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Biomedical subjects

Robert A Brodsky

Publications and source records attributed to Robert A Brodsky.

At least 19 recordsLinked to original sources
PubMed2006

The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.

BACKGROUND: We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed. RESULTS: Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae. CONCLUSIONS: Eculizumab is an effective therapy for PNH.

Adolescent↗
PubMed2006

Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions.

We retrospectively analyzed 83 consecutive recipients of donor lymphocyte infusions (DLI) after allogeneic transplantation for factors associated with disease response and graft-versus-host disease (GVHD). DLI was highly effective in relapsed chronic phase chronic myeloid leukemia (CML), with 71% of patients achieving durable complete remissions (CR). In relapsed acute myeloid leukemia, DLI led to durable CRs in 31% of patients; the rate was <20% in all other diseases. Achieving full donor chimerism and GVHD were predictive of CR. Grade II or higher acute or chronic GVHD occurred in 36 (43%) patients and contributed to death in 13 (16%). Even more patients, 33 (40%), died of their underlying malignancy, including 10 who developed active GVHD. In relapsed CML, most durable CRs occurred without clinically apparent GVHD, yet all responders achieved full donor chimerism, including 6 with coincident normal host hematopoiesis at the time of DLI. Thus, in CML, potent lymphohematopoietic graft-versus-host reactions occurred even in the absence of clinically apparent GVHD; this confirms the ability to dissociate these processes and argues against a leukemia-specific immunologic effect. DLI clearly has efficacy in the treatment of relapsed disease after allogeneic transplantation. However, with the exception of CML, most patients die of their underlying disease because of insufficient antitumor activity even with active GVHD.

Acute Disease↗
PubMed2006

PIG-A mutations in paroxysmal nocturnal hemoglobinuria and in normal hematopoiesis.

PIG-A is an X-linked gene that is essential for the first step in the biosynthesis of glycosylphosphatidyl-inositol (GPI) anchors. A rare clonal hematopoietic stem cell disease, paroxysmal nocturnal hemoglobinuria (PNH), is caused by mutations in the PIG-A gene. PNH is an acquired disease that may arise de novo or emanate from aplastic anemia. PNH blood cells have an absence or marked deficiency of all GPI anchored proteins. Interestingly, rare GPI anchor deficient blood and marrow cells that harbor PIG-A mutations can also be found in most healthy controls. This review examines the clinical and biological relevance of PIG-A mutations in PNH, aplastic anemia and healthy controls.

Anemia, Aplastic↗
PubMed2006

Catheter-directed thrombolysis and thrombectomy for the Budd-Chiari syndrome in paroxysmal nocturnal hemoglobinuria in three patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by hemolytic anemia, hemoglobinuria, bone marrow failure, and hypercoagulability. Thrombosis is the leading cause of mortality and occurs in one-half of PNH patients, with the hepatic veins being the most common site. Patients with hepatic vein thrombosis (Budd-Chiari syndrome) can present with abdominal pain, hepatomegaly, jaundice, and ascites. Prognosis is poor for these patients; death may occur from liver failure, vessel rupture, intestinal ischemia, infarction, necrosis, or sepsis. The authors report three consecutive cases of successful treatment with catheter-directed thrombolysis and thrombectomy directly in the hepatic veins in patients with PNH who developed acute hepatic vein thrombosis. This treatment represents a potential bridge toward more curative therapies such as allogeneic bone marrow transplant.

Adolescent↗
PubMed2006

New insights into paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A. PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis. Intravascular hemolysis leads to release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm, erectile dysfunction and possibly thrombosis. Interestingly, rare PIG-A mutations can be found in virtually all healthy control subjects, leading to speculation that PIG-A mutations in hematopoietic stem cells are common benign events. However, negative selection of PIG-A mutant colony-forming cells with proaerolysin, a toxin that targets GPI-anchored proteins, reveals that most of these mutations are not derived from stem cells. Recently, a humanized monoclonal antibody directed against the terminal complement protein C5 has been shown to reduce hemolysis and greatly improve symptoms and quality of life for PNH patients.

Antibodies, Monoclonal↗
PubMed2005

Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.

Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenita display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.

Adolescent↗
PubMed2005

PIG-A mutations in normal hematopoiesis.

