Catherine Daniel

Phase I, Dose-Finding, and Pharmacokinetic Study of Raltitrexed Combined With Oxaliplatin in Patients With Advanced Cancer

PURPOSE To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen, to explore its safety and pharmacokinetics, and to assess its antitumor activity in patients with advanced solid tumors. PATIENTS AND METHODS Forty-eight patients received the combination of raltitrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infusion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated every 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m(2) and from 85 to 130 mg/m(2) for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels. RESULTS Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2)). This combination was not myelosuppressive, eliciting only sporadic grades 3 and 4 neutropenia and/or thrombocytopenia without complications. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m(2) and oxaliplatin 130 mg/m(2)) was deemed to be the MTD. Eight confirmed partial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetics of both drugs did not suggest any drug interaction. CONCLUSION The combination of raltitrexed and oxaliplatin given as consecutive short infusions every 3 weeks seems to be an acceptable regimen that allows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2) every 3 weeks. Promising antitumor activity has been observed in patients with malignant mesothelioma.

Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results from a Multi-Center Study of 683 Patients.

Background Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.BACKGROUND Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the US. However, there is no guidance as to their optimal sequence. PATIENTS AND METHODS We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). RESULTS A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81% respectively. With a median follow up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (vs. idelalisib) as first KI had a significantly better PFS in all settings; front-line (HR 2.8, CI1.3-6.3 p=.01), relapsed-refractory (HR 2.8, CI 1.9-4.1 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), and complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS as compared to chemoimmunotherapy (CIT). Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, p=.06). CONCLUSIONS In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Further, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to CIT combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia.

To the editor: Chronic lymphocytic leukemia (CLL) is a B-cell lymphoproliferative disorder partly dependent on the B-cell receptor (BCR) signaling pathway. The novel BCR signal transduction inhibitor ibrutinib has emerged as an effective therapeutic agent for CLL.[1][1] Ibrutinib covalently binds

Deficiencies in the Management of Iron Deficiency Anemia During Childhood

Limited high‐quality evidence supports the management of iron deficiency anemia (IDA). To assess our institutional performance in this area, we retrospectively reviewed IDA treatment practices in 195 consecutive children referred to our center from 2006 to mid‐2010. The majority of children were ≤4 years old (64%) and had nutritional IDA (74%). In 11‐ to 18‐year‐old patients (31%), the primary etiology was menorrhagia (42%). Many were referred directly to the emergency department and/or prescribed iron doses outside the recommended range. Poor medication adherence and being lost‐to‐follow‐up were common. Substantial improvements are required in the management of IDA.

Hypertension, proteinuria, and overall survival in elderly cancer patients treated with bevacizumab.

186 Background: MARS is a multicentric, non-interventional, prospective study which first reported the high prevalence of both baseline and de novo hypertension (HTN) and proteinuria (Pu) in several sub group of cancer patients [Gligorov J et al. SABCS 2013; Ray-Coquard I et al. ASCO GI 2014; Ray-Coquard I et al. ASCO GU 2014; Goldwasser F et al. ECC 2013; Launay-Vacher V et al. ASCO 2013]. In this sub-group analysis, we focused on elderly cancer (EC) patients treated by bevacizumab. METHODS MARS included 1,124 patients, all naïve of any previous anti-VEGF treatment. A First Renal Assessment was performed at baseline before the anti-VEGF was started with periodic follow-up for 1 year. Elderly was defined as age ≥65 years at inclusion. Univariate (UA) and multivariate analyses (MA) tested the associations of HTN and Pu, at baseline or de novo, with overall survival (OS) (pre-planned) in EC patients. RESULTS 845 patients treated with bevacizumab were included. Among them 226 were EC patients (colorectal 81, breast 78, ovarian 26, lung 22). At inclusion, HTA was statistically higher in EC patients (table), mean aMDRD was 79.6 ml/min/1.73m2 and 15.1% had aMDRD<60. De novo HTA; de novo Pu and Scr increase were not statistically more frequent in EC patients than in non-EC patients. In addition, renal function decreased by -4.1 ml/min/1.73m²/year and 16.2% had aMDRD<60 at the end of follow-up. Baseline and de novoHTN and Pu were not associated with reduced OS in EC patients in both UA and MA analyses. CONCLUSIONS There were no differences in term of renovascular safety in EC patients treated by bevacizumab. Furthermore, HTN and Pu were not associated with OS in EC patients treated by bevacizumab. Therefore, renovascular events should not be contraindicated at the initiation of the treatment or when the patient is already on treatment. [Table: see text].