Clinical relevance of murine double minute 2 single nucleotide polymorphisms 309 in familial myeloproliferative neoplasm

Darinaparsin is a novel organic arsenic compound that is being developed to improve the efficacy and therapeutic index of arsenic as an antineoplastic agent. It has activity in preclinical models of hematological malignancies and we set out to test it in patients with refractory lymphoma. In this multicenter, Phase II trial, patients with relapsed or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) were treated with darinaparsin 300 mg/m intravenously daily for five consecutive days every 28 days, for up to six cycles. The primary endpoint was the overall response rate. Twenty-nine heavily pretreated patients with lymphoma (22 with NHL and 7 with HL) were enrolled. There was one complete response (CR), one unconfirmed CR (CRu), three partial responses (PRs), and four with stable disease (SD), with an overall response rate of 17% (95% confidence interval (CI) 6–36%). Among the seven patients with peripheral T-cell lymphoma (PTCL), there was one CR, one CRu, and two with prolonged SD. The most common toxicities were fatigue, nausea, diarrhea, and anemia. Darinaparsin was safe and showed preliminary activity in this heavily pretreated population of relapsed/refractory lymphoma patients. Encouraging responses were seen in PTCL and further study in this subtype is planned. An estimated 74,030 people in the United States are diagnosed with HL or NHL every year with a global disease burden of approximately 350,000 new cases per year [1,2]. Major advances have been made over the last few decades in the treatment of these disorders in the form of combination chemotherapy, monoclonal antibody therapy, and stem cell transplantation [3–5], resulting in cure for a substantial proportion of cases. However, there remains a subgroup of patients who do not respond to standard therapy or relapse after an initial response. PTCL accounts for 7–10% of NHL cases and is a particularly unfavorable subtype [6]. Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the usual treatment approach for PTCL, but outcomes are generally poor even with more intensive regimens [7]. Darinaparsin (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-glycine; S-dimethylarsino-glutathione, ZIO-101, Zinapar) is a novel organic arsenic molecule consisting of dimethylated arsenic conjugated to glutathione [8]. Darinaparsin achieves higher intracellular levels compared to inorganic arsenic trioxide (ATO), and has activity in vitro against leukemia, myeloma, lymphoma, and various solid tumor cell lines [9,10]. Darinaparsin’s multifaceted mechanisms of action include disruption of mitochondrial functions, increase in reactive oxygen species (ROS), and effects on signal transduction. Darinaparsin induces cell cycle arrest and apoptosis and has potent anti-angiogenic activity [11]. Unlike ATO, darinaparsin lacks affinity for the ABCC1 efflux proteins and is cytotoxic to certain ATO-resistant cell lines [12]. While other arsenicals have been used clinically, particularly for the treatment of acute promyelocytic leukemia, concerns about cardiac, hepatic, and central nervous system toxicities have limited their use [13–15]. Darinaparsin is being developed to broaden the clinical utility of arsenic while also improving its safety profile [9]. The safety, pharmacokinetics, and efficacy of darinaparsin have been evaluated in trials in patients with hematologic cancers [16], refractory solid tumors [17], multiple myeloma [18], and hepatocellular carcinoma [19]. Based on preclinical studies in hematological malignancies and a favorable safety profile from prior clinical trials, we designed this study to evaluate the safety and efficacy of darinaparsin in patients with hematologic cancers, and are reporting on a subset of the study population with relapsed HL or NHL. A total of 29 patients (22 with NHL and 7 with HL) were enrolled between January 2007 and January 2009. The database was locked for analysis at the end of December 2010. The median follow-up was 6.4 months (range 0.9–35.7 months). The patient characteristics are listed in the Supporting Information Table 1. A total of 90 cycles of darinaparsin were administered with a median