scholarly journals HLA-Haploidentical Hematopoietic Cell Transplantation of Ex Vivo Tcrαβ-Depleted Grafts with CD45RA-Depleted Memory T Cell Add-Back in Adults and Children with Hematological Malignancies: 4-Year Follow-up of Multicenter Study in Singapore

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 555-555
Author(s):  
Ian Q Wu ◽  
Yeh Ching Linn ◽  
Yang Liang Boo ◽  
Rajat Bhattacharyya ◽  
Zi Yi Lim ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Grade Ii

Abstract Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donors. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications are main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells will permit hematopoietic engraftment while effectively reducing GVHD and providing donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC products were divided into two fractions in 9:1 ratio and depleted using CliniMACS device after labelling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany) respectively. All except 6 patients received the standard conditioning regimen of fludarabine 160mg/m 2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70 - 140mg/m 2 for 1 day, in combination with either total lymphoid irradiation 6Gy (n=53) or 7.5Gy (n=12) over 3 equal fractions, or total body irradiation of 2Gy (n=17), or thymoglobulin (n=2). Short term GVHD prophylaxis was given for 30 days to 1 patient using MMF, 73 using tacrolimus, and 2 using sirolimus. Results: Between January 2017 and July 2021, we transplanted 85 patients, including 78 adults (median age, 48 years; range 20 - 70) and 7 children (median age, 13 years, range 7 - 17), with high risk AML (n=44), ALL (n=19), MDS (n=9), plasma cell neoplasm (n=4), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), CMMoL (n=2), CML (n=1) and lymphoma (n=2). Patients were infused with TCRαβ and CD45RA depleted grafts containing median of 6.19 x 10 6 (range 3.54 - 20.78) CD34+ cells/kg, 0.00 x 10 4 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 1.10 x 10 6 (range 0.15 - 11.67) CD45RO+CD3+ cells/kg. TCRαβ depleted graft fraction contained a median of 0.42 x 10 4 (range 0 - 11.30) TCRαβ+ cells/kg, and 7.61 x 10 6 (range 0.62 - 31.84) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure with no secondary graft failures. All others had engraftment of ANC > 500 cells/µL at median of 12 days (range 8 - 22) and PLT > 20,000 cells/µL at median of 11 days (range 7 - 17). 6 patients with high donor-specific HLA antibodies (DSA) titres engrafted successfully after desensitisation with plasma exchange, rituximab, and immunoglobulin. 29 patients (34%) developed acute GVHD of grade II - IV (Gd II, n=20; Gd III, n=5; Gd IV, n=4), with a cumulative incidence (CI) of grade II-IV and grade III-IV of 31% (95% CI 21-42%) and 11% (95% CI 5-19%) respectively, at 100 days. Chronic GVHD was seen in only 4 patients at a 2-year CI of 6% (95% CI 2-13%). 1-year CI of non-relapse mortality (NRM) and relapse were 22.7% (95% CI 13.9 - 32.9%) and 15.7% (95% CI 8.3 - 25.3%) respectively. 4 of the 17 NRM were attributed to aGVHD. Viral reactivation included CMV (n=32), HHV-6 (n=22), EBV (n=15), and adenovirus (n=8). 15 patients (17.6%) died of infection within 180 days, including 6 patients with fatal bacteraemia (bacteria, n=4; candidemia, n=2) and 1 patient from disseminated adenovirus infection. At a median follow up of 448 days (range 16- 1648) in surviving patients, 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 64.2 %, 54.0 %, and 49.0%, respectively (Figure 1). In multivariate analysis, only HCT-comorbidity index (HCT-CI) showed significant impact on OS (HR 3.38; 95% CI 1.42 - 8.02; p=0.0059), EFS (HR 2.62; 95% CI 1.18 - 5.76; p=0.0017), and NRM (HR 4.92; 95% CI 1.79 - 13.58; p=0.0021). Disease risk index (DRI) showed a trend in higher risk of relapse (HR 2.83; 95% CI 0.96 - 8.33; p=0.059). 2-year OS, EFS, and GRFS for the subset of 58 patients (adults, n=52; children, n=6) with HCT-CI score of 0 were 76.6 %, 63.4%, and 57.5 %, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allow successful allograft in high-risk patients lacking suitable matched donors, including patients with high levels of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD. Best outcomes are seen in patients with favourable HCT-CI. Further efforts are needed to reduce the risk of infection-related death in patients with high risk HCT-CI, and relapse in patients with high risk DRI, through optimization of anti-microbial prophylaxis or prophylactic infusion of memory-cell DLI. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Αβ and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies- Two-Year Follow-up of Multicenter Study in Singapore

