI-based conditioning regimen. Patients were divided retrospectively in two groups according to GvHD prophylaxis regimens. "Regimen 1" (n=35), which was used in 2012-2013 yrs.: horse ATG 50 mg/kg and post-transplant tacrolimus with short course of methotrexate. "Regimen 2" (n=46) started in 2014: rabbit ATG 5 mg/kg, rituximab 200mg/m2 and peri-transplant bortezomib 1,3 mg/m2 on days -5, -2, +2 and +5. The median dose of CD34+ cells in the transplant was 9 x106/kg (range 7-17), TCRαβ - 21x103/kg (range 1-305). Results: Groups differed significantly in regards to diagnosis: 57% of patients in "Regimen 1" had ALL, while most of the patients (78%) in "Regimen 2" were with AML (P= 0,002). Cumulative incidence of neutrophil and platelet engraftment at 30 days was 98% and did not differ between the groups. Median time to neutrophil and platelet engraftment was 14 days, (range, 9-33 and 9-25 days, respectively). Neutrophil engraftment was significantly faster among patients with "Regimen 2", 13 days vs. 16 days for patients with "Regimen 1" and CI of engraftment at day 30 after HSCT 98% (95% CI: 98%) vs. 94% (95% CI: 87-100, P<0,01). Overall cumulative incidence of acute GvHD II-IV grade was 23% (95% CI: 16-35); grade III-IV - 5% (95% CI: 2-13) and chronic GvHD - 18% (95% CI: 11-20). Cumulative incidence of acute GvHD II-IV was significantly lower within the group with "Regimen 2": 15% (95% CI: 7-30) vs. 34% (95% CI: 22-54), P=0,05. Amid patients with "Regimen2" there was one case of grade IV acute GvHD, most of the patients with grade II to IV developed visceral damage involving lower gut. "Regimen 2" was also more effective in prevention of chronic GvHD: CI at 1 year after HSCT was 7% vs. 31%, P=0,005. Only one patient with "Regimen 2" had extensive form of chronic GvHD. Median time of follow-up for survivors was 2 years (range, 0,3 - 4). Cumulative incidence of relapse at 2 years also differed between "Regimen 1" and "Regimen 2" groups, 31% (95% CI: 19-51) vs. 21% (95% CI: 11-39), respectively, though without statistical significance. TRM was 10% (95% CI: 5-20), without significant statistical difference between leukemia type, donor type or GvHD-prophylaxis regimens. EFS (event=death or relapse) at 2 years was 64% (95%CI: 53-75), OS - 69% (95%CI: 58-80). Statistically there was no significant difference in event-free or overall survival probabilities between leukemia type, donor type or GvHD-prophylaxis regimens Conclusion: In our retrospective single-center study we revealed that rATG, rituximab and bortezomib improve the control of acute and chronic GVHD in recipients of TCRαβ- depleted grafts in comparison to hATG, tacrolimus and methotrexate. Disclosures No relevant conflicts of interest to declare.

scholarly journals High Dose Convalescent Plasma in COVID-19: Results from the randomized Trial CAPSID

2021 ◽  
Author(s):  
Sixten Koerper ◽  
Manfred Weiss ◽  
Daniel Zickler ◽  
Thomas Wiesmann ◽  
Kai Zacharowski ◽  
...  
Keyword(s):  
Clinical Improvement ◽  
Median Time ◽  
Neutralizing Antibodies ◽  
Primary Outcome ◽  
Standard Treatment ◽  
Neutralizing Antibody ◽  
Control Group ◽  
High Dose ◽  
Intensive Care Treatment ◽  
Significant Difference

Rationale: COVID-19 convalescent plasma (CCP) has been considered a treatment option in COVID-19. Objectives:: To assess the efficacy of neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment. Methods: Patients (n=105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. Primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. The trial is registered: clinicaltrials.gov #NCT04433910. Measurements and main results: The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The median time to clinical improvement was 26 days (IQR 15-not reached (n.r.)) in the CCP group and 66 days (IQR 13-n.r.) in the control group (p=0.27). Median time to discharge from hospital was 31 days (IQR 16-n.r.) in the CCP and 51 days (IQR 20-n.r.) in the control group (p=0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (versus 32.1%), with a shorter interval to clinical improvement, shorter time to hospital discharge and better survival compared to the control group. Conclusion: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a significant benefit for CCP among those who received a larger amount of neutralizing antibodies. Primary Funding Source: Bundesministerium fuer Gesundheit

Results of a Phase I/II Study of Gemtuzumab Ozogamicin Added to Fludarabine (F), Melphalan (M) and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Relapsed Myeloid Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 841-841 ◽  
Author(s):  
Marcos de Lima ◽  
S. Giralt ◽  
Z. Caldera ◽  
G. McCormick ◽  
M. Qazilbash ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Failure ◽  
Stem Cell ◽  
Blast Crisis ◽  
Conditioning Regimen ◽  
Control Group ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Myeloid Leukemias ◽  
Active Disease

