Synergy of Unrelated Donor and Full Intensity Conditioning Breaks the Control of Graft Versus Host Disease By Alemtuzumab

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1206-1206
Author(s):  
Olivia Laverick ◽  
Amy Publicover ◽  
Laura Jardine ◽  
Kile Green ◽  
Alan Potter ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Gvhd Prophylaxis ◽  
Full Intensity ◽  
Conditioning Intensity ◽  
Reduced Intensity

Abstract Many variables influence the risk of graft versus host disease following hematopoietic stem cell transplantation. Comparison between preparative regimens is hampered by the use of many different combinations of chemotherapy and radiotherapy, varying intensity of conditioning, use of T cell depletion and donors who are either siblings or unrelated volunteers. Many reduced intensity regimens also incorporate enhanced GVHD prophylaxis with in vivo T cell depletion. Here we describe a cohort of patients prepared in a modular fashion with either reduced or full intensity conditioning combined with a uniform GVHD prophylaxis regimen for all transplants with sibling donors (alemtuzumab 30mg) and for all with unrelated donors (UD; alemtuzumab 60mg). Thus it was possible to dissect independently the effect of conditioning intensity and sibling or UD type upon GVHD risk in this settig of in vivo T cell depletion. Patients and analysis: the study was a retrospective analysis of 258 sequential transplants performed in adults with hematological malignancy between September 2005 and September 2013 at a single UK institution. Reduced intensity conditioning (n = 221) included fludarabine 150mg/m2 plus melphalan 140mg/m2 or fludarabine 150mg/m2 plus busulfan 9.6mg/kg. Full intensity transplants (n = 37) received 12Gy TBI plus melphalan 140mg/m2, 12Gy TBI plus cyclophosphamide 120mg/kg, or busulfan 16mg/kg plus cyclophosphamide 120mg/kg. All patients with sibling donors received 30mg alemtuzumab and those with UD received a 60mg of alemtuzumab. UD matching was similar in both reduced intensity and full intensity cohorts (92.2% and 86.5% 10/10 matches, respectively) but patients receiving reduced intensity were older than those receiving full intensity conditioning (median age 51 vs 31; p < 0.001). Outcome was analyzed according to EBMT guidelines. Relapse, non-relapse mortality and cGVHD were treated as competing risks and analysed as cumulative incidence. Outcome: the incidence of acute GVHD grades I-IV was comparable between reduced intensity and full intensity sibling transplants (45% vs 45%; p = NS) indicating a lack of effect of conditioning intensity upon GVHD risk in this setting. There was a slight increase in the risk of GVHD between reduced intensity UD compared with reduced intensity sibling donor transplants (57% vs 45%; p = NS) but a marked synergistic increase between UD transplants performed with full intensity compared with reduced intensity conditioning (100% vs 57%; p = < 0.001). The incidence of grades III-IV acute GVHD was also higher in full intensity UD transplants (16%) compared with reduced intensity UD transplants (5%). The incidence of chronic GVHD was also highest in full intensity UD transplants but both conditioning intensity and UD contributed in an additive manner: the rate of chronic GVHD progressed from 33% to 44% in reduced intensity and full intensity sibling transplants respectively and from 57% to 75% for reduced and full intensity UD transplants, respectively. Two year overall survival was comparable in all groups, ranging from 55% to 70%. In keeping with the higher rates of acute GVHD in full intensity transplants performed with UD, this group experienced the lowest relapse risk (15% vs 29% for all the other groups combined; p = 0.04) but the highest non-relapse mortality, reaching 41% at 2 years compared with 28% for all the other groups combined (p = 0.08). Conclusion: these results show that alemtuzumab provides good protection from acute GVHD in reduced intensity transplantation from sibling and UD. In sibling transplants given identical GVHD prophylaxis, full intensity conditioning does not increase the risk of GVHD. In contrast, a slight increase in GVHD risk with UD transplants seen with reduced intensity conditioning, is amplified in a synergistic manner by full intensity conditioning. This is associated with a high non-relapse mortality, even though the median age of full intensity patients is more than 20 years younger than those receiving reduced intensity conditioning. Disclosures No relevant conflicts of interest to declare.

