Cyclic thrombocytopenia associated with marked rebound thrombocytosis and fluctuating levels of endogenous thrombopoietin and reticulated platelets: A case report

Abstract

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 2 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 TM) 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 promye...

Cyclic thrombocytopenia with statistically significant neutrophil oscillations

“…Platelet cycling has previously been reported in patients with predominant cyclic neutropenia, which may be due to periodic interruptions of neutrophil production and fluctuations of endogenous granulocyte colony‐stimulating factor (G‐CSF) and other cytokines 11. Similarly, concomitant cycling of neutrophils has been previously claimed in a patient with pronounced CT,12 but when we tested the neutrophil data of that patient we found no evidence of statistically significant oscillations. A preliminary report13 of gene expression profile of two male patients with CT published in abstract form noted cyclic changes in interferon responsive genes as well as transcription factors controlling lineage differentiation.…”

Normal and pathological dynamics of platelets in humans

“…Table 2 in Sect. 5.2 shows the best parameter fit to τ e , α P , α T , and k T for the CT patients of Connor and Joseph [15], Kimura et al [39], and Zent et al [78]. As was done with the CT patient of Bruin et al [9] in Sect.…”

“…The curves on the right follow the eigenvalues. The rows represent the evolution from healthy subject to the CT patients of Connor and Joseph [15], Kimura et al [39], and Zent et al [78], respectively patients have slightly different changes in their eigenvalues, particularly in what happens to the imaginary part. All cases of the CT patients have their eigenvalues with positive real part, which is to be expected.…”

“…5 to fit the parameters τ e , α P , α T , and k T of our model to 15 published platelet and TPO data sets of patients with CT [9,10,15,20,31,39,40,54,60,63,65,75,76,78]. Of these 15 data sets, only four contained both platelet and TPO data [9,15,39,78]. We chose to analyze data sets of untreated CT patients only, as treatments may have altered platelet or TPO dynamics or both and is thus outside the scope of this model.…”

“…Fits to the platelet and thrombopoietin data from: (a) Bruin et al[9]; (b) Connor and Joseph[15]; (c) Kimura et al[39]; and (d) Zent et al[78] …”