Increasing the dose intensity of the conditioning regimen prior to allogeneic hematopoietic stem cell transplant: the role of pharmacokinetic monitoring

Shimoni, Avichai; Nagler, Arnon

doi:10.3109/10428194.2010.532892

Cited by 3 publications

(5 citation statements)

References 9 publications

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“…It is of course possible that the limited number of patients in some other studies and in the phase I part of our own study precluded detection of renal toxicity. It is unlikely that our policy of pretransplantation administraton of ganciclovir, trimethoprim/sulfamethoxazole, and an oral quinolone should be implicated as a cause of renal failure because it has been used as a standard in all our protocols, and we have not observed similar deteriorations in previous studies [4,41]. Neither melphalan nor alemtuzumab are associated with nephrotoxicity and both can even be safely administered to patients with renal failure [42].…”

Section: Discussionmentioning

confidence: 77%

“…Neither melphalan nor alemtuzumab are associated with nephrotoxicity and both can even be safely administered to patients with renal failure [42]. Furthermore, fludarabine, melphalan, and alemtuzumab or fludarabine, busulfan, and alemtuzumab combinations rarely invoke early renal injury [4,41]. Renal deterioration, often occurred early, after one or two doses of clofarabine and alemtuzumab but before administration of melphalan, tacrolimus, or other renal-damaging drugs.…”

Section: Discussionmentioning

confidence: 99%

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Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

Besien

Stock

Rich

et al. 2012

Biology of Blood and Marrow Transplantation

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We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m2 × 5, melphalan 140 mg/m2 × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

Besien

Stock

Rich

et al. 2012

Biology of Blood and Marrow Transplantation

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“…A suboptimal oral dose of BU, expressed as a low mean steady-state plasma concentration, is associated with graft rejection and relapse of the disease. 3,4,6,[17][18][19] On the other hand, high BU exposure has been associated with sinusoidal obstruction syndrome (SOS), interstitial pneumonia, and central nervous system toxicity. [20][21][22] High mean steady-state plasma concentrations of BU have also been shown to be correlated with transplantation-related mortality before Day þ100 posttransplant.…”

Section: Introductionmentioning

confidence: 99%

“…Oral BU is associated with other problems such as the large number of tablets administered at intervals of 6 hours and the difficulties in therapeutic drug monitoring. A suboptimal oral dose of BU, expressed as a low mean steady‐state plasma concentration, is associated with graft rejection and relapse of the disease . On the other hand, high BU exposure has been associated with sinusoidal obstruction syndrome (SOS), interstitial pneumonia, and central nervous system toxicity .…”

Section: Introductionmentioning

confidence: 99%

Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation

Castro

Lanchote

Voltarelli

et al. 2013

The Journal of Clinical Pharma

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This study evaluated the influence of fludarabine on the pharmacokinetics of busulfan administered orally to patients receiving a conditioning regimen for hematopoietic allogeneic stem cell transplantation (HSCT). Twenty-six patients treated with oral busulfan (1 mg/kg/6 h for 4 days) were divided into two groups according to the concomitant administration of fludarabine (n = 11; 30 mg/m(2) for 5 days) or subsequent administration of cyclophosphamide (n = 15; 60 mg/kg for 2 days). Serial blood samples were collected on Day 4 of busulfan administration. Plasma busulfan concentrations were determined by HPLC-UV and the pharmacokinetic parameters were calculated using the WinNonlin program. Patients concomitantly treated with fludarabine showed reduced apparent clearance of busulfan (110.5 mL/h/kg vs. 157.4 mL/h/kg) and higher AUC0-6 (area under the plasma concentrations vs. time curve) than patients subsequently treated with cyclophosphamide (7.9 µg h/mL vs. 5.7 µg h/mL). No association was observed between busulfan AUC0-6 and clinical evolution of the patients. Although plasma busulfan concentrations were higher in patients receiving concomitant fludarabine, myelosuppression-related toxicity was less frequent than in patients treated with busulfan and cyclophosphamide. The results suggest that patients treated with fludarabine should receive 30% lower busulfan doses during conditioning protocols for HSCT.

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“…It is true that some patients required the use of other potentially nephrotoxic drugs during the study period, as all patients received peri-transplant administration of ganciclovir, trimethoprim/sulfamethoxazole and an oral quinolone. However, these are standard prophylactic agents used at our transplant center and are unlikely to be significantly related to the AKI rate seen in this cohort, because our prior studies with other conditioning regimens have not revealed this frequency or severity of renal injury [26,27]. Additionally, melphalan and alemtuzumab have been used successfully in patients with renal failure and are not associated with renal toxicity [28].…”

Section: Discussionmentioning

confidence: 99%

Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant

Petri¹,

O’Donnell²,

Cao³

et al. 2014

Leukemia & Lymphoma

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We examined clofarabine pharmacokinetics and association with renal toxicity in 62 patients participating in a phase I–II study of clofarabine–melphalan–alemtuzumab conditioning for hematopoietic stem cell transplant (HSCT). Pharmacokinetic parameters, including clofarabine area under the concentration–time curve (AUC), maximum concentration and clearance, were measured, and patients were monitored for renal injury. All patients had normal pretreatment creatinine values, but over half (55%) experienced acute kidney injury (AKI) after clofarabine administration. Age was the strongest predictor of AKI, with older patients at greater risk (p = 0.002). Clofarabine AUC was higher in patients who developed AKI, and patients with the highest dose-normalized AUCs experienced the most severe grades of AKI (p = 0.01). Lower baseline renal function, even when normal, was associated with lower clofarabine clearance (p = 0.008). These data suggest that renal-adjustment of clofarabine dosing should be considered for older and at-risk patients even when renal function is ostensibly normal.

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Increasing the dose intensity of the conditioning regimen prior to allogeneic hematopoietic stem cell transplant: the role of pharmacokinetic monitoring

Cited by 3 publications

References 9 publications

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab Conditioning for Allogeneic Hematopoietic Cell Transplantation

Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation

Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant

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