Danazol for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal stem-cell disorder in which blood cells lack complement inhibiting membrane proteins, and become susceptible to complement-mediated injury, leading to chronic intravascular hemolysis and pancytopenia. Glucocorticoids have been a mainstay of therapy. For patients refractory to glucocorticoids and requiring blood transfusions, an alternative therapy is needed. We studied danazol therapy in 5 patients refractory to other treatments. Four of the 5 benefited, showing rise in hematocrit and eventual cessation of transfusion requirements. Remissions lasted ≥2 years in 3 and 10 years in 1 patient. Danazol was well-tolerated without serious side effects. Danazol appears to be a good alternative treatment in PNH. Am. J. Hematol. 54:149–154, 1997 © 1997 Wiley-Liss, Inc.     

Acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria: studies on clonality.

We used X-chromosome methylation patterns to study clonality in aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). AA is usually not considered to be a clonal stem cell disorder, although this has not been directly investigated. PNH is generally assumed to be a clonal disorder, although there is contradictory evidence. Methylation analysis was performed on DNA from separated granulocytes and mononuclear cells, using the M27 beta and hypoxanthine phosphoribosyl transferase (HPRT) probes. Six of seven AA patients showed a polyclonal pattern of X inactivation. In contrast, five of five PNH patients showed a monoclonal pattern. These results imply that at least 80% of the cell population derives from a single stem cell. Because this high proportion of PNH cells might be considered surprising, three patients were studied for membrane expression of decay accelerating factor (DAF). In support of the DNA data, more than 95% of the granulocytes were DAF--ve in all three cases. We conclude that AA is predominantly a polyclonal disorder, whereas PNH is a clonal stem cell disorder. Our data support a model in which a single PNH stem cell has a growth advantage over other remaining stem cells and eventually dominates hematopoiesis.     

Laboratory tests for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder that is often suspected in a patient presenting with non‐immune hemolytic anemia associated with pancytopenia or venous thrombosis. This disorder is a consequence of acquired somatic mutations in the phosphatidylinositol glycan class A (PIG‐A) gene in the hematopoietic stem cells (HSC) of patients. The presence of these mutations leads to production of blood cells with decreased glycosyl phosphatidylinositol‐anchored cell surface proteins, making red blood cells derived from the clone more sensitive to complement mediated hemolysis. The diagnosis of PNH may be difficult in some cases due a low proportion of PNH cells in the blood and occasionally due to difficulties in selecting the most appropriate diagnostic studies. The latest generation of tests allow for detection of very small populations of PNH cells, for following the natural course and response to therapy of the disease, and for helping to decide when to initiate therapy with monoclonal antibody targeting the terminal complement protein C5 (Eculizumab), anticoagulation, and in some cases allogeneic HSC transplant. In this article, we review the different diagnostic tests available to clinicians for PNH diagnosis. Am. J. Hematol. 89:339–341, 2014. © 2013 Wiley Periodicals, Inc.     

Long-term survival after marrow transplantation for paroxysmal nocturnal hemoglobinuria with aplastic anemia

Four patients with paroxysmal nocturnal hemoglobinuria and severe marrow aplasia were given marrow grafts either from allogeneic human-leukocyte-antigen-identical siblings (three patients) or from a syngeneic donor (one patient). The patients with allogeneic grafts were conditioned with regimens that included cyclophosphamide and had sustained and complete marrow engraftment; subsequent tests were negative for paroxysmal nocturnal hemoglobinuria. One patient developed chronic graft-versus-host disease that resolved over 4 years. The patient receiving a syngeneic graft received marrow infusion without preceding immunosuppression. He had prompt engraftment, and hematologic variables returned to normal. A Ham's test done at 3 years was negative, but a complement lysis sensitivity test done 10 years after grafting was positive; the patient, however, remains asymptomatic. All four patients are alive and well 4, 9, 10, and 12 years after transplantation. Paroxysmal nocturnal hemoglobinuria apparently can be treated successfully by allogeneic or syngeneic marrow transplantation without subsequent maintenance therapy.     

Lactic acidosis secondary to severe anemia in a patient with paroxysmal nocturnal hemoglobinuria

A patient with paroxysmal nocturnal hemoglobinuria developed lactic acidosis associated with severe anemia. The lactic acidosis corrected after blood transfusion. In the absence of shock, sepsis, or other identifiable causes of lactic acidosis, the severe anemia (hemoglobin 1.2 g/dl) appeared to be the primary etiologic factor. Am. J. Hematol. 55:110-111, 1997. © 1997 Wiley-Liss, Inc.     

Treatment of paroxysmal nocturnal hemoglobinuria

Patients with PNH may be treated with a number of known agents. As in all patients with a chronic disease, a regimen tolerable over a long period of time must be selected. Knowledge and anticipation of complications and their proper treatment are essential parts in the treatment. When these principals are used, many patients may live reasonable lives for very long periods of time.     

Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria

BACKGROUND AND OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of the hemopoietic stem cell (HSC) characterized by intravascular hemolysis and increased risk of venous thrombosis. There are different therapeutic approaches for PNH which do not cure the disease, but can decrease its complications. Allogeneic bone marrow transplantation (BMT) may cure PNH. We reports here our experience of seven PNH patients who underwent allogeneic BMT. DESIGN AND METHODS: Between January 1991 and January 1999 seven patients with PNH, aged 23 to 37, were transplanted with unmanipulated bone marrow from HLA identical siblings. Median time from diagnosis to BMT was 2.5 years (range: 1-16). All patients were transfusion-dependent and had received various treatments before BMT: steroids, vitamins, cyclosporin A (CyA), growth factors. One patient had also been treated with anti-thymocyte globulin. One patient was HbsAg positive and one anti-HCV positive. At the time of BMT the median value of hemoglobin (Hb) was 9 g/dL (range 6.5-11), white blood cells 5&10(9)/L (range: 2.9-7.7), platelets 97&10(9)/L (range: 31-355), LDH: 2726 U/L. The conditioning regimen was cyclophosphamide (160 mg/kg) and busulfan (10-14 mg/kg), followed by unmanipulated bone marrow (median of 5&10(8) cells/kg) and CyA (+MTX in two patients) for prophylaxis of graft-versus-host disease (GvHD). RESULTS: All seven patients are alive, full chimeras, with complete hematologic recovery and no evidence of PNH, at a median follow up of 51 months post-BMT (6-103). Time to achieve a granulocyte count of 0.5&10(9)/L, platelets 30&10(9)/L and Hb 10 g/dL was respectively 16, 19 and 22 days. Acute GvHD was limited or mild in six patients, and severe in one. Chronic GvHD was extensive in two patients. INTERPRETATION AND CONCLUSIONS: This study confirms that HLA identical sibling BMT is an effective therapeutic option for PNH, also in the hemolytic phase of the disease: it also suggests that HBV and HCV infections are not an absolute contraindication.     

Stem cell transplantation for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) represents a rare clonal disorder of hematopoiesis clinically characterized by acquired hemolytic anemia, intravascular hemolysis, hemoglobinuria and frequent occurrence of venous thrombosis. Stem cell transplantation is indicated in patients with severe bone marrow aplasia, repeated massive hemolysis or recurrent life threatening thrombotic complications. Almost 90 transplanted patients with PNH have been published. We report a case of successful allogeneic peripheral blood stem cell transplantation performed in a 24 years old woman with a severe form of PNH with frequent episodes of massive intravascular hemolysis. The patient is now alive completely engrafted 900 days after transplantation without signs of chronic GVHD and without recurrent infections. This case represents the first successfully transplanted patient with PNH in our country.     

Marrow transplantation for paroxysmal nocturnal hemoglobinuria.

Between 1971 and 1990, nine patients ranging in age from 14-38 years received marrow transplants for paroxysmal nocturnal hemoglobinuria (PNH). Six were transplanted for aplastic complications of PNH. Four of these were from HLA-identical siblings, and the patients were conditioned with cyclophosphamide. One graft was form a syngeneic twin without conditioning, and one from a two HLA-antigen nonidentical father after conditioning with cyclophosphamide and total body irradiation. Three of the four recipients of allogeneic marrow developed acute and two chronic graft-versus-host disease (GVHD). Five of six transplanted for severe aplastic anemia are long-term survivors with follow-up ranging from more than 6.2 to more than 19.1 years. The HLA nonidentical transplant recipient experienced graft rejection and died of a pulmonary hemorrhage. Three patients were transplanted for nonaplastic complications of PNH consisting of life threatening recurrent thromboses or refractory hemolysis. Two of these patients received marrow grafts from HLA-identical siblings after conditioning with busulfan and cyclophosphamide. They are surviving with normal hemograms greater than 2.2 and greater than 2.5 years and had mild chronic GVHD which resolved, although one has biochemical evidence of PNH in 15% of the red cells. One received a syngeneic marrow graft without conditioning but reverted to PNH. He is alive greater than 8.6 years after transplantation. Marrow transplantation for aplastic complications of PNH is successful, well tolerated, and compatible with long-term survival when an HLA-identical sibling or a syngeneic donor is available. For patients without aplasia, one must weigh the complications of transplantation with the life threatening nature of thrombotic episodes and hemolysis.     

Evans' syndrome in paroxysmal nocturnal hemoglobinuria

We describe the first case of paroxysmal nocturnal hemoglobinuria with Evans' syndrome. The immunohematological studies of this patient, a 27-year-old man, revealed the presence of red cell and platelet autoantibodies, related to an episode of anemia and thrombocytopenia.