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2039-2039 ◽  
Author(s):  
Li Mei Poon ◽  
Yeh Ching Linn ◽  
Poh Lin Tan ◽  
Ziyi LIM ◽  
Balamurugan Vellayappan ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hla Antibodies ◽  
Day Range ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Matched Donor

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. GVHD, engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK cells, γδ T cells and CD45RO+ memory T cells. Methods: Mobilized PBSC product were divided into two fractions in 9:1 ratio, and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of fludarabine 160 mg/m2 divided daily over 4 days, thiotepa 10 mg/kg divided twice daily for 1 day and melphalan 70-140 mg/m2 for 1 day, in combination with total lymphoid irradiation 6 Gy (n=23), or 7.5 Gy (n=12) over 3 equal fractions, or total body irradiation of 2 Gy (n=2). Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 25 patients using tacrolimus and 2 patients using sirolimus. Results: We transplanted 37 patients, including 32 adults (median age 47 years, range 20 - 69) and 5 children (median age 13 years, range 7-15 years) with high risk AML (n=17), ALL (n=11), MDS (n=5), myeloma (n=1), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1) or NK/T lymphoma (n=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 8.65 x 106 (range, 3.54 - 20.78) CD34+ cells/kg, 0.00 x 104 (range 0 - 0.97) CD45RA+CD3+ cells/kg, and 2.4 x 106 (range, 0.15 - 11.67) CD45RO+CD3+ cells/kg. The TCRαβ depleted graft fraction contained a median of 0.19 x 104 (range 0 - 8.53) TCRαβ+ cells/kg, and 8.76 x 106 (range 1.73 - 30.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure. All others had engraftment of ANC > 500 cells/µL at a median of 10 day (range, 8 - 22) and PLT > 20,000 cells/µL at a median of 12 day (range, 7 - 19). There was no secondary graft failure. Four patients with high titers of donor-specific HLA antibodies (DSA) engrafted successfully after effective desensitisation with plasma exchange, rituximab and immunoglobulin. Fourteen patients (38%) developed acute GVHD of grade II-IV (Gd II n=9 ; Gd III n=4 ; Gd IV n=1 ). Only one patient experienced chronic GVHD, giving 2 year cumulative incidence (CI) of chronic GVHD of 3.9 %. Day 180 CI of NRM and relapse were 22.7 % (95% 10.5-37.7%) and 12.0 % (95% CI 3.7-25.7%), respectively. NRM was attributed to aGVHD in 3 of the 13 deaths. Viral reactivation included CMV (n=13), HHV6 (n=4), EBV (n=3) and adenovirus (n=4), with no fatal viral infection occurred within 180 days. Seven patients died of infection, including 3 patients who had fatal blood stream infection (bacteria n=2; fusarium n=1) within 180 days. With a median follow up of 436 days (range 20- 916 days) in surviving patients, the 6 month and 2 year overall survival (OS) were 77.2% (95% CI 59.4-87.9%) and 57.7 % (95% CI 37.6-73.4%), respectively (Figure 1). The 2-year OS for patients with intermediate risk and high/very high risk disease risk index (DRI) were 60% and 24%, respectively (p=0.07) (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allows successful allograft in high-risk patients lacking a suitable matched donor, including patients with high level of donor-specific HLA antibodies. Acute GVHD was generally abortive, leading to chronic GVHD in <5% of the patients. Fatal viral infection was not observed. Further efforts are needed to lower the risk of death due to bacterial infection, and also relapse in patients with high risk DRI, such as antibiotic prophylaxis or repeated doses of memory-cell DLI. Disclosures Leung: Miltenyi Biotec: Employment.

HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Αβ and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies: Three-Year Follow-up of Multicenter Study in Singapore

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Yang Liang Boo ◽  
Yeh Ching Linn ◽  
Rajat Bhattacharyya ◽  
Michelle Li Mei Poon ◽  
Zi Yi Lim ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Blood Stream Infection ◽  
Chronic Gvhd ◽  
Blood Stream ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Matched Donor

Background: Haploidentical hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. Graft-versus-host disease (GVHD), engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T-cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK-cells, γδ T-cells, and CD45RO+ memory T-cells. Methods: Mobilized PBSC products were divided into two fractions in 9:1 ratio and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of fludarabine 160mg/m2 divided daily over 4 days, thiotepa 10mg/kg divided twice daily for 1 day, and melphalan 70-140mg/m2 for 1 day, in combination with total lymphoid irradiation 6Gy (n=35) or 7.5Gy (n=12) over 3 equal fractions, total body irradiation of 2Gy (n=13) or antithymocyte globuline (n=2). Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 50 patients using tacrolimus, and 2 patients using sirolimus. Results: We transplanted 62 patients, including 55 adults (median age, 47 years; range 20-69) and 7 children (median age, 13 years, range 7-17) with high risk AML (n=34), ALL (n=15), MDS (n=7), plasma cell neoplasm (n=2), mast cell leukemia (n=1), acute undifferentiated leukemia (n=1), and NK/T-cell lymphoma (n=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 6.79 x 106 (range 3.54-20.78) CD34+ cells/kg, 0.00 x 104 (range 0-0.97) CD45RA+CD3+ cells/kg, and 1.09 x 106 (range 0.15-11.67) CD45RO+CD3+ cells/kg. The TCRαβ depleted graft fraction contained a median of 0.20 x 104 (range 0-11.30) TCRαβ+ cells/kg, and 8.52 x 106 (range 0.62-30.00) TCRγδ+ cells/kg. Only 1 patient experienced primary graft failure. All others had engraftment of ANC &gt; 500 cells/µL at a median of 10 days (range 8-22) and platelet &gt; 20,000 cells/µL at a median of 12 days (range 8-22). There was no secondary graft failure. Six patients with high titers of donor-specific HLA antibodies (DSA) engrafted successfully after effective desensitisation with plasma exchange, rituximab, and immunoglobulin. Twenty-two patients (35%) developed acute GVHD of grade II - IV (Gd II, n=15; Gd III, n=5; Gd IV, n=2). Three patients experienced chronic GVHD, giving 2-year cumulative incidence of 7 %. Day 180 cumulative incidence of NRM and relapse were 24.8% (95% CI 14.3-36.8%) and 14.9% (95% CI 6.3-27.0%), respectively. Four of the 16 NRM were attributed to aGVHD. Viral reactivation included CMV (n=25), HHV-6 (n=14), EBV (n=11), and adenovirus (n=7). Fourteen patients died of infection, including 5 patients who had fatal blood stream infection (bacteria, n=3; candidemia, n=2) and 1 patient from disseminated adenovirus infection within 180 days. With a median follow-up of 298 days (range 21-1298) in surviving patients, the 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 58% (95% CI 37.6-73.4%), 43% (95% CI 27-57%), and 39% (95% CI 24-54%), respectively (Figure 1). In multivariable analysis, only HCT-comorbidity index (HCT-CI) showed significant impact on OS (HR 6.24; 95% CI 2.05-19.05; p=0.0013), EFS (HR 4.80; 95% CI 1.73-13.35; p=0.0027), and RRM (HR 6.49; 95% CI 1.44-29.25; p=0.015), whereas disease risk index (DRI) impacts risk of relapse (HR 4.50; 95% CI 1.39-14.52; p=0.012). The 2-year OS, EFS, and GRFS for the subset of 30 patients (adults, n=25; children, n=5) with HCT-CI score of 0 and low/intermediate risk DRI were 68%, 68%, and 60%, respectively (Figure 2). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allowed successful allograft in high-risk patients lacking a suitable matched donor, including patients with high level of DSA. Acute GVHD was generally abortive, leading to low incidence of chronic GVHD. The best outcome is seen in patients with favorable HCT-CI and DRI. Further efforts are needed to lower the risk of death due to blood stream infection, and relapse in patients with high risk DRI, such as optimisation of anti-microbial prophylaxis or repeated doses of memory-cell donor lymphocyte infusion (DLI). Disclosures No relevant conflicts of interest to declare.

