scholarly journals Impact of Donor-Derived CD34+ Infused Cell Dose on Outcomes of Patients Undergoing Allo-HCT Following Reduced Intensity Regimen for Myelofibrosis:a Study from the Chronic Malignancies Working Party of the EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3338-3338
Author(s):  
Tomasz Czerw ◽  
Vittoria Malpassuti ◽  
Simona Iacobelli ◽  
Linda Koster ◽  
Nicolaus Kröger ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Independent Predictor ◽  
Cell Depletion ◽  
Study Group ◽  
T Cell Depletion ◽  
Cd34 Cells ◽  
Donor Type ◽  
Higher Doses

Introduction: Cellular composition of grafts is believed to be one of the significant determinants of outcomes of reduced-intensity conditioning (RIC) allogenic hematopoietic cell transplantation (allo-HCT). However, inconsistent results of the influence of CD34+ cells dose on the incidence of graft-versus-host disease (GVHD), disease control and survival have been reported in studies published thus far. Allo-HCT remains the only potentially curative treatment modality for eligible patients with myelofibrosis (MF). As patients with this diagnosis were underrepresented or not included in the above mentioned analyses, this EBMT registry study aimed to determine impact of CD34+ cell counts on allo-HCT results in this population. Methods: Six hundred and fifty seven patients with primary or secondary MF transplanted with use of peripheral blood (PB) as a source of stem cells after RIC regimen (Fludarabine/Melphalan, N=536 (82%); Fludarabine/Busulphan, N=121 (18%)) between 2000 and 2016 were included. Stem cell donor type was HLA-identical sibling (MSD; N=249, 38%) or unrelated (UD; N=408, 62%). Use of ex vivo T-cell depletion and post-transplant cyclophosphamide to prevent GVHD were the exclusion criteria. Median patient age was 58 (range, 22-76) years. In-vivo T-cell depletion was used in 526 (80%) of cases. Median transplanted CD34+ dose was 6.6 (2-29) x 10^6 per kg of recipient body weight. Median follow-up was 46 (2-194) months. Patient and transplant characteristics are summarized in Table 1. Results: We did not observe any impact of CD34+ cells dose on outcome variables in the whole study group. However, in an analysis adjusted for donor type, among patients transplanted from a MSD, the 2yr overall survival (OS) probability was 77% for those transplanted with higher doses of CD34+ cells (defined as >7.0 x 10^6/kg) compared to 60% for lower CD34+ counts (below 7.0 x 10^6/kg), P=0.007 (Figure 1). The corresponding probabilities of 2yr non-relapse mortality (NRM) were 16% and 29% (P=0.04), respectively (Figure 2). In multivariate analysis, for patients transplanted from a MSD, higher CD34+ dose was an independent predictor for better survival (HR 0.56; P=0.01) and lower risk of NRM (HR 0.54; P=0.02). We did not find any association between CD34+ counts with probability of engraftment, the incidence of acute (aGVHD) and chronic (cGVHD) nor disease relapse. The effect of cell dose was not seen in the UD cohort. Factors associated independently with an unfavorable outcome in the whole study group were: older patient age and transplantation from CMV seronegative donors to seropositive recipients for OS and NRM and use of an UD and female donor for NRM. Allo-HCT from UD was also an independent predictor for higher incidence of aGVHD and lower probability of engraftment. Use of in vivo T-cell depletion was a protective factor for aGVHD. It was in turn associated with higher risk of relapse. Conclusions: Our analysis suggests a potential survival benefit for MF patients treated with RIC PB-allo-HCT from MSD with higher doses of CD34+ cells (threshold > 7.0 x 10^6/kg). We suggest that this factor should be taken into consideration when planning and performing hematopoietic cell apheresis. Disclosures Kröger: Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Robin:Novartis Neovii: Research Funding. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mielke:Bellicum: Consultancy, Honoraria, Other: Travel (via institution); EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; IACH: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; ISCT: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau. Snowden:Janssen: Honoraria; Mallinckrodt: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Blaise:Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria.

scholarly journals Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 424-424
Author(s):  
Mesire Aydin ◽  
Elisabeth Dovern ◽  
Mariska M.G. Leeflang ◽  
Josu de la Fuente ◽  
Adetola A. Kassim ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
Graft Failure ◽  
Meta Analysis ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Related Mortality