HLA-Mismatch Is Associated With Worse Outcomes After Unrelated Donor Reduced Intensity Conditioning Hematopoietic Cell Transplantation: A Cibmtr Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 547-547 ◽  
Author(s):  
John Koreth ◽  
Kwang Woo Ahn ◽  
Joseph Pidala ◽  
James L. Gajewski ◽  
Hailin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Gvhd Prophylaxis ◽  
Conditioning Intensity

Abstract In myeloablative unrelated donor allogeneic hematopoietic cell transplantation (HCT) a 1-locus HLA-mismatch (-A, -B, -C, -DRB1) is associated with lower survival compared to fully matched pairs. However data in reduced-intensity and non-myeloablative conditioning (together called RIC) HCT are limited. We analyzed adult AML/ALL/CML/MDS recipients of first 8/8 HLA-matched or 1-locus mismatched unrelated donor (MUD, MMUD) RIC HCT performed in the period 1999-2011 and registered in the CIBMTR. HLA-A, -B, -C and -DRB1 loci were typed in all pairs at high resolution; -DQB1 and -DPB1 loci could not be evaluated in all pairs. Transplants involving ex-vivo T-cell depletion, CD34+ selection, or post-transplant cyclophosphamide were excluded. Overall survival (OS) was the primary outcome. Secondary outcomes included non-relapse mortality (NRM), relapse, disease-free survival (DFS) and acute and chronic GVHD. Individual locus mismatch was also assessed. Apart from HLA matching, variables related to patient (age, race, sex, KPS, diagnosis, disease-risk), donor (age, parity), both (sex match/ABO match/CMV match) treatment (conditioning intensity, TBI use, in-vivo T-cell depletion (ATG), graft source (PB, BM) and GVHD prophylaxis (CyA-, Tac-based)) were considered. 2588 RIC HCT (8/8 MUD: 2025; 7/8 MMUD: 563) from 144 centers and 12 countries were analyzed. Median follow up in 8/8 MUD and 7/8 MMUD was 38 and 48 months respectively. Diagnoses were AML (65%), ALL (8%), CML (7%), MDS (20%). Conditioning intensity was RIC (79%), NMA (21%). 58% received in-vivo T-cell depletion. Graft source was PBSC (85%), BM (15%). GVHD prophylaxis was Tac-based (70%), CyA-based (27%). Mismatches involved HLA-A (188), -B (81), -C (219), and -DRB1 (75); with -DPB1 and -DQB1 typing available in 1382 and 2502 cases respectively. Compared to 8/8 MUD, 7/8 MMUD recipients were more likely to be younger and ethnic minorities and to have older and parous donors. In univariate analyses DQB1- and -DPB1 mismatch was not associated with worse OS, DFS, or NRM and was not further evaluated. There was a trend toward more grade II-IV acute GVHD in -DPB1 double (p=0.02) but not single mismatches. In multivariate models 7/8 MMUD RIC HCT had worse grade II-IV and III-IV acute GVHD, NRM, DFS and OS, but not relapse or chronic GVHD (Table). No significant interactions were identified between degree of HLA matching and other clinical variables. Adjusted 1- and 3-year NRM for 8/8 MUD vs. 7/8 MMUD was 20.4% vs. 28.9% (p<0.0001) and 29.2% vs. 38.1% (p<0.0007) respectively. Adjusted 1- and 3-year OS was 54.7% vs. 48.8% (p=0.01) and 37.4% vs. 30.9% (p=0.005) respectively (Figure). There was no difference between allele and antigen mismatches. HLA-A, -B, -C, and -DRB1 locus mismatches were each associated with 1 or more impaired outcomes (acute GVHD, NRM, DFS, and/or OS). Table 1 7/8 vs. 8/8 HLA HR (95% CI) p-value Acute GVHD II-IV 1.29 (1.09-1.53) 0.003 Acute GVHD III-IV 1.69 (1.00-3.36) 0.05 Chronic GVHD 1.11 (0.96-1.28) 0.15 Relapse 1.01 (0.87-1.17) 0.92 NRM 1.52 (1.29-1.79) <0.0001 DFS 1.20 (1.07-1.34) 0.0015 OS 1.25 (1.11-1.40) 0.0001 Compared to 8/8 MUD, both 7/8 allele and antigen MMUD RIC HCT have greater treatment toxicity and worse survival, of a magnitude similar to that seen in myeloablative transplantation. An isolated mismatch at HLA-A, -B, -C, or -DRB1 was associated with 1 or more adverse outcomes. In unrelated donor RIC HCT, matching for all alleles of HLA-A, -B, -C and -DRB1 loci results in superior outcomes. Disclosures: No relevant conflicts of interest to declare.

HLA-Haploidentical Familial Donor Hematopoietic Cell Transplantation without Ex Vivo- T Cell Depletion after Reduced-Intensity Conditioning of Busulfan, Fludarabine, and Anti-Thymocyte Globulin: A Preliminary Report.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3077-3077
Author(s):  
Kyoo-Hyung Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Ho-Jin Shin ◽  
Young-Shin Lee ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Reduced Intensity

