scholarly journals Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1247-1250
Author(s):  
JH Antin ◽  
D Ginsburg ◽  
BR Smith ◽  
DG Nathan ◽  
SH Orkin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Conditioning Regimen ◽  
Erythroid Cell ◽  
Polymorphism Analysis ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Pnh Clone

Paroxysmal nocturnal hemoglobinuria (PNH) involves the proliferation of an abnormal and possibly premalignant hematopoietic stem cell. Successful treatment of PNH by marrow grafting requires that the PNH clone be eradicated by the pretransplant conditioning regimen. Four patients with PNH-associated marrow aplasia were transplanted with marrow from their HLA-matched, MLR-nonreactive siblings. Three patients were conditioned with cyclophosphamide, procarbazine, and antithymocyte serum (CTX/PCZ/ATS), and one was conditioned with busulfan/CTX/PCZ/ATS. Persistent complete engraftment of myeloid, lymphoid, and erythroid cell lines was demonstrated in all four patients by DNA sequence polymorphism analysis or cytogenetics, and RBC typing. There was no recurrence of the abnormal clone of cells for up to five years after transplantation despite the use of a conditioning regimen in three of them, which is not usually associated with permanent marrow aplasia. Bone marrow transplantation is a curative therapy in patients whose illness is severe enough to warrant the risk.

scholarly journals Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1247-1250 ◽  
Author(s):  
JH Antin ◽  
D Ginsburg ◽  
BR Smith ◽  
DG Nathan ◽  
SH Orkin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Conditioning Regimen ◽  
Erythroid Cell ◽  
Polymorphism Analysis ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Pnh Clone

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) involves the proliferation of an abnormal and possibly premalignant hematopoietic stem cell. Successful treatment of PNH by marrow grafting requires that the PNH clone be eradicated by the pretransplant conditioning regimen. Four patients with PNH-associated marrow aplasia were transplanted with marrow from their HLA-matched, MLR-nonreactive siblings. Three patients were conditioned with cyclophosphamide, procarbazine, and antithymocyte serum (CTX/PCZ/ATS), and one was conditioned with busulfan/CTX/PCZ/ATS. Persistent complete engraftment of myeloid, lymphoid, and erythroid cell lines was demonstrated in all four patients by DNA sequence polymorphism analysis or cytogenetics, and RBC typing. There was no recurrence of the abnormal clone of cells for up to five years after transplantation despite the use of a conditioning regimen in three of them, which is not usually associated with permanent marrow aplasia. Bone marrow transplantation is a curative therapy in patients whose illness is severe enough to warrant the risk.

scholarly journals High Dose Cyclophosphamide Treatment for Autoimmune Disorders

2002 ◽  
Vol 2 ◽  
pp. 1808-1815 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aldehyde Dehydrogenase ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Conditioning Regimen ◽  
Autoimmune Disorders ◽  
High Dose ◽  
Allogeneic Bone ◽  
Hematopoietic Stem

High-dose cyclophosphamide (200 mg/kg) was initially developed as a conditioning regimen for allogeneic bone marrow transplantation. Recently, high-dose cyclophosphamide without bone marrow transplantation has been employed as a method to induce durable treatment-free remissions in severe aplastic anemia and a variety of other severe autoimmune disorders. The premise underlying this approach is that high-dose cyclophosphamide is maximally immunosuppressive, but not myeloablative. Early hematopoietic stem cells are spared the cytotoxicity of cyclophosphamide because of their high levels of aldehyde dehydrogenase, an enzyme that confers resistance to the drug. Conversely, autoimmune effector cells (T cells, B cells, and NK cells) are exquisitely sensitive to high-dose cyclophosphamide because of their relatively low levels of aldehyde dehydrogenase. Intensive investigation is underway to determine which autoimmune disorders will most benefit and where in the natural history of these diseases to employ this rapidly developing therapy.

scholarly journals How I treat paroxysmal nocturnal hemoglobinuria

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6522-6527 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Clinical Manifestations ◽  
Allogeneic Bone ◽  
Curative Therapy ◽  
Blood Disorder

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis. Allogeneic bone marrow transplantation is the only curative therapy for PNH. Eculizumab, a monoclonal antibody that blocks terminal complement activation, is highly effective in reducing hemolysis, improving quality of life, and reducing the risk for thrombosis in PNH patients. Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored.

Reduced-Intensity Bone Marrow Transplantation for Heavily Transfused Patients with Severe Aplastic Anemia - Japanese Single Center Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5384-5384
Author(s):  
Teruhiko Kozuka ◽  
Kazushi Tanimoto ◽  
Koichi Nakase ◽  
Yuichiro Nawa ◽  
Masamichi Hara
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aplastic Anemia ◽  
Graft Rejection ◽  
Marrow Transplantation ◽  
Conditioning Regimen ◽  
Organ Damage ◽  
Severe Aplastic Anemia ◽  
Curative Therapy ◽  
Reduced Intensity

Abstract Background: Bone marrow transplantation (BMT) is a curative therapy for severe aplastic anemia (SAA). Outcome of BMT can be negatively affected when there is organ damage such as heart failure, liver dysfunction and diabetes mellitus after multiple transfusions in patients with long-standing SAA. Multiple transfusions also sensitize SAA patients with alloantigens and place them at high risk of graft rejection; it is an important problem after BMT for patients with multiply transfused SAA. We investigated the use of the combination of fludarabine monophosphate (FLU), cyclophosphamide (CY) and anti-thymocyte globulin (ATG) as the conditioning regimen in heavily transfused SAA patients. Methods: Four patients with heavily transfused SAA were treated with allogeneic BMT from unrelated and sibling donor. They were treated with a reduced-intensity conditioning regimen that included FLU (120 mg/m2), CY (1,200 mg/m2) and ATG (horse 40 mg/kg, rabbit 15 mg/kg). Results: The regimen was well tolerated, and engraftment rapidly occurred with some therapy-related toxicity encountered. Chimerism analysis on day 30 after transplant showed reconstitution with 100% donor cells in three patients. Among these three patients, two patients showed late graft rejection. At this time of reporting, only one patient is alive with complete donor chimerism. Conclusion: The combination of FLU/CY/ATG was well tolerated also in heavily transfused SAA patients: problems such as graft rejection remain.

Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation.

1991 ◽  
Vol 9 (7) ◽  
pp. 1224-1232 ◽  
Author(s):  
T J Nevill ◽  
M J Barnett ◽  
H G Klingemann ◽  
D E Reece ◽  
J D Shepherd ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
High Risk ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Conditioning Regimen ◽  
Allogeneic Bone ◽  
Risk Patients ◽  
Standard Risk

The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac, bladder, renal, pulmonary, hepatic, CNS, stomatic, and gastrointestinal) according to a recently developed RRT scale. A set of patient, disease, and treatment parameters (age, sex, diagnosis, Eastern Cooperative Oncology Group [ECOG] score, preconditioning liver function tests [LFT], prior chemotherapy exposure, disease status, graft-versus-host disease [GVHD] prophylaxis, antimicrobial agent use, hematologic recovery, and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%, respectively) but were rarely serious (9% and 1% grades II to IV, respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven), pulmonary (two), bladder (two), and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis, only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%, with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.

scholarly journals Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4743-4748 ◽  
Author(s):  
Nada Jabado ◽  
Elizabeth R. de Graeff-Meeder ◽  
Marina Cavazzana-Calvo ◽  
Elie Haddad ◽  
Françoise Le Deist ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Rejection ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Marrow Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Disease Free

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

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