High Probability of Survival after Related and Alternate Donor Hematopoietic Cell Transplantation for Pediatric Patients with High Risk AML Using a Fludarabine Based Preparative Regimen

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4430-4430
Author(s):  
Poh-Lin Tan ◽  
Allen Yeoh ◽  
Thuan-Chong Quah ◽  
Joanne Kurtzberg ◽  
John E. Wagner
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Pediatric Patients ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Killer Cell ◽  
Hematopoietic Cell ◽  
Preparative Regimen

Abstract Hematopoietic cell transplantation (HCT) in pediatric patients with high risk acute myeloid leukemia (AML) such as those with non-Down de novo acute megakaryoblastic leukemia (AMKL), transformed myelodysplastic syndrome (MDS), therapy-related AML (tAML) and refractory/resistant AML (rAML) has been limited by graft failure, regimen related toxicity (RRT) and relapse. Between September 2005 and July 2008, 10 pediatric patients, median age of 7.6 (range, 1.3 – 17.0) years with such high risk AML (AMKL, n=2; MDS/AML, n=4; tAML, n=1; rAML; n=3) received a novel Fludarabinebased preparative regimen followed by T cell replete transplantation with bone marrow (BM, n=4), peripheral blood stem cell (PBSC, n=5) or umbilical cord blood (UCB, n=1) in a Singapore Pediatric BMT center. Seven patients received stem cells from alternate donors (AD) and 3 from matched related donors (MRD). Prior to HCT, 6 patients were in 1st complete remission (CR1), 2 in CR2 and 2 had progressive diseases. AD consisted of single antigen mismatched related and non-genoidentical unrelated donors (antigenic match at HLA-A, B, DRB1*). All patients received IV FLU 125 mg/m2, BU, 0.8 – 1.2 mg/kg 6 hourly, MEL, 140mg/m2. AD recipients received additional ATG (Thymoglobuline) 5mg/kg. GVHD prophylaxis consisted of cyclosporine and methotrexate or mycophenolate motfetil depending on the stem cell source. Excluding the 2 patients who entered HCT with progressive diseases, all other patients achieved myeloid engraftment at a median of 14 (range, 9 – 16) days and achieved sustained stable full donor chimera from 21 days after HCT. The median duration and costs of HCT admissions was 34 (range, 17 – 66) days and USD 51,317 (range, 41,416 – 155,905), respectively. Common post-HCT complications included engraftment syndrome (n=4) and reactivation of Herpes viruses (n=4). There was no severe RRT. Incidences of grade I–III acute GVHD and chronic GVHD were 63% and 67%, respectively. All these patients are alive in sustained CR at a median follow-up of 303 (range, 44 – 1037) days with Karnosky/Lansky scores of 90 – 100%. Both the patients with progressive diseases had graft failures and subsequently died of disease at a median of 138 (range, 77 – 198) days after HCT despite experimental salvage therapy with allogeneic natural killer cell transplantation from parental donors. In summary, this novel FLU based preparative regimen paired with non-genoidentical HCT is safe, inexpensive, allows prompt engraftment, and appears to provide anti-leukemia effects in pediatric patients with high risk AML entering HCT in remission. Long term follow-up will determine relapse risks and whether this non-irradiation based regimen is associated with a reduction in late effects including malignancy.

scholarly journals HLA-Haploidentical Hematopoietic Cell Transplantation after TCR-Alpha Beta and CD45RA+ Depletion Following Reduced Intensity Conditioning in Adults and Children with Hematological Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2093-2093
Author(s):  
Liang Piu Koh ◽  
Wing H. Leung ◽  
Michelle Poon ◽  
Lip Kun Tan ◽  
Poh Lin Tan ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Viral Reactivation ◽  
Day Range ◽  
Matched Donor

