David M. Mintzer

Persistent B19 Parvovirus Infection in Patients Infected with Human Immunodeficiency Virus Type 1 (HIV-1): A Treatable Cause of Anemia in AIDS

OBJECTIVE To determine the role of B19 parvovirus in red cell aplasia of patients infected with human immunodeficiency virus type 1 (HIV-1). DESIGN Uncontrolled clinical trial, with assay of serum, peripheral blood cells, and bone marrow for virus using DNA hybridization and immunocytochemistry techniques; these assays were then correlated with clinical findings, results of immunoassays for antivirus antibodies, and with immunoglobulin (Ig) therapy. SETTING Government medical referral center, and university and private hospitals. PATIENTS Seven patients with pure red cell aplasia and serologic evidence of infection with HIV-1. MEASUREMENTS AND MAIN RESULTS All patients had giant pronormoblasts in the bone marrow (present in transient aplastic crisis caused by acute B19 parvovirus infection). High concentrations of B19 parvovirus were demonstrated in sera, in several cases in samples separated by weeks or months. Viral DNA and capsid protein were present in the bone marrow of three patients studied, and active viral replication was detected by southern analysis. There was no antivirus IgG in capture immunoassay and no or very low levels of antivirus IgM. The patients did not have symptoms of fifth disease, the illness caused by this virus in immunologically normal persons. Six patients were treated with a regimen of intravenous commercial immunoglobulin. In all cases, this therapy resulted in rapid reduction in serum virus concentrations and full recovery of erythropoiesis. Relapses in two cases were predicted by DNA hybridization studies, and these cases were successfully retreated. CONCLUSIONS The B19 parvovirus is a remediable cause of severe chronic anemia in HIV-infected patients. Recognition of and therapy for parvovirus in this population will avoid erythrocyte transfusion and should prevent transmission of the virus to other persons, including immunosuppressed persons and women of child-bearing age.

Treatment of Kaposi's Sarcoma and Thrombocytopenia with Vincristine in Patients with the Acquired Immunodeficiency Syndrome

Kaposis sarcoma occurs in about one third of patients with the acquired immunodeficiency syndrome. Although in some patients the tumor is principally a cosmetic problem, other patients have progressive disease with significant morbidity. Twenty-three patients with Kaposis sarcoma related to the acquired immunodeficiency syndrome were treated with vincristine. Three patients had a coexisting immune thrombocytopenia. Of the 18 patients evaluable for response, 11 had a partial response and 7 had a minor response. The median duration of partial response was 4 + months. All 3 thrombocytopenic patients developed a significant increase in platelet count, which in 2 was sustained with continued treatment for 6 and 9 months, respectively. We conclude that vincristine has antitumor activity in the epidemic form of Kaposis sarcoma and that it is also effective in the treatment of associated immune thrombocytopenia.

Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.

Background: In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP). Patients and Methods: Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m2 alone (n = 91) or in combination with cisplatin 75 mg/m2 (n = 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmaco-vigilance database for all patients enrolled in the EAP. Results: Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27–87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate + stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). Conclusions: The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.

Drug-Induced Hematologic Syndromes

Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications.

Phase II Study of Paclitaxel, Carboplatin, and Cetuximab as First Line Treatment, for Patients with Advanced Non-small Cell Lung Cancer (NSCLC): Results of OPN-017

Background: Cetuximab has demonstrated synergy with taxanes in preclinical models; as well as single agent activity. We assessed the activity of cetuximab with carboplatin and paclitaxel given on a 4-week schedule, in advanced, chemo-naive non-small cell lung cancer. Patients and Methods: This phase II, single arm, multi-institution study featured standard dosage of cetuximab 400 mg/m2 day 1, then 250 mg/m2 with paclitaxel (100 mg/m2/wk, for 3 weeks), and carboplatin (area under curve = 6) day 1 of each 28 day cycle. After 4 to 6 cycles, in the absence of disease progression or excess toxicity, cetuximab was continued weekly. Primary end point was response rate. Results: Fifty-three patients (median age 63, 51% male) participated. Response rate was 57% (3 complete response and 27 partial response). At a median follow-up of 12.5 months, the estimated overall survival is 13.8 months (95% CI: 9.08–16.02) with an event-free survival rate of 5.53 months (95% CI: 4.77–7.99), 18.9% remain free from progression at 1 year. Improved survival was associated with female gender, absence of prior radiation, PS 0 and epidermal growth factor receptor expression. Toxicities included rash (28% grade 3), nail changes (3.7% grade 3), hypomagnesemia (7.5% grade 3 and 3.7% grade 4), and neutropenia (25% grade 3 and 13% grade 4) in addition to other typical side effects anticipated with paclitaxel/carboplatin. There were no grade 5 toxicities. Conclusion: Combination of cetuximab/paclitaxel/carboplatin in non-small cell lung cancer was well tolerated and clinically active with manageable toxicities. This unique schedule, integrating weekly paclitaxel and cetuximab has not yet been tested in a randomized trial.

