Myron S. Czuczman

Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: clinical, radiologic, and pathologic characteristics.

Invasive filamentous fungal infection (IFFI) is an important cause of mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We reviewed 22 consecutive cases of IFFI in allogeneic HSCT recipients at Roswell Park Cancer Institute. IFFI was diagnosed after neutrophil recovery in 21 patients (95%). All had received corticosteroids within 1 month prior to IFFI diagnosis. Fourteen (64%) presented with dyspnea, and only 7 (32%) were febrile. Aspergillus species were isolated in 18 (82%) cases. Thirty day mortality after IFFI diagnosis was associated with a higher mean daily dose of corticosteroids (P = 0.02) and receiving OKT3 (P = 0.01) within 1 month prior to IFFI diagnosis and serum creatinine >2 mg/dl at the time of diagnosis (P = 0.004). Histopathologic material from biopsy or autopsy was available in 15 patients (68%). In 8 (53%), the predominant lung histopathology was an acellular coagulative necrosis and hyphal angioinvasion was observed in some of these cases. These findings have generally been observed in neutropenic patients but not in non-neutropenic HSCT recipients. The predominance of coagulative necrosis in our series may reflect the high doses of corticosteroids used to treat graft-versus-host disease (GVHD), which may have disabled leukocyte trafficking and hyphal killing.

Severe respiratory depression after dimethylsulphoxide-containing autologous stem cell infusion in a patient with AL amyloidosis

Adverse reactions with DMSO-cryopreserved stem cell infusion are well-recognized. However, severe, life-threatening anaphylactic reactions with DMSO are very rarely described in the literature. We report here a 58-year-old female with AL amyloidosis who developed an unexpected episode of respiratory arrest a few seconds after the beginning of thawed stem cell product infusion. Fortunately, the patient was resuscitated successfully without the need for intubation. The prompt development of the reaction just a few seconds after the stem cell infusion convincingly implicates DMSO as the potential suspect. The presence of amyloid cardiomyopathy might have also contributed to this adverse event. Bone Marrow Transplantation (2000) 25, 1299–1301.

Respiratory syncytial virus infection in the late bone marrow transplant period: report of three cases and review.

Respiratory syncytial virus (RSV) infection is an important cause of respiratory mortality in immunosuppressed patients, including bone marrow transplant (BMT) recipients. The presence of lower respiratory tract infection and infection in the pre-engraftment phase of BMT is believed to confer a poor prognosis. Three patients who underwent allogeneic BMT at our institution developed RSV pneumonia over 1 year post BMT, with the underlying disease in remission. All three were hypoxic with extensive pulmonary disease at presentation. Treatment consisted of aerosolized ribavirin and intravenous immune globulin with successful clearing of viral shedding and excellent clinical outcomes. RSV infection is probably less severe in the late post-BMT period, but needs to be considered early in the differential diagnosis of pulmonary infiltrates in this patient population. Bone Marrow Transplantation (2001) 27, 1071–1073.

Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 μM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-κB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.

Cost-utility of darbepoetin alfa (DARBE) on an every-2 week (QOW) schedule in anemic non-myeloid hematologic malignancies: A positive overall impact on the healthcare system (HCS)

8278 Background: DARBE is a long-acting erythropoietin approved for chemotherapy-induced anemia. It is preferentially prescribed at 200 mcg subcutaneously QOW. This administration has shown equal efficacy and appears to be cost effective and convenient to patients (pts) in comparison to recombinant human erythropoietin (EPO). The actual cost-utility benenfit of this schedule has not been reported. We conducted a cost analysis at our institution in patients with non-myeloid hematological cancers to assess the projected cost savings by using DARBE and to determine its potential overall impact on the HCS.nnnMETHODSnThis is a single institution study. All pts with multiple myeloma and lymphomas, treated with EPO between 1/1/02-12/31/02 were captured by a report generated through the pharmacy computer system. We projected that the number of pts treated with EPO 40,000 units QW would receive DARBE 200 mcg QOW. HCS cost was calculated based on acquisition cost of drug, travel costs based on IRS reimbursement rates, wages lost by patient and caretaker conservatively estimated based on national minimum wage, and nursing (RN), pharmacy (RPh), physician (MD) wages from the US Dept of Labor. Data was also collected for administration of each growth factor injection from the clinic including RN, RPh, MD time, wait time, appointment time, infusion chair time and drive time (see Table 1).nnnRESULTSn300 doses of EPO were administered between 1/1/02 - 12/31/02. A summary of the financial and time costs is presented in Table 1. [Figure: see text] Conclusion: DARBE QOW is both more cost-effective and convenient for pts and clinical staff compared to EPO QW. Our limited analysis is suggestive of a global potential benefit to the HCS by use of longer acting HGF agents. No significant financial relationships to disclose.