Heather A. Leitch

Clinical progression and outcome of patients with monoclonal B-cell lymphocytosis.

Monoclonal B-cell lymphocytosis (MBL) is a clonal lymphoproliferation with the immunophenotype of chronic lymphocytic leukemia (CLL) but a B-lymphocyte count of less than 5 × 109/l and no lymphadenopathy, organomegaly, cytopenias or symptoms. We performed a retrospective analysis of patients with MBL (n = 46), Rai stage 0 CLL (n = 112) and Rai stage ≥1 CLL (n = 54). Median follow-up and range was 30 (0.1 – 120) months for MBL, 60 (0.1 – 309) months for stage 0 CLL and 54 (0.1 – 309) months for stage ≥1 CLL. None of the MBL patients required treatment compared with 24 of 112 (21%) stage 0 CLL and 28 of 54 (52%) stage ≥1 CLL patients (p < 0.0003). No MBL underwent aggressive transformation compared with 1 of 112 (0.8%) stage 0 CLL and 6 of 54 (11%) stage ≥1 CLL patients (p < 0.0003). Progression-free survival (PFS) appeared improved in MBL compared to stage 0 CLL, although this did not reach statistical significant (p = 0.07) due to the relatively short follow-up in the MBL group; two year PFS was 97.2% for MBL, 93.1% for stage 0 CLL, and 68% for stage ≥1 CLL patients (p < 0.0001 for stage ≥1 CLL compared with MBL and stage 0 CLL). This is the first study of outcome in MBL which demonstrates that patients have an improved disease course compared to stage 0 CLL patients. Over a median 2.5 years of follow-up, no MBL patients required treatment or died of CLL-related causes.

Controversies surrounding iron chelation therapy for MDS.

The myelodysplastic syndromes (MDS) are characterized by cytopenias and acute myeloid leukemia risk. Most MDS patients eventually require transfusion of red blood cells for anemia, placing them at risk of iron overload (IOL). In beta-thalassemia major, transfusional IOL leads to organ dysfunction and death, however, with iron chelation therapy survival improved to near normal and organ function was improved. In lower risk MDS, several non-randomized studies suggest an adverse effect of IOL on survival, and that lowering iron minimizes this impact and may improve organ function. While guidelines for MDS generally recommend chelation in selected lower risk patients, data are emerging suggesting IOL may impact adversely on the outcome of higher risk MDS and stem cell transplantation (SCT) and that lowering iron may be beneficial in these patients. Trials to determine whether these effects are truly from lowering iron are currently enrolling. Chelation is costly and potentially toxic, and in MDS should be initiated after weighing potential risks and benefits for each patient until more definitive data are available. In this paper, data on the impact of IOL in MDS and SCT, possible mechanisms of iron toxicity such as oxidative stress, and the impact of lowering iron on organ function and survival are reviewed.

Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome

Iron chelation therapy is often used to treat iron overload in patients requiring transfusion of red blood cells (RBC). A 76-year-old man with MDS type refractory cytopenia with multilineage dysplasia, intermediate-1 IPSS risk, was referred when he became transfusion dependent. He declined infusional chelation but subsequently accepted oral therapy. Following the initiation of chelation, RBC transfusion requirement ceased and he remained transfusion independent over 40 months later. Over the same time course, ferritin levels decreased but did not normalize. There have been eighteen other MDS patients reported showing improvement in hemoglobin level with iron chelation; nine became transfusion independent, nine had decreased transfusion requirements, and some showed improved trilineage myelopoiesis. The clinical features of these patients are summarized and possible mechanisms for such an effect of iron chelation on cytopenias are discussed.

Improved survival in red blood cell transfusion dependent patients with primary myelofibrosis (PMF) receiving iron chelation therapy

