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Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor-α, and c-kit. Phase I studies demonstrated 5 mg twice daily as the recommended starting dose with notable effects seen in renal cell carcinoma, an observation confirmed in Phase II trials. The trial of comparative effectivess of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS) was an international randomized Phase III study designed for registration purposes, compared axitinib to sunitinib. This trial randomized 723 patients with metastatic kidney cancer to axitinib or sunitinib in the second-line setting and demonstrated a median progression-free survival of 6.7 months for axitinib versus 4.7 months for sorafenib (P<0.0001). Clinical benefit was detected regardless of prior therapy, but no overall survival benefit has been observed. Axitinib is well tolerated without a significant effect on quality of life. The most common grade 3 toxicities are hypertension (16%), diarrhea (11%), and fatigue (11%), with other notable side effects being anorexia, nausea, hand–foot syndrome, and rash. Patients who developed diastolic blood pressure >90 mmHg were noted to have significantly longer median overall survival and overall response rates when compared to normotensive patients. Therefore, the manufacturer recommends escalating the twice-daily dose to 7 mg and 10 mg, as tolerated, if there is no significant increase in blood pressure on treatment. Currently, axitinib is approved for use in the second-line setting for patients with metastatic renal cell carcinoma. Research is ongoing in other disease settings.

PTLD is a heterogeneous group of neoplasms arising in patients after solid-organ or allogeneic stem-cell transplantation. Although most cases of PTLD are related to Epstein - Barr virus (EBV) infection, a subset (10–20%) shows no association with EBV infection. Anecdotal uncontrolled studies have described EBV-negative PTLD as appearing late in the post-transplant period and having poor response to reduction of immunosuppression and poor outcome in general. We identified 30 patients who were diagnosed with EBV-negative PTLD in the University of Pennsylvania between November 1990 and April 2008. We compared the clinical and pathological characteristics, response to therapy and survival of these patients with 51 control patients matched by organ type who had EBVpositive PTLD. The average age at diagnosis was 53.1 in the EBV (−) group and 49.2 in the EBV (+) group (p=NS). 3/30 (10%) of the EBV (−) cases and 16/51 (31.4%) appeared within the first year after transplant (p&lt;0.05). 7/30 (23%) of the EBV (−) patients and none of the EBV (+) patients had multiple transplants in their history (p&lt;0.005). Presenting signs and symptoms, stage at diagnosis, extranodal involvement and involvement of the allograft were similar in both groups but patients with EBV (−) PTLD were more likely to present with “allograft failure”. Pathological characteristics were significantly different. 27/30 (90%) of EBV(−) cases and 25/38 (66%) of EBV (+) cases had monomorphic PTLD (p&lt;0.05). The majority of the EBV (−) cases were subtyped as diffuse large B-cell lymphoma. 23/30 (76.7%) of EBV (−) PTLD cases and 41/51 (80.4%) of EBV (+) PTLD cases were treated with reduction of immunosuppression (RI) alone as initial therapy. Overall response rates to RI were 47.6% and 58.5% in the EBV (−) and EBV (+) groups respectively (p=NS). Overall response rates to the monoclonal anti-CD-20 antibody rituximab when it was used as a single agent were 47% and 48% in the EBV(−) and EBV (+) groups respectively. In both groups, less than 20% of the patients encountered allograft rejection during therapy and a total of 6 patients (3 in each group) underwent another transplant without having a relapse of their PTLD. 2-year survival rates for EBV (−) and EBV (+) PTLD were 48% and 67% respectively (p&lt;0.05). Kaplan-Meier survival analysis showed a trend towards higher early mortality in EBV (−) patients; however overall survival and disease-free survival were not affected by EBV status by log-rank test (p=0.35 & p=0.84 respectively). Median follow-up on living patients was 60 months (range 3.9–196.9 months). Univariate analysis using the Cox proportional hazards model revealed that stage at diagnosis, B symptoms, initial albumin level, bulky disease and age&gt;60 were significant predictors for poor prognosis in both groups, verifying that some of the classic risk factors for lymphoid malignancies are valid in PTLD. The strongest predictor of mortality was the type of transplanted organ, where lung transplant recipients had the worst outcome and kidney transplant recipients did well (log rank p-value=0.02 for both overall survival and disease-free survival). We conclude that in our single-center series, EBV-negative PTLD is a distinct subtype which appears later in the post-transplant period. Compared with EBV-positive PTLD, it is more likely to be monomorphic and similar to common B-cell malignancies; however it still responds well to reduction of immunosuppression and specific anti-B-cell immunotherapy without compromising allograft survival. It does not necessarily require chemotherapy and can be cured similarly to EBV-positive PTLD. Figure Figure

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