scholarly journals Stable long term engraftment and amelioration of clinical phenotype following hematopoietic stem cell transplantation from a matched sibling donor for sickle cell disease using a reduced intensity conditioning regimen

2005 ◽  
Vol 11 (2) ◽  
pp. 28 ◽  
Author(s):  
L. Krishnamurti ◽  
C. Wu ◽  
S. Baker ◽  
A.M. Yeager ◽  
J.E. Wagner
Keyword(s):  
Stem Cell ◽  
Clinical Phenotype ◽  
Conditioning Regimen ◽  
Cell Disease ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Matched Sibling ◽  
Reduced Intensity

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.

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.

Effective Hematopoietic Stem Cell Transplantation with Reduced Intensity Conditioning for Patients with Chronic Granulomatous Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3339-3339
Author(s):  
Yoko Mizoguchi ◽  
Mizuka Miki ◽  
Teruyuki Kajiume ◽  
Hiroshi Kawaguchi ◽  
Kazuhiro Nakamura ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Conditioning Regimen ◽  
Granulomatous Disease ◽  
Reduced Intensity Conditioning ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Life Threatening ◽  
Reduced Intensity

Abstract Abstract 3339 Poster Board III-227 Chronic granulomatous disease (CGD) is the most common inherited disorders of phagocytic function caused by abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which produces reactive oxygen species. Defects in four of the NADPH components are responsible for CGD: gp91phox, p47phox, p67phox and p22phox. Due to the defects in production of superoxide, patients are highly susceptible to catalase-positive infections including fungi, as well as developing granuloma and autoimmune complications. To date, hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with CGD. The HSCT for CGD patients using myeloablative conditioning regimen consisting of busulfan and cyclophosphamide (CY) has been proven to cure the disease. However, HSCT with this myeloablative conditioning regimen has considerable risk of transplantation-related morbidity (TRM) and mortality in patients with life-threatening infection and long-term complications including graft-versus host disease (GVHD), pulmonary late effects, and gonadal failure. To avoid the risk of TRM and long-term complications, we underwent bone marrow transplantation (BMT) with reduced-intensity conditioning (RIC) for 12 patients with CGD from 2002 to 2009 in Hiroshima University. Seven patients were transplanted from related donors and five patients from unrelated donors. Conditioning regimens consisted of fludarabine, CY and TBI (3 Gy) with or without antithymoglobulin or melphalan (L-PAM). Three of twelve patients who had severe life-threatening infections such as multiple brain abscesses, multiple liver abscesses or multiple pulmonary abscesses with high level of CRP (>15 mg/dl) underwent BMT. One of three patients who had suffered from severe fungal infection in both lungs was died from pulmonary hemorrhage due to the engraftment syndrome on day 45 after BMT. No TRM during the conditioning and early period after BMT was observed in the remaining 11 patients, irrespective of the presence of active and intractable infections/inflammation. The patients alive were eliminated from infections and/or inflammation with complete chimerism. Four patients undergoing BMT using fludarabine-based regimen without L-PAM required donor lymphocyte infusion to achieve complete donor chimerism. The addition of L-PAM to fludarabine-based RIC rapidly induced the complete engraftment of donor cells without any toxicity in 7 patients. The frequency and severity of acute or chronic GVHD were not significant and sufficiently tolerable. Karnofsky performance scale of all patients alive has been 100% after BMT. Furthermore, apparent endocrinological problems including gonadal function were not observed during the limited period after BMT. These results suggest HSCT using RIC with L-PAM is effective therapy for CGD patients for successful complete engraftment and minimal toxicity. Disclosures No relevant conflicts of interest to declare.

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