Donor Lymphocyte Infusion Management and Impact on Transplant Outcome after Reduced Intensity Conditioning Allogeneic Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2305-2305
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Anne-Sophie Michallet ◽  
Anne Thiebaut ◽  
Emannuelle Tavernier ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Prospective Studies ◽  
Acute Gvhd ◽  
Mixed Chimerism ◽  
Reduced Intensity Conditioning ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract Management of donor lymphocyte infusions (DLI) after reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation (RICT) remains not clear and needs prospective studies. We performed a retrospective analysis on 47 patients (29 males and 18 females) who received 94 DLI among 96 patients who underwent RICT in our institution. Twenty-four patients received 1 DLI (D) [mean dose: 0.3x108 CD3 /Kg (0.01–1)] and 70 escalating doses (ED) [2 DLI (n=10), 3 DLI (n=9), 4 DLI (n=1), 5 DLI (n=1), 6 DLI (n=1) and 8 DLI (n=1)] from 0.1 to 5.6x108 CD3/Kg. The diagnosis pretransplant was acute leukemias (n=10) and myelodysplasia (n=3), chronic myeloid leukemia (n=2), Hodgkin (n=7) and non Hodgkin lymphomas (n=6), multiple myeloma (n=14) and solid tumours (n=5). Twenty patients have already been transplanted before RICT and 9 patients were in complete remission (CR), 19 in partial response (PR), 18 in evolutive disease (EDis). As hematopoietic stem cells, 22 patients received peripheral blood and 25 bone marrow and as conditioning 26 patients received busulfan, fludarabine and anti-thymocytes globulines (ATG), 13 patients TBI 2 grays associated to fludarabine (n=8) and 6 grays associated with cyclophosphamide (n=5), 5 patients received cyclophosphamide and ATG and 3 patients aracytine, idarubicine and fludarabine. After transplant and before any DLI, 21 developped acute GVHD (11 grade I, 8 grade II and 2 grade III). The indications and results after DLI are given in the Table 1. Only 4 patients received DLI for two different indications within time: 2 for relapse firstly and partial chimerism secondly and 2 according to protocol requirement firstly and for relapse secondly. After DLI, we noted 18 acute GVHD (7 grade I, 4 grade II, 6 grade III and 1 grade IV), 9 were resolutive after specific therapy and 18 patients developed chronic GVHD (13 limited and 5 extensive). Probability of overall survival at 2 years of patients who underwent RICT including DLI (n=47) was significantly better than for patients undergoing RICT without DLI (n=57) [43% (95%CI 30.5–60.4) vs 31.5 (95%CI 18.8–52.8) (p=0.01)] but there was no difference when we consider EFS [20.7% (95%CI 11.6–36.8) vs 21.6% (11–42.5) (p=0.49)]. We performed for patients receiving DLI a multivariate analysis stratified on diagnosis studying sex, age, status at transplant and mean dose of infused lymphocytes and we demonstrated that lymphocyte dose had a significant negative impact on EFS (HR= 1.06 95% CI 1.01–1.10) (p=0.01). To better understand the real place of DLI within allogeneic immunotherapy against malignancies, we need more details about the results of DLI in retrospective analysis but principally prospective studies in the future. TABLE 1 Indication of DLI Nb of patients Nb of DLI DLI (D) DLI (ED) Dose x 10 exp8 CD3/Kg Response to DLI Evolutive Disease N = 34 23 2.26 10 13 1.46 EDis 5 1.6 2 3 0.66 CR 6 1.5 2 4 0.45 PR Mixed Chimerism N = 7 6 1.5 5 1 0.7 Total Donor 1 1 1 0 0.7 Mixed Chimerism Protocol N = 6 1 1 1 0 0.1 CR 3 1.6 2 1 0.34 PR 2 2 1 2 0.52 EDis

GM-CSF Secreting Leukemia Cell Vaccination after Allogeneic Reduced Intensity Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 825-825 ◽  
Author(s):  
Vincent Ho ◽  
Glenn Dranoff ◽  
Haesook Kim ◽  
Matthew Vanneman ◽  
Mildred Pasek ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Leukemia Cell ◽  