Abstract Background Allogeneic hematopoietic stem cell transplantation (SCT) is the only established curative treatment option for patients with sickle cell disease (SCD). Transplantations with an HLA-identical matched sibling donor (MSD) have resulted in excellent disease-free survival of >90% and overall survival (OS) of >95%. However, lack of HLA-identical siblings is a limiting factor. The chance of finding a potential matched unrelated donor is low for patients with a non-Western ethnic background (< 20%). Haploidentical related donors are a promising pool of donors potentially extending SCT as a curative treatment to a larger group of SCD patients with no other meaningful treatment options. Myeloablative conditioning regimens (MAC) are not recommended for adult SCD patients, as cumulative SCD-related organ damage renders these patients susceptible to increased toxicity and higher risk of transplant-related mortality. Using reduced-intensity conditioning (RIC) or non-myeloablative conditioning (NMC) in both adult and pediatric patients has resulted in decreased transplant-related toxicity and mortality. However, while successful in hematologic malignancies, NMC has been associated with significant risk of graft failure in hemoglobinopathies. In the present study, we aimed to systematically review (1) the outcomes of haploidentical SCT (Haplo-SCT), (2) the effects of conditioning intensity and modes of T-cell depletion on Haplo-SCT outcomes and (3) comparative outcomes between matched sibling donor SCT (MSD-SCT) and Haplo-SCT in selected studies. Methods A comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data was extracted by two reviewers independently and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Only studies reporting at least one of the outcomes: graft failure, OS, transplant-related mortality, and acute/chronic graft-versus-host disease (GvHD) were included. Fourteen studies met the inclusion criteria. To have an overview of the results of Haplo-SCT, we divided the included studies in four groups according to the conditioning intensity (MAC versus NMC/RIC) and the T-cell depletion method (in vivo (post-transplant cyclophosphamide (PTCy)) vs. in vitro). Results All included studies were observational cohort studies. A subgroup meta-analysis of the results of Haplo-SCT showed relatively low overall pooled proportions of graft failure (7%, 95% CI: 2 - 20), acute (4%, 95% CI: 2 - 12) and chronic (11%, 95% CI: 7 - 16) GvHD. Overall survival was high (91%, 95% CI: 85 - 94). Graft failure in MAC-in vitro, MAC-in vivo, NMC/RIC-in vitro and NMC/RIC-in vivo groups was 4% (95% CI: 1 - 14), 0% (95% CI: 0 - 100), 25% (95% CI: 10 - 51) and 11% (95% CI: 3 - 36) respectively (Figure 1). OS was 100% and 93% for MAC and NMC/RIC groups with PTCy (in vivo T-cell depletion) respectively. In patients with in vitro T-cell depletion, OS was 87% and 81% in MAC and NMC/RIC groups respectively (Figure 2). Based on a comparative meta-analysis of the three studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio 5.3, 95% CI: 1.0 - 27.6). Overall survival, transplant-related mortality and acute/chronic GvHD were not significantly different between the groups. Conclusions This systematic review shows that modifications in the intensity of the conditioning regimen and improved T-cell depletion approaches in Haplo-SCT in SCD have led to reduced transplantation-related toxicity while keeping graft failure rates low. Both in vitro and in vivo (PTCy) T-cell depletions result in very low transplantation-related mortality, though in vitro T-cell depletion is associated with a higher incidence of viral reactivations and other infectious complications. Haploidentical stem cell transplantation is becoming a viable alternative curative option for SCD, extending the availability of allogeneic SCT as a treatment option to many more transplant eligible SCD patients. Novel immunosuppression (immunoablation) and improvement in supportive care have allowed the use of RIC or NMC regimens, resulting in low risk of transplantation-related complications and improvement in engraftment rates. Figure 1 Figure 1. Disclosures Biemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria; Sanquin: Research Funding; Novo Nordisk: Honoraria; Celgene: Honoraria. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

