Howard Ozer

Microbial contamination of hematopoietic progenitor cell grafts—incidence, clinical outcome, and cost-effectiveness: an analysis of 735 grafts

BACKGROUND: Screening of progenitor cell grafts (marrow, peripheral blood, and cord blood) for microbial contamination is required by the standards of AABB. Clinical sequelae from infusion of these contaminated grafts, however, is uncommon.

Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer

Background: The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. Objectives: To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. Methods: A Medline search using Pubmed was conducted using the keywords neratinib, HKI-272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. Conclusions: Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development.

AIDS-related plasmablastic lymphoma with dramatic, early response to bortezomib.

To the Editor: Plasmablastic lymphomas (PBL) are an aggressive group of non-Hodgkin’s lymphomas occurring primarily in human immunodeficiency virus (HIV)-infected individuals with absolute CD4 counts less than 200 lL. They comprise 2.6% of all AIDS-related lymphomas and represent an AIDS-defining malignancy (1). There is a marked predilection for extra-nodal sites of involvement, with the oral cavity most frequently (58%) involved (2). PBL are characterized by their typical morphologic features and a high proliferative rate, but their most distinguishing feature is their unique immunophenotype (3). They represent terminally differentiated B-cell neoplasms that have the morphologic appearance of immunoblasts but have acquired the antigen profile of plasma cells. The absence of common B-cell and T-cell markers, coupled with the extranodal location of these tumors, often presents a diagnostic challenge. There is strong expression of the postgerminal center B-cell ⁄plasma cell-associated antigens MUM-1 ⁄ IRF4, CD38 and CD138 ⁄ syndecan-1. PAX-5 ⁄BSAP, a nuclear factor that is present from the precursor B-cell stage and in all mature B cells but is lost in the terminal differentiation to plasma cells, is typically negative, as is CD20. The tumor cells show consistent positivity for the plasma cell specific antibody VS38c. Epstein–Barr encoded RNA (EBER) is detected in 74% of cases by in situ hybridization (ISH) (2). Traditionally, PBL have been considered to be a variant of diffuse large B-cell lymphoma (4), although the 2008 World Health Organization (WHO) classification of lymphomas recognizes PBL as a distinct entity (5). Accordingly, almost all efforts at treatment have focused on CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CHOP-like regimens. The response to such therapies has been discouraging, perhaps in accordance with the inherent resistance of plasma cells to chemotherapy. We report the first case of the successful use of bortezomib, a proteasome inhibitor widely used in multiple myeloma, in PBL with a dramatic and early therapeutic response. A 42-yr-old bisexual man presented to our hospital with 4 months of progressive dyspnea, a productive cough, fevers, chills, a 22-kg weight loss, drenching night sweats, and epigastric pain. He was diagnosed with HIV infection and Pneumocystis jiroveci pneumonia (PJP). His absolute CD4 count was 61 ⁄ lL. He was treated appropriately for his PJP but developed nausea, vomiting, blood-tinged diarrhea, and worsening epigastric pain. Laboratory studies revealed a persistently elevated lactate dehydrogenase (LDH) level, transaminitis, and renal insufficiency. Over the following week, the patient developed a marked cholestasis. Imaging of the biliary tree showed dilation of the common bile duct. Esophagogastroduodenoscopy with biopsy revealed a high-grade lymphoma with plasmablastic features in the stomach, most consistent with plasmablastic lymphoma of the oral mucosa type. Flow cytometry was negative for leukocyte common antigen, all common epithelial, Tcell and B-cell markers (except weak positivity for BCL6 and CD10), and was positive for CD138, vimentin, and P63 (VS38c). ISH for EBER was negative. The bone marrow biopsy showed clusters of atypical cells, as well as clusters of CD138positive cells with relatively fine nuclear chromatin and distinct nucleoli. Plasma cells were increased in number. Karyotyping revealed t(8;14), amongst many other abnormalities. Taken together, the findings were suggestive of marrow involvement by the lymphoma. Positron emission tomography ⁄ computed tomography (PET ⁄CT) showed significant hypermetabolism in multiple thoracic and abdominal lymph nodes, the left lung, liver, and several bones (Fig. 1), confirming stage IVBE plasmablastic lymphoma. The patient was started on highly active anti-retroviral therapy. Anthracycline-containing chemotherapeutic regimens were avoided secondary to persistent hyperbilirubinemia. Bortezomib was then administered at a dose of 1.3 mg ⁄m intravenously on days 1, 4, 8, and 11. Seven days from the initiation of bortezomib, a PET ⁄CT (Fig. 2) showed a marked decrease in fluoro-deoxy glucose uptake after only two doses, signifying a dramatic treatment response and suggesting potential survival benefit. His LDH, bilirubin, and creatinine normalized. Our patient received a total of four doses of bortezomib, but unfortunately succumbed to severe septic shock due to multiple organisms 15 days after the last dose of bortezomib, before a repeat PET ⁄CT could be obtained. There was no evidence of tumor lysis. The treatment of PBL in general has been disappointing, and the overall outlook is grim. Median survival in doi:10.1111/j.1600-0609.2009.01235.x European Journal of Haematology 82 (490–492)