Abstract Background: Haploidentical (Haplo) hematopoietic cell transplantation (HCT) provides an alternative option for patients without HLA-matched donor. GVHD, engraftment failure, and infectious complications continue to be the main causes of non-relapse mortality (NRM). We hypothesized that selective depletion of TCRαβ+ and CD45RA+ naïve T cells subset will permit hematopoietic engraftment, while effectively reducing GVHD, and provide improved donor immune reconstitution through adoptive transfer of donor's mature NK and γδ T cells and CD45RA- memory T cells. Methods: GCSF +/- plarixefor (N=13) mobilized PBSC apheresis product were divided into two fractions in 9:1 ratio, and depleted using CliniMACS device after labeling with TCRαβ and CD45RA reagents (Miltenyi Biotec, Bergish-Gladbach, Germany), respectively. The conditioning regimen consisted of total nodal irradiation 6 - 7.5 Gy over 3 equal fractions, 160 mg/m2 Fludarabine divided daily over 4 days, Thiotepa 10 mg/kg divided twice daily for 1 day and Melphalan 70-140 mg/m2 for 1 day. Short term GVHD prophylaxis for 30 days was given to 1 patient using MMF, 11 using tacrolimus or 2 using Sirolimus. Results: We transplanted 20 adults (median age 42 years, range 20 - 68 ) and 3 children (age range 7-14 years) with high risk AML (n=14), ALL (n=6), MDS (n=2), myeloma (N=1). The patients were infused with TCRαβ and CD45RA depleted graft containing a median of 9.94 x 106 (range, 5.58 - 20.78) CD34+ cells/kg, 0.19 x 104 (range 0 - 8.53) CD45RA+CD3+ cells/kg, and 4.21 x 106 (range, 0.15 - 11.67) CD45RO+CD3+ cells/kg. In addition, the TCRαβ depleted graft fraction contained a median of 0.19 x 104 (range 0 - 8.53) TCRαβ+ cells/kg, and 8.87 x 106 (range 1.73 - 29.74) TCRγδ + cells/kg. All patients except 1 had engraftment of ANC > 500 cells/µL at a median of 11 day (range, 8 - 19) and PLT > 20,000 cells/µL at a median of 12 day (range, 7 - 19). Complete donor chimerism was seen at the time of engraftment in all patients with primary engraftment. Only 1 patient experienced primary graft failure. There was no secondary graft failure. Eleven patients developed acute GVHD of grade II-IV, with the day 100 cumulative incidence (C.I.) of acute GVHD of Gd II-IV, and Gd III-IV of 50% (95% CI 27.3 - 69.0%) and 17.9 % (95% CI 5.3- 36.4%), respectively. One patient experienced chronic GVHD. Day 180 C.I. of NRM and relapse were 23.9 % (95% 8.3-43.9%) and 5.6 % (95% CI 0.3-23.3%), respectively. NRM was attributed to aGVHD in 3 of the 6 deaths. Viral reactivation included CMV (n=7), HHV6 (N=4), EBV (N=3) and adenovirus (N=2), with no fatal viral infection occurred within 100 days. Two patients had fatal blood stream infection within 100 days. With a median follow up of 306 days (range 18 - 551 days) in surviving patients, the 6 month and 1 year overall survival (OS) were 76.9% (95% CI 52.9-89.7%) and 71 % (95% CI 46-85.9%), respectively. (Figure 1). Conclusions: Our preliminary results suggest that RIC haplo-HCT with TCRαβ and CD45RA+ depleted grafts allows successful allograft in high-risk patients lacking a suitable matched donor. NRM due to GVHD remains the major obstacle for the successful HCT. Fine adjustment of T cell dose with short course of immunosuppressant may reduce GVHD while preserving antitumor and antimicrobial immunocompetence. Disclosures No relevant conflicts of interest to declare.

Patterns of Acute and Chronic Graft-Versus-Host Disease Following ATG-Based Conditioning for Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4479-4479
Author(s):  
Nandita Khera ◽  
Amylou C. Dueck ◽  
Veena Devi Salem Fauble ◽  
Lisa Sproat ◽  
Pierre Noel ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Median Time ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Median Number ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Grade Ii