Sustained Remission ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Studies have shown that leukemia specific donor immune responses can be elicited by cancer vaccination after allogeneic SCT. Given the likelihood of disease progression in patients with active leukemia at the time of transplant, potential anti-tumor vaccines must be administered early post-transplant if they are to exert a meaningful effect. Early vaccination after SCT could capitalize upon the rapid homeostatic lymphoid expansion associated with post conditioning lymphopenia. However, there is concern about the efficacy of vaccinations early after allogeneic transplant when patients remain on immune suppression to prevent GVHD. GVAX, a cancer vaccine composed of leukemia cells genetically modified to secrete GM-CSF, has demonstrated activity in MDS and AML. We completed a trial investigating the feasibility and safety of administering GVAX early after allogeneic HLA matched reduced intensity conditioning (RIC) SCT for patients with MDS-RAEB or active AML. Prior to SCT, autologous myeloblasts were harvested and transfected with an adenovirus vector bearing the GM-CSF gene to generate the GVAX vaccine. Conditioning consisted of fludarabine 30mg/m2/d IV × 4, and busulfan 0.8mg/kg IV q12H × 8 doses prior to allogeneic PBSC infusion. GVHD prophylaxis included tacrolimus and mini-methotrexate. Vaccination started between day +30 to +45 post SCT if there was adequate count recovery and no grade II–IV acute GVHD. GVAX was administered SC/ID weekly × 3 doses, then q2 wks × 3 doses. Taper of tacrolimus began after vaccine completion (» d+120). Twenty four patients (13 URD, 11 MRD) were transplanted: 16 AML, 6 MDS/RAEB, 2 CML myeloid blast crisis. Median age was 62 (range, 41–71 years). Median marrow blast content at transplant was 22% (range, 6–91%). GVAX was successfully generated for all patients. Of the 24 patients transplanted, 9 could not start vaccine due to rapid leukemia progression (4); acute GVHD requiring systemic steroids (3); sepsis (1) and IPS (1); Among the 15 patients who started vaccination per protocol, 10 completed all 6 vaccines. Mild injection site reaction with induration, erythema, and pruritus was the only common side effect. After vaccination, 3/15 patients developed grade II acute GVHD and 7/15 had cGVHD. Relapse free (RFS) and overall survival (OS) at 2 years for patients who started GVAX were 46% and 56%, respectively. This is superior to the 2-yr DFS and OS of 12% and 16% (p=0.02), respectively, in a matched cohort of 34 patients with the same disease receiving RIC SCT during the same time period. Among the patients who completed all 6 vaccines, 9/10 remain in complete remission (6 AML, 3 MDS-RAEB) with median follow-up of 22.5 months post SCT (range, 7–38 mos). Three patients with disease relapse/progression early post SCT entered CR after vaccination and taper of tacrolimus. Pathologic examination of vaccination and leukemia cell DTH sites revealed significant infiltration with inflammatory cells and eosinophils in all patients who responded. Concordant with prior studies showing that anti-cancer activity after GM-CSF secreting tumor cell vaccines is associated with NKG2D-target-cell interactions mediated by NK and NK-T cells, our immunologic studies revealed progressively decreasing levels of soluble NKG2D ligands in patients with sustained remission after GVAX. Our results demonstrate that GVAX vaccination early after RIC SCT elicits important biologic activity despite administration during full immune suppression with tacrolimus. Given that all of the patients had active disease at transplant and received a reduced intensity conditioning regimen, we would have expected few to enter complete and sustained remission. Our encouraging results suggest GVAX vaccination is safe and may have anticancer activity in patients with MDS/AML after allogeneic SCT.