of two cycles per patient (range 1–20). Two patients who had clinical benefit at the end of six cycles of therapy were allowed to continue with one patient receiving two additional cycles and one coming off study for progressive disease after completing cycle 20. The Supporting Information Table 2 summarizes the treatment and reasons for study discontinuation. There was one CR, one unconfirmed CR (CRu) and three PRs, corresponding to an overall response rate (ORR) of 17.2% (95% CI 5.9–35.8%). An additional four patients achieved SD. Among the seven evaluable patients with PTCL, there was one CR, one CRu, and two SD, giving an ORR of 28.6% (95% CI 3.7–71.0%). The patient who achieved a CRu met all the 1999 IWG criteria [20] for a CR including >75% reduction in the sum of the product of the diameters of the target lesions, but still had a residual lymph node mass more than 1.5 cm. Table I summarizes the prior therapies and survival for the patients who benefited from therapy. Among all patients enrolled, the Kaplan–Meier estimates for exploratory endpoints of median time to treatment failure (TTF) and overall survival (OS) was 1.8 months (95% CI 1.1–2.5) and 6.4 months (95% CI 0.0–13.6), respectively. For the nine patients with clinical benefit (CR, PR, or SD), the TTF and OS were 6.5 months (95% CI 6.2–6.8) and 9.7 months (95% CI 9.4–10), respectively. Among the seven patients with PTCL, the Kaplan– Meier estimates for the median TTF and OS were 3.6 and 6.4 months (95% CI 2.3–4.9 and 1.6–11.2), respectively. The Supporting Information Figure 1 shows the Kaplan–Meier survival curves for TTF and OS. All patients experienced at least one adverse event (AE), of which 52% were investigator-assessed as being related to study therapy. Table II lists AEs that were reported in more than 10% of patients. Severe hematological toxicities were infrequent and there was only one episode of febrile neutropenia. The most frequently reported AEs were constitutional (fatigue and fever) and gastrointestinal (nausea, vomiting, and diarrhea). Eighteen patients experienced AEs of Grade 3 or higher with 4 judged by the investigators to be related to darinaparsin. These included fatigue, an increase in alkaline phosphatase, anemia, thrombocytopenia, and neutropenic fever. Three patients died during the first two cycles of therapy, and one died within 30 days of ending study treatment, all considered to be unrelated to study drug, and all due to disease progression. Three patients were taken off study due to AEs considered related to therapy; one patient had neutropenic fever (Grade 3), one had thrombocytopenia (Grade 4), and another had recurrent unsteady gait (Grade 2). Nine patients were included in the extensive electrocardiogram (ECG) monitoring cohort and had concomitant ECG and pharmacokinetic (PK) analysis done. Because of the low number of patients in this cohort, Cmax was the only PK parameter analyzed. The Cmax values varied between subjects for each time point with the highest standard deviation on Cycle 1, Day 5. Of the eight subjects with samples collected on Day 5 of Cycle 1, seven had higher darinaparsin concentrations on Day 5 compared with those on Day 1. For Cycles 2 and 3, all subjects had increased concentrations on Day 5 compared with those on Day 1. Mean Cmax values increased approximately twofold from Day 1 to Day 5 for each cycle. Mean concentrations of darinaparsin for all collection times are shown in Fig. 1. Although darinaparsin concentrations increased from Day 1 to Day 5, concentrations returned close to baseline levels by the start of the subsequent cycle. The mean Cmax calculated from samples taken 28 ± 3 days after the last dose of darinaparsin was also similar to baseline. One patient who had a normal corrected QT interval (QTc) at screening was later found on central review to have a Cycle 1 Day 1 pre-infusion QTc exceeding 450 msec. The number of patients with a QTc > 450 msec (Grade 1 prolonged QTc) increased to 4 and 6 at pre-infusion and post-infusion on Day 5, respectively (all cycles pooled). Among all patients and time-points, there was only one ECG with a QTc exceeding 480 msec (Grade 2 prolonged QTc); no ECGs had a QTc > 500 msec. The concentration: effect (C:E) fitted slope proLetters