Malignant mesothelioma following radiation therapy

BACKGROUND Studies of the growing population of long-term survivors of cancer have led to increased recognition of the neoplastic complications of therapy. The causes of secondary malignancies are probably multifactorial, but radiation therapy and chemotherapy have certainly been implicated in the development of posttherapy neoplasia. PATIENTS AND METHODS A case of pleural mesothelioma after successful radiation therapy for Hodgkins disease is described with a review of radiation-associated mesotheliomas reported in the literature. In Hodgkins disease, patients may receive radiation, chemotherapy, or combined treatment; the most common secondary malignancy is acute nonlymphocytic leukemia while sarcomas are the second most common solid tumors. CONCLUSIONS Although mesothelioma is an uncommon sarcoma, its occurrence has been documented numerous times after exposure to diagnostic or therapeutic radiation.

On How Increasing Numbers of Newer Cancer Therapies Further Delay Referral to Hospice: The Increasing Palliative Care Imperative

Delay in referral of cancer patients to hospice until very near the end of life may deny patients and families optimal palliative care. A variety of factors may contribute to these delays. This article describes how the proliferation of newer anticancer therapies, although desirable overall, may further increase these delays. It is important for hospice personnel to understand these changes in medical oncology and to work to optimize palliative care delivery concomitantly with disease-remitting therapies.

Phase II Multicenter Trial of Albumin-Bound Paclitaxel and Capecitabine in First-Line Treatment of Patients With Metastatic Breast Cancer

BACKGROUND Capecitabine, a tumor-activated oral fluoropyrimidine, and albumin-bound paclitaxel (ab-paclitaxel) have substantial single-agent activity in patients with metastatic breast cancer (MBC). Taxane and antimetabolite doublets have improved efficacy compared with single agents. This phase II open-label trial was designed to test the safety and efficacy of capecitabine and ab-paclitaxel in previously untreated MBC. PATIENTS AND METHODS Patients received capecitabine (825 mg/m(2) orally twice daily, approximately 12 hours apart, on days 1 to 15) and ab-paclitaxel (125 mg/m(2) intravenously on days 1 and 8 of each cycle with no premedication) every 3 weeks. The primary endpoint was overall objective response rate (ORR), with evaluation performed after every 2 cycles. Entry criteria included measurable MBC, human epidermal growth factor receptor 2 (HER2) negativity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no previous chemotherapy for metastatic disease, and > 6 months since adjuvant fluoropyrimidine or paclitaxel treatment. RESULTS Fifty patients received at least 1 dose of study drug, with 46 patients evaluable for efficacy evaluation. Three hundred seventy-four cycles of therapy were delivered. Eighty percent of patients completed 8 cycles. The ORR was 61% (complete response [CR], 4%; partial response [PR], 57%), and 7 patients had sustained (≥ 24 weeks) stable disease for a clinical benefit rate of 76.1%. The median progression-free survival (PFS) was 10.6 months, and the median overall survival was 19.9 months. The most common adverse events (AEs) that were ≥ grade 3 were pain, hand-foot syndrome, and neutropenia. CONCLUSION The combination of weekly ab-paclitaxel plus daily capecitabine orally at these doses and scheduling was well tolerated and showed substantial efficacy.

Lymphosarcoma cell leukemia and other non-Hodgkin's lymphomas in leukemic phase

Lymphosarcoma cell leukemia has been used to refer to three related clinical syndromes. As originally described, it refers to the invasion of peripheral blood by poorly-differentiated lymphocytic lymphoma. Blood involvement occurs in 10 to 70 percent of patients with poorly-differentiated lymphocytic lymphoma, depending on the methods and criteria used to define leukemic phase, but it may have little impact on the clinical course of such patients. Second, lymphosarcoma cell leukemia can describe a variant of chronic lymphocytic leukemia, presenting clinically without lymphoma. Although not all hematologists recognize this as a distinct entity, others believe that such patients have a poorer prognosis than those with typical chronic lymphocytic leukemia. In the absence of a lymph node biopsy diagnostic of poorly-differentiated lymphocytic lymphoma, the diagnosis of lymphosarcoma cell leukemia should be reserved for cases demonstrating immunologic features of poorly-differentiated lymphocytic lymphoma, namely bright surface immunoglobulin immunofluorescence, normal capping, and low mouse red cell rosette formation. Finally, lymphosarcoma cell leukemia has been used to describe the invasion of blood by other types of lymphoma, including large cell, lymphoblastic, and Burkitts lymphoma, although these are better designated as the particular lymphoma in leukemic phase. When abnormal cells appear in the blood samples of patients with lymphoma, acute myelogenous leukemia must also always be considered, particularly in patients who have received substantial prior chemotherapy or irradiation.

BRAF V600E is also seen in unclassifiable splenic B-cell lymphoma/leukemia, a potential mimic of hairy cell leukemia

To the editor: The virtually 100% diagnostic sensitivity and specificity of the BRAF V600E mutation for hairy cell leukemia (HCL), within the context of mature B-cell neoplasms, originally described by Tiacci et al,[1][1] was recently confirmed in Blood .[2][2],[3][3] We report this mutation in a