Abstract Animal hematopoietic cell transplantation (HCT) models and several small clinical trials showed that successful engraftment can be achieved across HLA-haplotype difference after reduced-intensity conditioning (RIC). Furthermore, decreased graft-versus-host disease (GVHD) and transplantation-related mortality (TRM) after RIC was shown in a swine leukocyte antigen-haploidentical HCT experiment. Therefore, a protocol investigating the role of RIC in HLA-haploidentical familial donor HCT was initiated in April 2004 and 20 patients [13 male and 7 female; median age 26.5 years (16–65)] without HLA-matched donor enrolled until June 2007. The diagnosis were AML (n=9), ALL (n=4), acute biphenotypic leukemia (n=1), MDS (n=4), and SAA (n=2), and all patients had high-risk features, i.e. first complete remission (CR) but with high-risk chromosomal abnormality (n=1), first CR after salvage (n=1), second CR (n=6), recurrent/refractory state (n=7), immunotherapy failure (n=4), and high-risk MDS (RAEB-1, n=1). The RIC included iv busulfan 3.2 mg/kg × 2, fludarabine 30 mg/m2 × 6, plus anti-thymocyte globulin [Thymoglobuline 3 mg/kg (n=17) or Lymphoglobuline 15 mg/kg (n=3)] × 4. After receiving G-CSF, the donors (13 mothers; 5 offsprings; and 2 HLA-haploidentical siblings) underwent 2 or 3 daily leukapheresis, and the collected cells were given to patients without T cell depletion [medians of; 7.9 (3.7–12.1)×108/kg MNC, 6.9 (3.6–73.5)×106/kg CD34+ cells, and 4.6 (1.8–8.5)×108/kg CD3+ cells]. GVHD prophylaxis was cyclosporine 3 mg/kg/day iv from day -1 and a short course of methotrexate. As a part of separate phase 1 study, the two most-recently enrolled patients received additional donor CD34+ cell-derived NK cells 6 weeks after HCT. Except one patients with SAA who died due to K. pneumoniae sepsis on day 18, all 19 evaluable patients engrafted with ANC> 500/μl median 17 days (12–53) and platelet> 20,000/μl median 23 days (12–100) after HCT. Eight patients experienced acute GVHD (grades I, II, III, and IV; 2, 3, 2, and 1, respectively). Cumulative incidences (CI) of overall and grade II-IV acute GVHD were 40 and 30%, respectively. Eight patients experienced chronic GVHD (limited, 4; extensive, 4; CI, 51%). Fourteen showed positive CMV antigenemia, while 2 suffered CMV colitis, which resolved after treatment. As early as 2 weeks after HCT, 15 of 16 evaluable patients, and, by 4 weeks, all of 17 evaluable patients showed donor chimerism ≥95% on STR-PCR, which was maintained until 24 weeks in all 11 patients tested. Thirteen patients are alive after median follow-up of 13.6 months (1.5–37.9; Kaplan-Meier survival, 55.6%). Of 16 patients with acute leukemia and high-risk MDS, 8 remain alive without recurrence (event-free-survival, 40.9%). Two patients died of K. pneumoniae sepsis and grade IV acute GVHD, respectively (CI of TRM, 11%). Immune recovery in 10 patients without relapse for > 6 months showed robust lymphocyte contents and immunoglobulin levels at 6 months (means of; 1,060/ul CD3+, 222/ul CD4+, 767/ul CD8+ cells, and 1,317 mg/dl IgG) and 12 months. After RIC, consistent engraftment and durable complete donor hematopoietic chimerism can be achieved from HLA-haploidentical familial donor. The frequencies of GVHD and TRM were low.

scholarly journals Improved Gvhd Free, Relapse Free Survival Using Dual T-Cell Depletion with ATG and Ptcy in Matched Unrelated Donor RIC Allo-HSCT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4594-4594
Author(s):  
Maria Queralt Salas ◽  
Wilson Lam ◽  
Arjun Law ◽  
Fotios V. Michelis ◽  
Dennis Dong Hwan Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Effective Control ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
The Impact

