Bone marrow transplant using fludarabine‐based reduced intensity conditioning regimen with in vivo T cell depletion in patients with Fanconi anemia

2021 ◽  
Author(s):  
Lev Gorfinkel ◽  
Carolyn Demsky ◽  
Farzana Pashankar ◽  
Gary Kupfer ◽  
Niketa C. Shah
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Bone Marrow Transplant ◽  
Fanconi Anemia ◽  
Conditioning Regimen ◽  
Marrow Transplant ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

A Prospective Feasibility Trial of Unrelated Bone Marrow Transplantation with Reduced Intensity Conditioning Regimen for Elderly Patients with Adult T-Cell Leukemia/Lymphoma (ATL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4163-4163
Author(s):  
Tetsuya Eto ◽  
Ilseung Choi ◽  
Ryuji Tanosaki ◽  
Yoshifusa Takatsuka ◽  
Atae Utsunomiya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Elderly Patients ◽  
Bone Marrow Cells ◽  
Conditioning Regimen ◽  
Marrow Transplant ◽  
Reduced Intensity Conditioning ◽  
Donor Chimerism ◽  
Reduced Intensity Conditioning Regimen ◽  
Unrelated Donors ◽  
Reduced Intensity

Abstract Abstract 4163 Introduction: ATL is a peripheral T-cell malignancy that is caused by human T-lymphotropic virus type 1 (HTLV-1) infection and commonly affects individuals at an average age of 60 years. Since the prognosis of elderly patients with the disease has been unsatisfactory by conventional chemotherapy, we had so far conducted two clinical trials to evaluate the feasibility of allogeneic hematopoietic stem cell transplantation (allo-SCT) using G-CSF-mobilized peripheral blood stem cells from HLA-identical sibling donors combined with reduced-intensity conditioning regimen (RIC) and reported promising results (Okamura et al, Blood, 2005; Tanosaki et al, Biol Blood Marrow Transplant, 2008; Choi et al, Bone Marrow Transplant, 2011). The availability of suitable sibling donors, however, will become more and more difficult due to the aging as well as complications of donors. In this study, we conducted a clinical trial of an alternative strategy of allo-SCT using bone marrow cells from unrelated donors with RIC for elderly patients with ATL. Study design: Patients between 50 and 65 years of age who satisfied the diagnostic criteria for acute or lymphoma type ATL and had no available HLA matched family donors were eligible. It was required at the time of registration that they were in either complete remission (CR) or partial remission after chemotherapy and had an unrelated donor whose HLA-A, B and DR loci were genotypically matched. DR one locus-mismatched donors were acceptable. All patients were needed their written informed consent to participate in this study which was approved by the institutional review board of each participating institution. The conditioning regimen consisted of fludarabine (180 mg/m2), intravenous busulfan (6.4 mg/kg) and low dose total body irradiation (2Gy). Bone marrow grafts from the Japan Marrow Donor Program were transplanted on day 0. To prevent graft versus host disease (GVHD), tacrolimus (0.03 mg/kg/day) and short-term methotrexate were administered. The primary endpoints of the study were both engraftment, as judged by the achievement of complete donor chimerism before day 100, and survival at day 100 after SCT. The severity of GVHD was graded according to the consensus criteria. The degrees of donor-recipient chimerism and HTLV-1 proviral DNA in peripheral blood mononuclear cells were quantified by published methods. Results and discussion: Fifteen patients were registered between February 2009 and April 2011 at 8 institutions in Japan. The median age of the patients was 58 (range, 51–62). Seven were male, 12 had acute type, and 7 were in CR. Median period from diagnosis to SCT was 7 months (range, 4–12). There were 9 pairs of patient and donor with HLA fully matched, and HLA-DR one locus-mismatched pairs were six. All donors were negative for anti-HTLV-1 antibody. One patient who developed an early relapse failed to achieve complete donor chimerism before day 100, resulting in 14 out of 15 patients with complete donor chimerism. One other patient developed an early treatment-related death on day 34 due to sever thrombotic microangiopathy-related toxicities. Thus, 13 of 15 patients achieved the primary objective. Disease progression was observed in 3 patients at a median follow-up period of 530 (range, 108–864) days. Acute GVHD was observed in 10 of 15 patients, where 2/6/2 patients experienced grade 3/2/1. Kinetics of the HTLV-1 proviral load after SCT showed that it decreased to an undetectable level (< 0.5 copies) in 10 of 14 patients who survived beyond 100 days. In conclusion, this study firstly indicated that SCT using bone marrow cells with RIC from unrelated donors is a feasible therapeutic procedure for elderly patients with ATL. Disclosures: No relevant conflicts of interest to declare.