In-Vivo T-Cell Depletion with Rabbit Anti-Thymocyte Globulin (r-ATG) Prevents Severe Acute and Chronic Graft Versus Host Disease (GVHD) and Allows Safe Allogeneic Stem Cell Transplantation (allo-SCT) From Mismatched, Unrelated Donors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1977-1977
Author(s):  
James L. Slack ◽  
Jose F. Leis ◽  
Craig B. Reeder ◽  
Joseph R. Mikhael ◽  
Pierre Noel ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Cell Depletion ◽  
Donor Pool ◽  
T Cell Depletion ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Abstract 1977 Introduction: Transplant options are limited for adult patients (pts) who lack a fully matched related or unrelated donor. We hypothesized that in-vivo T-cell depletion with r-ATG would allow safe allo-SCT from mismatched, unrelated donors, thus expanding the potential donor pool for pts with hematologic malignancies who require allo-SCT. Patients and Methods: Thirty seven adult pts (age 20 – 70, median 45) underwent a first unrelated, mismatched, allo-SCT between 1/1/2006 and 6/30/2011 at Mayo Clinic Arizona for hematologic malignancy (35 PBSC, 2 marrow). All pts had at least a one allele or one antigen mismatch (MM) at HLA-A, -B, -C, or -DRB1, and all except one pt received r-ATG as part of the GVHD prophylaxis strategy (dose range 2.5 – 10 mg/kg in daily dose of 2.5 mg/kg depending on degree of mismatch, with the last dose generally given on day −1). One pt received Campath after experiencing anaphylaxis to r-ATG. Pts were transplanted for acute myeloid leukemia (n = 19; 10 CR1, 6 CR2, 3 other), acute lymphoblastic leukemia (n = 8; 4 CR1, 4 CR>/= 2), chronic myeloid leukemia (n = 1), myelodysplastic syndrome (n = 5), or non-Hodgkin lymphoma (n = 4). Conditioning was myeloablative in 20, reduced intensity in 16, and non-myeloablative in 1. Mismatches were as follows: 1-allele MM (n = 7); 1 antigen MM (n = 15); 2 allele MM (n = 4); 1 antigen, 1 allele MM (n = 7); and 2 antigen MM (n = 4). Additional GVHD prophylaxis included tacrolimus plus either methotrexate (n =21), mycophenolate mofetil (n = 14), or other (n = 2). Results: The median follow-up for surviving pts is 12 months. As of 6/30/11, 31 pts were alive, and 6 had died of the following causes: multiorgan failure (n = 1), relapse (n = 3), and veno-occlusive disease (n = 2). To date, there have been no deaths related to acute or chronic GVHD. The 1- and 2-year estimated rates of overall survival are 84.5%/78.8% (Fig. 1); of progression-free survival 79.7%/72.0%. The estimated rate of relapse at 1 and 2 years is 11.8%/18.7%, and of non-relapse mortality 8.1%/10.5%. Four pts (10.8%) have developed severe (grades III-IV) acute GVHD by day 100 (days 19, 27, 30, 43; one pt after withdrawal of prograf due to transplant-associated microangiopathy). No late onset severe acute GVHD has been seen. Moderate to severe NIH-defined chronic GVHD occurred in a single pt at risk (cumulative incidence estimate 2.4% at 1 year, 4.7% at 2 years; Fig. 2). Four pts have reactivated EBV, with one developing PTLD (all have been treated with Rituximab). CMV reactivation was seen in 24 pts (65%), CMV disease in 4, with no deaths directly related to CMV. Conclusions: In vivo T-cell depletion with r-ATG abrogates severe acute and chronic GVHD, and allows use of mismatched unrelated donors for allo-SCT in adult pts with otherwise incurable hematologic malignancies. Long-term survivors are generally free of severe chronic GVHD, with good quality of life. There does not appear to be an increased incidence of disease relapse, and non-relapse mortality is low. This approach is safe, effective, and considerably expands the donor pool for adult pts who require allo-SCT. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML): Low Incidence of Relapse and Graft Versus Host Disease (GVHD) in Patients (pts) Transplanted without Active Leukemia Using in-Vivo T-Cell Depletion with Rabbit Anti-Thymocyte Globulin (r-ATG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4527-4527
Author(s):  
James L. Slack ◽  
Jose F. Leis ◽  
Craig B. Reeder ◽  
Joseph R. Mikhael ◽  
Raoul Tibes ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
T Cell Depletion

