scholarly journals Long-term outcomes of fludarabine, melphalan and antithymocyte globulin as reduced-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiency disorders: a prospective single center study

2015 ◽  
Vol 51 (2) ◽  
pp. 219-226 ◽  
Author(s):  
A A Hamidieh ◽  
M Behfar ◽  
Z Pourpak ◽  
S Faghihi-Kashani ◽  
M R Fazlollahi ◽  
...  
Keyword(s):  
Antithymocyte Globulin ◽  
Conditioning Regimen ◽  
Long Term Outcomes ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Single Center Study ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity ◽  
Center Study

Efficient MGMTP140K-Mediated In Vivo Selection and Chemoprotection of Long-Term Repopulating Cells in Nonhuman Primates Following Reduced Intensity Conditioning.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3572-3572
Author(s):  
Brian C Beard ◽  
Grant D Trobridge ◽  
Jeannine S McCune ◽  
Hans-Peter Kiem
Keyword(s):  
Nonhuman Primates ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
In Vivo Selection ◽  
Reduced Intensity Conditioning Regimen ◽  
Hematopoietic Toxicity ◽  
Reduced Intensity

Abstract Abstract 3572 Poster Board III-509 Strategies using gene-modified hematopoietic stem cells to treat various severe hematopoietic diseases, including but not limited to hemoglobinopathies, will likely require high levels of gene marking. Here we have established efficient and stable in vivo selection in nonhuman primates using methylguanine methyltransferase (MGMTP140K). In the macaque (Macaca nemestrina) we were able to increase pre-chemotherapy lentiviral gene marking levels of 11.3% in granulocytes and 15.3% in lymphocytes to a post-chemotherapy gene marking level of 76.9% in granulocytes and 49.0% in lymphocytes. Furthermore, stable increases in gene marking were also observed in red blood cells (RBCs) and platelets (PLTs) with a pre-chemotherapy gene marking level of 5.6% and 6.7%, respectively, and a post-chemotherapy gene marking level of 15.2% and 64.0%, respectively. Importantly, the chemotherapy regimen was well tolerated, and engraftment was polyclonal as determined by analyzing long-term repopulating clones by LAM-PCR. In order to minimize extra-hematopoietic toxicity we have began to test a more clinically applicable conditioning regimen in the macaque model. This reduced intensity conditioning regimen should allow treatment of patients with severe hematopoietic or infectious diseases, who may not tolerate a high dose conditioning regimen. We tested targeted busulfan for conditioning to provide sufficient myelosuppression and to facilitate engraftment of chemoprotected hematopoietic stem cells while minimizing extra-hematopoietic toxicity. Following conditioning with busulfan (4 mg/kg/day for 2 days) and infusion of gene modified cells (∼1.7 × 107 CD34-selected cells/kg), there was moderate cytopenia with ANC <500/mL for 7 days and thrombocytopenia with a nadir of 18,000/mL. Following stable hematopoietic recovery, we observed gene marking, determined by RT-PCR, in total white blood cells as a provirus copy number of 0.04 (∼4% gene marking) that, following a single cycle of O6BG (x2) and BCNU, rose to 0.16 (∼16% gene marking). Currently, gene marking has been stable for more than 9 months following chemotherapy. The treatment was well tolerated with only transient elevated liver enzymes following O6BG/BCNU treatment and no additional extra-hematopoietic toxicity has been observed. Clonality studies before and after in vivo selection is underway using a combination of LAM-PCR and a modified whole genome pyrosequencing approach. In summary, we have attained efficient and stable in vivo selection of long-term repopulating cells in nonhuman primates, and have extended this approach to use a reduced intensity conditioning regimen that should be well tolerated in patients with many hematopoietic diseases. Disclosures: No relevant conflicts of interest to declare.

Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5311-5311
Author(s):  
Xiaohua Chen ◽  
Gregory A. Hale ◽  
Raymond C. Barfield ◽  
Ely Benaim ◽  
Wing H. Leung ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

scholarly journals Does antithymocyte globulin have a place in reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation?

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 246-250 ◽  
Author(s):  
Tanya Siddiqi ◽  
Didier Blaise
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Antithymocyte Globulin ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract A 63-year-old male patient without siblings is treated for acute myeloid leukemia with poor prognostic cytogenetics. Despite achieving a first complete remission, he relapsed within the first year of diagnosis. He then achieved a second complete remission. A search for an HLA-identical unrelated donor identified a 10/10 possible match. The patient has several comorbidities (hematopoietic stem cell comorbidity index = 3) and it is recommended that he undergo a reduced-intensity conditioning regimen for allogeneic peripheral blood stem cell transplantation. The patient is well-read on allogeneic stem cell transplantation and asks you the merits of antithymocyte globulin that you propose to include in the conditioning regimen.

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