Management of a patient with mantle cell lymphoma who developed severe neurotoxicity after chimeric antigen receptor T-cell therapy in ZUMA-2.

Cerebral edema following chimeric antigen receptor (CAR) T-cell therapy can be fatal. ZUMA-2 is a pivotal phase 2, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in relapsed/refractory mantle cell lymphoma. We describe a 65-year-old patient in ZUMA-2 who developed cerebral edema following CAR T-cell therapy and had complete recovery after multimodality clinical intervention including rabbit antithymocyte globulin (ATG). Biomarker results show early and robust CAR T-cell expansion and related induction of inflammatory cytokines, followed by rapid declines in CAR T-cell and proinflammatory cytokine levels after ATG administration. This clinical profile highlights a potential relevance of ATG in treating severe CAR T-cell-related neurotoxicity.

Cyclophosphamide desensitization in patients with severe hypersensitivity reactions to bendamustine.

INTRODUCTION: Cyclophosphamide is a nitrogen mustard alkylator employed in the treatment of many malignancies and autoimmune disorders. Despite reports of cyclophosphamide hypersensitivity ranging from rash to anaphylaxis, no cases of desensitization have been reported in the oncologic setting. CASE REPORT: We report a cyclophosphamide desensitization protocol used for two patients who experienced severe hypersensitivity to bendamustine, a structurally related drug with potential cross immunogenicity. MANAGEMENT AND OUTCOME: An interdisciplinary approach including immunologist, oncologist, and clinical pharmacists resulted in the development of a multi-step desensitization protocol for cyclophosphamide. The desensitization protocol described enabled the safe administration of cyclophosphamide for the two patients with limited treatment alternatives. DISCUSSION: To the authors' knowledge, this is the first report of cyclophosphamide desensitization in the oncologic setting. Two patients with advanced hematologic malignancies were able to receive cyclophosphamide with minimal adverse effects, despite experiencing previous severe hypersensitivity to another nitrogen mustard analogue.

Chimeric Antigen Receptor T Cells in Hematologic Malignancies.

Patients with B-cell hematologic malignancies who progress through first- or second-line chemotherapy have a poor prognosis. Early clinical trials with autologous anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising results for patients who have relapsed or refractory disease. Lymphodepleting conditioning regimens, including cyclophosphamide, fludarabine, pentostatin, bendamustine, interleukin-2, and total body irradiation, are often administered before the infusion of CAR T cells, allowing for greater T-cell expansion. The major toxicity associated with CAR T-cell infusions is cytokine release syndrome (CRS), a potentially life-threatening systemic inflammatory disorder. The quick onset and progression of CRS require rapid detection and intervention to reduce treatment-related mortality. Management with tocilizumab can help ameliorate the symptoms of severe CRS, allowing steroids, which diminish the expansion and persistence of CAR T cells, to be reserved for tocilizumab-refractory patients. Other toxicities of CAR T-cell therapy include neutropenia and/or febrile neutropenia, infection, tumor lysis syndrome, neurotoxicity and nausea/vomiting. A review of patients' medications is imperative to eliminate medications that may contribute to treatment-related toxicities. Studies are ongoing to help optimize patient selection, preparation, safety, and management of individuals receiving CAR T cells. Long-term follow-up will help establish the place of CAR T cells in therapy.

Carfilzomib and pomalidomide: recent advances in the treatment of multiple myeloma.