Introduction The combination of anti-thymoglobulin (ATG), post-transplant cyclophosphamide (PTCy) and cyclosporine (CsA) provides an effective control of graft-versus host disease (GVHD) in allo-HSCT using peripheral blood stem cell (PBSC) grafts, as has been reported by Dr. Viswabandya et al. We aim to report a large, single center experience in reduced intensity conditioning (RIC) allo-HSCT using dual T-cell depletion with ATG and PTCy combined with CsA for GVHD prophylaxis using grafts from 10/10 matched unrelated donors. Patients and methods Between October 2015 and April 2019, 167 adult patients diagnosed with hematological malignancies underwent first 10/10 MUD RIC allo-HSCT. RIC regimen was composed by fludarabine, busulfan, and 200cGy of total body irradiation. For GVHD prophylaxis all recipients received rabbit-ATG, PTCy 50mg/m2/day on day +3 and +4, and CsA since day +5. One hundred sixteen (69.5%) recipients, transplanted between 2015 and May 2018, received a total dose of 4.5mg/kg of rabbit-ATG (given on day -3,-2 and -1). In May 2018, the dose of ATG was lowered to a total of 2mg/kg (given on day -3 and -2). A total of 51 (30.5%) recipients received the lowered dose of ATG. The median follow-up of the entire cohort was 14 months (range: 0.4-44.5). For those patients who got a higher dose of ATG was 20 months and for those who received a lower dose of ATG was 8.8 months. Data was collected retrospectively and updated on July 2019. Cumulative incidence (Cum.Inc) of GVHD analysis was assessed accounting relapse and death as competing events. Results Baseline and post-transplant information are summarized in the Table 1 and 2. Ninety-three (55.7%) recipients were diagnosed with acute myeloid leukemia (AML). The cum.Inc of grade II-IV and grade III-IV acute GVHD at day +100 was respectively 15.6% (95% confidence interval (CI) 10.6-21.6) and 3.6% (95% CI 1.5-7.3). The cum.Inc of acute GVHD was not significantly affected by the dose of ATG (P>0.05). The cum.Inc of chronic GVHD was 10.9% (95% CI 6.6-16.4). Due to the shorter median follow up of the cohort that received a lower dose of ATG, the impact of the reduction of the dose in the cum.Inc of chronic GVHD was not explored. Overall, 48 (28.7%) recipients died and 35 (20.4%) relapsed. Main causes of death were relapse (14.4%) and infection (9.6%). Outcome information is reported in the Table 2 and Plot A, B and C. One-year overall survival (OS), relapse-free survival (RFS) and GVHD-free/RFS (GFRFS) were respectively 75.6%, 70.3%, 60.4%. Table 3 summarizes the impact of the use of a different dose of ATG in acute GVHD and post-transplant outcome. No significant differences were found between the two groups that receive a different dose of ATG. However, median follow-up was shorter in the cohort that received 2mg/kg of ATG. Table 4 reports the main post-allo-HSCT information of patients diagnosed with AML. One-year OS, RFS and GRFRS for this subgroup of patients were 76.8%, 71.9% and 65.9%. Conclusion The unique and modern combination of RIC PB allo-HSCT using ATG, PTCY and CsA for GVHD prophylaxis results in impressive post-transplant outcomes using 10/10 MUD. The use of dual T-cell depletion with ATG and PTCy is safe and provides an extraordinary control of GVHD with acceptable relapse rates using PB stem cell 10/10 MUD grafts. ATG of only 2mg/kg when it is combined with PTCy and CsA, results in an effective control of acute GVHD rates. The optimal dose of ATG for GVHD prophylaxis is not well established. Further investigations need to be done to determine the efficacy of a lower dose of ATG controlling chronic GVHD in this setting. For patients diagnosed with AML, this protocol is safe and an effective approach when a 10/10 MUD is available. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Celgene: Honoraria; Gilead: Honoraria; Therakos: Honoraria.

