Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.

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Nivolumab in renal cancer: French evaluation of use, current practices and medico economic approach.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16093 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16093-e16093

Author(s):

Francoise Grude ◽

Gildas Appéré ◽

Fanny Marhuenda ◽

Delphine Deniel Lagadec ◽

Elouen Boughalem ◽

...

Keyword(s):

Survival Data ◽

Renal Carcinoma ◽

Real Life ◽

Progression Free Survival ◽

Complete Response ◽

Median Number ◽

Real Life Setting ◽

Medico Economic ◽

Ecog Ps ◽

Grade Iii

e16093 Background: Since April 2016 (EMA approval), Nivolumab could be prescribed in advanced renal carcinoma after prior treatment. The Brittany and Pays de la Loire Cancer Observatory has collected data on their real-life indications, current management, safety, efficacy and medico-economics. Methods: All non opposing adult patients with renal carcinoma initiated nivolumab (3 mg/kg q2w) in 2016 and 2017 were included. Minimum follow-up for survival was 12 months. Sex, age, performans status PS ECOG, toxicities, response rate, Progression Free Survival (PFS) and Overall Survival (OS) have been studied. Results: 141 pts were treated by nivolumab in 2016 and 2017 with a median age of 68 years old [39-94] and with 26% aged at least 75 years. The median number of courses was 7 [1-47]. 68 pts (48%) had 1 to 6 courses, 16 pts (11%) 7 to 12 courses, 25 pts (18%) 13 to 24 courses and 32 pts (23%) more than 25 courses. 81 (58%) pts were treated in 2nd line, 34 (24%) in 3rd line, and 25 (18%) in further lines. All lines combined, Complete Response (CR) was observed for 3 pts (2%), Partial Response (PR) for 26 pts (18%), Stable Disease (SD) for 36 pts (26%) (disease control DC : 46%) and disease progression for 51 pts (36%). For 25 pts (18%), nivolumab treatment has been stopped before first medical imaging. PS ECOG was 0-1 for 88 pts (62%), 2 for 21pts (15%), 3-4 for 8 pts (6%) and unknown for 24 pts. Median OS and PFS were 18.2 months and 3.2 months, respectively. No difference on survival has been noticed according to gender, treatment line, age (cut-off 70 or 75 yo) and grade III/IV toxicity. However, OS and PFS were significantly influenced by general health (p < 0.0001). PFS for PS 0-1 pts was 6.5 months, for PS2 2.3 months and for PS3-4 0.8 months. OS was not reached for PS0-1 pts, 3.8 months for PS2 pts and 0.8 months for PS3-4 pts. OS for patients with DC (RC+RP+SD) has not reached and PFS was 14.9 months respectively. 17% of patients presented grade III/IV toxicities. Nivolumab courses during the 2 years costed 5.1 millions of euros (drug, hospitalisation and transportation). 80% of this costs were dedicated to pts who experienced DC. Conclusions: In real life setting, survival outcomes and toxicities with nivolumab in advanced renal carcinoma are comparable to literature’s data. ECOG PS≥2 pts presented shorter survival than PS0-1 pts. Interestingly, 80% of the cost incurred for these treatments benefited to pts with DC. Updated survival data will be available be shown at the meeting.

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Venetoclax-Based Regimens for Relapsed/Refractory Acute Myeloid Leukemia in a Real-Life Setting: A Retrospective Single-Center Experience

Journal of Clinical Medicine ◽

10.3390/jcm10081684 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1684

Author(s):

Matteo Piccini ◽

Sofia Pilerci ◽

Marta Merlini ◽

Pietro Grieco ◽

Barbara Scappini ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Real Life ◽

Complete Response ◽

Hematopoietic Stem ◽

Single Center Experience ◽

Medical Need ◽

Real Life Setting ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical need, owing to the lack of standardized, effective treatment approaches, resulting in an overall dismal outcome. The only curative option for R/R AML patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is only applicable in a fraction of patients due to the scarce efficacy and high toxicity of salvage regimens. Recently, a number of targeted agents with relatively favorable toxicity profiles have been explored in clinical trials for R/R AML patients. The Bcl-2 inhibitor venetoclax, in combination with hypomethylating agents or low dose cytarabine, has produced impressive results for newly diagnosed AML, while its role in R/R disease is not well defined yet. We retrospectively analyzed the clinical outcomes of 47 R/R AML patients treated with venetoclax-based regimens between March 2018 and December 2020 at our institution. Overall, we report a composite complete response rate of 55% with an overall acceptable toxicity profile. Outcomes were particularly favorable for NPM1 mutated patients, unlike for FLT3-ITD positive patients irrespective of NPM1 status. For patients treated with intention to transplant, the procedure could be finally performed in 54%. These findings suggest a role for venetoclax-based regimens in R/R AML patients and support the design of prospective studies.

