Stefania Crisci

Tumor flare reactions and response to lenalidomide in patients with refractory classic Hodgkin lymphoma

Patients with Hodgkin lymphoma (HL) failing salvage stem cell transplantation are candidates to investigational strategies. Lenalidomide represents an attractive option as it targets several signaling pathways, which regulate survival of HL cells and their microenvironmental interactions. We report the occurrence of Grades 2 and 3 tumor flare reactions in the first three patients entered a lenalidomide-based compassionate program for treatment-refractory HL. Flares occurred in concomitance of the scheduled week-off lenalidomide and upon withdrawal of symptomatic steroid treatment, and were associated with changes in B-cell regulatory cytokines and the concurrent expansion of polyclonal B-cells. Flares mimicked tumor progression but were effectively managed with anti-inflammatory treatment and followed by a clinical response, suggesting that they may mirror the pleiotropic actions of lenalidomide on HL microenvironment.

Elevation of clonal serum free light chains in patients with HIV-negative primary effusion lymphoma (PEL) and PEL-like lymphoma.

Primary effusion lymphoma (PEL) is a human herpesvirus 8 (HHV-8)-associated malignancy that presents in the serous body cavities as lymphomatous effusions, usually without extracavitary tumour masses (Carbone & Gloghini, 2008). Most cases occur in human immunodeficiency virus type-1 (HIV)-infected patients, but PEL can also develop in HIV-seronegative individuals following prolonged immunosuppressive therapy and/or in association to age-related immunodepression (Carbone & Gloghini, 2008). Other agents, including hepatitis C virus (HCV), may be associated to PEL and HHV-8 negative cases have been also described as HHV8-unrelated PEL-like lymphoma (Paner et al, 2003; Kobayashi et al, 2007; Carbone & Gloghini, 2008). This lymphoma arises from mature post-germinal centre B-cells which, despite having a pre-plasma cell genotype and gene expression signature (Jenner et al, 2003; Carbone & Gloghini, 2008), rarely express surface immunoglobulins (Igs) due to the defective expression of some B-cell-specific transcription factors (Arguello et al, 2003; Di Bartolo et al, 2009). By applying highly sensitive techniques, however, light chain mRNA was frequently demonstrated and a minority (10%) of tumour cells was found to display low levels of cytoplasmic monoclonal light chains (Wakely et al, 2002; Di Bartolo et al, 2009). The prognosis of PEL is poor with a median survival of 6 months also due to the lack of specific prognostic factors and tumour markers to optimize therapy (Nador et al, 1996; Boulanger et al, 2005). This report shows that elevated levels of clonally-restricted serum free light chain (sFLC) can be found in some PEL cases and that variations in such levels may reflect therapyrelated changes in the tumour cell mass, so representing a possible marker for treatment monitoring/modulation. The sFLC assay specifically quantifies circulating light chains unbound to heavy chains into intact Ig molecules and allows disease monitoring in non-secretory/oligo-secretory (NS-OS) multiple myeloma and other situations where, at the tumour plasma cells level, the compromised heavy chains production leads to unbalanced, excess production of clonal light chains or to expression of light chains only (Pratt, 2008). Patients’ characteristics are shown in Table I. Patient 1 had HCV-related cirrhosis and a previous left nephrectomy due to kidney carcinoma. He presented with bulky ascites and computed tomography disclosed a left pleural effusion and a diffuse thickening of the peritoneal membrane with mesenteric nodulations. Peritoneal fluid was removed and a laparoscopic peritoneal biopsy performed. Morphology (Fig 1A, B), immunophenotypic (Fig 1C, D) and molecular studies (Fig 1E) were consistent with HHV-8-unrelated PEL-like lymphoma. The patient was given bortezomib, cyclophosphamide and steroids, which resulted, in complete effusions control after 3 weeks. Abdominal ultrasounds confirmed the clinical response but, 2 weeks after the second course of treatment, effusions recurred leading to death with progressive lymphoma. Patient 2 had been receiving continuous immunosuppression for 9 years after kidney transplantation. He presented with fever, right pleural effusion and bulky ascites. Tumour cell features were consistent with HHV-8 PEL. The patient refused chemotherapy and was given oral thalidomide (200 mg/d), which resulted in ascites and pleural effusion control lasting 3 months. Due to neurotoxicity, thalidomide was reduced to 100 mg/d for 1 month and then withdrawn. Bulky effusions recurred, leading to death despite further treatment. Patient 3 had HCV-related cirrhosis, a severe cardiomyopathy and presented with pleural, pericardial and abdominal effusions containing HHV-8 PEL cells (Table I, Fig 1E). The patient received two courses of cyclophosphamide, vincristine and prednisone leading to substantial control of effusions but bulky disease recurred shortly after the third course of treatment, leading to death 1 month later. The free j and k concentrations (normal ranges, j: 3Æ3–19Æ4 mg/l; k: 5Æ71–26Æ3 mg/l) were assayed by immunonephelometry (Freelite; The Binding Site, Ltd., Birmingham, UK) on cryopreserved ()80 C) serum samples and the FLC j/k ratio was calculated (free j concentration divided by free k concentration, reference range 0Æ26–1Æ65). All of the patients displayed an abnormal baseline sFLC j/k ratio (ranging from 0Æ04 to 0Æ15) due to a k chain clonal involvement, with absolute free k levels ranging from 143Æ5 to 790 mg/l (Table I). Cytoplasmic k chains were documented in tumour cells in Patients 1 and 2, while imunohistochemistry was negative in the remaining case (Table I, Fig 1D). Most interestingly, serial measurements during the course of disease showed changes in sFLC levels that correlated with clinical progress. At the time of maximal response to treatment, levels of free k chains displayed a higher than 75% drop from baseline levels in all patients followed by a rise at tumour progression (Fig 1F). This was paralleled by corresponding modifications of the sFLC j/k Correspondence

Pharmacological Profile and Pharmacogenomics of Anti-Cancer Drugs Used for Targeted Therapy

BACKGROUND Drugs for targeted therapies are primarily Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA molecules and microRNA. The use of these new agents generates a multifaceted step in the pharmacokinetics (PK) of these drugs. Individual PK variability is often large, and unpredictability observed in the response to the pharmacogenetic profile of the patient (e.g. cytochome P450 enzyme), patient characteristics such as adherence to treatment and environmental factors. OBJECTIVE This review aims to overview the latest anticancer drugs eligible for targeted therapies and the most recent finding in pharmacogenomics related to toxicity/resistance of either individual gene polymorphisms or acquired mutation in a cancer cell. In addition, an early outline evaluation of the genotyping costs and methods has been taken into consideration. Future Outlook: To date, therapeutic drug monitoring (TDM) of mAbs and SMIs is not yet supported by heavy scientific evidence. Extensive effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomized trials of classic dosing versus PK-guided adaptive dosing. The detection of individual pharmacogenomics profile could be the key for the oncologists that will have new resources to make treatment decisions for their patients in order to maximize the benefit and minimize the toxicity. Based on this purpose, the clinician should evaluate advantages and limitations, in terms of costs and applicability, of the most appropriate pharmacological approach to performing a tailored therapy.