Comparison of Two Doses of Antithymocyte Globulin (ATG) in Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4328-4328
Author(s):  
Hassan Issa ◽  
Amy S. Ruppert ◽  
Patrick Elder ◽  
Craig Hofmeister ◽  
Don M Benson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Competing Risks ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Cmv Reactivation ◽  
Grade Iii

Abstract Introduction: The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. In our previous retrospective analysis we compared two dosing schedules of ATG (7.5 mg/kg vs 6 mg/kg) in 136 patients who had undergone RIC allo-HSCT, and found no significant differences in the incidence of acute or chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse, progression-free survival (PFS) or overall survival (OS). As of October 2013, our ATG dosing was lowered from 6.5 to 4.5 mg/kg. We now compare the outcomes of patients who received ATG at a dose of 4.5 mg/kg (r-ATG) to 6 mg/kg (R-ATG) Methods: We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo HSCT for hematologic malignancies and received r-ATG (40 patients) vs R-ATG (216 patients) at The Ohio State University Comprehensive Cancer Center between October 2007 and September 2014. Cumulative incidences of GVHD, infection, NRM, and relapse were analyzed using Gray's test, accounting for competing risks. PFS and OS were analyzed using the log-rank test. Results: Patients with hematologic malignancies included AML/MDS (53%), NHL/Hodgkin's (19%), CLL (12%), and other hematologic malignancies including ALL (16%). There was a significant association between disease group and ATG dose (p<0.001), with none of the patients diagnosed with CLL receiving r-ATG and a higher percentage of those with other malignancies receiving r-ATG vs R-ATG than expected. Secondary to the imbalance in disease groups, those receiving r-ATG were younger (median 50 vs 59 yrs, p=0.01) and more likely to have bone marrow stem cell source (18% vs 5%, p=0.008). There were no significant differences in recipient or donor sex, degree of HLA match, prior autografts, comorbidity index, donor/recipient CMV status and CD34 cell dose between the two groups. The cumulative incidences of acute GVHD grade II-IV at day 180 in the r-ATG and R-ATG groups were 63% and 44% (p=0.009), and of grade III-IV 18% and 11% (p=0.25) respectively (Figure 1A and B). When controlling for differences in underlying disease, the estimated risk of acute GVHD grade II-IV was 1.6 times higher with r-ATG (p=0.04). The respective cumulative incidences at 6 months of chronic GVHD were 14% and 16% (p=0.65), and of extensive chronic GVHD 14% and 13% (p= 0.29). With limited follow-up in patients receiving r-ATG (median 10 months), significant differences were not observed in longer-term outcomes between the two groups including relapse rate (p=0.83), NRM (p=0.91), PFS (p=0.92), and OS (p=0.996). The incidence of CMV reactivation at day 180 was lower in the r-ATG group (5% vs 26%, p=0.005), though the incidence of competing risks including GVHD, relapse and death prior to documented reactivation was higher in the r-ATG group (p<0.0001). No statistically significant differences were seen in Epstein-Barr virus reactivation (p=0.74), BK-virus associated hemorrhagic cystitis (p=0.79), bacterial infections (p=0.11), or Clostridium Difficile infections (p=0.22). Conclusions While there was an increase in grade II-IV acute GVHD with r-ATG, there was no significant difference in acute GVHD grade III-IV, relapse, NRM, PFS and OS between the two cohorts. r-ATG resulted in a lower proportion of CMV reactivation, but in a higher proportion of other competing risks. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pilot Study of Telmisartan (Micardis) for Prevention of Acute Graft Vs. Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: Interim Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4546-4546
Author(s):  
Sujatha Iyengar ◽  
Scott D. Rowley ◽  
Caixin Zhan ◽  
Michele L. Donato ◽  
Themba Nyirenda ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Adverse Reactions ◽  
Acute Gvhd ◽  
Medical Center ◽  
Hematopoietic Stem ◽  
Graft Vs Host Disease ◽  
Grade Ii ◽  
Pre Treatment ◽  
Historical Controls ◽  
Grade Iii