Feasibility of Cyclosporine and Short-Term Methotrexate for Graft-Vs.-Host disease Prophylaxis in T-Cell-Replete, Reduced-Intensity Allogeneic Bone Marrow Transplantation From Unrelated Donors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4347-4347
Author(s):  
Takahiko Nakane ◽  
Hirohisa Nakamae ◽  
Hideo Koh ◽  
Mika Nakamae ◽  
Yoshiki Hayashi ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Risk Group ◽  
Cell Depletion ◽  
Short Term ◽  
T Cell Depletion ◽  
Prior Chemotherapy ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Abstract 4347 Optimal graft-vs.-host disease (GVHD) prophylaxis in T-cell-replete, reduced-intensity allogeneic stem cell transplantation from an unrelated donor (u-RIST) has not been established yet. Tacrolimus-based acute GVHD prophylaxis has been widely used in allogeneic stem cell transplantation from unrelated donors. In addition, T-cell-depletion conditioning regimen containing anti-thymocyte globulin (ATG), or alemtuzumab with/without 2-4 Gy total body irradiation (TBI) has been reportedly applied in u-RIST. However, in-vivo T cell depletion using ATG or alemtuzumab may cause increased risk of infection or relapse after transplantation. TBI may also possibly cause increased incidence of GVHD via tissue damage. Here we report the feasibility of using cyclosporine and short-term methotrexate for GVHD prophylaxis in u-RIST. The conditioning regimen consisted of fludarabine and busulfan (Flu+Bu) without T-cell depletion, such as ATG or alemtuzumab, and without TBI for u-RIST in patients who received prior chemotherapy. In this study, we retrospectively analyzed 30 consecutive patients with hematologic malignancies (median age: 53; range: 22 to 69 years; AML: 11; ALL: 9; MDS: 2; NHL: 5; ATL/L: 3) who received unrelated-donor bone marrow transplantation from HLA 6/6 (A, B, DRB1), either allele-matched (n = 24 patients), one DRB1 allele-mismatched (n = 5 patients), or one A allele-mismatched (n=1) donor at our institution between September 2002 and June 2009. All patients received at least one cycle of prior chemotherapy (median cycle: 6; range: 1 to 19). Of these, 15 patients (50%) were at high risk of relapse. For all, acute GVHD prophylaxis consisted of cyclosporine and short-term methotrexate (day 1: 10mg/m2; day 3 and 5: 7 mg/m2). The reduced intensity conditioning consisted of fludarabine 180mg/m2 and oral busulfan 8 mg/kg for 12 patients; the other 18 patients' conditioning consisted of fludarabine 180 mg/m2 and intravenous busulfan 8mg/kg. Neutrophil and platelet engraftments were achieved in 100% (30/30) and 93% (28/30) of patients, respectively. The median times for neutrophil and platelet engraftments were 16 days (range: 12 to 26 days) and 24.5 days (range: 18 to 291 days), respectively. In patients receiving oral and intravenous busulfan for conditioning, the achievement rates of complete T-cell chimerism by day 100 were 75% (9/12) and 100% (18/18), respectively (p = 0.03). The median period of follow-up was 280 days (range: 34∼1987). During the follow-up our observational periods, 19 patients were alive and 11 patients died of relapse (n = 8) or transplant-related mortality (n = 3). The cumulative incidences of acute GVHD of grade II to IV and III to IV at day 100 were 40% and 17%, respectively. Extensive type of chronic GVHD was 30% in 23 evaluable patients. The 2-year overall survival (OS) and event-free survival rates were 58% (low/standard risk group: 78%; high risk group: 43%; p = 0.04) and 52% (low/standard risk group: 72%; high risk group: 33%; p = 0.01), respectively. In multivariate analysis, grade III to IV acute GVHD and disease status at high relapse were significantly associated with worse OS (p = 0.03 and 0.008, respectively). Day 100 and 2-year TRM were 3% and 10%, respectively. Cyclosporine and short-term methotrexate for GVHD prophylaxis without T-cell deplete-conditioning allowed acceptable incidence of GVHD even in u-RIST. Additionally, only Flu+Bu conditioning for uRIST ensured high rate of complete T-cell chimerism especially in patients receiving intravenous busulfan. Our results suggested that we might be required to determine optimal conditioning and GVHD prophylaxis regimens based on patient characteristics, including a history of prior chemotherapy. Disclosures: Hino: Kyowa Hakko Kirin Co., Ltd. : Research Funding.

scholarly journals Association between preconditioning absolute lymphocyte count and transplant outcomes in patients undergoing matched unrelated donor allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning and anti-thymocyte globulin

2021 ◽  
Vol 12 ◽  
pp. 204062072110637
Author(s):  
Jeongmin Seo ◽  
Dong-Yeop Shin ◽  
Youngil Koh ◽  
Inho Kim ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Matched Unrelated Donor ◽  
T Cell Depletion ◽  
Reduced Intensity

Background: Allogeneic stem cell transplantation (alloSCT) offers cure chance for various hematologic malignancies, but graft- versus-host disease (GVHD) remains a major impediment. Anti-thymocyte globulin (ATG) is used for prophylactic T-cell depletion and GVHD prevention, but there are no clear guidelines for the optimal dosing of ATG. It is suspected that for patients with low absolute lymphocyte counts (ALCs), current weight-based dosing of ATG can be excessive, which can result in profound T-cell depletion and poor transplant outcome. Methods: The objective of the study is to evaluate the association of low preconditioning ALC with outcomes in patients undergoing matched unrelated donor (MUD) alloSCT with reduced-intensity conditioning (RIC) and ATG. We conducted a single-center retrospective longitudinal cohort study of acute leukemia and myelodysplastic syndrome patients over 18 years old undergoing alloSCT. In total, 64 patients were included and dichotomized into lower ALC and higher ALC groups with the cutoff of 500/μl on D-7. Results: Patients with preconditioning ALC <500/μl were associated with shorter overall survival (OS) and higher infectious mortality. The incidence of acute GVHD and moderate-severe chronic GVHD as well as relapse rates did not differ according to preconditioning ALC. In multivariate analyses, low preconditioning ALC was recognized as an independent adverse prognostic factor for OS. Conclusion: Patients with lower ALC are exposed to excessive dose of ATG, leading to profound T-cell depletion that results in higher infectious mortality and shorter OS. Our results call for the implementation of more creative dosing regimens for patients with low preconditioning ALC.

