Paul Kettle

Bortezomib is effective in primary plasma cell leukemia

The ubiquitin proteasome pathway plays a critical role in regulating a number of cellular processes crucial to tumorigenesis and has recently emerged as a new molecular target for cancer therapy [1]. Sensitivity to proteasome inhibitors has been demonstrated in a number of malignancies, particularly multiple myeloma. The first proteasome inhibitor to enter clinical trials, bortezomib (Velcade) has demonstrated marked anti-myeloma activity and has been approved for the treatment of relapsed and refractory myeloma. Plasma cell leukemia (PCL) has been defined as circulating peripheral blood plasma cells exceeding 2610/l or 20% of peripheral blood cells [2]. If observed at the time of diagnosis, it is known as primary PCL and has a poor outcome from both conventional therapy and autologous or allogeneic transplantation [3,4].

Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression

Abstract:  Objective: Serum thymidine kinase (TK) levels have been shown to be correlated with survival in many malignancies, including chronic lymphocytic leukaemia (CLL). This study was designed to investigate associations between TK levels and other prognostic markers, in newly and previously diagnosed Binet stage A patients. Furthermore, the use of serum TK measurement to identify subcategories of disease within those defined by IgVH mutational status, gene usage and chromosomal aberrations was investigated. Methods: Ninety‐one CLL patients were enrolled. Serum TK levels were measured using a radioenzyme assay. IgVH mutational status and VH gene usage were determined using BIOMED‐2 primers and protocol. Recurring chromosomal abnormalities were detected by interphase fluorescent in situ hybridisation (FISH). Flow cytometry and reverse transcriptase polymerase chain reaction (RT‐PCR) determined CD38 and Zap‐70 expression, respectively. Results: Significantly higher serum TK levels were found in IgVH unmutated, compared with IgVH mutated, patients (P < 0.001). Elevated TK levels were also found in patients with CD38 and Zap‐70 positivity (P = 0.004, P < 0.001, respectively), short lymphocyte doubling time (LDT) (P = 0.044) and poor or intermediate prognosis chromosomal aberrations (P < 0.001). Conclusion: A TK level of >8.5 U/L best identified patients with progressive disease. Elevated TK levels could identify patients categorised, at diagnosis, into good prognosis subgroups by the various biological markers (mutated IgVH, good prognosis chromosomal aberrations, Zap‐70− and CD38−) who subsequently showed disease progression. Additionally, patients with VH3‐21 gene usage showed high TK levels, irrespective of mutational status, and serum TK measurement retained predictive power as disease progressed in all subcategories studied.

ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 × 10−2). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.

Clarithromycin with low dose dexamethasone and thalidomide is effective therapy in relapsed/refractory myeloma.

A combination of clarithromycin, low dose of thalidomide and low dose dexamethasone was used in a phase II study to treat patients with relapsed and refractory myeloma. Thirty patients received clarithromycin 250 mg twice daily and thalidomide 50 mg at night on an ongoing basis with 4‐d pulses of 10 mg dexamethasone given monthly. Eight patients had permitted escalation of thalidomide dosage up to 200 mg daily. The combination was well tolerated and could be given to elderly, infirm and severely cytopenic patients. Response rates were high, with 89% achieving at least 50% reduction in paraprotein and a 96% overall response rate. Although clarithromycin has only minimal anti‐myeloma properties when used as a single agent, its combination with thalidomide and dexamethasone appears very effective, allowing these to be used in lower and more tolerable doses with good clinical effects.

Multidrug resistance gene expression and ABCB1 SNPs in plasma cell myeloma

Multi-drug resistance (MDR) leads to impaired treatment efficacy in all forms of malignancy. The main forms of MDR are thought to be mediated by the substrate transporting actions of certain adenosine triphosphate binding cassette (ABC) transport proteins. The genes ABCB1, ABCB4, ABCC1, ABCG2 and LRP1 have been identified as the most prominent contributors to clinically significant MDR. To date, no study has investigated the expression of these genes in plasma cell myeloma (PCM), or attempted to relate their expression to the incidence of relapse and/or stage at presentation. Here, we show that ABCB4 may be a prominent mediator of tumour cell MDR within PCM. Additionally, there are three SNPs (rs1045642, rs2032582 and rs1128503) within the most widely studied of these genes, ABCB1, which have been suggested to have a potential impact on OS in PCM and which may form a haplotype in ABCB1. rs1045642 in ABCB1 appears to be the only SNP affecting OS within the PCM patients studied, with minimal linkage disequilibrium demonstrated between it and rs2032582 and rs1128503.

Central line-related bacteremia due to Roseomonas mucosa in a patient with diffuse large B-cell non-Hodgkin's lymphoma.

A 42-year-old male patient with a history of diffuse large B-cell non-Hodgkins lymphoma (DLBCL) developed a central line-related bacteremia due to the presence of a Gram-negative bacillus, which was difficult to identify conventionally. Sequencing of a partial region of the 16S rRNA gene identified the organism as Roseomonas mucosa with a homology score of 100% with 1003 bases called. Due to difficulties with the phenotypic identification of this genus, coupled with its emergence in line-related bacteremia in hematology patients with malignancy, Roseomonas spp. should be considered in cases of line-related infection in such patients with atypical Gram-negative organisms. Although several cases have been reported in the literature of line-related sepsis due to Roseomonas gilardii, only a few cases have been reported of Roseomonas mucosa infection in patients with hematological malignancy. This report highlights the benefits of the integration of a sequence-based typing approach in the identification of difficult-to-identify bacterial isolates employing partial regions of the 16S rRNA gene. Continued routine adoption of such techniques by clinical diagnostic laboratories may prove beneficial for the correct identification of blood-borne infections, as well as for the correct epidemiological characterization of unusual causal agents of bacteremia in immunocompromised individuals.

