Marciano D. Reis

Reporting of near-miss events for transfusion medicine: improving transfusion safety

BACKGROUND: Half of the reported serious adverse events from transfusion are a consequence of medical error. A no‐fault medical‐event reporting system for transfusion medicine (MERS‐TM) was developed to capture and analyze both near‐miss and actual transfusion‐related errors.

Immunosuppressive Toxicity of CAMPATH®1H Monoclonal Antibody in the Treatment of Patients with Recurrent Low Grade Lymphoma

We have studied, as part of a group of international multicenter phase II clinical trials, the toxicity and effectiveness of CAMPATH1H administered intravenously three times a week in an outpatient setting to patients with recurrent or progressive low grade lymphoma. We report here on the toxicity and therapeutic results of the first seven patients treated before the study was closed prematurely because of unacceptable toxicity. Classical complete or partial responses of treatment were seen in three of seven patients. One complete response lasted 8.5 months and the other complete response is ongoing at 1 year. Responses occurred in nodal sites as well as in skin and peripheral blood. The first three or four antibody infusions in each patient was associated with grade 1 or 2 side-effects including rigor, fever, facial flushing, nausea, vomiting, hives, wheezes, hypotension, and/or diarrhea but these subsequently decreased or disappeared. The most significant toxicity was profound lymphopenia and associated infection, usually viral. Six of seven patients had culture or serologically documented infections and four patients had two or more such episodes. All infections responded to temporary discontinuation of antibody therapy and appropriate antiviral or antibiotic agents. We conclude that CAMPATH1H monoclonal antibody has therapeutic activity against low grade non-Hodgkins lymphoma but that this activity is limited by marked lymphopenia and an unacceptably high frequency of serious infection at the dose and schedule used in this trial.

Estimating the prevalence of myelodysplastic syndromes in patients with unexplained cytopenias: a retrospective study of 322 bone marrows.

Although unexplained anemia is common in the elderly, the prevalence of MDS is poorly defined. We reviewed 2267 bone marrows reviewed at our center between the years 2002 and 2005. Of these, 322 met our criteria for inclusion (14%). Seventy-three patients (22.6%) had a confirmed diagnosis of MDS and 32 (9.9%) had suspected MDS. Confirmed or suspected MDS was more likely in patients aged >65 (31.5% and 11%, respectively). Age, MCV, LDH and RDW were independently predictive of MDS. Extrapolation of our findings to the elderly anemic individuals in the community suggests MDS prevalence may be higher than previously postulated.

Establishment of a cytokine-producing anaplastic large-cell lymphoma cell line containing the t(2;5) translocation: potential role of cytokines in clinical manifestations.

A permanent cell line, HSC-M1, was established from a child with advanced CD30 (Ki-1)+ anaplastic large-cell lymphoma (ALCL). Clinical features included irritability, fever, weight loss, tender lymphadenopathy, pneumonitis, neutrophilia, and bone marrow erythrophagocytosis. While HSC-M1 cells exhibited an immunophenotype characteristic of ALCL of T-cell lineage, the cell line also demonstrated features of monocyte-macrophage lineage. Cytogenetic and polymerase chain reaction (PCR) analysis of the HSC-M1 cell line and involved bone marrow demonstrated the characteristic non-random chromosomal translocation t(2;5)(p23;q35). Reverse transcriptase PCR for mRNA expression of cytokines and cytokine receptors showed that HSC-M1 cells expressed the message for multiple cytokines and their receptors. Measurement of cytokine levels in serum samples using enzyme-linked immunosorbent assays showed increased concentrations of several cytokines. The increased levels of some cytokines correlated with disease activity and clinical symptoms. Although spontaneous production by HSC-M 1 cells of some of these cytokines was demonstrated, the production of others was only detectable after stimulation with exogenous CD30 ligand. With few exceptions, there was good correlation between serum cytokine levels and cytokines produced by HSC-M1 cells. These findings indicate that cytokine production is a feature of ALCL cells and that some of the clinical manifestations in ALCL may result from cytokines produced by either the malignant or accessory cells.

Lenalidomide and metronomic melphalan for CMML and higher risk MDS: A phase 2 clinical study with biomarkers of angiogenesis

Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.