Abstract Abstract 4527 Introduction: The prognosis for pts with intermediate or high risk AML remains dismal, with relapse rates typically in the 60–80% range after treatment with chemotherapy alone. While allo-SCT can decrease the risk of relapse to 10–20%, widespread use of this modality is limited by relatively high rates of non-relapse mortality (NRM), often due to severe acute and/or chronic GVHD. Attenuation of severe GVHD, without a concomitant increase in relapse or NRM, should improve outcomes and result in cure of a larger fraction of AML pts. We therefore investigated the use of in-vivo T-cell depletion with r-ATG in pts with intermediate- or high-risk AML but without active leukemia at the time of allo-SCT. Patients and Methods: Pts (n = 43) were included in this retrospective analysis if they were between 18 and 65 years of age and had no evidence of active AML at the time of allo-SCT (see Table). All pts had 1 or more high-risk features: 1) adverse or intermediate risk cytogenetics (without NPM1 mutation if cytogenetically normal); 2) therapy-related or secondary AML; 3) high WBC count at diagnosis; 4) failure to achieve CR after 1 cycle of induction; or 5) not in CR1 at allo-SCT. Among the 43 pts, 10 received grafts from related donors, 14 from 10/10 matched unrelated donors (URDs), and 19 from mismatched URDs (9/10, n = 11; 8/10, n = 8). All pts received r-ATG according to institutional standard operating policy, with doses ranging from 2.5 – 10 mg/kg depending on donor type and degree of mismatch. All transplants were performed using PBSC. Additional GVHD prophylaxis included tacrolimus plus either methotrexate or mycophenolate mofetil. Results: The median age was 47 (range 20 – 65), and median follow-up for surviving pts is 12 (range 1 – 66) months. As of 8/5/11, 39 pts were alive, and 4 had died from multiorgan failure (n = 1), relapse (n = 1), GVHD (n = 1), and veno-occlusive disease (n = 1). The 2-year estimate of PFS is 84.7% (Fig. 1). The 2-year cumulative incidence of relapse is 6.8% (2 pts, days 97 and 147), and of non-relapse mortality 9.4%. Three pts developed severe (grades III-IV) acute GVHD by day 100 (cumulative incidence 4.6% at day 100) with no additional cases of severe acute GVHD beyond day 100. To date, 4 pts have developed moderate/severe chronic GVHD (cumulative incidence 16.8% at 2 yrs), with one death at day 344 related to complications of acute and chronic GVHD. CMV reactivation occurred in 29 pts (56%), with no deaths related to CMV. Three pts have reactivated EBV, with one case of PTLD (all treated with Rituximab). Conclusions: In this retrospective analysis of single center data, the inclusion of r-ATG in the GVHD prophylactic strategy appeared to significantly attenuate the incidence and severity of both acute and chronic GVHD. Although follow-up is relatively early, the incidence of relapse and NRM does not appear to be increased compared to contemporaneous pts treated without ATG. Given that almost half of the pts received grafts from mismatched URDs, this abrogation in risk of GVHD is significant and clinically relevant. While randomized studies are needed, these data suggest that in-vivo T-cell depletion with r-ATG ameliorates severe GVHD, without increasing relapse or non-relapse mortality, in AML pts without overt leukemia at the time of allo-SCT. Using this strategy, cure rates of 70 – 80% may be realistic and attainable for younger (</= age 65) AML patients who achieve a leukemia-free state and who have a reasonably matched related or unrelated donor. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

scholarly journals Impact of CD3+ and CD34+ Doses in the Mobilized Peripheral Blood Stem Cell Grafts on the Outcome of Reduced-Intensity Conditioning Allogenic Transplantation from Matched Unrelated Donors for Acute Myeloid Leukemia – an Analysis from the Acute Leukemia Working Party of the EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 190-190
Author(s):  
Tomasz Czerw ◽  
Myriam Labopin ◽  
Christoph Schmid ◽  
Jan J. Cornelissen ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
T Cell ◽  
Myeloid Leukemia ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Cd34 Cells ◽  
Unrelated Donors ◽  
Grade 3 ◽  
The Impact