Final Results of a Placebo-Controlled Study of Filgrastim in Small-Cell Lung Cancer: Exploration of Risk Factors for Febrile Neutropenia

BACKGROUNDnA phase III study of filgrastim as an adjunct to combination chemotherapy in previously untreated patients with limited- or extensive-stage small-cell lung cancer was conducted. This final analysis explores baseline factors that might predict febrile neutropenia and also reports the results of 463 open-label filgrastim cycles that were delivered after patients initial episode of the primary endpoint, ie, febrile neutropenia.nnnPATIENTS AND METHODSnA total of 244 patients were randomized to receive placebo or filgrastim in </= 6 cycles of chemotherapy (cyclophosphamide/doxorubicin/etoposide).nnnRESULTSnThe cumulative percent of patients receiving filgrastim who experienced febrile neutropenia was approximately 50% lower than those given placebo (38% vs. 74%, respectively; P < 0.0001). Significant treatment-related reductions were also seen in the incidence and duration of grade 4 neutropenia. Cycle 1 displayed the highest incidence of neutropenia with or without fever and the longest duration of neutropenia relative to later cycles. Patients crossing over to open-label filgrastim from their blinded treatment assignment displayed event rates similar to those in the blinded filgrastim group. Patients who experienced febrile neutropenia in cycle 1 were at a significantly higher risk for subsequent events compared with those who were event-free in cycle 1. Women displayed a higher risk for febrile neutropenia than men, but no other baseline risk factors were detected.nnnCONCLUSIONnGiven the high rate of febrile neutropenia in cycle 1 and the higher risk for subsequent events in patients with a cycle 1 event, we conclude that growth factor administration starting in cycle 1 should be considered for patients receiving moderately to highly myelosuppressive chemotherapy regimens.

Evaluation of the Combination of Docetaxel/Carboplatin in Patients with Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck (SCCHN): A Southwest Oncology Group Phase II Study

Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with Zubrod performance status 0–2. Docetaxel 65 mg/m2 and carboplatin (AUC of 6) were given IV in a 21-day cycle to 68 patients. Response probability was 25 percent (95%CI: 15–38). The major toxicity observed was neutropenia, with 36 patients (61 percent) experiencing Grade 3 or worse. Median progression-free survival was 3.8 months (95%CI, 3.1–4.8) Median overall survival was 7.4 months (95%CI, 6.2–8.9). The results of this study suggest this regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status.

Symptomatic metastases to the pituitary infundibulum resulting from primary breast cancer.

Metastatic spread into the brain is not infrequently seen in association with epithelial neoplasms such as lung and breast cancer, among others. In the majority of cases such spread entails a poor prognosis. Metastasic spread to the pituitary gland, specifically to the area of the infundibulum is, however, a more rare presentation. Most reported cases of metastatic disease to the pituitary are confined to the posterior lobe, probably related to the richer blood supply as compared to the anterior counterpart. The detection of pituitary metastasis is further complicated by the lack of specific associated symptomatology or definite radiologic diagnostic findings. We here describe the different clinical presentations of two patients with symptomatic pituitary stalk metastasis resulting from primary breast cancer; we also provide a systematic review of the literature.

Management of platinum-based chemotherapy-induced acute nausea and vomiting: is there a superior serotonin receptor antagonist?