Deletion of the long arm of chromosome 5 in essential thrombocythemia

A 51-year-old woman with no history of prior chemotherapy or radiation therapy was diagnosed with essential thrombocythemia (ET) according to the diagnostic criteria established by the Polycythemia Vera Study Group (PVSG). Cytogenetic analysis of bone marrow metaphases revealed both normal female karyotype and a single clonal abnormality, 46,XX,del(5)(q22q35). While chromosomal abnormalities have been reported in ET, their incidence is very low, and no specific abnormality has been found. Many of the reported cases of ET with chromosomal aberrations, including 5q-, do not meet the diagnostic criteria proposed by the PVSG, and may represent one of the other myeloproliferative disorders or a myelodysplastic syndrome. Furthermore, it is important to distinguish the 5q- syndrome, which may present with thrombocytosis and megakaryocytic hyperplasia, from ET. Our patient appears to be the first example of untreated ET clearly meeting the PVSG criteria in which 5q- was the only clonal abnormality seen at diagnosis.

Validation of a scoring system to establish the probability of myelodysplastic syndrome in patients with unexplained cytopenias or macrocytosis.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders primarily seen in the elderly that are characterized by ineffective hematopoiesis and a propensity to develop AML. Clinicians may be hesitant to refer older patients with unexplained cytopenias and/or macrocytosis for a bone marrow biopsy (BM), and consequently undiagnosed patients may be deprived access to effective treatments. Previously, we described factors which were independently predictive of a diagnosis of MDS at time of bone marrow: age ≥65, mean cell volume (MCV), red cell distribution width (RDW), and lactate dehydrogenase (LDH), and suggested a scoring system to calculate the post-test probability of MDS [1]. In this study we validate this scoring system in a cohort of 313 individuals who underwent bone marrow examinations for the investigation of unexplained cytopenias and or macrocytosis over a 3 year period at our institution (2006-2008). Thirty-two percent of all patients were diagnosed with MDS and 9% had suspected MDS. The post-test likelihood of a diagnosis of MDS increased from 12% when none of the four identified factors were present to 48% when 3 or more factors were present. This scoring system can be used to guide the diagnostic testing of patients presenting with unexplained cytopenias or macrocytosis.

Oncogene Involvement in Myelodysplasia and Acute Myeloid Leukemia

The clonal malignancies of acute myeloid leukemia and the myelodysplastic syndromes are associated with numerous chromosomal and oncogenic abnormalities. Activation of oncogenes has been demonstrated, although there is little evidence that this alone causes malignant transformation of diploid cells as a consequence. Patterns of abnormalities can be seen as the patient progresses from myelodysplastic syndrome to acute myeloid leukemia, but no unique or invariant findings have been described. Chromosomal changes, with the exception of some translocations, are neither disease nor lineage specific. At this time the data provide good support for the multistep view of carcinogenesis, and there is indirect or circumstantial evidence for the presence of tumor suppressor genes on 5q and 7q. The continued study of these clonal hematological disorders will provide considerable insight into mechanisms of tumorigenesis and possibly may lead to new modes of therapy, for example, through altering the microenvironment, interfering with deranged signal transmission, or introducing antioncogenes.

Multiply relapsing hairy cell leukemia responsive to repeated courses of rituximab: A case report

Abstract While cladribine is a highly effective therapy for patients with symptomatic hairy cell leukemia (HCL), up to 37% of patients ultimately relapse and incompletely responding patients relapse more frequently. Rituximab is a monoclonal antibody against CD20 that has been shown to be effective in patients with relapsed HCL. We present an unusual case of successful multiple re-treatments with rituximab in a patient with heavily pre-treated HCL and briefly review the relevant literature.

A lineage-specific t(1;14)(q21;q32) as an early event in development of B-cell clonal expansion

We report a patient in whom a cell line of 47,XY,+X,t(1;14)(q21;q32) constitution was found in a lymph node excised from the neck. Histologic examination and immunophenotyping both in situ and by flow cytometry failed to confirm a diagnosis of B-cell lymphoma, but Southern analysis indicated the presence of B-cell clonal expansion. These observations support the concept that primary chromosomal abnormalities occur in clonal expansions in the very earliest stages of tumorigenesis.