Many patients with primary myelofibrosis (PMF) become red blood cell (RBC) transfusion dependent (TD), risking iron overload (IOL). Iron chelation therapy (ICT) may decrease the risk of haemosiderosis associated organ dysfunction, though its benefit in PMF is undefined. To assess the effect of TD and ICT on survival in PMF, we retrospectively reviewed 41 patients. Clinical data were collected from the database and by chart review. The median age at PMF diagnosis was 64 (range 43–86) years. Median white blood cell (WBC) count at diagnosis was 7.6 (range 1.2–70.9)u2009×u2009109/L; haemoglobin 104 (62–145)u2009G/L; platelets 300 (38–2088)u2009×u2009109/L. Lille, Strasser, Mayo and International Prognostic System (IPS) scores were: low risk, nu2009=u200915, 8, 11, 3; intermediate, nu2009=u200915, 19, 9, 16; high, nu2009=u20095, 11, 5, 7; respectively. Primary PMF treatment was: supportive care, nu2009=u200923; hydroxyurea, nu2009=u200910; immunomodulatory, nu2009=u20094; splenectomy, nu2009=u20092. Sixteen patients were RBC transfusion independent (TI) and 25 TD; of these 10 received ICT for a median of 18.3 (0.1–117) months. Pre‐ICT ferritin levels were a median of 2318 (range 263–8400) and at follow up 1571 (1005–3211u2009µg/L (pu2009=u20090.01). In an analysis of TD patients, factors significant for overall survival (OS) were: WBC count at diagnosis (pu2009=u20090.002); monocyte count (pu2009=u20090.0001); Mayo score (pu2009=u20090.05); IPS (pu2009=u20090.02); number of RBC units (NRBCU) transfused (pu2009=u20090.02) and ICT (pu2009=u20090.003). In a multivariate analysis, significant factors were: NRBCU (pu2009=u20090.001) and ICT (pu2009=u20090.0001). Five year OS for TI, TD‐ICT and TD‐NO ICT were: 100, 89 and 34%, respectively (pu2009=u20090.003). The hazard ratio (HR) for receiving >20 RBCU was 7.6 (95% Confidence Intervals [CI] 1.2–49.3) and for ICT was 0.15 (0.03–0.77). In conclusion, 61% of PMF patients developed RBC‐TD which portended inferior OS; however patients receiving ICT had comparatively improved OS, suggesting a clinical benefit. Prospective studies of IOL and the impact of ICT in PMF are warranted. Copyright

Treatment of relapsed and refractory myeloma.

Multiple myeloma is a malignancy of plasma cells that remains incurable and almost all patients will eventually require some form of salvage therapy. Increasing insight into the biology of myeloma and the availability of new therapeutic options has resulted in rapid change in its management. Clinical trials have investigated numerous agents and regimens for the treatment of patients with relapsed/refractory myeloma, presenting a host of treatment options. Important questions in determining optimal therapy for patients with relapsed/refractory myeloma include the influence of prior therapy, optimal sequencing of regimens, sequential versus combination use of agents, and the role of cytogenetic and other prognostic factors. This article reviews the literature for the treatment of relapsed/refractory myeloma and considers the ability of the evidence to answer these questions, both for established regimens and newer regimens incorporating thalidomide, bortezomib and lenalidomide.

Rapid determination of Epstein-Barr virus latent or lytic infection in single human cells using in situ hybridization.

Epstein–Barr (EBV) virus is associated with malignancies such as lymphoma and carcinoma. Infection of cells with EBV may result in either lytic infection with production of viral particles, characterized by the presence of linear DNA forms, or latent infection, characterized by either episomal or integrated DNA forms. To examine whether the different lytic and latent EBV DNA forms can reliably be distinguished in single human cells, in situ hybridization was performed in EBV-positive cell lines. Immunocytochemistry and Southern blot analysis were performed supplementary to in situ hybridization. In latent infection, three in situ hybridization patterns were observed: large-disperse (episomal), small-punctate (integrated) and combined (both), signal types 1, 2 and 3 respectively. These were associated with expression of latent membrane protein 1, but not with Z fragment of Epstein–Barr replication activator or viral capsid antigen. In lytic infection, three additional in situ hybridization patterns were observed: nuclear membrane associated, bubble (filling up the nucleus) and spillover (covering the lysed cells) signals types 4, 5 and 6 respectively. Signal types 4 and 5 were associated with expression of latent membrane protein 1 and Z fragment of Epstein–Barr replication activator but not viral capsid antigen, whereas type 6 was associated with expression of viral capsid antigen only. Southern blot analysis confirmed these results; however, low copy numbers of integrated virus were often missed by Southern blot, confirming that in situ hybridization is more sensitive in determining the presence of all types of EBV DNA. In situ hybridization may prove useful in rapidly screening large series of tissue microarrays and other clinical specimens for the presence of lytic or latent EBV.

Plasmablastic lymphoma in the ano-rectal junction presenting in an immunocompetent man: a case report

IntroductionPlasmablastic lymphoma is an aggressive non-Hodgkin lymphoma classically occurring in individuals infected with HIV. Plasmablastic lymphoma has a predilection for the oral cavity and jaw. However, recent case reports have shown lymphoma in the stomach, lung, nasal cavity, cervical lymph nodes and jejunum in HIV-negative individuals. We report what is, to the best of our knowledge, the first case of plasmablastic lymphoma occurring in the ano-rectal junction of an HIV-negative man.Case PresentationA previously healthy 59-year-old Caucasian man presented with painless rectal bleeding. Colonoscopy revealed a lesion in the ano-rectal junction, with pathological examination demonstrating atypical lymphoid cells consisting primarily of plasmablasts with rounded nuclei, coarse chromatin, small nucleoli and multiple mitotic figures. Immunohistochemical analysis showed the atypical cells were negative for CD45, CD20, CD79a and immunoglobulin light chains, but were strongly positive for CD138 and EBV-encoded RNA. The results were consistent with a diagnosis of plasmablastic lymphoma. Aggressive systemic chemotherapy and involved field radiation therapy resulted in complete clinical and pathological remission.ConclusionIncreasing awareness of plasmablastic lymphoma in HIV-negative individuals and in this location is warranted.

