Durable Treatment-Free Remission after High-Dose Cyclophosphamide Therapy for Previously Untreated Severe Aplastic Anemia

Sensenbrenner, Lyle L.; Smith, B. Douglas; Dorr, Donna; Seaman, Phillip; Lee, S M; Karp, JE; Brodsky, Isadore; Jones, Richard J.

doi:10.7326/0003-4819-135-7-200110020-00006

Cited by 99 publications

(76 citation statements)

References 24 publications

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“…10 However, in recent years, the percentage of patients receiving singleagent HD cyclophosphamide up to 7 g/m 2 or 200 mg/kg experiencing cardiotoxicity has diminished to nearly zero with the adoption of multifractionated schedule of administration. 4,5,[7][8][9]25 Available evidence indicates that singleagent HD cyclophosphamide-associated cardiac toxicity is dose and schedule dependent, and it is not related to the cumulative drug dose. 13,16,21 No pharmacokinetic parameter has been consistently associated with cardiotoxicity, although a significant inverse association between a reduced HD cyclophosphamide area under the curve (AUC) (ie accelerated clearance due to an increased conversion to active metabolites) and cardiotoxicity was found in three independent studies, 17,26,27 but not confirmed in a larger one.…”

Section: Cardiac Toxicity Due To Conditioning Regimenmentioning

confidence: 99%

“…Total dose pmaximum-tolerated dose as single agent 4,5,[7][8][9]25 Schedule of administration Adopt the least cardiotoxic schedule (eg multifractionated schedule for HD cyclophosphamide) 4,5,[7][8][9]25 Concomitant administration of other chemotherapeutic agents Avoid reportedly cardiotoxic associations or treatment schedules 10,12,14,15,[39][40][41][42] History of radiation therapy to the mediastinum or left chest wall…”

Section: Dosagementioning

confidence: 99%

“…1,2 Moreover, HD melphalan and HD cyclophosphamide have been successfully used to treat primary amyloidosis 3 and autoimmune diseases, 4,5 respectively. Finally, in the last few years reduced-intensity conditioning regimens have been applied to patients undergoing allogeneic HSC transplantation to reduce drug toxicity while maintaining the potential for achieving disease remission exploiting the graft-versus-leukemia effect.…”

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confidence: 99%

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Cardiac toxicity of high-dose chemotherapy

Morandi

Ruffini

Benvenuto

et al. 2004

Bone Marrow Transplant

148

104

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Summary:Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.

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Section: Cardiac Toxicity Due To Conditioning Regimenmentioning

confidence: 99%

Section: Dosagementioning

confidence: 99%

mentioning

confidence: 99%

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Cardiac toxicity of high-dose chemotherapy

Morandi

Ruffini

Benvenuto

et al. 2004

Bone Marrow Transplant

148

104

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“…High-dose immunoablative cyclophosphamide alone has led to long-term remissions in aplastic anemia (15,16) and other autoimmune disorders (17). The unique pharmacology of high-dose cyclophosphamide is responsible for its ability to induce maximal immunosuppression without myeloablation.…”

mentioning

confidence: 99%

High‐dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus

Petri

Jones

Brodsky

2003

Arthritis & Rheumatism

Self Cite

138

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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 moderateto-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 g/kg granulocyte colony-stimulating factor until the neutrophil count was 1 ؋ 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 ؋ 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.Despite improved survival rates in patients with systemic lupus erythematosus (SLE) and other autoimmune disorders, there remains a subset of patients in whom the disease is refractory to therapy or who require toxic dosages of immunosuppressive drugs. Standard therapy for severe renal or central nervous system (CNS) SLE is monthly intravenous (IV) bolus cyclophosphamide in doses of 500-1,000 mg/m 2 body surface area. The superior efficacy of this therapy compared with corticosteroids alone has been proven for diffuse proliferative glomerulonephritis (1,2) and has been suggested in case series of SLE with CNS involvement (3). Monthly IV bolus cyclophosphamide has a safety profile superior to that of daily oral cyclophosphamide, but important toxicitie...

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“…All four patients with marrow trilineage dysplasia exhibited neoplastic progression. Patients 16-32 (Table 1) met clinical criteria, 15 and were treated, for AA: 10 with high-dose cyclophosphamide, 18,19 four with immunosuppressive therapy (antithymocyte globulin and/or cyclosporine), 20 and three with allogeneic transplantation after high-dose cyclophosphamide conditioning. 21 None of these 17 patients has shown any evidence of neoplastic progression, and only two have died, both ( Table 1, Patients 28 and 29) with refractory neutropenia and infection while on immunosupporessive therapy.…”

Section: Resultsmentioning

confidence: 99%