Telmisartan (TMS) is an angiotensin receptor blocker with anti-inflammatory properties and little or no clinical immunosuppressive effect. We undertook an unblinded, single arm, pilot study of TMS (160 mg/d p.o.) for prevention of acute graft vs. host disease (aGvHD) in recipients of HLA matched allogeneic hematopoietic stem cell transplants (HSCTs). Primary endpoints of Grade II or >Grade III aGvHD (1994 Consensus Conference on Acute GVHD Grading) were compared with 178 similar HSCT historical controls over the preceding 3 yrs at our institution: 26% >Grade III, 74% Grade II. Safety endpoints included engraftment, relapse/progression by day (d) 180, non-relapse mortality by d 180, and serious drug-related adverse reactions. Experimental data were collected on blood endotoxin levels and stool microbiome composition. The study was powered to detect 20% or 50% reduced rates of, respectively, Grade II or >Grade III. We report results from a planned interim analysis triggered when the first 22 evaluable patients (pts) reached d 100. Of 27 evaluable pts, 24 were beyond d 180 by completion of this interim analysis. The study was designed to treat pts for two days prior to, and day of HSCT, and for an additional 98 days post-transplant, but pts were considered evaluable if they completed >14 days of post- transplant TMS, including pre-determined dose reductions. One enrollee received TMS for 13 days post-HSCT and was excluded from analysis. Five pts received 14-24 days of drug (4 by choice, 1 died of sepsis). More than half the evaluable patients (17/27) completed >94 days of post-HSCT therapy, including 6 who experienced an episode of hypotension. Almost half (13/27) received >80% of the full 101 day dose (16,160 mg), including 5 who experienced hypotension. Of the 6 enrollees receiving <24 days of drug, two had documented hypotension. No other serious drug-attributed adverse reactions were reported. Reasons cited for pts choosing to discontinue TMS were inconvenience of taking pills, and home stool sampling. Safety Endpoints: All pts engrafted promptly (ANC >500/uL, platelet >20,000/uL). Peripheral donor CD3+ T cell median and range of chimerism on days 28 and 84 were 99.5% (37-100) and 100.0% (36-100); bone marrow donor CD34+ cell chimerism was 97.0% (62-100). There was a single NRM during the 180 d study, and no graft rejection or increase in relapse or progression. Four relapses occurred within 180 days, and 2 more after d 180, resulting in two relapse deaths (d 370, and d 600). Primary Endpoints:A single individual developed hyperacute Grade III skin GvHD on day 7 p-HSCT. Another 12 of 27 patients developed Grade 2 aGvHD, one after the conventional 100 d window (d 141). Compared with historical controls, the incidence of aGvHD was significantly reduced for Grade II (p < 0.005) and Grade >III (p = 0.01), using the two-tailed Z-test of proportions. Experimental Endpoints: Acute GvHD is associated with increased gut permeability, bacterial translocation, and loss of gut microbiome diversity. Endotoxemia, an indicator of intestinal integrity, as measured by the endotoxin activity assay (EAA, Spectral Medical) reached septic levels in 40% of patients during pre-transplant conditioning (d -3 - d 0), and subsequently returned to, or maintained, non-septic levels from week 5 onward in 90% of patients, with an overall downward group trend of EAA scores during 180 days of follow up. Genotyping and analysis of bacterial V4 16S ribosomal DNA from weekly stool samples of the first 10 evaluable patients revealed no decrease in OTU richness or Shannon diversity at any time point pre- vs. post- treatment. Among the 5 most abundant phyla, Bacteroidetes was significantly less abundant post-treatment compared to pre-treatment. Among the 8 most abundant families, Bacteroidaceae significantly decreased post- vs. pre- treatment. While historic microbiome controls from our institution are not available, our finding of increased Bacteroidetes is in contrast to reported decreased Bacteroidetes in allogeneic HSCTs not receiving TMS, but may resemble changes after autologous HSCT. This trial, funded by the Gateway Foundation, is ongoing. Preliminary results indicate TMS is well tolerated, with a beneficial impact on aGvHD and no increased relapse or NRM, with excellent engraftment, and preservation of anti-tumor effect, intestinal barrier integrity, and gut microbial diversity. Disclosures Iyengar: Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent.. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Schwartz:Hackensack University Medical Center: Patents & Royalties: Telmisartan use patent. OffLabel Disclosure: Telmisartan. Indicated for treatment of hypertension.