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by phosphatidylinositol glycan-class A (PIG-A) mutations in hematopoietic stem cells (HSCs). PIG-A mutations have been found in granulocytes from most healthy individuals, suggesting that these spontaneous PIG-A mutations are important in the pathogenesis of PNH. It remains unclear if these PIG-A mutations have relevance to those found in PNH. We isolated CD34+ progenitors from 4 patients with PNH and 27 controls. The frequency of PIG-A mutant progenitors was determined by assaying for colony-forming cells (CFCs) in methylcellulose containing toxic doses of aerolysin (1 x 10(-9) M). Glycosylphosphatidylinositol (GPI)-anchored proteins serve as receptors for aerolysin; thus, PNH cells are resistant to aerolysin. The frequency of aerolysin resistant CFC was 14.7 +/- 4.0 x 10(-6) in the bone marrow of healthy donors and was 57.0 +/- 6.7 x 10(-6) from mobilized peripheral blood. DNA was extracted from individual day-14 aerolysin-resistant CFCs and the PIG-A gene was sequenced to determine clonality. Aerolysin-resistant CFCs from patients with PNH exhibited clonal PIG-A mutations. In contrast, PIG-A mutations in the CFCs from controls were polyclonal, and did not involve T cells. Our data confirm the finding that PIG-A mutations are relatively common in normal hematopoiesis; however, the finding suggests that these mutations occur in differentiated progenitors rather than HSCs.

Bacterial Toxins↗
PubMed2005

High-dose therapy for autoimmune neurologic diseases.

PURPOSE OF REVIEW: Autoimmune neurologic diseases are being increasingly recognized, and treated with conventional immunosuppressive agents. Patients with 'refractory' conditions have been treated with high-dose therapy, with or without autologous stem cell transplants. This paper reviews the rationale, methods, and recent results of high-dose therapy and the questions that it raises. RECENT FINDINGS: High-dose therapy has been used in progressive multiple sclerosis and in myasthenia gravis and autoimmune neuropathies that are refractory to conventional immunotherapy. A variety of methods of immune ablation have been used; most require hematopoietic 'rescue' with stem cell transplantation. High-dose cyclophosphamide alone is immunoablative but not myeloablative, permitting the patient's endogenous stem cells to repopulate the hematopoietic/immune systems. The results have been highly encouraging in many but not all cases, with durable responses in the limited time they have been followed up. The treatments carry some risks and have been reserved for refractory cases until now. SUMMARY: High-dose therapy, without or with stem cell transplantation, is a valuable resource for the treatment of patients with refractory autoimmune neurologic diseases. It is important to define the diseases and patient characteristics likely to lead to benefit, to optimize the methods of treatment and to establish when in the patient's course to administer it. High-dose therapy may eventually become the standard for treatment of severe progressive autoimmune neurologic disorders.

Animals↗
PubMed2004

High-dose cyclophosphamide as salvage therapy for severe aplastic anemia.

OBJECTIVE: The treatment options for patients with aplastic anemia who do not respond to conventional immunosuppression are limited. The aim of this study was to evaluate high-dose cyclophosphamide in patients with refractory severe aplastic anemia (SAA). MATERIALS AND METHODS: We treated 17 SAA patients with high-dose cyclophosphamide (50 mg/kg/day for 4 consecutive days) who previously did not respond to one or more courses of immunosuppressive therapy. Median age was 31 years (range 6-58); median disease duration was 14 months (range 6-58), and 8 patients met criteria for very severe aplastic anemia (absolute neutrophil count <0.2 x 10(9)/L) at the time of treatment. RESULTS: At median follow-up of 29 months, 10 patients (59%) are alive. Nine patients (53%) achieved a drug-free remission after high-dose cyclophosphamide; 4 patients achieved a complete remission and 5 patients currently meet criteria for a partial remission but continue to improve. One nonresponder to high-dose cyclophosphamide developed paroxysmal nocturnal hemoglobinuria; another nonresponder developed a myelodysplastic syndrome. In responding patients, median time to 500 neutrophils was 54 days (range 35-119), median time to the last platelet transfusion was 99 days (range 51-751), and median time to the last red cell transfusion was 125 days (range 63-796). CONCLUSION: High-dose cyclophosphamide shows promise for salvaging patients with refractory SAA.

Adolescent↗
PubMed2004

Enhanced cytotoxicity of rituximab following genetic and biochemical disruption of glycosylphosphatidylinositol anchored proteins.

