scholarly journals Considerations in Preparative Regimen Selection to Minimize Rejection in Pediatric Hematopoietic Transplantation in Non-Malignant Diseases

2020 ◽  
Vol 11 ◽  
Author(s):  
Robert J. Hayashi
Keyword(s):  
Malignant Diseases ◽  
Hematopoietic Transplantation ◽  
Preparative Regimen

Alloreactive Nk Cells to Augment Antileukemia Cytotoxicity with Allogeneic Stem Cell Transplantation for Aml/Mds: A Phase I Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 489-489
Author(s):  
Richard Champlin ◽  
Dean A. Lee ◽  
Marcelo Fernandez-Vina ◽  
Gabriela Rondon ◽  
Patricia McAdams ◽  
...  
Keyword(s):  
Nk Cells ◽  
Phase I Study ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Product ◽  
Hematopoietic Transplantation ◽  
Preparative Regimen ◽  
Allogeneic Hematopoietic Transplantation ◽  
Active Disease

Abstract Abstract 489 Relapse remains the major cause of treatment failure after allogeneic hematopoietic transplantation for AML and MDS. Alloreactive NK cells mediate a potent antileukemic effect and may also enhance engraftment and reduce GVHD. We performed a phase I study infusing “third party” alloreactive NK cells from a haploidentical related donor as a component of the preparative regimen for allotransplantation from a separate HLA identical donor. The goal was to augment the antileukemia cytotoxicity of the preparative regimen by infusion of alloreactive NK cells and improve the overall outcome of hematopoietic transplantation. Patients with advanced AML or high risk MDS in relapse or beyond first remission were eligible. They received the busulfan-fludarabine preparative regimen, followed by infusion of NK cells predicted to be alloreactive by KIR:KIR ligand incompatibility. The NK cell enriched product was produced from a steady state apheresis product by depleting CD3+ cells using the CliniMACS device (Miltenyi Corp). A second step positively selecting CD56+ cells was performed for the first dose level, but discontinued thereafter in order to increase the cell yield. The NK cell product was then cultured in complete media containing rIL-2 for 16 hours and infused intravenously following completion of the busulfan-fludarabine chemotherapy. After 5 days, ATG was administered followed by PBSC infusion from the HLA identical sibling or unrelated donor. Patients received tacrolimus and methotrexate for GVHD prophylaxis. Patients were treated in 4 dose levels of the NK cell enriched product; 1) 106 cells/kg, 2) 5 × 106/kg, 3) 3 × 107/kg, and 4) 3 × 107/kg followed by systemic interleukin-2 0.5 million units/m2 SQ daily for 5 days. CD3+ cells in the NK cell product were required to be <105/kg (median infused 1.1 x104/kg). Median CD56+ cells infused (x106/kg) were from 0.9 (level 1), 1.5 (level 2), and 4.9 (levels 3 and 4). 13 patients were entered. Median age was 51 years (range 2–60). 11 had active disease and 2 were in a second remission. Only mild infusion toxicity occurred with the NK cell infusion. Other toxicities were similar to that experienced with the preparative regimen without NK cells. The 2 patients at dose level 4 tolerated interleukin-2 systemic treatment without fever or increased toxicity. The haploidentical NK cells were transiently detected in the blood by chimerism studies in one patient. Rapid engraftment and hematologic recovery uniformly occurred from the HLA matched PBPC donor in all patients. None had graft failure. Grade 2 acute GVHD developed in 3 patients; all responded to corticosteroid treatment. None developed grade 3 or 4 acute GVHD. 9 of 11 patients with active disease achieved a complete remission. Only one patient died of nonrelapse mortality; she died in remission from infection 2 months post transplant. This trial confirms the feasibility of producing the haploidentical NK cell product, and the lack of major toxicity attributable to the NK cell infusion in combination with an HLA compatible allogeneic transplantation. Infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GVHD after allogeneic hematopoietic transplantation. This approach merits further phase II and III study designed to reduce relapse and improve the outcome of allogeneic hematopoietic transplantation for AML/MDS. N NK cell doseCells/kg grade 2 GVHD Relapse NRM Alive in CR 4 106 1 4 0 0 4 5 × 106 0 3 0 1 (27+ m) 3 3 × 107 2 1 1 1 (11+ m) 2 3 × 107 + IL-2 0 0 0 2 (9+ m, 4+ m) Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Randomized Study of Fludarabine-Clofarabine Vs Fludarabine Alone Combined with Busulfan and Allogeneic Hematopoietic Transplantation for AML and MDS