Improved Survival in HIV-Associated Diffuse Large B-Cell Lymphoma with the Addition of Rituximab to Chemotherapy in Patients Receiving Highly Active Antiretroviral Therapy

Abstract Purpose: Recent trials suggest serious toxicity in HIV-associated non-Hodgkin’s lymphoma (NHL) with rituximab (R) and chemotherapy (CT), offsetting the benefit of rituximab. Method: We retrospectively reviewed experience with CHOP-R vs. CT in 40 patients with HIV-associated diffuse large B-cell lymphoma (DLBCL) diagnosed between December 1992 and February 2006, all of whom were treated with curative intent. Results: In a univariate analysis, International Prognostic Index (IPI) score, prior AIDS, HAART, and rituximab were significant for overall survival (OS). In a multivariate analysis, IPI 0-1 (p < .02), no prior AIDS (p < .0002), and receiving CHOP-R (p < .01) were significant for improved OS, and HAART use (p < .09) retained a trend for improved OS. The hazard ratio (HR) for patients with high IPI receiving CHOP-R was 0.3 (95% CI 0.1-0.8). Patients without prior AIDS receiving CHOP-R had an HR of 0.5 (95% CI 0.1-1.7). The OS at 30 months in patients not receiving HAART was 0%. With HAART, OS was 33% for CT and 86% for CHOP-R; HR for CHOP-R was 0.4 (95% CI 0.1-1.2). Toxic deaths were 3 (33%) for CHOP-R and 6 (25%) for CT (p = ns); all toxic deaths with CHOP-R were in patients not receiving HAART. Rituximab-treated patients had a lower death rate from lymphoma (CHOP-R, 2 [16%] vs. CT, 15 [63%]; p < .04), and overall mortality (CHOP-R, 5 [42%] vs. CT, 21 [88%]; p < .01). Conclusion: These retrospective data suggest that fatal toxicity of rituximab in HIV-NHL is not increased provided HAART is used, that the addition of rituximab to CT improved outcome, and that further prospective trials investigating this issue are warranted.

Excessive neurotoxicity with ABVD when combined with protease inhibitor-based antiretroviral therapy in the treatment of AIDS-related Hodgkin lymphoma.

Hodgkin lymphoma (HL) is the second most common non-AIDS-defining malignancy among persons infected with HIV, and its incidence might be increasing in the current era of combination antiretroviral therapy (cART). With the immune reconstitution afforded by cART, most patients are now able to tolerate the standard-dose chemotherapies administered to immunocompetent individuals with HL, such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine). Antiretroviral therapy is commonly prescribed concomitantly with chemotherapy in the treatment of AIDS-related malignancies. However, little is known about the pharmacokinetic consequences of combined therapy. In particular, the potential for excessive vinca alkaloid-associated toxicity is significant, given the metabolism of drugs such as vinblastine by the 3A4 isoenzyme of the cytochrome P450 system and the inhibition of this isoenzyme by protease inhibitors. We report 3 patients who experienced severe vinblastine-associated neurotoxicity during concomitant treatment with ritonavirboosted antiretrovirals. The implications for the treatment of patients with HL in the current era of cART are discussed.

Array comparative genomic hybridization of peripheral blood granulocytes of patients with myelodysplastic syndrome detects karyotypic abnormalities.

The diagnosis of myelodysplastic syndromes (MDSs) relies largely on morphologic and karyotypic abnormalities, present in about 50% of patients with MDS. Array-based genomic platforms have identified copy number alterations in 50% to 70% of bone marrow samples of patients with MDS with a normal karyotype, suggesting a diagnostic role for these platforms. We investigated whether blood granulocytes harbor the same copy number alterations as the marrow of affected patients. Of 11 patients, 4 had cytogenetic abnormalities shown by conventional karyotyping involving chromosomes 5, 8, 11, 20, and X, and these changes were seen in the granulocytes of all 4 patients by using array comparative genomic hybridization (aCGH). Cryptic alterations were identified at a significantly higher level in marrow CD34+ cells compared with granulocytes (P < .0001). These data suggest that aCGH analysis of circulating granulocytes may be useful in detecting gross karyotypic alterations in patients with MDS when marrow examination has failed or not been done.