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Clinical Response and Pharmacokinetics of Bendamustine As a Component of Salvage R-B(O)AD Therapy for the Treatment of Primary C

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Clinical Response and Pharmacokinetics of Bendamustine As a Component of Salvage R-B(O)AD Therapy for the Treatment of Primary C Kim et al. BMC Cancer (2018) 18:729 https://doi.org/10.1186/s12885-018-4632-y RESEARCH ARTICLE Open Access Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL) Therasa Kim1, He Yun Choi2, Hyun-Seo Lee2, Sung-Hoon Jung3, Jae-Sook Ahn3, Hyeoung-Joon Kim3, Je-Jung Lee2,3, Hee-Doo Yoo4* and Deok-Hwan Yang2,3* Abstract Background: A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF. Methods: Patients received bendamustine 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine. Results: Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669 ng/mL and 0.397 ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four- compartment model with first-order elimination of drug from central plasma and CSF compartments. Conclusions: R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response. Trial registration: ClinicalTrials.gov NCT03392714; retrospectively registered January 8, 2018. Keywords: Bendamustine, CSF, Pharmacokinetics, Primary CNS lymphoma, Salvage therapy * Correspondence: [email protected]; [email protected] 4Department of Biostatistics and Bioinformatics, Pharma Partnering Inc., 74 Olympicro, Songpagu, Seoul 05556, Republic of Korea 2Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo 58128, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. BMC Cancer (2018) 18:729 Page 2 of 10 Background pharmacokinetics (PK) of bendamustine in the CSF. In light Primary central nervous system lymphoma (PCNSL) is a of rarity of the disease and difficulties in obtaining extensive rare form of CNS malignancy representing 2–4% of all data samples, a nonlinear mixed-effects modeling approach primary CNS tumors and is of mainly diffuse large B-cell was considered appropriate for drug evaluation. Thus, we lymphoma (DLBCL) origin [1, 2]. Despite high sensitivity evaluated the PK of plasma and CSF drug levels through a to radiation and chemotherapy, one third of the patient population based model approach in a R/R PCNSL cohort population is refractory to first-line therapy and up to half with the goals to define the currently unknown PK profile of the responders will relapse after remission from initial of bendamustine in the CSF and to further characterize the treatment, mostly within the CNS [3, 4]. Salvage therapy relationship between plasma and CSF drug levels, and the will be required for a significant percentage of the PCNSL influenceofexposureonresponsetotherapy. population, yet there is no current standard of therapy in the relapsed/refractory (R/R) setting due to the lack of Methods data from randomized clinical trials. High dose metho- Study eligibility trexate (HD-MTX) re-challenge in patients with previ- Eligible patients were ≥ 19 years of age with PCNSL of ously MTX responsive disease is a feasible option DLBCL origin diagnosed by CNS lesion tissue biopsy, and reporting high response rates, [5, 6] and numerous single in relapse or refractory to frontline chemotherapy or radi- or combination therapy regimens have been examined in ation, with confirmed evidence of disease progression by small prospective studies with overall response rates ran- contrast enhanced magnetic resonance imaging (MRI). ging from 30 to 55% [7–9]. Additional requirements were Eastern Cooperative Oncol- Bendamustine is a bifunctional alkylating agent posses- ogy Group (ECOG) performance status 0–2 and adequate sing both alkylator and antimetabolite properties from a hematologic and organ function including absolute neu- mechlorethamine moiety and benzimidazole ring, respect- trophil count (ANC) ≥ 1000/uL, platelets ≥100,000/uL, ively. [10] Recently, several case reports have suggested total bilirubin ≤1.5 x upper limit of normal (ULN), trans- that bendamustine has modest clinical activity as single aminases ≤3 x ULN, and serum creatinine ≤2.0 x ULN. agent therapy against relapsed PCNSL with reasonable Patients with uncontrolled infection, therapy with myelo- tolerability [11, 12]. However, the effect of this agent as suppressive chemotherapy or biologic therapy < 21 days part of combination salvage therapy in patients with prior to registration, persistent toxicities ≥ grade 3 from PCNSL has not been established. The purine analog-like prior chemotherapy, history of thromboembolic episodes properties of bendamustine are thought to augment the ≤3 months prior to registration, active hepatitis B or C apoptotic effects of pyrimidine analogs such as cytarabine, with uncontrolled disease, or with active other malignancy and synergy against DLBCL cell lines has been shown to requiring treatment that would interfere with assessments be greatest when administered sequentially [13]where of lymphoma response to protocol treatment were ex- therapeutic impact has been validated in several trials in- cluded from enrollment. volving mantle cell lymphoma patients [14, 15]. Similarly, vincristine has documented efficacy against lymphoid ma- Study design and treatment lignancies when used in combination with bendamustine This was a prospective, open-label, pilot study investigating in both in vitro and clinical studies [16, 17]. the safety and efficacy of the bendamustine-based combin- Although the role of rituximab in PCNSL has some con- ation regimen R-B(O)AD, designed to define CSF and troversy, a recent meta-analysis has shown that additional plasma PK profiles of bendamustine in R/R patients. All pa- use of the CD20-targeted monoclonal antibody in initial tients received either R-BOAD or R-BAD intravenously (ri- therapy correlates with higher response rates [18], and tuximab 375 mg/m2 on day 1; vincristine 1.4 mg/m2 on day other studies in the salvage setting have reported positive 1, omitted in patients ≥70 years of age due to risk of neuro- outcomes, albeit a more modest response in prospectively toxicity; bendamustine 75 mg/m2 over 1 h on days 2 and 3; conducted trials [19, 20]. Based on the demonstrated activ- cytarabine 1000 mg/m2 over 3 h on days 2–4; dexametha- ity and proposed additive mechanisms of these chemother- sone 20 mg on days 1–4), every 4 weeks up to 4 cycles. Ini- apeutic agents, we investigated the bendamustine-based tial reduction of bendamustine or cytarabine dosage was combination regimen R-B(O)AD in patients with refractory allowed if deemed necessary by the physician due to elderly or relapsed primary CNS lymphoma. Evidence from previ- age or poor performance status. Subcutaneous granulocyte ous preclinical tissue distribution studies and single agent colony-stimulating factor support was administered post intravenous drug therapy trials in CNS malignancies sug- chemotherapy on starting day 7 of the cycle in all patients gests that bendamustine penetrates brain and tumor tissue until ANC ≥ 500/uL. Treatment cycles were delayed until [12, 21–23], and while cerebrospinal fluid (CSF) drug con- hematologic parameters allowed for the next cycle of centrations are commonly used as a surrogate marker of therapy (i.e. ANC ≥1000/uL, platelets ≥75,000/uL). If a CNS delivery, there are no clinical data available on the cycle was postponed > 1 week due to hematologic toxicity Kim et al. BMC Cancer (2018) 18:729 Page 3 of 10 bendamustine and cytarabine doses were reduced by was of bendamustine concentrations were ≤ 3.0% and ≤ 9.4% 25% in subsequent cycles. For vincristine, drug dose was re- for plasma and CSF, respectively. duced by 50% in the case of moderate neurotoxicity (grade 2), and if severe (grade 3 or 4) was discontinued for all sub- CSF exposure estimates and PK model sequent cycles. CSF exposure was estimated as Cmax,CSF/Cmax,plasma and AUCCSF/AUCplasma ratios. Non-compartmental methods Efficacy and safety measurements were used to calculate the area under the concentration–
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