Objective. The last decade has witnessed the great impact of 5-hydroxytryptamine-3 receptor (5-HT3) antagonists in revolutionizing the management of platinum-based chemotherapy–induced acute nausea and vomiting (CINV). However, despite the availability of a variety of 5-HT3 antagonists, little data is published to support superiority of one drug over another, leaving the choice of serotonin receptor antagonist largely empirical. The National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines for management of chemotherapy-associated nausea and vomiting clearly endorse the use of serotonin receptor antagonist; however, no single agent is preferred over the rest. Methods. Data for patients (n¼159) receiving platinum-based chemotherapy regimens were retrospectively collected. Patients getting 5-HT3 antagonists without steroids or those with known history of brain metastasis, gastroparesis, and intestinal obstruction were not eligible for the study. Patient characteristics including age, gender, primary diagnosis, history of heavy alcohol intake, chemotherapy regimen administered, number of cycles, and Eastern Cooperative Oncology Group performance status at the start of therapy were noted. Primary outcome was the complete control of platinum-induced acute nausea and vomiting. Secondary outcome measures included control of >grade 1 nausea or vomiting, comparison of two doses of dexamethasone, and antiemetic efficacy among various platinum drugs. National Cancer Institute Common Toxicity Criteria version 2.0 was used to assess toxicity. Results. A total of 126 patients received 369 cycles of platinum-based therapy. Dolasetron (n¼157), granisetron (n¼81), and ondansetron (n¼131) achieved complete control of vomiting in 89.8, 95.5, and 92.3% (p¼0.67) of cycles, respectively. Respectively, complete nausea control was observed in 68.1, 75.3 and, 69.4% (p¼0.50). Dexamethasone 20 mg was not superior to 10 mg in complete control of nausea and vomiting (p¼0.15 and p¼0.63, respectively). However, complete nausea control was significantly better in the subgroup of patients getting cisplatin-compared with carboplatin-based regimens (78.8% vs. 67.7%, p50.05). Conclusion. No significant difference exists in the antiemetic efficacy of the three 5-HT3 antagonists studied in controlling CINV when administered in combination with dexamethasone. Choice of antiemetic regimen should therefore be based on drug cost.

Successful treatment of Helicobacter pylori-negative gastric MALT lymphoma with rituximab.

Helicobacter pylori infection is strongly associated with low-grade gastric lymphoma, commonly known as mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori eradication leads to complete remission in 80% of early stage MALT lymphomas. The treatment for early stage H. pylori-negative gastric MALT lymphoma is evolving. Rituximab, a chimeric anti-CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with B-cell non-Hodgkin lymphoma. We describe herein the clinical, endoscopic, and histologic features of a patient with H. pylori-negative gastric MALT lymphoma treated successfully with rituximab.

New Directions in the Management of Chemotherapy-Induced Neutropenia: Risk Models, Special Populations, and Quality of Life

New directions in managing chemotherapy-induced neutropenia include the development and validation of patient-based predictive risk models to guide the use of prophylactic colony-stimulating factors (CSFs) and an emerging recognition of the possible impact of chemotherapy-induced neutropenia on patient quality of life. Predictive risk models are being developed to identify patients who are at greater risk of neutropenic complications so that prophylactic CSF can be targeted to them in a timely and cost-effective manner. Current practice dictates the use of CSF prophylaxis primarily on the basis of the chemotherapy regimen; the risk-model approach is based on individual patient risk factors, which may be unconditional (before treatment) or conditional (after the first cycle). Within this new paradigm are patients with special circumstances, in whom prophylactic CSF treatment is currently recommended. Clinical evidence suggests that elderly patients are at particular risk for myelosuppression and should be considered for prophylactic CSF treatment starting with the first chemotherapy cycle. Analytical tools to measure the facets of quality of life related to neutropenia are being tested for validity and will be incorporated in future clinical trials. Thus, the future of neutropenia management promises to further refine the cost-effective use of CSF, while improving our understanding of the impact that chemotherapy-induced neutropenia has on quality of life.

Protein kinase C blockade inhibits differentiation of myeloid blasts into dendritic cells by calcium ionophore A23187

Direct differentiation of myeloid leukemia blasts into antigen-presenting dendritic cells (DCs) for use as cellular vaccines is unique in that identification of tumor-specific antigens may not be necessary because the antigens should already be endogenously expressed.We hypothesized that signaling through protein kinase C (PKC) is required for differentiation of HL-60 promyeloblasts into DCs upon stimulation with calcium ionophore A23187. To demonstrate the inhibitory effect of PKC blockade, we pretreated HL-60 myeloid blasts with the protein kinase inhibitor bisindolylmaleimide I (Bis-1) for 24 hours and then treated the cells with calcium ionophore A23187 for an additional 24 hours. Controls consisted of HL-60 blasts treated with A23187, Bis-1 alone, or media.We noted that blasts cultured in media, Bis-1, or Bis-1 then A23187 did not develop the morphologic and phenotypic DC characteristics, up-regulate Rel B, or activate allogeneic T-cells. Our findings suggested that PKC blockade inhibits morphologic, phenotypic, and functional differentiation of HL-60 promyeloblasts into antigen-presenting DCs. Our findings supported the role of PKC as an obligatory pathway for calcium ionophore A23187-induced differentiation of HL-60 myeloblasts into antigen-presenting DCs.