Abstract Introduction: The impact of peripheral blood stem cell (PBSC) grafts composition on the outcome of reduced-intensity conditioning (RIC) allogenic transplantations (allo-SCT) is still controversial. Inconsistent results have been reported regarding the influence of CD3+ and CD34+ cells dose on incidence of GVHD, disease control and survival. These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. Aim and methods: This retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose in PBSC grafts on the outcome of RIC allo-SCT in patients with acute myeloid leukemia (AML) allografted from matched unrelated donors (MUD). Two hundred and three adults with AML in first complete remission (CR1) treated with RIC allo-PBSCT from MUD (10 of 10 match) between 2000 and 2012 (median 2011) were included. Ex-vivo T-cell depletion was an exclusion criterion. Median age was 58 (range, 21-73) years; gender: male-116, female-87; 142 had intermediate, 42 unfavorable, 4 favorable, and 15 unknown cytogenetic features; median time to achieve CR1 was 51 (range, 21-350) days, whereas time from CR1 to allo-SCT was 115 days (15-351). Median donor age was 34 (range, 19-61) years. The preparative regimen was based on chemotherapy in 143 (70%) of the RIC allo-CST (Flu-Bu:110; Flu-Mel:12; Flu-Treosulfan:14, other:7), whereas in 60 (30%) low dose TBI was applied (2 Gy:57; 4 Gy:3). In-vivo T-cell depletion (ATG or Campath) was used in 166 (82%) of the transplants. Median transplanted CD3+ and CD34+ doses were 250 (50-885) x 10^6 and 6.53 (1.34-413) per kg of recipient b.w., respectively. Follow-up was 22 months (3-105). Results: The engraftment rate equaled 99% (202 pts) and was not affected by CD3+ nor CD34+ counts. In univariate analysis, patients transplanted with the highest CD3+ doses (above the third quartile cut-off point value, >347 x 10^6/kg) had an increased incidence of acute (a) GVHD grade >2 (45% vs. 26%, p=0.007) and grade 3-4 (20% vs. 6%, p=0.003), respectively. In the quartile of pts transplanted with the highest CD34+ graft content (>8.25 x 10^6 /kg) increased incidence of grade 3-4 aGVHD (18% vs. 7%, p=0.02) was observed. Other risk factors for aGVHD were transplantation from CMV seropositive donors (grade >2; 44% vs. 24%, p=0.005) and from females to males (grade 3-4; 19% vs. 8%, p=0.04). There was no association between cellular composition of grafts and non-relapse mortality (NRM), AML relapse, incidence of chronic (c) GVHD and survival. There was also no significant correlation between CD3+ and CD34+ cells infused. In multivariate analysis, CD3+ dose was the only adverse predicting factor for aGVHD grade >2 (HR= 2.1; 95%CI: 1.25-3.55, p=0.005) and together with CD34+ dose for aGVHD grade 3-4 (CD3+, HR=3.6; 95%CI: 1.45-9.96, p=0.006; CD34+, HR=2.65; 95%CI: 1.07-6.57, p=0.04). Other factors that independently affected unfavorable outcome were: time from diagnosis to CR1 above median for NRM, transplantation without in-vivo T-cell depletion for cGVHD, time from CR1 to allo-SCT above median and unfavorable karyotype for leukemia-free and overall survival and unfavorable karyotype for relapse incidence. Conclusions: These results suggest that the incidence of severe acute GVHD post RIC allo-SCT, still a major cause of morbidity and mortality, is associated with the composition of the PBSC grafts, specifically higher numbers of infused CD3+ and CD34+ cells. As graft composition can be manipulated, careful assessing the CD3+ and CD34+ graft content and the cell dose infused may help in reducing severe aGVHD risk and improving transplantation outcome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Different In Vivo T Cell Depletion Strategies on Outcomes Following Hematopoietic Stem Cell Transplantation for Idiopathic Aplastic Anaemia: A Study on Behalf of the EBMT SAA Working Party

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1210-1210 ◽  
Author(s):  
Sujith Samarasinghe ◽  
Simona Iacobelli ◽  
Cora Knol ◽  
Rose-Marie Hamladji ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Event Free Survival ◽  
T Cell Depletion ◽  
Educational Support ◽  
Free Survival

Abstract To determine the optimal serotherapy regimen in idiopathic aplastic anaemia stem cell transplantation, we analysed 1837 patients who underwent either in vivo T cell depletion with either ATG (n=1283) or Alemtuzumab (n=261) or no serotherapy (n=293) as part of their conditioning regimen. All patients had either undergone a matched sibling or matched unrelated donor stem cell transplant (at least 6 out of 6). Data was obtained retrospectively from the EBMT SAA database, between the periods 2000-2013. The major endpoints were graft versus host disease, overall survival and event free survival. Events were classified as graft failure, secondary malignancy, relapse and requirement for second transplant. The median follow up was 34 months in the ATG group, 30.9 months in the Alemtuzumab group and 47.9 months in the no serotherapy group. Rate of grade 2-4 acute GVHD was 19.1% without serotherapy; this was higher than that observed with both ATG (13.3%, p<0.001) and Alemtuzumab (6.7%, p<0.001; ATG vs Alemtuzumab: p=0.012). Cumulative incidence of chronic GVHD at 36 months was 30.4% without serotherapy; this was higher than that observed with both ATG (20.8%, p=0.021) and Alemtuzumab (14.7%, p=0.003; ATG vs Alemtuzumab: p=0.083). In multivariate analysis, grade 2-4 acute and chronic GVHD rates were significantly lower with Alemtuzumab compared to no serotherapy (Odds Ratio ratio (OR) = 0.16, p< 0.001 95%CI 0.08-0.31 and HR= 0.38, 95% CI 0.24-0.62, p< 0.001 respectively). Similarly, acute and chronic GVHD were lower with Alemtuzumab compared to ATG (OR = 0.26;p<0.001 95%CI 0.14-0.47 and HR = 0.58; 95%CI 0.38-0.89, p=0.012 , respectively). Acute and chronic GVHD were higher without serotherapy compared to ATG (OR = 1.65; p =0.01 95%CI 1.12-2.41 and HR = 1.51; 95%CI 1.12-2.04, p=0.008 , respectively). There was no difference in event free survival between the three groups. However, overall survival at 36 months was 73.3%, 81.3% and 81.5 in no serotherapy, ATG and alemtuzumab, respectively (ATG vs no serotherapy p=0.01; Alemtuzumab vs no serotherapy p=0.025; Alentuzumab vs ATG p=0.604). In multivariate analysis overall survival favoured in vivo T cell depletion compared to no serotherapy; (Alemtuzumab vs no serotherapy, HR=0.44; 95%CI 0.29-0.67, p<0.001); (no serotherapy vs. ATG HR=1.55; 95%CI 1.19-2.01, p=0.001). Among serotherapy, Alemtuzumab was associated with better OS as compared with ATG (OR=0.68; 95%CI 0.48-0.98, p=0.037). Our results suggest that use of in vivo T cell depletion in sibling and unrelated matched stem cell transplantation in idiopathic aplastic anaemia leads to a survival advantage. Alemtuzumab is associated with less GVHD than ATG without affecting event free survival. Figure 1. Figure 1. Disclosures Snowden: Celgene: Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; MSD: Consultancy, Other: Educational support, Speakers Bureau; Sanofi: Consultancy. Dufour:Pfizer: Consultancy. Risitano:Pfizer: Consultancy; Novartis: Research Funding; Rapharma: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: this paper includes discussion of the use of alentuzumab for GVHD prophylaxis, which is currently off-label.