Tetrasomy 13 as the sole cytogenetic abnormality in acute myeloid leukemia M1 without maturation

We report a case of acute myeloid leukemia (AML) M1 showing a 48,XY,+13,+13 karyotype. Treatment was according to the Medical Research Council AML14 trial protocol with two courses of DAT chemotherapy. Postchemotherapy bone marrow examination failed to show complete remission or cytogenetic normalization. Despite having resistant disease, the patient initially remained clinically well although requiring regular blood transfusions for anemia. However his leukocyte count gradually increased and he became symptomatic. He was treated subsequently with FLAG but died approximately 2 weeks later, 6 months after first presenting. Tetrasomy 13 as the sole cytogenetic abnormality has not been reported previously in M1 AML and has only been reported in three other AML cases, all with an immature phenotype and poor outcome.

Re‐transplantation after bortezomib‐based therapy

Whilst the use of high dose alkylating agents and autologous stem cell transplantation (ASCT) has a fundamental role in consolidating initial anti-tumour induction therapy, its role in salvage therapy consolidation remains to be determined. Bortezomib has been shown to be an effective agent at first and subsequent relapse, with responses equivalent or better than the response to previously used conventional therapies in first-line therapy (Richardson et al, 2005; Laubach et al, 2009). Combining bortezomib re-induction with a second ASCT after maximal anti-tumour response is, therefore, an attractive concept. Accordingly, we undertook a retrospective review of patients proceeding to a second ASCT after bortezomib-based re-induction therapy. Patients undergoing a second ASCT after progression from an initial ASCT and subsequent bortezomib re-induction therapy in 12 centres were identified (n = 40). Detailed information on the patients was obtained through anonymized clinical data retrieval forms, capturing critical patient and disease-specific factors including response to initial induction therapy, response to first ASCT, time to progression, subsequent therapies, bortezomib-based re-induction therapy and response to second ASCT (including the type of transplant and stem cell source). Response to therapy was categorized according to the International Myeloma Working Group criteria (Durie et al, 2006). Kaplan Meier plots were made using the Statistical Package for the Social Sciences (spss) IBM, Chicago, Illinois, USA. There were insufficient cytogenetic data for analysis. A total of 40 patients were identified in this retrospective study. Two patients had planned reduced intensity allogeneic (RIC-Allo) transplants after their second autologous transplant and weren excluded from further analysis. Patient characteristics including age, sex, type of myeloma, therapy prior to their first and second transplants are shown in Table Ia. One patient who relapsed 10 months after their bortezomib therapy was transplanted in relapse. All other patients were transplanted prior to disease progression. Twenty-six patients were treated with a combination of bortezomib and dexamethasone, eight patients had PAD chemotherapy (bortezomib, adriamycin and dexamethasone (Oakervee et al, 2005). Two patients had bortezomib monotherapy, one patient had bortezomib plus intravenous melphalan and one patient had bortezomib plus cyclophosphamide, dexamethasone and idarubicin. The median number of cycles of bortezomib therapy was 4 (range 2–12). Patients receiving PAD chemotherapy also had a median of four cycles

Neither P-gp SNP variants, P-gp expression nor functional P-gp activity predicts MDR in a preliminary study of plasma cell myeloma†

Multidrug resistance (MDR) mediated by P‐glycoprotein (P‐gp) can compromise the successful treatment of many malignancies including plasma cell myeloma (PCM). However, methods do not yet exist that can accurately determine P‐gp activity in PCM patient samples.

Massive Tracheal-Esophageal Fistula Secondary to Lymphoma Treated With an Esophageal Stent

T b A man, previously fit and healthy, presented in late 2008 with weight loss and mediastinal lymphadenopthy. Biopsy from the lymph nodes confirmed diffuse large -cell lymphoma, and he received chemotherapy in the form of ituximab, cyclophosphamide, doxorubicin-(hydroxy-daunoruicin), vincristine (Oncovin; Genus Pharmaceuticals, Berkshire, ngland), and prednisolone and was in remission. He presented 4 months later with recurrent lower respiratory chest infecions and dysphagia for solids and liquids. An upper gastroinestinal endoscopy revealed a massive ulcerated tracheal-esophgeal fistula 26 to 31 cm from the incisors, with an unusual ouble-lumen appearance. Biopsies revealed a diffuse large Bell lymphoma (BCL 6 –positive and MUM 1–positive, confirmng large B-cell lymphoma on CD-20 staining) (Figures A and ). He was re-treated with rituximab, cyclophosphamide, doxoubicin-(hydroxy-daunorubicin), vincristine (Oncovin), and rednisolone, but 48 hours posttreatment he developed bilatral bronchopneumonia. A Cook Evolution 15-cm 24F, partially overed stent (Cook Medical, Bloomington, IN) was inserted ith the proximal end of the stent at 23 cm (from the incisors). he endoscopic view of the tracheal-esophageal fistula (TOF) efore and after stent placement is shown in Figures C and D (arrow points to site of fistula). Five hemoclips (Resolution; Boston Scientific, Natick, MA) were applied proximally to secure the proximal portion of the stent. A chest computed tomography scan after stent insertion (Figure E) clearly shows the esophageal stent in situ with the adjacent trachea and fistula. The development of malignant TOF carries a very poor prognosis. However, TOF rarely develop secondary to lymphoma,1 and when they do, it usually is after treatment with chemotherapy or radiotherapy. Management of malignant TOF usually is palliative and can include stent insertion. Yamamoto et al2 assessed out-