Alternative Donor Stem Cell Transplantation after Reduced Intensity Conditioning Regimen for Patients with Bone Marrow Failure.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2894-2894
Author(s):  
Nabil Kabbara ◽  
Vanderson Rocha ◽  
Marie Robin ◽  
Agnes Devergie ◽  
Patricia Ribaud ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Gvhd ◽  
Bone Marrow Failure ◽  
Conditioning Regimen ◽  
Adenovirus Infection ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity Conditioning Regimen ◽  
One Year ◽  
Reduced Intensity

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) with HLA geno-identical sibling donor is the treatment of choice for children and young adults with constitutional or acquired (SAA) bone marrow failure (BMF). However, results of unrelated HSCT for BMF have been poorer due to high transplant related mortality mainly related to rejection and GVHD. Generally, a myeloablative regimen HSCT is used for acquired and some constitutional BMF but not for Fanconi anemia (FA) patients for whom a low dose conditioning regimen is employed. We have driven the hypothesis that immunosuppressive reduced intensity conditioning regimen should decrease TRM, decreasing GVHD and allowing engraftment. In a Phase I-II trial, 20 patients (pts) with BMF were enrolled and transplanted between 2002 and 2004. Thirteen pts had a constitutional aplasia: FA n=11, congenital megakaryocytopenia (CMK) n=1, Rothmund-Thomson syndrome n=1 and 7 pts had SAA among those two had paroxystic nocturnal hemoglobinuria (PNH). There were 12 male and 8 female. Median age was 8 years for constitutional BMF and 26 years for SAA. The HSC source was bone marrow for 11 pts, PBSC for 1 pt and cord blood for 8 pts. Ten of the twelve BM or PBSC donors were HLA matched for 10 loci (A, B, C, DRB1, and DQB1) and eight cord blood donors were HLA mismatched with 2 generic differences and were used for FA. All pts received the same conditioning regimen consisting of Busulfan (3mg/kg x 2), cyclophosphamide (10mg/kg x 4), fludarabine (30mg/m2 x3) and ATG (2.5mg/kg x4). The mean of nucleated stem cells infused and CD34 + cells was 2.8x108/kg and 5.9x106/kg respectively for the 12 pts who received BM stem cells and PBSC and 6.4x107/kg and 4.6x106/kg respectively for the eight pts who received CB cells. Acute GVH disease prophylaxis consisted of ciclosporine A (CsA) for pts with constitutional BMF and CsA and short course methotrexate for 6 of the 7 pts with acquired BMF, (one received tacrolimus instead of CsA due to thrombotic pre-existing co-morbidity). One pt (with CMK) died on day 0 from cerebral haemorrhage. Eighteen pts out of 19 had WBC recovery with a median time of 23 days (11–42); one FA pt did never reach sustained engraftment and died at D+291 from adenovirus infection. Three others had late graft rejection: in a context of acute GvHD and EBV infection and pulmonary aspergillosis for two pts with SAA who received BM graft and with acute GvHD and adenovirus infection for one FA pt who received CB graft. The conditioning was well tolerated without severe mucositis even in FA patients, sixteen patients experienced transient liver abnormalities. Nine patients developed reversible haemorrhagic cystitis at a median of 47 days post-transplant. There were 3 bacterial, 10 viral and 5 fungal infections with a cumulative incidence of TRM at one year of 45 ±24%. The cumulative incidence of acute GVH (II–IV) was 50 ±23%. Overall survival (OS) at one year was 55±11 %. It was 86%± 13 for SAA and 38% ± 13 for constitutional BMF. In spite of the short follow-up and few patients included, reduced intensity conditioning regimen provides encouraging results for patients with SAA. For constitutional BMF, low toxicity was observed, however the overall results seem similar to those reported in the literature using other RIC regimen and are probably related to other factors than the conditioning regimen.

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.

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