Reconstitution of CD52-Negative CD4 T Cells after Alemtuzumab-Based T Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1182-1182
Author(s):  
Eva M Wagner ◽  
Aline N Lay ◽  
Sina Wenzel ◽  
Timo Schmitt ◽  
Julia Hemmerling ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Lymphocytic Leukemia ◽  
Cell Depletion ◽  
Down Regulation ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Abstract The human CD52 molecule is the target of the monoclonal antibody Alemtuzumab, which is used for treating patients with chemo-refractory chronic lymphocytic leukemia as well as for T cell depletion (TCD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT). The molecule is expressed on the surface of lymphocytes, dendritic cells and to a lesser extent on blood-derived monocytes. Previously, investigators have demonstrated that the surface expression of CD52 on T cells is down-regulated after in vitro incubation with Alemtuzumab. By treating purified human CD4 T cells over 4 hours with 10 μg/mL Alemtuzumab in medium supplemented with 10% human AB serum in vitro, we observed a strong decrease of CD52 expression by flow cytometry with a maximum 3–7 days after incubation. The CD52 down-regulation was also found at weaker intensity on CD8 T cells. From previous studies in chronic lymphocytic leukemia patients, it is known that Alemtuzumab treatment also leads to a down-regulation of CD52 on T cells in vivo. However, similar experiments have not been performed in allogeneic HSCT patients receiving Alemtuzumab in vivo for T cell depletion. We therefore analyzed the expression of CD52 on human peripheral blood mononuclear cells isolated at repeated time points from 22 allogeneic HSCT patients after reduced-intensity conditioning with fludarabine and melphalan and in vivo T cell depletion with Alemtuzumab (100 mg). Half of the patients received prophylactic CD8-depleted donor lymphocyte infusions (DLI) to promote immune reconstitution. By flow cytometry, we observed that the CD52 expression on monocytes, B cells, and natural killer cells remained unaltered after transplantation and was not influenced by the application of DLI. In contrast, the majority of CD4 T cells were CD52-negative (median, 72%) after transplantation and they remained CD52-negative in patients who did not receive DLI throughout the first year after HSCT. The permanent lack of CD52 expression could not be explained by a continuous effect of Alemtuzumab, because earlier studies have shown that the antibody is not present in active plasma concentrations beyond day +60 after HSCT. In contrast, patients receiving CD8-depleted DLI demonstrated a significant increase in the proportion of CD52-positive CD4 T cells. In three of our patients (DLI: n=2, non-DLI: n=1) we analyzed the donor chimerism of CD52-positive and CD52-negative CD4 T cells sorted with high purity by flow cytometry. Three months after HSCT (before DLI), the proportion of donor T cells was clearly higher among the CD52-negative compared to the small proportion of CD52-positive cells in all patients (44% vs. 10%, 83% vs. 0%, and 100% vs. 40%). In the patient who did not receive DLI, the donor T cell chimerism remained mixed in the CD52-negative and CD52-positive fractions on days 200 (CD52-negative: 95%; CD52-positive: 15%) and 350 (CD52-negative: 92%; CD52-positive: 65%). In contrast, the two patients receiving CD8-depleted DLI showed a strong increase in the proportion of CD52-positive CD4 T cells that were of complete donor origin. Altogether, CD52 is permanently down-regulated in reconstituting CD4 T cells following HSCT with an Alemtuzumab-based TCD regimen unless DLI are applied. Our data support the idea of an active mechanism for CD52 down-regulation in CD4 T cells that is not related to B cells and natural killer cells and that appears to differently affect donor and host T cells, respectively.

