Response to post-axitinib treatment in patients with metastatic renal cell carcinoma.

BACKGROUND: Axitinib is a potent inhibitor of the vascular endothelial growth factor (VEGF) receptor family with clinical activity in patients with metastatic renal cell carcinoma (mRCC). Given this biochemical potency, the clinical activity of subsequent treatment with targeted therapies in patients progressing on axitinib is of interest. METHODS: Patients with advanced renal cell carcinoma of any pathologic subtype treated with at least one cycle (four weeks) of axitinib followed by at least one subsequent targeted therapy were investigated in a retrospective analysis. Patient characteristics, duration of treatment and clinical outcomes were analyzed for axitinib and each subsequent line of therapy by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty-five mRCC patients who received at least one approved targeted agent following axitinib were identified. Eight percent of patients achieved a partial response (one patient each to sunitinib and pazopanib) and 42 % had a best response of stable disease to the first therapy after axitinib. The estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Twelve patients received a second post-axitinib targeted therapy. Six out of 11 evaluable patients (55 %) had a best response of SD. The estimated median duration of treatment was 4.8 months (range, 0.7-19.1+). CONCLUSION: Objective responses and stable disease is observed to post-axitinib targeted therapies and prospective studies are needed for validating role of predictive biomarkers.

Acute myeloid leukemia developing in a granulocyte colony-stimulating factor-mobilized stem cell donor: A case report and review of the literature.

We describe the first case of a FLT-3 mutated AML in a healthy donor, 3years after recombinant human granulocyte colony stimulating factor (rhG-CSF)-mobilized peripheral blood stem cell (PBSC) harvest. The patient had a myeloablative (MA) matched unrelated donor (MUD) stem cell transplant (SCT) for refractory AML. However, he experienced a secondary graft failure. He had a second non myeloablative (NMA) on day +75 from a second MUD. He achieved a complete neutrophil and platelet engraftment. After 4years of follow up, he is alive in complete remission with full second donor chimerism.

Alternative Donor Transplantation for Acute Myeloid Leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for adult patients with acute myeloid leukemia (AML), but its use for consolidation therapy after first remission with induction chemotherapy used to be limited to younger patients and those with suitable donors. The median age of AML diagnosis is in the late 60s. With the introduction of reduced-intensity conditioning (RIC), many older adults are now eligible to receive allo-HCT, including those who are medically less fit to receive myeloablative conditioning. Furthermore, AML patients commonly have no human leukocyte antigen (HLA)-identical or medically suitable sibling donor available to proceed with allo-HCT. Technical advances in donor matching, suppression of alloreactivity, and supportive care have made it possible to use alternative donors, such as unrelated umbilical cord blood (UCB) and partially HLA-matched related (haploidentical) donors. Outcomes after alternative donor allo-HCT are now approaching the outcomes observed for conventional allo-HCT with matched related and unrelated donors. Thus, with both UCB and haploidentical donors available, lack of donor should rarely be a limiting factor in offering an allo-HCT to adults with AML.

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA-identical sibling donor allogeneic hematopoietic cell transplantation.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA+MTX. Patients receiving MMF + CSA had rapid neutrophil (median 11 vs. 19 days with MTX+CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF+CSA 37% vs. MTX+CSA 39%) or 3-4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non-relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P = NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, P = 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed.

Acute promyelocytic leukaemia (APL) in a patient with Crohn's disease and exposure to infliximab: a rare clinical presentation and review of the literature.

With the introduction of potent immunosuppressive and chemotherapeutic medications for various diseases, there is an increased incidence of therapy-related myeloid neoplasms. They are the result of mutational rearrangement and historically, have a grave prognosis compared with de novo myeloid neoplasms. We did a short review on various types of myeloid leukaemias reported after therapy with antitumour necrosis factor and also report, to the best of our knowledge, one among the very few cases of therapy-related acute promyelocytic leukaemia in a patient on infliximab therapy for refractory Crohn's disease. The patient responded well to the traditional treatment and is in complete remission for more than 5 years.

Bendamustine-induced immune hemolytic anemia in a chronic lymphocytic leukemia patient: A case report and review of the literature.

Bendamustine is an alkylating agent approved for the treatment of chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma. There are scant reports on bendamustine-induced immune hemolytic anemia occurring mainly in CLL patients. We report a case of immune hemolytic anemia that developed after exposure to bendamustine in a 70-year-old female with CLL who was previously exposed to fludarabine. Previous exposure to fludarabine is a common finding in the majority of reported cases of bendamustine drug-induced immune hemolytic anemia (DIIHA), including our case. Bendamustine should be suspected as the cause of any hemolytic anemia that develops while on this drug, especially in CLL patients treated previously with fludarabine.

Eosinophilic fasciitis as a paraneoplastic syndrome, a case report and review of the literature.