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P14.73 Toxicity and outcomes of reduced-dose whole brain radiotherapy as consolidation treatment for patients with CNS lymphoma in real life setting

Neuro-Oncology ◽

10.1093/neuonc/noz126.308 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii84-iii85

Author(s):

P Lesueur ◽

G Damaj ◽

K Hoang-Xuan ◽

V Rolland ◽

A Schmitt ◽

...

Keyword(s):

Retrospective Study ◽

Real Life ◽

Young Patients ◽

Complete Response ◽

Induction Treatment ◽

High Dose ◽

First Line ◽

Reduced Dose ◽

Real Life Setting

Abstract BACKGROUND Optimal treatment strategy for newly diagnosed primary PCNSL remains controversial. The high risk of radio-induced late-delayed neurotoxicity in patients who achieve long-term disease control constrains the use of classical consolidation WBRT. So as to reduce side cognitive effects, Morris et al, reported a phase II study, to assess the efficacy and toxicity of consolidation reduced-dose (23.4Gy) WBRT (rdWBRT) for patients with complete response after high dose methotrexate based chemotherapy. The study reported a 2-year PFS rate for these patients of 77%, with no evidence of significant cognitive decline during the follow-up (FU) period. The aim of this retrospective study was to report toxicity and outcomes of rdWBRT, in patients < 60 years old with complete response (CR) after HD-MTX based chemotherapy, in real life setting, without selection bias. MATERIAL AND METHODS Patients were selected from the French LOC network database, a nationwide database centralizing since 2011 information from 28 different centers in France, representing the main centers involved in PCNSL management. Patients were retrospectively selected according to the following criteria: 1) Pathological diagnosis of diffuse large B cell PCNSL; 2) age>18 and <60 years; 3) immunocompetent status; 4) First line induction treatment based on high dose MTX (At least MTX>1.5 g/m2); 5) CR according to the IPCG criteria after first-line induction treatment. Patients should have received a rdWBRT (23.4Gy in 13 fractions of 1.8Gy). RESULTS Twenty seven patients, were included. The median FU from initial diagnosis was 28.5 months [9.6–50.7]. Median age was 50.2 years [25–60]. Median Karnofsky Performans Status (KPS) was 90% [40–100%]. Seventeen patients had a multi focal disease at diagnosis (meningeal involvement n=6, in ophthalmic involvement n=4). PFS rates were 85% IC95[76–100 %], 65% IC95 [45–85%] and 65% IC95 [45–85%] at 1, 2, and 3 years respectively. The OS rates were 100%, 90,5% IC95 [77–100%] and 85%IC95 [69–100%]. 8 patients relapsed, with a median time from radiotherapy to recurrence of 6.5months [2.4–17]. All recurrences were outside the initially involved site(s), and 62.5% of tumors recurred as multifocal disease. All patients received salvage treatment, including intensive chemotherapy with autologous stem cell transplantation in 4 cases. No acute grade III-IV toxicity related to rdWBRT was reported. Neuropsychological follow up was available for 14 patients with no cognitive impairment at last follow up. CONCLUSION This is the largest retrospective study evaluating outcomes of rdWBRT for PCNSL young patients with CR after HD-MTX chemotherapy. Real life setting data from this study are quite reassuring, and rdWBRT could be considered as an efficient and safe consolidation strategy in this population. We need a longer FU to confirm the absence of cognitive deterioration.

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Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.4.996 ◽

1995 ◽

Vol 13 (4) ◽

pp. 996-1003 ◽

Cited By ~ 169

Author(s):

P S Gill ◽

B M Espina ◽

F Muggia ◽

S Cabriales ◽

A Tulpule ◽

...

Keyword(s):

Antitumor Activity ◽

Complete Response ◽

Pharmacokinetic Profile ◽

Survival Duration ◽

Liposomal Daunorubicin ◽

Potential Efficacy ◽

Moderate Fatigue ◽

Cd4 Lymphocyte ◽

Pharmacokinetic Evaluation

PURPOSE Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposi's sarcoma (AIDS-KS). PATIENTS AND METHODS Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation. RESULTS The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02). CONCLUSION DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.

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