Christopher Fausel

Randomized, Double-Blind, Placebo-Controlled, Phase III Cross-Over Study Evaluating the Oral Neurokinin-1 Antagonist Aprepitant in Combination With a 5HT3 Receptor Antagonist and Dexamethasone in Patients With Germ Cell Tumors Receiving 5-Day Cisplatin Combination Chemotherapy Regimens: A Hoosier Oncology Group Study

PURPOSE Aprepitant, a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone are standard antiemetic therapy for prevention of single-day, cisplatin-induced nausea and vomiting. We conducted a double-blind, placebo-controlled phase III cross-over study that compared aprepitant to placebo combined with standard antiemetic prophylaxis (a 5HT3-RA and dexamethasone) in patients receiving 5 days of cisplatin combination chemotherapy for testicular cancer. PATIENTS AND METHODS Patients receiving two consecutive identical courses of a 5-day cisplatin-based chemotherapy were randomly assigned to aprepitant 125 mg on day 3 and 80 mg per day on days 4 through 7 or to placebo with the initial course and crossover to the opposite treatment with the second course. The primary objective was complete response (CR). Secondary end points were emetic episodes (acute and delayed), nausea measurement based on a visual analog scale (VAS), and patient-stated preference after the second study cycle. RESULTS In all, 71 patients were screened for the study and 69 were evaluable. Thirty-five patients were randomly assigned to receive aprepitant and 34 to receive placebo for the first course. Forty-two percent achieved CR with aprepitant compared with 13% with placebo (P < .001). Eleven patients (16.2%) had at least one emetic episode during the aprepitant cycle versus 32 patients (47.1%) with placebo. Thirty-eight patients preferred the aprepitant cycle whereas 11 preferred placebo (P < .001). There was no statistical difference in VAS for nausea, but it was numerically superior with aprepitant. There was no toxicity with aprepitant compared with placebo. CONCLUSION There was a significant improvement in CR rate with aprepitant combined with a 5HT3-RA and dexamethasone. Patient preference strongly favored the aprepitant cycle.

Central nervous system infections due to Stomatococcus mucilaginosus in immunocompromised hosts.

We present a case of central nervous system (CNS) infection due to Stomatococcus mucilaginosus involving a patient with leukemia and summarize 12 additional published reports of CNS infection due to this organism in immunocompromised hosts. The infection was diagnosed most commonly in the setting of hematologic malignancy accompanied by chemotherapy-induced neutropenia. S. mucilaginosus was recovered from blood prior to discovery of the CNS infection in 62% of cases. Signs or symptoms of CNS infection were observed in all patients. Although a number of patients responded to regimens containing intravenous vancomycin, the addition of intrathecal vancomycin appeared to be of benefit in some cases.

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia.

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)±mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan–Meier analysis, year 1–4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Observations of second primary malignancy in patients with multiple myeloma

BACKGROUND Advances in the treatment of multiple myeloma have resulted in immunomodulatory (IMiD) agents becoming integral to the standard treatment armamentarium. IMiD agents are effective in the initial and relapsed settings of multiple myeloma. Three studies evaluating the duration of remission in maintenance lenalidomide vs. placebo reported an increased incidence of second primary malignancies in patients receiving maintenance therapy. The purpose of this study was to evaluate the incidence of second primary malignancies after IMiD exposure for standard induction and relapsed therapy in myeloma. PATIENTS AND METHODS A retrospective chart review was conducted at the Indiana University Simon Cancer Center in Indianapolis, Indiana. Patients were older than 18 years and had been diagnosed with multiple myeloma. Patients with a previous diagnosis of cancer were excluded. The primary objective was to assess the incidence of second primary malignancies in all patients. Secondary objectives included the type of malignancy, whether patients had been previously treated with IMiD therapy and the time from treatment initiation to diagnosis of a second malignancy. RESULTS Three hundred twenty-five patients were reviewed and 279 were included in the study. Ten patients were diagnosed with a second primary malignancy (3.5%). Nine of the 10 patients were treated with IMiD therapy before diagnosis (P = .169). The mean time to diagnosis was 360 days for all patients. CONCLUSION The incidence of second primary malignancy was not statistically significant in the IMiD-treated patients. Further long-term follow-up is needed to better assess the potential adverse events of these novel agents.

Comparison of an assumption‐free Bayesian approach with Optimal Sampling Schedule to a maximum a posteriori Approach for Personalizing Cyclophosphamide Dosing

Variable metabolism, dose‐dependent efficacy, and a narrow therapeutic target of cyclophosphamide (CY) suggest that dosing based on individual pharmacokinetics (PK) will improve efficacy and minimize toxicity. Real‐time individualized CY dose adjustment was previously explored using a maximum a posteriori (MAP) approach based on a five serum–PK sampling in patients with hematologic malignancy undergoing stem cell transplantation. The MAP approach resulted in an improved toxicity profile without sacrificing efficacy. However, extensive PK sampling is costly and not generally applicable in the clinic. We hypothesize that the assumption‐free Bayesian approach (AFBA) can reduce sampling requirements, while improving the accuracy of results.

Iron chelation therapy in myelodysplastic syndromes

PURPOSE To understand how to appropriately recognize and manage iron overload with iron chelation therapy (ICT) in patients with myelodysplastic syndromes (MDS), evaluation of the role of different agents available for management of iron overload, including efficacy, safety, and economic considerations for transfusion-dependent patients with MDS, is provided. SUMMARY Patients with MDS have a high incidence of anemia, which often requires treatment. Supportive care measures such as red blood cell transfusions and erythroid colony stimulating factors are mainstays of therapy. Use of long-term transfusion therapy has limitations in patients with MDS due to the risk of developing iron overload. Strategies to manage iron overload include phlebotomy and ICT with agents such as deferoxamine and deferasirox. Data evaluating pharmacologic therapy for treatment of iron overload in patients with MDS suggest timely intervention can mitigate the morbidity associated with this clinical syndrome. CONCLUSION Development of practical management strategies to implement and optimize ICT using deferoxamine and deferasirox will be important to provide optimal care for transfusion-dependent patients with MDS.