Meyer R. Heyman

Neurotoxicity of bortezomib therapy in multiple myeloma: A single‐center experience and review of the literature

Bortezomib is active in heavily pretreated multiple myeloma patients; the dose‐limiting toxicity is peripheral neuropathy (PN).

High-dose cyclophosphamide with or without etoposide for mobilization of peripheral blood progenitor cells in patients with multiple myeloma: Efficacy and toxicity

Summary:The purpose of the study was to examine the yield of CD34+ cells, response rates, and toxicity of high-dose cyclophosphamide with or without etoposide in patients with multiple myeloma. In total, 77 myeloma patients received either cyclophosphamide 4.5 g/m2 (n=28) alone or with etoposide 2 g/m2 (n=49) in a nonrandomized manner, followed by G-CSF 10 μg/kg/day for the purpose of stem cell mobilization. The effects of various factors on CD34+ cell yield, response rate and engraftment were explored. A median of 22.39 × 106 CD34+ cells/kg were collected on the first day of leukapheresis (range 0.59–114.71 × 106/kg) in 71 (92%) of patients. Greater marrow plasma cell infiltration (P=0.02) or prior radiation therapy (P=0.02) adversely affected CD34+ cell yield. In total, 45% of patients receiving cyclophosphamide and 56% of those receiving cyclophosphamide/etoposide had at least a minimum response by EBMT criteria. In all, 25% of patients who received cyclophosphamide alone vs 75.5% of patients who received combined chemotherapy required hospitalization mainly for treatment of neutropenic fever. Cyclophosphamide alone is associated with impressive CD34+ cell yields and clear antimyeloma activity. The addition of etoposide resulted in increased toxicity without significant improvement in CD34+ cell yield or response rates.

Phase I clinical trial of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil (cellcept) in advanced multiple myeloma patients.

Purpose: Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity. Experimental Design: A Phase I MMF dose escalation study was conducted in relapsed and refractory myeloma patients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response. Results: Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease. Conclusions: MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.

Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma

Summary:Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkins disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine–BCNU–melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI=42–76%) and 86% (95% CI=71–99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS=87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study.

Case Report: Prolonged Vancomycin-Associated Neutropenia in a Chronic Hemodialysis Patient

ABSTRACT A chronic hemodialysis patient developed severe marrow granulocytic hypoplasia and peripheral blood neutropenia related to vancomycin therapy for an infected arteriovenous fistula. Neutropenia was prolonged and associated with sustained serum levels of vancomycin that persisted for more than 4 weeks following the last dose of vancomycin. No vancomycin-dependent leukoagglutinins were demonstrable in the patient’s serum. Although a direct toxic effect on marrow granulocyte production seems likely, a vancomycin-dependent immune suppression of granulopoiesis cannot be ruled out.

Autoimmune neutropenia and Hodgkin's disease

Isolated neutropenia developed in a patient who had been treated 4 years previously for Stage IIA nodular sclerosing Hodgkins disease with mantle radiation therapy. Bone marrow revealed myeloid hyperplasia with a virtual absence of bands and polymorphonuclear leukocytes. The serum was positive for antigranulocyte antibodies. There was no evidence of recurrent Hodgkins disease. Guidelines for the evaluation and treatment of immune neutropenia in Hodgkins disease are suggested.