Reduced-intensity conditioning regimen with low-dose ATG-F for unrelated bone marrow transplant is associated with lower non-relapse mortality than a regimen with low-dose TBI: a single-center retrospective analysis of 103 cases

2013 ◽  
Vol 98 (5) ◽  
pp. 608-614 ◽  
Author(s):  
Shigeo Fuji ◽  
Niina Ueno ◽  
Nobuhiro Hiramoto ◽  
Yoshitaka Asakura ◽  
Kimikazu Yakushijin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retrospective Analysis ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Marrow Transplant ◽  
Single Center ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity Conditioning Regimen ◽  
Unrelated Bone Marrow Transplant ◽  
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.

Tacrolimus and Mycophenolate Mofetil as Post-Grafting Immunosuppression After Conditioning with Fludarabine and Low-Dose Total Body Irradiation for Recipients of HLA-Matched Sibling or Unrelated Donor Hematopoietic Cell Transplants in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3354-3354
Author(s):  
Tara Gregory ◽  
Mark W. Brunvand ◽  
Peter A. McSweeney ◽  
Scott I. Bearman ◽  
Michael Maris ◽  
...  
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity Conditioning Regimen ◽  
Matched Sibling ◽  
Total Body ◽  
Reduced Intensity

Abstract Abstract 3354 Poster Board III-242 Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder of hematopoiesis that results in bone marrow failure and myelodysplasia. Hematopoietic cell transplantation is the only curative therapy. The success of allogeneic stem cell transplantation has been limited, in part, by regimen-related toxicity associated with high-dose preparative regimens. Nonrandomized studies suggest that long-term remissions are achievable when using allogeneic SCT as treatment for PNH. Mikolajewska, et al. reported treatment of 7 patients with high risk PNH with a reduced intensity conditioning regimen of fludarabine and total body irradiation (TBI). Mycophenolate mofetil (MMF) and cyclosporine were utilized as graft versus host disease (GvHD) prophylaxis (2008 ASH Annual Meeting Abstracts, 4407). The objective of this study is to evaluate the combination of tacrolimus and MMF as GvHD prophylaxis after conditioning with fludarabine and low dose TBI in PNH patients who are not candidates for conventional ablative allografting. This is a novel approach to immunosuppression incorporating an early but extended taper of tacrolimus on day +80. Patients and Methods: Four patients with PNH underwent allogeneic SCT after a reduced intensity regimen. Patients received fludarabine (30mg/m2/day) on days -4 to -2 and low dose TBI (200 or 400 cGy at 6-7 cGy/min from a linear accelerator) on day 0. Two patients received TBI 200 cGy and three received 400 cGy. One patient failed to engraft with TBI 200 cGy and was transplanted again with TBI 400 cGy. GvHD prophylaxis was with tacrolimus (0.06mg/kg PO BID) starting on day -3 and MMF (15mg/kg PO BID for related and TID for unrelated donors) starting from day 0. All patients received filgrastim-mobilized peripheral blood stem cells from either from an HLA-matched sibling (n=1) or matched unrelated (n=4) donor. Results: The median follow up was 20 (range 3 to 36) months after SCT. One patient who received TBI at 200 cGy failed to engraft after an unrelated transplant. She underwent a second transplant from a different unrelated donor with TBI with 400 cGy with engraftment after the second procedure. The patients engrafted reaching a neutrophil count ≥ 500 a median of 16 (range 15 to 18) days post-transplant. Each achieved eradication of their PNH clone based on subsequent marrow and blood chimerism studies together with absence of clinical signs of PNH. Acute GvHD (grades II-IV) occurred in three patients. Chronic GvHD occurred in two patients. Day 100 mortality was 0% and all four patients are alive with an EGOG status of 0-1. Conclusions: A reduced intensity conditioning regimen consisting of fludarabine and TBI at 200 cGy or 400 cGy with tacrolimus and MMF as post grafting immunosuppression appears well tolerated for performing allogeneic transplants in PNH. Donor cell engraftment with eradication of the PNH clone was observed with this approach. The higher dose of TBI (400 cGy) might be more effective in overcoming graft rejection and warrants further investigation. Disclosures: No relevant conflicts of interest to declare.

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