Eosinophilic fasciitis (EF) is a rare disease with characteristic clinical and histological features, previously reported to be associated with various hematological and solid malignancies. We report a typical case of eosinophilic fasciitis in a 67-year-old man in association with myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and subsequently bladder cancer. On the two occasions, the eosinophilic fasciitis completely resolved upon successful treatment of the concomitant malignancy. The diagnosis of EF should trigger further evaluation for any associated hematological disorder, which, if adequately treated, can result in the resolution of EF.

Defining incidence, risk factors, and impact on survival of central line-associated blood stream infections following hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome.

Central line-associated blood stream infections (CLABSI) commonly complicate the care of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic stem cell transplantation (HCT). We developed a modified CLABSI (MCLABSI) definition that attempts to exclude pathogens usually acquired because of disruption of mucosal barriers during the vulnerable neutropenic period following HCT that are generally included under the original definition (OCLABSI). We conducted a retrospective study of all AML and MDS patients undergoing HCT between August 2009 and December 2011 at the Cleveland Clinic (N = 73), identifying both OCLABSI and MCLABSI incidence. The median age at transplantation was 52 years (range, 16 to 70); 34 had a high (≥3) HCT comorbidity index (HCT-CI); 34 received bone marrow (BM), 24 received peripheral stem cells (PSC), and 15 received umbilical cord blood cells (UCB). Among these 73 patients, 23 (31.5%) developed OCLABSI, of whom 16 (69.6%) died, and 8 (11%) developed MCLABSI, of whom 7 (87.5%) died. OCLABSI was diagnosed a median of 9 days from HCT: 5 days (range, 2 to 12) for UCB and 78 days (range, 7 to 211) for BM/PSC (P < .001). MCLABSI occurred a median of 12 days from HCT, with similar earlier UCB and later BM/PSC diagnosis (P = .030). Risk factors for OCLABSI in univariate analysis included CBC (P < .001), human leukocyte antigen (HLA)-mismatch (P = .005), low CD34(+) count (P = .007), low total nucleated cell dose (P = .016), and non-Caucasian race (P = .017). Risk factors for OCLABSI in multivariable analysis were UCB (P < .001) and high HCT-CI (P = .002). There was a significant increase in mortality for both OCLABSI (hazard ratio, 7.14; CI, 3.31 to 15.37; P < .001) and MCLABSI (hazard ratio, 6.44; CI, 2.28 to 18.18; P < .001). CLABSI is common and associated with high mortality in AML and MDS patients undergoing HCT, especially in UCB recipients and those with high HCT-CI. We propose the MCLABSI definition to replace the OCLABSI definition, given its greater precision for identifying preventable infection in HCT patients.

Novel agents for the management of castration-resistant prostate cancer.

PURPOSE OF REVIEW: Over the past 2 years, four new treatments have entered the treatment armamentarium for patients with castration-resistant prostate cancer (CRPC). Although these novel agents differ in their mechanism of action, they all face the same challenges: patient selection, timing of therapy and the cost/benefit of their use. In this review, we will discuss their development and implications when selecting treatment options for CRPC patients. RECENT FINDINGS: Over the past few years, a better understanding of the biology of CRPC has allowed us to develop rational therapies that have resulted in an improvement in the outcome of prostate cancer patients. Immunotherapy has entered the field and despite its limitations and challenges is here to stay. A better understanding of the long-term complications of androgen deprivation has changed the initial approach to most patients with advanced disease, and bone health has become a major focus in their management. Understanding the importance of the androgen receptor and other ligands has led to a dramatic paradigm shift in the treatment of patients with metastatic disease in which the androgen receptor becomes a central therapeutic target in the disease. Specific adrenal inhibitors and engineered super androgen receptor inhibitors have become the most promising agents in the disease. Similarly, chemotherapy has demonstrated clinical benefit and is now a standard of care in docetaxel-refractory patients. SUMMARY: The management of CRPC patients continues to evolve. Novel treatments recently approved by the US Food and Drug Administration have significantly impacted the outcome of CRPC. With the economic impact of their use, selecting the right patient, defining the appropriate timing and sequence of therapy have become critical facts that need to be followed when defining the contemporary treatment options for men with CRPC.

Current treatment considerations in metastatic renal cell carcinoma.

OPINION STATEMENT: In general, debulking neprhectomy is still considered for metastatic RCC patients with primary tumor in place, assuming good performance status. Initial systemic therapy should consider high-dose IL-2 for the highly select patient. One reason for initial consideration of this therapy is the less certain risk/benefit profile if employed after targeted therapy. Notably, due to its potential toxicity and emergence of new effective and more tolerable drugs, IL-2 has become a less favorable and subsequently a less utilized therapeutic tool in the current era. Otherwise, VEGF-targeted therapy is the treatment of choice, preferably on a clinical trial. Off trial, sunitinib has long been favored but pazopanib is gaining more use for tolerance pending the comparative trial. Continued VEGF targeting is favored by these authors given the underlying biology of RCC and the prospective clinical data, noting no direct comparison of mTOR and VEGF agents has yet occurred. Maintaining patient dose is critical and requires optimal supportive care and appreciation/early intervention for toxicity. Predictive biomarkers are desperately needed, and enrollment on clinical trials remains a priority to optimize patient outcome.