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 257-257
Author(s):  
Richard E. Champlin ◽  
Uday Popat ◽  
Betul Oran ◽  
Stefan O. Ciurea ◽  
Partow Kebriaei ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Advisory Committees ◽  
Hematopoietic Transplantation ◽  
Preparative Regimen ◽  
Reduced Risk ◽  
Risk Of Relapse

Disease relapse remains the major cause of treatment failure following hematopoietic transplantation for AML/MDS. A major goal is to develop more effective antileukemic regimens without excessive toxicity. Busulfan (Bu)-fludarabine (Flu) is a widely used preparative regimen. We demonstrated that targeting a relatively high busulfan systemic exposure pharmacokinetic (PK) dose adjustment was superior to fixed busulfan dosing. Clofarabine (Clo) has improved antileukemic activity compared to fludarabine. We previously reported a phase I/II study of different dosing combinations of busulfan with Flu and Clo; the best results were obtained with Bu with Flu 10 mg/m2 and Clo 30 mg/m2 daily for four daily doses. We performed a phase III randomized controlled trial to determine if Flu/Clo/Bu improved progression free survival compared to the Flu/Bu regimen. Busulfan was given with PK dose adjustment AUC 6000 mM x min for age &lt;=60 years or 4000 mM x min for older patients and those with performance status (PS) &lt;80%. GVHD prophylaxis was tacrolimus-mini methotrexate. Unrelated donor recipients also received ATG. Patients aged 3-70 with intermediate or high risk AML or MDS, with PS&gt;60% and adequate organ function were eligible if they had an HLA identical related or 9/10 or 10/10 matched unrelated donor. Patients were randomized to receive either Flu/Bu or Flu/Clo/Bu as the preparative regimen and stratified based on disease status, in complete remission (CR) or not in CR (NCR). 250 patients were entered; 130 received Flu/Bu, 120 Flu/Clo/Bu. 95 had a matched sibling, 155 a matched unrelated donor. Median age was 51 yrs. 181 had AML, 69 MDS. Poor risk cytogenetics was present in 37%. 133 patients were in remission; 117 had active disease. Comorbidity index was &lt;3 in 60%. Performance status was &gt;90% in 88%. 249 patients achieved engraftment. 41% had grade 2 and 6% grade 3-4 acute GVHD. 93 patients developed chronic GVHD. The Kaplan Meier 3-year PFS was 0.52 (95%CI: 0.44 - 0.62) for Flu/Clo/Bu and 0.48 (95%CI: 0.41 - 0.58) for Flu/Bu (P=0.44). For the Flu Bu group, 52 patients progressed and 16 died with nonrelapse mortality (NRM). For the Flu/Clo Bu group, 32 progressed and 27 died with NRM. There was a significantly lower risk of progression with Flu/Clo/Bu (p=0.025), but a significantly higher risk of NRM (p=0.018). There was no difference in PFS for patients in CR, but there was a trend for improved PFS (p=0.17) with a significantly reduced risk of relapse (p=0.002) for patients over age 60 who were not in CR. In conclusion, Flu/Clo/Bu reduced the risk of relapse but had greater NRM compared to Flu/Bu. In patients over age 60 who were not in remission at transplant, there was a reduced risk of relapse and a trend towards improved PFS. Figure Disclosures Champlin: Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Nieto:Astra-Zeneca: Research Funding; Novartis: Research Funding; Affimed: Research Funding; Affimed: Consultancy. Qazilbash:Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Genzyme: Other: Speaker. OffLabel Disclosure: Clofarabine and fludarabine for hematopoietic transplantation

Using the hematopoietic transplantation platform for TCR-engineered adoptive immunotherapy of leukemia

2009 ◽  
Vol 221 (03) ◽  
Author(s):  
W Koestner ◽  
M Hapke ◽  
C Klein ◽  
K Welte ◽  
M Sauer
Keyword(s):  
Adoptive Immunotherapy ◽  
Hematopoietic Transplantation
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