Abstract Abstract 4479 Background: In vivo T-cell depletion with antithymocyte globulin (ATG) is known to decrease the incidence of acute and chronic graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). However, the detailed patterns of GVHD (incidence, severity, timing, and quality) after ATG-based conditioning have not been examined in large patient cohorts, and it is unknown whether they differ from those seen in patients who do not receive ATG during conditioning therapy. Patients and Methods: We analyzed the incidence and characteristics of acute and chronic GVHD, requirements for immunosuppressive therapy (IST) and survival in a cohort of 174 patients who underwent a first HCT for hematologic malignancy with ATG as a part of their conditioning regimen. The median age was 54 years (range 19–76); all but 5 pts received PBSC, and median follow-up of survivors was 16.9 months (range 3–70 months). Donors were matched related in 18% (n=32), matched unrelated in 44% (n=77), and mismatched unrelated in 37% (n=65). Conditioning regimens were myeloablative in 33% (n=57) and reduced intensity in 67% (n=117). Additional GVHD prophylaxis included tacrolimus in all patients combined with either methotrexate (42%) or MMF (58%). Results: The cumulative incidence of grade II-IV and III-IV acute GVHD at 100 days was 34% and 7%, respectively, with the median time of onset at 43 days (range 11–98 days) after transplant. Eleven patients (6.3%) required additional immunosuppressive treatment due to steroid refractory GVHD. Late/persistent acute GVHD without any evidence of chronic occurred in 25% of patients. NIH chronic GVHD developed in 25 patients, with a cumulative incidence of 24.4% at 2 years. Forty four percent of these patients were classified as classic chronic, and 56% as overlap. The onset of chronic GVHD was quiescent in 20 (80%), progressive in 3 (12%), and de-novo in 2 (8%) patients. The global severity was mild in 9 (36%), moderate in 11 (44%) and severe in 5 (20%) cases. The median time of onset for chronic GVHD was 185 days (range 99–763). In a multivariate analysis of factors predictive for development of chronic GVHD, the only factor associated with development of chronic GVHD was prior grade II-IV acute GVHD (HR 2.5, p =.03). The most common diagnostic organ was mouth (n=16), followed by skin (n=8) and eye (n=1). The median number of sites involved during the course of chronic GVHD was 4 (range 1–7), and the median number of systemic immunosuppressive agents for treatment was 2 (range 0–4). Among the 25 chronic GVHD patients, 5 have discontinued immunosuppression at a median time of 13.1 months (range 6–26) since the diagnosis of chronic GVHD. The cumulative incidence of discontinuation of IST was 23% at one year and 50% at two years. Three deaths in the overall cohort were attributed to complications related to acute (n=2) or chronic GVHD (n=1). At 2 years, the overall survival among all 174 pts was 62.4%, cumulative incidence of relapse was 23.1%, and non-relapse mortality was 22.7%. Conclusion: These data from a large, uniformly treated and graded, predominantly peripheral blood stem cell transplant recipient population, confirm that ATG decreases both the incidence and severity of acute and chronic GVHD. In particular, the rate of moderate to severe chronic GVHD is extremely low, resulting in minimal need for tertiary treatment and decreased duration of immunosupression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

2011 ◽  
Vol 208 (5) ◽  
pp. 1069-1082 ◽  
Author(s):  
Daigo Hashimoto ◽  
Andrew Chow ◽  
Melanie Greter ◽  
Yvonne Saenger ◽  
Wing-Hong Kwan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Expansion ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Host Macrophage

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

Serious Acute or Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplantation: A Comparison of Myeloablative and Non-Myeloablative Conditioning Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 755-755
Author(s):  
Olga Sala-Torra ◽  
Paul J. Martin ◽  
Barry Storer ◽  
Mohamed Sorror ◽  
Rainer F. Storb ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hematopoietic Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Co Morbidity