Transplant Outcome of Unrelated Hematopoietic Stem Cell Transplantation (HSCT) after Myelo-Ablative or Reduced Intensity Conditioning (RIC) for Chronic Lymphocytic Leukemia(CLL). A Study of EBMT Registry.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 561-561 ◽  
Author(s):  
Mauricette Michallet ◽  
Thomas Prebet ◽  
Quoc-Hung Le ◽  
Anne-Sophie Michallet ◽  
Anja Van Biezen ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Hla Matching ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Significant Difference ◽  
Unrelated Donors ◽  
Global Population ◽  
Reduced Intensity ◽  
Grade Iii

Abstract Place of allogeneic HSCT in the therapeutical strategy of CLL remains still controversial and unrelated allogeneic transplantation has to be better explored. This retrospective analysis concerned 214 patients (164 males and 50 females) who underwent allogeneic HSCT for CLL from unrelated donors (150 males and 64 females) and who were reported on EBMT registry. The median age was 49 years. Fifty two patients received bone marrow (BM) and 162 peripheral blood stem cells (PBSC) from 48 HLA mismatched and 166 HLA matched unrelated donors. Sex mismatch and ABO incompatibility were found in 33% and 52% of cases respectively. On 194 evaluated patients for conditioning, 80 received a myelo-ablative regimen, 114 a reduced intensity conditioning and a Total Boby Irradiation was performed in 70 cases. After transplant, 72 patients (37%) developed an acute GVHD grade II-IV (36% in BM patients and 37% in PBSC patients; 49% in myelo-ablative group and 28% in RIC group). On evaluated patients, a chronic GVHD was present in 61% of the patients (50% in BM patients and 67% in PBSC patients, 66% in myelo-ablative group and 63% in RIC group). With a median follow-up of 20 months, we found no significant difference for 3-year probability of Overall Survival between myelo-ablative group (59%, 46–76) and RIC group (48%, 37–63). No significant difference was observed when comparing BM and PBSC patients whatever the conditioning they received. OS was significantly better in HLA matched compared to HLA mismatched patients in RIC population (51% vs 36%, p=0.01) but not in myelo-ablative population. In multivariate analysis (table 1) studying pre and post transplantation factors, a significant impact of 2 variables, age and aGVHD (grade III-IV vs 0-I), was shown on OS for the global population, myelo-ablative and RIC groups. Other variables influenced also significantly the OS: HLA matching (global and RIC populations), sex matching (myelo-ablative and RIC), TBI (myelo-ablative group). Concerning BM and PBSC groups, we demonstrated the influence of age and aGVHD. In conclusion, besides the known influence of severe aGVHD on survival, this study points out the importance of age and HLA matching in allogeneic unrelated HSCT transplantation setting for CLL. No difference was found regarding conditioning regimen and further studies are needed to determine the most adequate regimen for this disease. Multivariate analyses Variables OS (HR) p Global population Age 1.04 (1-1.07) 0.05 HLA matching: yes vs no 0.44 (0.22-0.89) 0.02 aGVHD grade III-IV vs 0-I 1.37 (1.1-1.74) 0.01 Myelo-ablative group Age 1.07 (1-1.13) 0.04 Sex Mismatch: F to M vs F to F 6.26 (1.53-25.6) 0.01 TBI: yes vs no 16.3 (3.26-80.2) 0.0006 aGVHD grade III-IV vs 0-I 1.9 (1.18-3.06) 0.008 RIC group Age 1.05 (1-1.1) 0.05 HLA matching: yes vs no 0.28 (0.1-0.76) 0.01 Sex Mismatch M to F vs F to F 0.63 (0.42-0.96) 0.03 aGVHD grade III-IV vs 0-I 1.66 (1.16-2.39) 0.005 BM group Age 1.12 (1-1.24) 0.03 aGVHD grade III-IV vs 0-I 1.88 (1-1.36) 0.05 PBSC group aGVHD grade III-IV vs 0-I 1.38 (1.02-1.86) 0.03

Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5311-5311
Author(s):  
Xiaohua Chen ◽  
Gregory A. Hale ◽  
Raymond C. Barfield ◽  
Ely Benaim ◽  
Wing H. Leung ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

Killer Immunoglobulin-Like Receptor and NOD2/CARD15 Polymorphisms Independently Influence Survival after Allogeneic Hematopoietic Stem Cell Transplanation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2167-2167
Author(s):  
Sebastian Giebel ◽  
Aleksandra Holowecka-Goral ◽  
Izabela Nowak ◽  
Tomasz Czerw ◽  
Jerzy Wojnar ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Kir Genes ◽  
Increased Risk ◽  
Grade Ii ◽  
Card15 Gene ◽  
Grade Iii

