Crizotinib in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma in the setting of renal insufficiency: a case report.

BACKGROUND: In vitro studies confirmed cytoreductive anti-tumor activity of crizotinib in experimental models of anaplastic large cell lymphoma in 2007. One case series and a few case reports describe the use of crizotinib in relapsed or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Even though data are limited regarding the dose of crizotinib in renal insufficiency, our case was successfully treated with a lower dose of crizotinib. CASE PRESENTATION: We report the case of a 48-year-old white man who had progressive disease after three prior cycles of cyclophosphamide, doxorubicin, vincristine and prednisone and three cycles of ifosfamide, carboplatin, and etoposide, and was not a candidate for high-dose chemotherapy and transplant due to poor performance status and renal insufficiency; he had a complete and durable response to single agent crizotinib. Crizotinib was given at a reduced dose (250 mg once daily) due to his renal insufficiency. He has been in complete remission for more than 2 years. CONCLUSIONS: Our experience confirms the activity of crizotinib in this disease; it suggests that long-term treatment with crizotinib is a reasonable option in patients who are not candidates for more aggressive therapy and indicates that crizotinib can be used successfully at reduced doses in patients with pre-existing renal insufficiency. The role and timing of crizotinib in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma is unclear, but the current literature that we review here provides promising results that may lead to studies of crizotinib earlier in the course of disease.

Bleomycin induced pulmonary toxicity in patients with germ cell tumours.

BACKGROUND: Bleomycin is a cytotoxic drug used in treatment of Germ Cell Tumours (GCTs) and is associated with pulmonary toxicity. Bleomycin pulmonary toxicity (BPT) manifests predominantly as pulmonary fibrosis, organising pneumonia (OP) or Nonspecific Interstitial Pneumonitis (NSIP). Our objectives were to determine the incidence of BPT, describe the common HRCT patterns of pulmonary toxicity and to find out the correlation of variables (cumulative dose of bleomycin, age and glomerular filtration rate) with pulmonary toxicity. METHODS: The study included the data of 96 patients from March 2006 to September 2008. All patients had histologically proven GCT and received bleomycin containing regimes. Variables age, GFR at the time of initial presentation along with cumulative dose of bleomycin at completion of chemotherapy or at the time of BPT were recorded. The High resolution CT chest (HRCT) of these patients was independently reviewed by two radiologists. Bleomycin toxicity was reported on the radiologic features of pulmonary fibrosis, OP or NSIP. RESULTS: Fourteen patients (14.6%) developed BPT. Common patterns of BPT were, pulmonary fibrosis (5.2%), OP (5.2%) and NSIP (4.2%). Using the Univariate regression analysis there was significant relationship between BPT and age, cumulative bleomycin dose and initial GFR at the beginning of treatment. CONCLUSIONS: Because BPT can be progressive and fatal, early recognition is important. The diagnosis of pulmonary toxicity should be considered in any patient with new or progressive respiratory complaints. BPT can be difficult to diagnose; therefore, knowledge and understanding of radiologic manifestations of toxicity caused by Bleomycin are necessary for institution of appropriate treatment. There is increasing incidence of BPT with increasing age, cumulative dose and decreasing GFR.

Targeting lymphotoxin beta receptor with tumor-specific T lymphocytes for tumor regression.

PURPOSE: One of the impediments of immunotherapy against cancer is the suppression of tumor-specific CTLs in the tumor microenvironment, partly due to the selective inhibition of the perforin pathway and the emergence of Fas-resistant tumors. Therefore, we sought to identify perforin- and Fas-independent cytotoxic pathways and explored the potential of targeting LTbetaR with tumor-specific CTLs to induce tumor rejection in vivo. EXPERIMENTAL DESIGN: Fas-resistant tumors were examined for their susceptibility to perforin-deficient (pfp) CTLs via CTL adoptive transfer in mouse models of experimental lung metastasis. The specificity of LTbetaR, a cell surface death receptor, in causing tumor rejection by CTLs was analyzed by LTbetaR-specific neutralizing monoclonal antibody in vitro. The specificity and efficacy of LTbetaR in the suppression of established tumors was further investigated by silencing LTbetaR in tumor cells in vivo. RESULTS: pfp CTLs exhibited significant cytotoxicity against Fas-resistant tumors in vivo. The perforin- and Fas-independent cytotoxicity was directly mediated, at least in part, by the adoptively transferred CTLs. It was observed that LTbetaR was expressed on the tumor cell surface, and LTalpha, LTbeta, and LIGHT, all of which are ligands for LTbetaR, were either constitutively expressed or activated in the tumor-specific CTLs and primary CD8(+) T cells. Blocking LTbetaR with LTbetaR-specific neutralizing monoclonal antibody decreased CTL cytotoxicity in vitro. Silencing LTbetaR using LTbetaR-specific short hairpin RNA reduced the ability of pfp CTLs to induce tumor rejection in vivo. CONCLUSION: LTbetaR directly mediates CTL-directed tumor rejection in vivo. Targeting LTbetaR with tumor-specific CTLs is a potential therapeutic approach.