Mortality rate in patients with chronic myeloid leukemia in chronic phase treated with frontline second generation tyrosine kinase inhibitors: a retrospective analysis by the monitoring registries of the Italian Medicines Agency (AIFA).

The introduction of tyrosine kinase inhibitors (TKIs) has improved the overall survival of chronic myeloid leukemia patients in chronic phase (CP-CML) and reduced the rate of disease-related mortality. Conflicting results have been however reported between data emerged from sponsored clinical trials and from population-based registries. Moreover, no data are so far available for patients treated with frontline second-generation TKIs, excluding those from sponsored studies. We analyzed the mortality rate of 2315 CP-CML patients treated with frontline second-generation TKIs through the Italian Medicines Agency (AIFA) registries and compared it with the ISTAT mortality rate of the general population. The estimated differences show that the increased rate of mortality in CP-CML patients is less than 1% for the class 0-29 years, stable around 2% for the intervals 30-44 years and 45-59 years, and 1.4% for the interval 60-74 years; interestingly this rate is reduced for patients aged 75 years and more as compared to the general population (- 0.65%). The difference between potential and estimated deaths is higher among women in the age classes between 30 and 74 years.

How many chronic myeloid leukemia patients who started a frontline second-generation tyrosine kinase inhibitor have to switch to a second-line treatment? A retrospective analysis from the monitoring registries of the italian medicines agency (AIFA).

The frequency of patients who switch to a second-line therapy from a frontline second-generation (2gen) tyrosine kinase inhibitor (TKI) such as dasatinib and nilotinib, is still substantially unknown. We retrospectively investigated a large series of chronic phase chronic myeloid leukemia (CP-CML) patients initially treated with 2gen TKIs monitored through the Italian Medicines Agency (AIFA Agenzia Italiana del farmaco) registries. Overall, 2420 patients were analyzed over a period of 6 years. One hundred and fifty-seven patients (16.3%) treated with dasatinib and 164 treated with nilotinib (11.3%) have switched to another drug, with an overall frequency of 13.2%. In the dasatinib cohort, 39.4% of patients changed treatment for failure and 36.3% for intolerance as compared to 45.7% and 27.4% respectively in the nilotinib cohort. Overall, the median time to switch due to resistance was 293 days, whereas it was 317 days in case of intolerance. Resistance was observed mainly in younger male patients with high-risk features, while intolerance was not related to any baseline parameter. After resistance/intolerance to nilotinib, the majority of patients switched to dasatinib (53.8%) whereas in case of frontline dasatinib to ponatinib (43.2%). To the best of our knowledge these data provide the first report on the frequency of discontinuation of frontline 2gen TKIs and on the main causes and pattern of choice to a second-line therapy in the real-life setting.

Growth inhibition of cervix carcinoma cells in vivo by endothelin A receptor blockade.

In human papillomavirus (HPV)-positive cervical cancer cells, the endothelin A receptor (ET(A)R) mediates an endothelin-1-induced mitogenic effect, thus representing a relevant target for antitumor therapy. Here, we describe the complete inhibition of human cervix carcinoma growth by blocking the ET(A)R. In nude mice, the ET(A)R-selective antagonist atrasentan inhibits the growth and the neoangiogenesis of cervical carcinoma cell xenografts. Two cycles of treatment completely revert tumor growth. Atrasentan displays additive effects when administered in combination with the cytotoxic drug paclitaxel. These results demonstrate that by inhibiting cell proliferation and angiogenesis, this small molecule may help to control cervical cancer by either monotherapy or combination therapy.

Plant-derived human papillomavirus 16 E7 oncoprotein induces immune response and specific tumor protection.

Vaccine strategies for treatment of human papillomavirus-induced cervical cancer are based on either the recombinant E7 fusion oncoprotein or E7 CTL peptides. The therapeutic potential of the E7-based vaccine depends on the use of different adjuvants. In this study, we describe for the first time the expression of the human papillomavirus 16 E7 protein in Nicotiana benthamiana plant using a potato virus X-derived vector. C57BL/6 mice immunized with E7-containing crude foliar extracts developed both humoral and cell-mediated immune responses and were protected from tumor development after challenge with the E7-expressing C3 tumoral cell line. Our data support the possibility of producing a cost-effective anticancer vaccine in plant with intrinsic adjuvant-like properties.

Targeting endothelin receptor type A in human cervical carcinoma cells.

Human papilloma viruses are associated with cervical cancer and enhance signal transduction of growth factors. In human papilloma virus-positive cervical cancer cells, the endothelin-A receptor mediates the endothelin-1-induced mitogenic effect, and sustains the basal growth rate of unstimulated cervical tumor cells. In this study, the action of a specific endothelin-A receptor antagonist (atrasentan) and a truly 'balanced' endothelin-A/endothelin-B antagonist (A-182086), was analysed in the human cervical carcinoma cells, CaSki and C33A. CaSki cells are human papilloma virus-16-positive, produce endothelin-1 and possess endothelin-A and endothelin-B receptors, whereas the C33A line is human papilloma virus-negative, does not secrete endothelin-1 and has only endothelin-B receptors. In human papilloma virus-positive cancer cells both antagonists caused a similar drastic reduction in BrdU incorporation and in the growth rate. These data clearly demonstrate that A-182086 and atrasentan show similar potency and also indicate that blocking of the endothelin-B receptor by A- 182086 does not increase the anti-proliferative effect. This finding suggests that the endothelin-B receptor does not participate in the growth control of CaSki cells. Results from C33A cells reinforce this previous conclusion as both compounds are ineffective in altering the BrdU uptake of these cells in basal and endothelin-1 stimulated conditions. In conclusion, targeting the endothelin-A receptor, but not the endothelin-B receptor, may be a valid tool in the therapy of cervical carcinoma.

Endothelin receptor blockade inhibits the growth of human papillomavirus-associated cervical carcinoma.

Human papillomaviruses (HPVs) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV-transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. HPV-positive cancer cells secrete ET-1 and express mRNA for ET-1 and its receptors, whereas HPV-negative carcinoma cell lines express only the ET(B) receptor (ET(B)R) mRNA and do not secrete ET-1. In HPV-positive cancer cells, ET(A)R mediates the ET-1-induced mitogenic effect and sustains the basal growth rate of unstimulated cervical tumour cells. Therefore, ET-1 may be involved in the neoplastic growth of HPV-associated cervical carcinoma, where the increased ET-1 autocrine loop can be targeted for antitumour therapy. In the present work, the action of specific antagonists of ET(A)R (BQ-123 and ABT-627), was analysed in CaSki and C33A cells that are derived from human cervical carcinoma. CaSki cells are HPV-16-positive, produce ET-1 and possess ET(A)R and ET(B)R, whereas the C33A line is HPV-negative, does not secrete ET-1 and has no ET(A)R. In HPV-positive cancer cells ABT-627 strongly inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumour cells, whereas the ET(B)R antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ET(A)R expression is increased and could be targeted for antitumour therapy. In conclusion, an ET-1 autocrine loop is involved in tumour cell proliferation via ET(A)R, and ABT-627 is effective in controlling proliferation of cervical carcinoma cells.