Abstract Background: Activating and inhibitory killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and a subset of T cells. KIR genotype, in particular the content of activating KIR genes is highly polymorphic. NOD2/CARD15 protein is broadly expressed in APCs and lymphocytes. Single nucleotide polymorphisms (SNPs) of this gene have been reported to impair the pathogen elimination and trigger pathologic immunologic reactions like GvHD. The goal of this prospective study was to evaluate the impact of donor’s and recipient’s KIR and NOD2/CARD15 genotypes on outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT). Pateints and methods: One-hundred-two consecutive patients with hematological malignancies, aged 32(18–58)y, treated with alloHSCT from HLA-matched related (n=34) or matched unrelated donor (MUD) (n=68) were included. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of CsA, Mtx, and, in case of MUD-HSCT, pre-transplant ATG. Donors and recipients were tested for 11 KIR genes as well as SNP8,12,13 of the NOD2/CARD15 gene. In addition, immune reconstitution including KIR expression on T cells, was analyzed on days +28, +56, +100, +180, and +360. Results: Overall survival (OS) rate at 2y was significantly lower in alloHSCT with at least one activating KIR mismatch compared to transplants with full compatibility (62% vs. 86%, p=0.01). In particular, the presence of at least one activating KIR in the donor with its absence in the recipient (D+R−) was associated with decreased probability of OS (60% vs. 78%, p=0.01) and DFS (58% vs. 82%, p=0.005), as well as increased incidence of non-relapse mortality (NRM) (27% vs. 7%). KIR2DS1 and KIR3DS1 D+R− mismatches resulted in increased risk of grade II–IV acute GvHD, whereas KIR2DS3 and KIR2DS2 D+R− mismatches were associated with increased risk of chronic GvHD. The presence of at least one activating KIR D+R− mismatch was associated with increased CD8+/CD4+ T cell ratio up to day +100. In all cases of incompatibility regarding KIR2DS1, KIR2DS2 and KIR3DS1, T cells with expression of respective receptors could be detected up to 360 days after alloHSCT. The presence of SNP8 of the NOD2/CARD15 gene in the recipient was associated with decreased probability of OS (20% vs. 70%, p=0.005) and DFS (20% vs. 70%, p=0.01) as well as increased incidence of NRM (60% vs. 17%) and grade III–IV acute GvHD (67% vs. 8%). In a multivariate analysis including KIR and NOD2/CARD15 polymorphisms together with other potential risk factors, increasing number of D+R− activating KIR mismatches as a linear variable appeared to independently influence OS (HR: 1.3, p=0.02), DFS (HR: 1.3, p=0.008), NRM (HR: 1.4, p=0.02), grade II–IV acute GvHD (HR: 1.4, p=0.001), and chronic GvHD (HR: 1.2; p=0.02). Recipient SNP8 of NOD2/CARD15 was predictive for OS (HR: 5.5, p=0.003), DFS (HR: 4.4, p=0.008), NRM (HR: 5.9, p=0.006), grade III–IV acute GvHD (HR: 6.1, p=0.02), and chronic GvHD (HR: 3.7; p=0.03). Conclusions: Both activating KIR D+R− mismatches and recipient SNP8 of NOD2/CARD15 appear to enhance alloreactivity and independently influence survival after alloHSCT. Evaluation of these polymorphisms may contribute to better donor selection and optimization of the alloHCT procedure.

Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1170-1170 ◽  
Author(s):  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shotaro Hagiwara ◽  
Tsunehiko Komatsu ◽  
Tetsuya Goto ◽  
...  
Keyword(s):  
Whole Blood ◽  
Acute Gvhd ◽  
Trough Level ◽  
Chronic Gvhd ◽  
Gvhd Prophylaxis ◽  
Starting Dose ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii ◽  
Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 873-873
Author(s):  
Andrea Toma ◽  
Marie-Lorraine Balère-Appert ◽  
Jean-Michel Boiron ◽  
Pierre Bordigoni ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Abstract 873 The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures: No relevant conflicts of interest to declare.

Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2353-2353 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Stephane Morisset ◽  
Nathalie Tedone ◽  
Jacques-Olivier Bay ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Abstract 2353 Background: The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective: To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods: This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included: Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results: Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/&minus; and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2) Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/&minus; (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion: We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. Disclosures: No relevant conflicts of interest to declare.