Pentostatin Is Advantageous Relative to Fludarabine for in Vivo Murine T Cell Depletion, Suppression of T Cell Cytokine Secretion, and Inhibition of HVGR

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3483-3483
Author(s):  
Jacopo Mariotti ◽  
Jason Foley ◽  
Kaitlyn Ryan ◽  
Nicole Buxhoeveden ◽  
Daniel Fowler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytokine Secretion ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
T Cell Suppression ◽  
Ifn Γ ◽  
Cell Suppression

Abstract Although fludarabine and pentostatin are variably utilized for conditioning prior to clinical allogeneic transplantation, limited data exists with respect to their relative efficacy in terms of host immune T cell depletion and T cell suppression. To directly compare these agents in vivo in a murine model, we compared a regimen of fludarabine plus cyclophosphamide (FC) similar to one that we previously developed (Petrus et al, BBMT, 2000) to a new regimen of pentostatin plus cyclophosphamide (PC). Cohorts of mice (n=5–10) received a three-day regimen consisting of P alone (1 mg/kg/d), F alone (100 mg/kg/d), C alone (50 mg/kg/d), or combination PC or FC. Similar to our previous data, administration of P, F, or C alone yielded minimal host T cell depletion (as measured by enumeration of splenic CD4+ and CD8+ T cells) and minimal T cell suppression (as determined by CD3, CD28 co-stimulation of a constant number of remaining splenic T cells and measuring resultant cytokine secretion by multi-analyte assay). The PC and FC regimens were similar in terms of myeloid suppression (p=.2). However, the PC regimen was more potent in terms of depleting host CD4+ T cells (remaining host CD4 number [× 10^6/spleen], 2.1±0.3 [PC] vs. 4.4±0.6 [FC], p<0.01) and CD8+ T cells (remaining host CD8 number, 1.7±0.2 [PC] vs. 2.4±0.5 [FC], p<0.01). Moreover, the PC regimen yielded greater T cell immune suppression than the FC regimen (cytokine values are pg/ml/0.5×10^6 cells/ml; all comparisons p<0.05) with respect to capacity to secrete IFN-γ (13±5 [PC] vs. 48±12 [FC]), IL-2 (59±44 [PC] vs. 258±32 [FC]), IL-4 (34±10 [PC] vs. 104±12 [FC]), and IL-10 (15±3 [PC] vs. 34±5 [FC]). In light of this differential in both immune T cell depletion and suppression of T cell effector function, we hypothesized that T cells from PC-treated recipients would have reduced capacity to mediate a host-versus-graft rejection response (HVGR) relative to FC-treated recipients. To directly test this hypothesis, we utilized a host T cell add-back model of rejection whereby BALB/c hosts were lethally irradiated (1050 cGy; day -2), reconstituted with host-type T cells from PC- or FC-treated recipients (day -1; 0.1 × 10^6 T cells transferred), and finally challenged with fully MHC-disparate transplantation (B6 donor bone marrow cells, 10 × 10^6 cells; day 0). In vivo HVGR was quantified by the following method at day 7 post-BMT: harvest of splenic T cells, stimulation with host- or donor-type dendritic cells, and use of six-color flow cytometry to detect host T cells, CD4 and CD8 subsets, and cytokine secretion by capture method. Consistent with our hypothesis, PC-treated cells acquired greatly reduced alloreactivity in vivo relative to FC-treated cells: the percentage of host CD4+ T cells secreting IFN-γ in an allospecific manner was 2.3±0.8% in recipients of PC-treated T cells and 62.7±13.4% in recipients of FC-treated cells (p<0.001). Similarly, the percentage of host CD8+ T cells secreting IFN-γ in an allospecific manner was 8.6±2.8% in recipients of PC-treated T cells and 92.7±4.1% in recipients of FC-treated T cells (p<0.001). We therefore conclude that at similar levels of myeloid suppression, the PC regimen is superior to the FC regimen in terms of murine T cell depletion, suppression of global T cell cytokine secretion, and inhibition of in vivo capacity to acquire allospecificity in response to fully genetically disparate marrow allografts. These data provide a rationale to develop PC regimens as an alternative to currently utilized FC regimens.