Reduced‐intensity conditioning allogeneic transplant with dual T‐cell depletion in myelofibrosis

2019 ◽  
Vol 103 (6) ◽  
pp. 597-606 ◽  
Author(s):  
Maria Queralt Salas ◽  
Wilson Lam ◽  
Arjun Datt Law ◽  
Dennis (Dong Hwan) Kim ◽  
Fotios V. Michelis ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Depletion ◽  
Allogeneic Transplant ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Reduced Intensity

A Comparative Analysis of Immune Reconstitution Following Reduced Intensity Conditioning with CAMPATH-1H and Total Lymphoid Irradiation/Anti-Thymocyte Globulin Prior to Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1148-1148
Author(s):  
Brett Glotzbecker ◽  
Heidi Mills ◽  
Jacalyn Rosenblatt ◽  
Zekui Wu ◽  
Kerry Wellenstein ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Depletion ◽  
T Cell Proliferation ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Post Transplant ◽  
Initial Cohort ◽  
Reduced Intensity

Abstract Abstract 1148 Poster Board I-170 Graft versus host disease (GVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). In vivo quantitative T-cell depletion using CAMPATH-1h (anti-CD52) has been explored in an effort to prevent acute GVHD. More recently, a regimen consisting of total lymphoid irradiation and anti-thymocyte globulin (ATG) has been shown to polarize T cells towards an inhibitory phenotype potentially reducing the associated risk for GVHD. However, these strategies may be associated with impaired post-transplant immune reconstitution, increased risk of tumor relapse and opportunistic infection. In this study we examined the pattern of cellular immune recovery following T cell depletion with CAMPATH-1h and compared results with an initial cohort of patients undergoing reduced intensity conditioning with TLI and ATG. Immunologic analyses were performed on twenty patients undergoing reduced intensity conditioning in conjunction with low dose CAMPATH -1h (50 mg) and an initial cohort of 5 patients treated with TLI/ATG. Conditioning with CAMPATH-1h resulted in the significant depletion of CD3, CD4, and CD8 T cells in the early post-transplant period and persistence of CD4 T cell depletion (< 200 cells /uL) for more than 6 months. Following TLI/ATG, persistent depletion of CD4+ T cells was also observed but no significant decrease in CD8 T cells was seen. A two-fold increase in circulating CD56+ NK cells, 21.8 to 41.6% (p=0.004), was seen following TLI-ATG, which was not noted following Campath conditioning. CAMPATH-1h conditioning was associated with a significant decrease in mean CD45RO+ memory T cells in the early post-transplant period (27.2 to 5.7% of the total population of nonadherent peripheral blood mononuclear cells, p=0.034). Relative percentages of naïve T cells (CD45RA+), central memory (CD45RO+CD62L+CCR7+) (CM), and effector memory (CD45RO+CD62L-CCR7-) (EM) T cells remained stable in the pre- and post-transplantation period. The CM:EM was 0.6 pre-transplant and at day 60, respectively. In contrast, T cell recovery in early post-transplant following the TLI/ATG regimen was associated with no reduction in CD45RO+ memory T cells. A significant rise in the relative percentages of naïve T cells from 39 to 61.3% (p=0.04), CM cells from 12 to 32.8% (p=0.05), a corresponding fall in EM cells from 57.9 to 32.5% (p=0.10), and a significant change in the CM:EM levels (0.2 pre-transplant, 1.0 day 60 post-transplant) was noted after TLI/ATG. The mean percentage of regulatory T cells as defined by the percentage of CD4+/CD25+ cells that express FoxP3 rose in the early post-transplant period following both regimens (8 to 20.7% at Day 30, p=0.003 in the CAMPATH group; 5.6 to 16.9% at Day 30, p=0.03 in the ATG/TLI group). Functional analyses demonstrated that the T cell proliferative response to the mitogen, Phytohemagglutinin (PHA), was profoundly depressed following CAMPATH-1h with mean SI decreasing from 34 pre-transplant to 1.4 at Day 30. In contrast, treatment with TLI/ATG resulted in no significant change in T cell proliferation in response to PHA with SI only decreasing from 45 pre-transplant to 36 at Day 30. Assessment of T cell polarization following stimulation with PHA or phorbol-ester (PMA)/ionomycin, recipient derived dendritic cells (DCs) or third party DCs demonstrated a rise of CD8+ T cells expressing, IL-4 and IL-10 consistent with a suppressor phenotype. Minimal T cell proliferation was observed following stimulation with patient derived DCs, which is consistent with suppression of the expansion of alloreactive T cells. In summary, both CAMPATH and TLI/ATG result in CD4+ T cell depletion but TLI/ATG resulted in relative preservation of CD8+ T cells, persistence of memory cells, relative preservation of central memory as compared to memory effector cells and intact response to mitogens. TLI/ATG therapy was also associated with the polarization of CD8+ T cells towards a Tc2 phenotype and lack of proliferation in response to recipient derived DCs. As such, TLI/ATG appears to be associated with more modest level of functional T cell depletion characterized by Tc2 polarization and suppression of host/donor alloreactivity. Disclosures Spitzer: Genzyme: Consultancy. Avigan:Genzyme: Consultancy.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2305-2305 ◽  
Author(s):  
Robert J Soiffer ◽  
Jennifer LeRademacher ◽  
Vincent T Ho ◽  
Fangyu Kan ◽  
Andrew Artz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Cell Depletion ◽  
P Value ◽  
Unrelated Donor ◽  
T Cell Depletion

