Open-label Bendamustine Monotherapy for Pediatric Patients With Relapsed or Refractory Acute Leukemia

Fraser, Chris; Brown, Patrick; Megason, Gail; Ahn, Hyo Seop; Cho, Bin; Kirov, Ivan I.; Frankel, Lawrence S.; Aplenc, Richard; Bensen-Kennedy, Debra; Munteanu, Mihaela; Weaver, Jennifer; Harker‐Murray, Paul

doi:10.1097/mph.0000000000000021

Cited by 13 publications

(24 citation statements)

References 11 publications

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“…Bendamustine monotherapy was recently investigated in an international, open-label, single-arm, multicenter, phase 1/2 study of heavily pretreated pediatric patients aged 1–20 years with relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) [ 26 ]. Secondary study objectives included determining the pediatric pharmacokinetic profile of bendamustine relative to the adult pharmacokinetic profile [ 27 ].…”

Section: Comparison Of Adult and Pediatric Pharmacokinetic Profilesmentioning

confidence: 99%

“…Systemic exposure to bendamustine 120 mg/m 2 in children was similar to that previously reported in the phase 3 adult NHL study [ 17 , 27 ]. In the 120 mg/m 2 pediatric group ( n = 38), mean C max was 6806 ng/mL (mean t max , 1.1 h) and mean area under the curve (AUC) 0–24 was 8240 ng h/mL, compared with a mean C max of 5746 ng/mL and mean AUC 0–24 of 7121 ng h/mL in adults ( n = 78) [ 26 , 27 ].…”

Section: Comparison Of Adult and Pediatric Pharmacokinetic Profilesmentioning

confidence: 99%

“…2 ) [ 27 ]. No dose-limiting toxicities were reported [ 26 ]. Because systemic exposure to bendamustine 120 mg/m 2 was similar between adult and pediatric patients—with mean AUC 0–24 and C max values <16 % higher in the pediatric patients population—higher doses were not assessed in the pediatric study, per protocol [ 17 , 27 ].…”

Section: Bendamustine Dosing Paradigmmentioning

confidence: 99%

“…Of the 22 patients receiving 120 mg/m 2 with a defined best overall response, 9 % achieved a partial response, 32 % had stable disease, and 59 % had progressive disease. The remaining five patients received bendamustine 90 mg/m 2 , two of whom achieved a complete response (both with ALL) [ 26 ]. Although no clear exposure–response relationship was observed in the efficacy analysis [ 27 ], two ALL patients with partial response as their best overall response had slightly higher bendamustine AUC and C max values than the median systemic exposures of patients with stable or progressive disease [ 26 ].…”

Section: Bendamustine Exposure–response Relationshipmentioning

confidence: 99%

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Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

Darwish¹,

Bond

Hellriegel

et al. 2015

Cancer Chemother Pharmacol

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PurposeBendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin’s lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug–drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies.MethodsA literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion.ResultsBendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t1/2 (~40 min) as the effective t1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug–drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m2 is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure–efficacy response relationship has been observed.ConclusionsAltogether, the findings support dosing based on body surface area for most patient populations.

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Section: Comparison Of Adult and Pediatric Pharmacokinetic Profilesmentioning

confidence: 99%

Section: Comparison Of Adult and Pediatric Pharmacokinetic Profilesmentioning

confidence: 99%

Section: Bendamustine Dosing Paradigmmentioning

confidence: 99%

Section: Bendamustine Exposure–response Relationshipmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

Darwish¹,

Bond

Hellriegel

et al. 2015

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

“…Bendamustine is an alkylating agent that induces DNA damage leading to cell apoptosis that has already had its benefits well described in chronic lymphocytic leukemia and recurrent and refractory non-Hodgkins lymphomas 4 . In the context of new drugs, Bendamustine was used in children as monotherapy for treatment of acute relapsed/refractory leukemias of both myeloid as lymphoid lineages with satisfactory response 8 . Approximately 90% of the B-lymphoid precursor cells express the CD19 surface antigen.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Acute Lymphoid Leukemia Refractory to Classic First-Line and Rescue Protocols

Russo

Macedo

Fernades

et al. 2020

IJHOSCR

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Acute Lymphoblastic Leukemia is a very aggressive malignant disorder of lymphoid cells in adults, with recurrence (30 to 60% of the cases) after the initial treatment. Until this moment, there is no gold standard therapy for the treatment of adult patients with acute relapsed/refractory lymphoblastic leukemia. In this case report, we describe two cases of relapsed leukemia: one of lymphocytic leukemia B and one of trilineage leukemia, which presented a satisfactory response to treatment with Bortezomib associated with Vincristine, Dexamethasone, and Bendamustine.

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Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies

Jeha

Crews

Pei

et al. 2021

Cancer

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BACKGROUND:A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies. METHODS: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m 2 /d) in combination with clofarabine (40 mg/m 2 ), etoposide (100 mg/m 2 ), and dexamethasone (8 mg/m 2 ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5. RESULTS: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m 2 /d, 6 were treated at the dose level of 40 mg/m 2 /d, and 4 were treated at the dose level of 60 mg/m 2 /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m 2 /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years. CONCLUSIONS: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509).

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Open-label Bendamustine Monotherapy for Pediatric Patients With Relapsed or Refractory Acute Leukemia

Abstract: Supplemental Digital Content is available in the text.

Cited by 13 publications

References 11 publications

Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

Treatment of Acute Lymphoid Leukemia Refractory to Classic First-Line and Rescue Protocols

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies

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