Abstract Most patients (pts) transplanted with active myeloid leukemias will relapse after HSCT. Intensity of the conditioning regimen is an important component of disease control. We hypothesized that GO could safely increase the anti-disease activity of FM, and investigated this hypothesis in the trial reported here. Patients and Methods: Objective: to determine the dose of GO with the lowest toxicity (tox), and the highest response probabilities. Tox: grade 3–4 organ tox, engraftment failure or early death (ED; first 30 days post HSCT). Response was defined as no tox, engraftment, and remission (CR) on day +30. Trial was designed with GO doses of 4, 6 and 9 mg/m2 but given tox observed at 4mg/m2, doses 6 and 9 mg/m2 were not used and dose 2mg/m2 was added. Eligible were pts aged 12–75 years, not candidates for high-dose regimens or with high-risk CD33+ disease. Treatment: GO 2 or 4mg/m2 day -12, F 30mg/m2 (days -5 to -2), M 140mg/m2 (day -2); HSCT day zero. ATG was added in unrelated (UD) HSCT. Graft-versus-host disease (GVHD) prophylaxis: tacrolimus and mini-methotrexate (5mg/m2 day+1,+3,+6,+11). GO was given on day -12 to minimize probability of delaying engraftment. We treated 52 pts, median age 53 yrs (13–72), with AML (n=47), MDS (n=4) or blast crisis CML(n=1). Disease status at HSCT: CR (n=3),induction failure (n=15), first/second relapse (n=33), untreated MDS (n=1). 18 pts had a previous HSCT (allogeneic, n=11 or autologous, n=7). At study entry, median number of bone marrow blasts was 17% (0–95%); 33% of the pts had circulating blasts, 4 pts were FLT3 positive and 38% had poor prognosis cytogenetics. Median blast CD33 expression: 89% (22.5–99.6). Donors: related (n=33) or UD (n=19). Stem cell source was peripheral blood (n=43) or bone marrow (n=9). Results: Median day 30 donor cell chimerism was 100%. Median time to ANC&gt; 500/mm3 was 13 days. Eight pts received GO at 4 mg/m2; 2 died early (due to pneumonia and renal failure) and 2 developed gd III gastro-intestinal and renal tox. 44 pts were then treated at 2 mg/m2: 3 pts died of regimen-related tox (2 ED due to pulmonary bleeding and sepsis, and 1 death within the first 100 days due to pneumonia, renal failure/TTP/HUS). 100-day treatment-related mortality (including 2 deaths due to aGVHD and 1 due to infection) was 15% (n=8). Tox included reversible gd III-IV bilirubin (n=2), transaminase elevation (n=5), moderate hepatic VOD (n=1) and gd I-II GI tract (n=39). CR rate was 90%; 1 pt failed to respond. Gd II-IV and III-IV aGVHD rates were 44% and 23%, respectively, and 58% developed cGVHD. Median follow-up is 9 months (2.5–36) for surviving pts (n=29); 17 pts have relapsed. Median event-free-survival (EFS) is 3.8 mos. Median EFS of a historic control group treated with FM140 (n=36) was 2.2 mos (Figure). Tox of GOFM is similar to that documented by our group with FM140 mg/m2 in a somewhat better prognosis population.(de Lima et al. Blood.2004; 104:865–72) Conclusion: GO 2mg/m2 can be safely added to FM, and may improve the anti-leukemic efficacy of the regimen. EFS - patients with active disease at HSCT EFS - patients with active disease at HSCT

scholarly journals Post-Transplant Cyclophosphamide Versus MTX-CSA As Gvhd Prophylaxis in HLA-Identical Sibling HSCT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3394-3394
Author(s):  
Rebeca Bailén ◽  
Maria-Jesús Pascual ◽  
Pascual Balsalobre ◽  
Anabel Gallardo-Morillo ◽  
Abel García-Sola ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). However, the use of PT-CY in HLA-identical HSCT is less explored. In this study, we analyzed the results of PT-CY as GVHD prophylaxis in HLA-identical sibling HSCT and compared them with those obtained after prophylaxis with methotrexate (MTX) plus cyclosporine (CsA). Methods: 107 HLA-identical sibling (10/10) HSCT from 2 Spanish centers have been analyzed: 50 performed consecutively between 2010 and 2015 using MTX-CsA as GVHD prophylaxis, and 57 performed consecutively between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. GVHD prophylaxis consisted in MTX days +1, +3, +6 and +11, and CsA from day -1 in the MTX-CsA group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +5 in 38 patients (65%), combined with CsA from day +5, and cyclophosphamide on days +3 and +4 in 19 patients (35%), followed by CsA and mycophenolate mofetil from day +5. Graft source was PBSC in 96% in the MTX-CsA group and 86% in the PT-CY group. Conditioning regimen was myeloablative in 64% and 40%, respectively. Neutrophil and platelet engraftment was significantly delayed in the PT-CY group (14.5 (11-27) vs 15.5 (13-37), p=0.02; 11.5 (8-180) vs 20.5 (10-43), p=0.02). After a median follow-up of 60 months for the MTX-CsA group and 15 months for the PT-CY group, 2-year overall survival (OS) was 56% (42-70) and 78% (67-90) (p=0.088), and event-free survival (EFS) was 48% (34-62) and 62.5% (42.5-82.5) (p=0.054), respectively. Cumulative incidence at 100 days of grade II-IV (52.2% vs. 22.6%, p=0.0015), and III-IV (24.4% vs. 8.8%, p=0.016) acute GVHD were significantly higher in the MTX-CsA group (Figure 1A). No differences were observed in the 2-year cumulative incidence of chronic moderate to severe GVHD (26% vs. 16.7% (p=0.306)). No differences were observed in the 2-years cumulative incidence of relapse (27% vs. 28% (p=0.47)). Non-relapse mortality (NRM) at 2-years showed a higher trend in the MTX-CsA cohort (24% vs. 8.8%, p=0.054). Finally, the composite endpoint of GVHD and relapse-free survival (GRFS) at 2-years was significantly better in the PT-CY group (48% vs. 24%, p=0.011) (Figure 1B). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after HLA-identical sibling HSCT, using mostly peripheral blood as graft source, reduced the cumulative incidence of acute GVHD compared to standard prophylaxis with MTX-CsA, leading to an impact on GRFS. To our knowledge, this is the largest comparative retrospective cohort reported. Further prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

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