Abstract Abstract 2305 HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial. Alemtuzumab vs. T-cell replete ATG vs. T-cell replete Alemtuzumab vs. ATG Hazard ratio, p-value Hazard ratio, p-value Hazard ratio, p-value Grade 2-4 acute GVHD 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 Grade 3-4 acute GVHD 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse mortality 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 Relapse 1.54, p=0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 Disclosures: No relevant conflicts of interest to declare.

Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplant with in Vivo T-Cell Depletion By Alemtuzumab: Incidence, Outcome and Pattern of Organ Involvement

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3912-3912 ◽  
Author(s):  
Maria Chiara Finazzi ◽  
Cristina Boschini ◽  
Janice Ward ◽  
Charles Craddock ◽  
Alessandro Rambaldi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Organ Involvement ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
T Cell Depletion

Abstract Introduction Graft-versus-Host Disease (GvHD) is one of the leading causes of mortality and morbidity following allogeneic stem cell transplant. In vivo T cell depletion by alemtuzumab as part of the transplant conditioning is an effective strategy to reduce the risk of GvHD. While it is recognised that the overall incidence of GvHD is reduced by alemtuzumab, the incidence of chronic GvHD as defined by the National Institute of Health (NIH) consensus criteria, the impact on outcome, and the pattern of organ involvement have not been defined yet in this transplant setting. Methods Consecutive patients (n = 323) undergoing allogeneic stem cell transplantation at the Queen Elizabeth Hospital, Birmingham, between January 1 2008 and June 30 2012 were reviewed in this retrospective, single centre study. Medical records were examined and data regarding the development of GvHD were collected; NIH consensus criteria for diagnosis and staging of chronic GvHD were stringently applied. Clinical characteristics of GvHD occurring in patients transplanted following T cell depletion by alemtuzumab administration (n=248) were compared with those of patients transplanted with a T cell replete graft (n=75). Patients receiving alemtuzumab were mainly treated with reduced-intensity conditioning protocols, while patients in the no-T-cell depletion group were mainly treated with a myeloablative, sibling transplant. Results After a median follow up of 38.4 months, the cumulative incidence (CI) of grade II-IV classic acute GvHD was 35% and 48% for patients transplanted respectively with or without T cell depletion by alemtuzumab (p= 0.041, Figure 1); with a CI of grade III-IV classic acute GvHD of 13% and 27% (p=0.007). The 2-years CI of grade II-IV late acute GvHD was not significantly different in the two groups (20% and 23% for patients respectively treated with or without alemtuzumab, p=0.589, Figure 2). T cell depletion by alemtuzumab significantly reduces the 3 years cumulative incidence of classic chronic GvHD (5% versus 31%, p<0.0001, Figure 3.A), but without a significant difference in the incidence of overlap syndrome between patients with and without T cell depletion (3 years CI respectively 6% and 7%, p=0.839, Figure 3.B). The pattern of organ involvement by classic acute GvHD was similar in patients with and without T cell depletion. The pattern of organ involvement by late acute GvHD in the alemtuzumab group was, however, significantly different compared to the T cell replete group (skin-gut-liver involvement reported respectively in 83%-28%-4% of patients and 56%-48%-20% of patients, p=0.003). Distribution of organ involvement by classic chronic and overlap syndrome was similar in the two groups; however, it seems that alemtuzumab prevents the development of lung GvHD (lung GvHD developed in 4 patients over the 75 patients of the no-T-cell depletion group, while none of the 248 patients transplanted with alemtuzumab experienced lung GvHD). In a multivariate analysis, the development of chronic GvHD was an independent predictor of higher mortality risk (HR 1.66, p = 0.04) and severe NIH global score at peak was confirmed as a poor prognostic factor for survival (HR 2.27, p=0.02). The negative impact of chronic GvHD and of the severe forms of chronic GvHD was independent of age and alemtuzumab administration. Conclusion This retrospective analysis provides for the first time data on the incidence rates of NIH-defined GvHD categories in patients transplanted after T cell depletion by alemtuzumab. Patients transplanted with alemtuzumab experienced a lower incidence of classic acute and classic chronic GvHD compared to patients not receiving T cell depletion. In contrast, alemtuzumab conditioning appeared to have no effect on the incidence of late acute GvHD or overlap syndrome, suggesting that these two entities of GvHD are driven by different immunological mechanisms as compared to classic acute and classic chronic GvHD. We also confirmed the utility of the NIH classification of GvHD and of the NIH global severity score to predict survival in alemtuzumab-conditioned allogeneic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