Higher Infused CD34+ Cell Dose Improves Survival In Patients Undergoing In Vivo T-Cell Depleted, but Not T-Cell Replete Peripheral Blood Hematopoietic Cell Transplant

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1272-1272
Author(s):  
Abraham S Kanate ◽  
Salman Osman ◽  
Aaron Cumpston ◽  
Gerry Hobbs ◽  
Sonia Leadmon ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Univariate Analysis ◽  
Cell Depletion ◽  
Cell Transplant ◽  
Cellular Composition ◽  
T Cell Depletion ◽  
Cell Dose ◽  
Cd8 Cell

Abstract Abstract 1272 Introduction: Allogeneic hematopoietic cell transplant (HCT) remains a potentially curative modality for various hematological disorders. The cellular composition of the infused allograft has important ramifications for transplantation outcomes, for example higher infused CD34+ cell doses have previously been shown to be is associated with early engraftment, improved survival and possibly increased acute graft-versus-host disease (GVHD) following HCT. The influence of cellular composition of infused allograft on transplant outcomes has been the subject of many previous studies. There is paucity of data on the impact of cellular composition of allograft on transplant outcomes of patients undergoing HCT with in vivo T-cell depletion (TCD) compared to patients receiving T-cell replete allografts. We report here a comparative analysis of the impact of CD34+, CD3+, CD4+ and CD8+ cell doses and survival outcomes of allogeneic, peripheral blood HCT patients receiving in vivo T-cell depletion with alemtuzumab or anti thymocyte globulin (TCD group) versus patients who underwent T-cell replete HCT (non-TCD group). Methods: The study cohort includes 150 consecutive patients who underwent allogeneic HCT between January 2003 through December 2009. All patients received peripheral blood allografts from matched sibling or unrelated donors (URD). In vivo T-cell depletion consisted of alemtuzumab 40mg in two divided doses on days -4 and -1 (n=39) or Thymoglobulin at a total dose of 6 mg/kg for ablative and reduced intensity conditioning (RIC) transplants and 7.5 mg/kg total dose for non myeloablative allografts (n=51). 4 patients received Atgam at 30mg/kg on days -5, -4 and -3. Impact of CD34+, CD3+, CD4+ and CD8+ cell doses divided into two groups; >/= 50th and < 50th percentile on overall survival (OS), progression free survival (PFS) and non relapse mortality (NRM) was initially measured by univariate analysis. Multivariate logistic regression analysis was constructed for variables showing significance on univariate analysis (p<0.1). Cellular components of allografts was done by standard flow cytometric techniques. Results: Of the 150 patients, 94 (62.7%) were males. Median age was 49 (range 17–69). Baseline diagnosis included acute leukemia and myelodysplastic syndrome (n=88; 58.6%), chronic myeloid leukemia (n=19; 12.7%), non-Hodgkin lymphoma (n=27; 18%) and others (10.7%). There were 95 patients (63.3%) in the TCD group and 55 (36.7%) in the non-TCD group. The baseline characteristics of the TCD group and non-TCD group were well matched except that significantly more patients in the TCD group had high risk disease (86.3% vs. 61.8%, p = 0.0005) and received allografts from unrelated donors (62.1% vs. 29.1%, p < 0.001). Median doses of the infused cellular components in the allograft were; CD 34+ = 5.8 × 106/Kg (range 1.2 – 16), CD3+ = 30.8 × 107 (4.5 – 100.8), CD4+ = 18.6 × 107 (1.9 – 63) and CD8+ = 11.3 × 107 (0.8 – 52.4). Median follow-up time for surviving patients was 3 years. In the TCD group, multivariate analysis showed that CD34+ cell doses >/= 5.8 × 106 was associated with improved OS (p=0.0085; CI 0.28–0.83), PFS (p=0.03; CI 0.31–0.93) and NRM (p=0.02; CI 0.21–0.89). Multivariate analysis also showed that CD3+ cell dose >/= 30.8×107 improved OS (p=0.03; CI 0.25–0.92), but not PFS (p=0.14; CI 0.16–1.31) and NRM (p=0.15; CI 0.23–1.26). No association was noted between CD4+ and CD8+ cell doses and OS, PFS and NRM (p>0.05), in the TCD group. In the non-TCD group, univariate analysis of CD34+, CD3+, CD4+ and CD8+ cell doses failed to show any statistical significance for NRM, OS and PFS (p>0.1). Conclusion: Our limited, retrospective analysis of 150 peripheral blood allogeneic HCT shows improved OS, PFS and NRM in patients receiving CD34+ cell dose >/= 5.8×106/Kg and improved OS with CD3+ dose >/= 30.8×107/Kg, limited only to the TCD group. No such association was seen in the non-TCD group. We hypothesize that higher CD34+ in TCD transplants probably improved survival by rapid engraftment and by robust immune reconstitution thereby reducing infectious complication otherwise associated with TCD. Disclosures: Abraham: Genentech: Membership on an entity's Board of Directors or advisory committees. Hamadani:Celgene: Honoraria, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau.

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