Pharmacokinetic Modeling of Fludarabine to Control Exposure and Improve Outcomes after Reduced Intensity Conditioning Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3869-3869
Author(s):  
Kinjal Sanghavi ◽  
Anthony C. Wiseman ◽  
Qing Cao ◽  
Erica D. Warlick ◽  
Claudio G Brunstein ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Pharmacokinetic Model ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Population Pharmacokinetic ◽  
Reduced Intensity Conditioning ◽  
High Exposure ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Fludarabine (FLU) is a chemotherapeutic and immunosuppressive agent used in reduced intensity conditioning (RIC) regimens prior to hematopoietic stem cell transplantation. High exposure to F-ara-A, the active metabolite of FLU, has been associated with more treatment related mortality (TRM). No standard dosing models allow estimation of exposure and individualized dosing. We developed a population pharmacokinetic model for adults that estimates F-ara-A clearance (Cl) from which area under the curve (AUC0-∞) is calculated.(Clin Pharmacol Ther, Vol95, S87, March 2014) We retrospectively tested the performance of the model by associating individual predicted AUC 0-∞to clinical outcomes. TV F-ara-A CL (L/hr) = (7.04 + 3.9 * (CrCl/85) * (70/IBW)) * (IBW/70)0.75 AUC 0-∞ (μg-hr/ml) = Administered dose in F-ara-A equivalents (mg)/Estimated TV F-ara-A Cl (L/hr) Adult HCT patients (n=301, 2008 to 2014) who received IV FLU in their conditioning regimen were included. FLU doses, actual body weight, height, serum creatinine, along with TRM, engraftment and acute GVHD were reviewed. TRM was defined as death without relapse or disease progression. GVHD was staged and graded according to the standard GVHD criteria. The median age (range) was 58 yrs. (18-75). 131(43.5%) received PBSCT, 31(10.3%) bone marrow and cord blood in 139(46.2%). FLU doses were 25-40 mg/m2/day; nearly all x 5 days. The median (range) daily dose was 67 mg (38 mg-100 mg). The pharmacokinetic model was used to estimate the F-ara-A Cl and then predict their AUC0-∞ from the first dose and the total cumulative AUC0-∞. Recursive partitioning regression analysis was used to determine the optimal cut points for the first dose AUC0-∞ and cumulative AUC0-∞towards clinical outcomes. The cumulative incidence of engraftment, TRM and acute GVHD (grades II-IV and III-IV) was calculated using death prior to event as a competing risk. The proportional hazards model of Fine and Gray was used to assess the association of F-ara-A exposures towards TRM, acute GVHD and engraftment. The median (range) F-ara-A Cl, AUC0-∞ and cumulative AUC0-∞ predicted from the model were 10.92 L/hr (7.51-15.37), 4.79 μg-hr/ml (2.40 -7.52) and 23.93 μg-hr/ml (11.20-37.62), respectively. Patients with a higher first dose AUC0-∞ ≥6 μg-hr/ml had a higher incidence [95%CI] of day 100 TRM (20% [7-33%] vs 6% [4-9%], p<0.01) compared to those with <6 μg-hr/ml. Similarly, higher cumulative AUC0-∞ ≥30 μg-hr/ml was also associated with higher risk of day 100 TRM (21% [7-34%] vs 6% [3-9%], p<0.01) compared to those <30 μg-hr/ml. Both PK measures [first dose AUC0-∞ ≥6 μg-hr/ml and cumulative AUC0-∞≥30 μg-hr/ml] had higher risks of 12 month TRM (32% [16-48%] vs 15% [11-20%], p=0.02) and (34% [17-51%] vs 15% [11-20%], p=0.02), respectively. An AUC0-∞ ≥4 μg-hr/mL led only to a marginally higher risk of 6 month GVHD grades II-IV and III-IV (42% [35-48%] vs 28% [14-41%] p=0.07 and 43% [37-50] vs. 30%[16-44%], p=0.06, respectively) compared to <4 μg-hr/ml. However a cumulative AUC0-∞≥20 μg-hr/ml was associated with a significantly greater risk of acute GVHD grades II-IV (43% [36-49%] vs. 26% [14-38%], p= 0.02) and grades III-IV (44%, [38-51%] vs, 28% [15-41%], p=0.03). Lower F-ara-A clearance and higher AUC 0-∞ were associated with greater risks of TRM and acute GVHD. These data support personalizing FLU dose rather than using empirical body surface area based dosing. Targeting FLU therapy may improve outcomes after HCT. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document