Multiple myeloma is a hematologic malignancy characterized by plasma cell clonal expansion as well as end-organ damage due to increased levels of monoclonal proteins in both the plasma and urine. The clinical syndrome is characterized by hypercalcemia, renal insufficiency, anemia, and bone involvement that leads to pathologic fractures. This progressive disease can result in significant patient morbidity and mortality. Despite advances with treatment options and autologous stem cell transplantation, multiple myeloma remains incurable. Current front-line therapies include proteasome inhibitors, immunomodulators, anthracyclines, and steroids. Due to the advent of the immunomodulatory agents thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, overall survival in patients with multiple myeloma has improved greatly. However, once patients progress through front-line therapy and have relapsed or refractory disease, treatment options have historically been very limited. Carfilzomib, a second-generation proteasome inhibitor, has shown impressive response rates as a single agent in the relapsed and refractory patient setting; this includes patients who are refractory to previous bortezomib therapy. In addition, a third-generation immunomodulator, pomalidomide, has also shown promising results in a similar patient population, including those patients who have been shown to be refractory to lenalidomide and bortezomib. Adverse effects of both of these medications have been considered tolerable in the relapsed or refractory population, especially considering the benefits that have been shown. Continuing clinical research will reveal the utility of these agents in combination regimens or in a front-line setting for patients with multiple myeloma.

Isotretinoin maintenance therapy for glioblastoma: a retrospective review.

OBJECTIVES: The current standard treatment of glioblastoma includes maximal safe surgical resection, radiation, and temozolomide. Although isotretinoin has been used for maintenance therapy to delay tumor recurrence, this approach has not been proven to be effective. The objectives of the study are to compare the overall survival, progression-free survival and tolerability of isotretinoin maintenance therapy in patients who received isotretinoin maintenance therapy to patients who did not receive this treatment. METHODS: This study is a retrospective review of adult patients with glioblastoma treated at MD Anderson Cancer Center from 2004 to 2009. Patients who underwent surgical resection, radiation with concurrent temozolomide, and adjuvant treatment with temozolomide were included in the control group, and compared to similarly treated patients who received isotretinoin maintenance following adjuvant temozolomide. RESULTS: Eighteen patients who received isotretinoin maintenance therapy and 70 control patients were included in the analysis. Progression-free survival was 25.3 months with maintenance therapy versus 8.3 months for those not receiving maintenance (p = 0.04). There was no difference in the 2-year or 3-year overall survival estimates (p = 0.11). The common toxicities of isotretinoin included dermatologic-, metabolic-, and psychiatric-related adverse effects. CONCLUSIONS: Isotretinoin maintenance therapy was associated with increased progression-free survival, but did not increase the overall survival in this retrospective review. The potential benefit of maintenance therapy should be weighed against toxicities and negative impact on quality of life in this patient population.

Malignant pleural mesothelioma.

UNLABELLED: PURPOSE The etiology, diagnosis, staging, and management of malignant pleural mesothelioma (MPM) are reviewed, with an emphasis on clinical trials of newer approaches to first-line, second-line, and adjuvant chemotherapy. SUMMARY: In the past decade, more effective chemotherapy regimens have been developed for patients with MPM, a rapidly progressing disease linked to a history of asbestos exposure in about 70% of cases. Patients with MPM often require multimodal treatment with surgery, radiotherapy, and adjuvant or neoadjuvant (presurgical) chemotherapy. The current standard of first-line chemotherapy for MPM is cisplatin or carboplatin in combination with pemetrexed, an antifolate compound that has been shown to increase the cytotoxic effects of platinum-based drugs. In Phase II and III clinical trials, combination therapy with pemetrexed and either cisplatin or carboplatin yielded some of the highest rates of tumor response (21-41%) and overall survival (about 12-14 months) reported to date. Dual-agent neoadjuvant chemotherapy (cisplatin plus gemcitabine or pemetrexed) followed by radical surgery with or without radiotherapy has been reported to yield median survival of up to 23-29 months in small clinical trials, but larger randomized controlled studies are needed to better define the role of neoadjuvant therapy in MPM management. Other chemotherapeutic agents that have been used against MPM, with variable results, include gemcitabine, vinorelbine, taxanes, anthracyclines, and molecular-targeted agents. CONCLUSION: Treatment approaches for MPM include surgery, radiation, and systemic chemotherapy. MPM carries a poor prognosis, but recent studies of pemetrexed and platinum analogue combination therapies have demonstrated improved response rates over other treatments.