Rituximab, an anti-CD20 monoclonal antibody used to treat B cell lymphoproliferative disorders and autoimmune diseases, kills cells through complement dependent cytotoxicity, antibody-dependent cellular toxicity and apoptosis. A mechanism of resistance to rituximab is upregulation of the complement regulatory proteins, CD59 and CD55. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic disorder caused by PIGA mutations that lead to a loss of all glycosylphospatidylinositol (GPI)-anchored proteins including, CD55 and CD59. We compared the cytotoxic activity of rituximab against a PNH B cell line, LD -, and the isogenic cell line LD - PIGA + in which GPI-anchor expression was restored by stable transfection of PIGA. The PNH cell line was more sensitive to rituximab-mediated killing than the LD - PIGA + cells. Biochemical disruption of GPI anchors with phosphatidylinositol specific phospholipase C (PIPLC), a phospholipase that cleaves GPI-anchored proteins, also increased rituximab-mediated killing. Thus, genetic and biochemical interruption of GPI anchor proteins augments sensitivity to rituximab.

Antibodies, Monoclonal↗
PubMed2004

Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays.

Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, acquired disorder of blood cells caused by mutation of the phosphatidylinositol glycan class A (PIG-A) gene. The disease often manifests with haemoglobinuria, peripheral blood cytopenias, and venous thrombosis. The natural history of PNH has been documented in retrospective series; but there has only been one study that correlated the more sensitive and specific flow cytometric assays that have become available in the last decade with severe symptoms associated with PNH. In a retrospective analysis of 49 consecutive patients with PNH evaluated at Johns Hopkins, large PNH clones were associated with an increased risk for thrombosis as well as haemoglobinuria, abdominal pain, oesophageal spasm, and impotence. Of the 14 (29%) patients that developed thrombosis, nine died; six of these from complications related to thromboses. According to logistic regression modelling, for a 10% change in PNH clone size, the odds ratio for risk of thrombosis was estimated to be 1.64. No patient with <61% PNH granulocytes developed a thrombosis, whereas 12 of 22 patients (54.5%) with > or =61% PNH granulocytes manifested with thrombosis. These data not only confirm that the size of the PNH clone correlates with the risk for thrombosis, but they also suggest a correlation of PNH clone size to more symptomatic PNH.

Adolescent↗
PubMed2003

Treatment of refractory myasthenia: "rebooting" with high-dose cyclophosphamide.

Patients with myasthenia gravis (MG) who do not respond to conventional immunotherapeutic agents, or cannot tolerate their side effects, are considered "refractory." Ablation of the immune system followed by bone marrow transplant has been shown to cure experimental MG in rats. It is now known that immunoablative treatment with high-dose cyclophosphamide does not damage hematopoietic "stem cells," permitting repopulation of the immune system without bone marrow transplant. Recent evidence indicates that this treatment can induce durable remissions in autoimmune diseases. We treated three myasthenic patients, for whom treatment with thymectomy, plasmapheresis, and conventional immunotherapeutic agents failed, by using high-dose cyclophosphamide (50mg/kg/day intravenously for 4 days) followed by granulocyte colony stimulating factor. All three patients tolerated the treatment well and have had marked improvement in myasthenic weakness, permitting reduction of immunosuppressive medication to minimal levels. Acetylcholine receptor (AChR) antibody levels decreased in two AChR antibody-positive patients, and anti-MuSK antibody levels decreased in one "AChR antibody-negative" patient. The patients have been followed for up to 3.5 years, with no recurrence of symptoms. High-dose cyclophosphamide treatment appears to be an effective and safe treatment for selected patients with refractory MG. Further follow-up of these and additional patients will be needed to determine whether the benefit is durable.

Adult↗
PubMed2003

High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus.