Abstract We have previously described serious graft-versus-host disease (GVHD) as a highly undesirable outcome after allogeneic hematopoietic cell transplantation (HCT). Serious GVHD encompasses death, lengthy hospitalization, major disability, or recurrent major infections related to either acute or chronic GVHD. In a previous study, we found a 25% incidence of serious GVHD among 171 consecutive patients who had HCT after non-myeloablative (NMA) conditioning between January 1998 and May 2002. To put this observation into perspective, we applied the same criteria for serious GVHD in a cohort of 264 consecutive patients who had HCT after myeloablative (MA) conditioning during the same period of time and compared results with those of the previous study. The overall incidence of serious GVHD was 17% (44/264) in the MA group, compared to 25% (43/171) in the NMA group. There were no statistically significant differences in the incidence of grades III–IV GVHD, extensive chronic GVHD or nonrelapse mortality between the two groups (Table). Patients in the NMA group were older and had higher comorbidity scores than those in the MA group. In the univariate analysis, the hazard ratio (HR) of serious GVHD for the NMA group compared to the MA group was 1.71 (95% C.I., 1.1–2.6) (p = 0.01). After adjusting for patient age, patient and donor gender, donor type, HLA-mismatch, aggressive versus indolent malignancy at HCT, remission versus relapse at HCT, myeloid versus non–myeloid malignancy, HCT co–morbidity index, and prior donor lymphocyte infusion, the HR of serious GVHD was 1.50 (95% C.I., 0.8–2.7) (p = 0.17). After censoring for recurrent or progressive malignancy after HCT, the cumulative incidence of serious GVHD at 3 years was 21% for the NMA group and 14% for the MA group, and the HR was 1.33 (95% C.I., 0.7–2.6) (p = 0.40). Reasons for categorization of GVHD as serious (i.e., death, lengthy hospitalization, major disability, or recurrent major infections) were similar between the MA and NMA cohorts. Among the 44 patients with serious GVHD in the MA group, 19 (43%) had serious acute GVHD, and 25 (57%) had serious chronic GVHD. Among the 43 patients with serious GVHD in the NMA group, 20 (46%) had serious acute GVHD, and 30 (70%) had serious chronic GVHD. Among the 264 MA patients, 28 (11%) had grade III–IV acute GVHD and 147 (56%) had extensive chronic GVHD that did not meet the criteria for serious GVHD, compared to 7 (4%) and 84 (49%) of the 171 NMA patients, respectively. We conclude that the type of pretransplant conditioning regimen does not have a large effect on the incidence of serious GVHD after HCT. Assessment of serious GVHD provides additional useful information to acute GVHD grades and the classification of limited and extensive chronic GVHD in describing overall GVHD-related outcomes after HCT. MA NMA Outcome, n (%) n = 264 n = 171 Serious GVHD 44 (17) 43 (25) Grades III–IV acute GVHD 54 (20) 27 (16) Extensive chronic GVHD 174 (66) 114 (68) 2-year nonrelapse mortality 66 (25) 43 (25)

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.

Allogeneic Hematopoietic Cell Transplantation Can Cure Some Patients with Acute Leukemia in Relapse or Primary Induction Failure: A CIBMTR Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 528-528
Author(s):  
Michel Duval ◽  
Wensheng He ◽  
John P. Klein ◽  
Martin S. Tallman ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Karnofsky Score ◽  
Risk Criteria ◽  
Primary Induction ◽  
Induction Failure

Abstract Abstract 528 Acute leukemia refractory to chemotherapy is uniformly fatal without hematopoietic cell transplantation (HCT). However, the benefit of transplantation for patients not in complete remission (CR) is controversial. PATIENTS AND METHODS: 2,255 patients transplanted (at 252 centers in 38 countries) with an allogeneic donor after myeloablative conditioning regimen between 1995 and 2004 for acute leukemia in relapse or with primary induction failure were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). 1,673 had acute myeloid leukemia (AML) and 582 acute lymphoblastic leukemia (ALL). Median age was 38 and 29 years for AML and ALL patients, respectively. Presence of circulating blasts, >25% marrow blasts, Karnofsky score < 90 %, or transplant in first relapse was observed in nearly half of the patients (see Table). RESULTS: 100 day mortality was 39% in AML and 41% in ALL. The median follow-up of survivors was 5 years. Overall survival (OS) was 19% (95% confidence interval (CI) 17-21) for AML and 16% (13-20) for ALL patients. For AML patients, five adverse pre-transplant variables significantly impacted OS : first CR duration < 6 months, blasts in the blood, donor other than HLA-identical sibling or partially matched unrelated, Karnofsky score < 90%, poor-risk cytogenetics. 106 AML patients had none of these high risk criteria, with a 3 years OS of 44% (35-54). For ALL patients, survival was worse with either: 1st refractory or ' 2nd relapse, ≥ 25% marrow blasts, CMV seropositive recipient, age ≥10 years. 8 ALL patients had no high risk criteria, with a 3 years OS of 85% (53-100). Grade 3-4 acute graft-vs-host disease (GVHD) occurred in 23% of AML and 27% of ALL patients. Chronic GVHD developed in 27%. Leukemia was the cause in 42 % of AML and 37% of ALL patients' deaths. CONCLUSIONS: 1. HCT can cure some patients with acute leukemia in relapse or with PIF, particularly those lacking defined high risk features. 2. These pre-transplant variables should be considered when deciding whether or not to offer HCT to such patients. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document