PF761 REDUCED INTENSITY CONDITIONING REGIMEN WITH ALEMTUZUMAB BASED T CELL DEPLETION ENABLES EARLY POST-TRANSPLANTATION CELLULAR INTERVENTION RESTORING GRAFT VERSUS LEUKEMIA EFFECTS IN OLDER AML PATIENTS

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.

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

European Journal Of Haematology ◽

10.1111/ejh.13327 ◽

2019 ◽

Vol 103 (6) ◽

pp. 597-606 ◽

Cited By ~ 1

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

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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 ◽

10.1182/blood.v110.11.3077.3077 ◽

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.

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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 ◽

10.1182/blood.v114.22.1148.1148 ◽

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.

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

Blood ◽

10.1182/blood.v124.21.1206.1206 ◽

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.

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