OBJECTIVE: High-dose chemotherapy followed by hematopoietic stem cell transplantation is increasingly being studied as a treatment for severe autoimmune disorders, such as systemic lupus erythematosus (SLE). High-dose cyclophosphamide, the foundation of virtually all conditioning regimens for stem cell transplantation, is not myeloablative; therefore, when high-dose cyclophosphamide is used alone, autografting, with its potential for reinfusing autoreactive effector cells, is not required. We undertook this study to investigate the safety and efficacy of high-dose cyclophosphamide without stem cell transplantation in refractory SLE. METHODS: We treated 14 patients with moderate-to-severe SLE that had been refractory to corticosteroids and one or more additional immunosuppressive drugs. All patients received 50 mg/kg of cyclophosphamide for 4 consecutive days followed by 5 microg/kg granulocyte colony-stimulating factor until the neutrophil count was 1 x 10(9)/liter for 2 consecutive days. Patients were followed up monthly for disease activity using the physician's global assessment, SLE Disease Activity Index, and assessment of functioning of involved organs. The Responder Index for Lupus Erythematosus was used to define partial or complete response. RESULTS: The median time to achieve a neutrophil count of 0.5 x 10(9)/liter was 14 days (range 11-22 days) after the last dose of cyclophosphamide. Patients required a median of 2 units (range 2-5) of packed red blood cells, and a median of 16 days (range 0-23 days) elapsed from the last dose of cyclophosphamide to the last platelet transfusion. There were no deaths or fungal infections. Significant improvements in physician's global assessment (mean difference 1.4; P < 0.0001), SLE Disease Activity Index (mean difference 4.1; P = 0.0039), and prednisone dosage (mean difference 14.9 mg/day; P = 0.002) were observed. Responses, including 5 durable complete responses, were observed in all organ systems (renal, central nervous system, and skin) with involvement that had led to patient enrollment. CONCLUSION: High-dose cyclophosphamide without stem cell transplantation leads to rapid hematopoietic reconstitution and has significant clinical benefit in patients with refractory SLE. Therefore, this approach deserves further study.

Adult↗
PubMed2003

Long-term follow-up of T cell-depleted allogeneic bone marrow transplantation in refractory multiple myeloma: importance of allogeneic T cells.

Multiple myeloma may be cured by myeloablative conditioning and allogeneic blood or marrow transplantation (alloBMT), but this occurs at the expense of high transplant-related mortality. In an endeavor to reduce procedure-related toxicity, this study retrospectively evaluated the safety, tolerability, and efficacy of T cell depletion by counterflow centrifugal elutriation before alloBMT. Fifty-one patients with stage II (6) or III (45) multiple myeloma received alloBMTs using T cell depletion by elutriation. Fifty-three percent (27 of 51) of patients had primary refractory disease at the time of transplantation, 10% (5 of 51) had relapsed disease, and 4% (2 of 51) had refractory relapsed disease. The median age was 49 (range, 32 to 62) years, and the median time from diagnosis to transplantation was 9 (range, 4 to 58) months. Patients had received a median of 1 (range, 1 to 3) regimen and 4 (range, 2 to 16) cycles of chemotherapy. In this population, transplant-related mortality rate was 24% (12 of 51) with 2 patients dying of graft-versus-host disease (GVHD). Thirty-one of 39 evaluable patients have experienced relapse, and the probability of progression-free survival 5 years after alloBMT alone is 16%. Sixteen patients were given donor lymphocyte infusions (DLI) at the time of relapse (n = 11) or for persistent disease 1 year after transplantation (n = 5). Acute or chronic GVHD was seen in 63% (10 of 16) of patients given DLI. Responses were seen in 8 of 16 patients (6 complete response [CR], 2 partial response [PR]) with 6 of 8 responding patients having GVHD. Five recipients of DLI remain in a continuous CR, ranging from 3 to 64 months in duration. Thus, like chronic myelogenous leukemia, allogeneic T cells appear to have potent antimyeloma activity that is critical for achieving a cure. DLI-induced remissions of multiple myeloma can be durable, even in patients with refractory multiple myeloma. Unlike chronic myelogenous leukemia, the antimyeloma effect of allogeneic T cells rarely occurs in the absence of clinically significant GVHD.

Adult↗
PubMed2002

High-dose cyclophosphamide for refractory autoimmune hemolytic anemia.

High-dose cyclophosphamide, without stem cell rescue, has been used successfully to treat aplastic anemia and other autoimmune disorders. To determine the safety and efficacy of high-dose cyclophosphamide among patients with severe refractory autoimmune hemolytic anemia, we treated 9 patients with cyclophosphamide (50 mg. kg(-1). d(-1) for 4 days) who had failed a median of 3 (range, 1-7) other treatments. The median hemoglobin before treatment was 6.7 g/dL (range, 5-10 g/dL). The median time to reach an absolute neutrophil count of 500/microL or greater was 16 days (range, 12-18 days). Six patients achieved complete remission (normal untransfused hemoglobin for age and sex), and none have relapsed after a median follow-up of 15 months (range, 4-29 months). Three patients achieved and continue in partial remission (hemoglobin at least 10 g/dL without transfusion support). High-dose cyclophosphamide was well tolerated and induced durable remissions in patients with severe refractory autoimmune hemolytic anemia.

Adult↗