Comparable Outcomes after Allogeneic Stem-Cell Transplantation with Intravenous Busulfan or Treosulfan-Based Reduced-Intensity and Reduced Toxicity Regimens in Acute Myeloid Leukemia. a Study on Behalf of the Acute Leukemia Working Party of EBMT

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2280-2280
Author(s):  
Avichai Shimoni ◽  
Myriam Labopin ◽  
Bipin N. Savani ◽  
Rose-Marie Hamladji ◽  
Dietrich W. Beelen ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Advanced Disease ◽  
Chronic Gvhd ◽  
Working Party ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Reduced Toxicity

Abstract Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). Myeloablative conditioning (MAC) is associated with prohibitive rates of non-relapse mortality (NRM) in older and less medically fit patients. Several reduced intensity conditioning regimens (RIC) and more recently the more dose-intensive reduced toxicity myeloablative (RTC) regimens were designed to replace MAC in this setting. The backbone of these regimens is usually fludarabine with busulfan and more recently also with treosulfan, but there is no clear data on the comparative outcomes with these different regimens in the different SCT settings. The current study included 3561 patients with AML given a first allogeneic SCT from an HLA-matched sibling (n=1683) or a 10/10 matched unrelated donor (n=1878) between the years 2000-2014 and reported to the acute leukemia working party (ALWP) of EBMT. Only patients given fludarabine with either intravenous busulfan (ivBu), (FB, n=2990) or treosulfan (FT, n=571) alone were analyzed. Fludarabine and ivBu at 6.4 mg/kg (n=1457) or treosulfan at 30-36 gr/m2 (n=168) were considered RIC regimens while fludarabine with ivBu at a total dose of 9.6-12.8 mg/kg (n=1533) or treosulfan at 42 gr/m2(n=403) were considered RTC regimens according to EBMT criteria. The median age of FB and FT recipients was 55.5 and 58.3 years, respectively (P< 0.0001). The status at SCT was 72.5% CR1, 15.0% CR2 and 12.5% advanced disease in the FB group compared to 55.0%, 20.3% and 24.7% in the FT group, respectively (P<0.0001). More FT recipients had SCT from unrelated donors (64.8% Vs. 50.4%, P<0.0001) but less had in-vivo T-cell depletion (58.4%Vs 70.5%, P<0.0001). Cytogenetic subgroup distribution was similar between the groups. Ninety percent had peripheral blood stem cell grafts in both groups. The median follow-up was 19 and 43 months after FB and FT, respectively. Using univariant analysis, the 2-year relapse incidence (RI) was 32.7% and 35.5%, respectively (P=0.49). NRM was 17.6% and 19.4%, respectively (P=0.09). Leukemia-free survival (LFS) and overall survival (OS) were 49.5% and 54.8% after FB and 45.1% and 52.6% after FT, respectively (P=0.04, P=0.17). Acute GVHD grade II-IV and chronic GVHD were 23.1% and 35.7% after FB and 18.8% and 39.8% after FT, respectively (P=0.03, P=0.04). In all, the GVHD/ relapse-free survival (GRFS) was 36.5% and 31.5%, respectively (P=0.08). After adjusting for the differences in patient characteristics, there was no difference between the FB and FT groups in RI, NRM, LFS, OS and GRFS. However, acute GVHD grade (II-IV) was higher after FB (HR, 1.49, P=0.0004). The same observations were seen when the analysis was limited to RIC or RTC regimens only, or when only patients in remission were analyzed. However, when analyzing only the 516 patients with advanced disease at SCT, 2-year OS was 29.7% and 43.0% after FB and FT (P=0.002) and this difference remained significant in the multivariant analysis (HR, 1.50, p=0.003). Among the entire group, the factors associated with reduced survival were advanced age (HR 1.01, P<0.0001), secondary AML (HR 1.19, P=0.005), CR2 (HR 1.21, P=0.007) and advanced disease (HR 2.02, P<0.0001) compared to CR1, and female donor to male recipient (HR 1.15, P=0.03). Conditioning type and intensity, donor type, CMV status and in vivo T-cell depletion were not significant. Relapse was lower and NRM was higher with RTC compared with RIC, but OS was similar. The same factors predicted for GRFS, a surrogate for quality of life, with the only difference been the positive role of in vivo T-cell depletion (HR 0.8, P=0.0002). In conclusion, RIC and RTC regimens with ivBu or treosulfan-based regimens are associated with similar transplantation outcomes. OS is primarily affected by disease factors such as status of disease at SCT and secondary leukemia. Treosulfan- based conditioning is associated with a lower rate of acute GVHD, but with similar rates of chronic GVHD, NRM and GRFS. Treosulfan conditioning may have some advantage in patients with advanced disease at SCT. Disclosures No relevant conflicts of interest to declare.

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