Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.
Farrell K & Jarrett R F (2011) Histopathology 58, 15–25 The molecular pathogenesis of Hodgkin lymphoma
Hodgkin lymphoma (HL) is an unusual malignancy in that the tumour cells, the Hodgkin and Reed–Sternberg (HRS) cells, are a minor component of the tumour mass, the bulk of which is a mixed cellular infiltrate. There is compelling evidence that HRS cells are clonal B cells that have lost their B cell phenotype. Mature B cells lacking B cell receptors would normally die by apoptosis, and therefore HRS cells must have developed mechanisms to facilitate survival. The escape from apoptosis and transcriptional reprogramming of HRS cells are interlinked and appear central to disease pathogenesis. Epstein–Barr virus (EBV) is present in the HRS cells of a proportion of cases and expresses genes with a plausible oncogenic function. It is likely that EBV plays a role in reprogramming and survival through dysregulation of several signalling networks and transcription factors, including nuclear factor (NF)‐κB. Activation of NF‐κB is a feature of all HRS cells and gene mutations affecting this pathway appear common in EBV‐negative HL. The HRS cell furthers its own survival by attracting a supportive microenvironment of immune and stromal cells, and suppressing local immune responsiveness. Although many questions remain unanswered, the last two decades have witnessed a considerable increase in our knowledge of this complex disease.
Clinically and biologically, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has much more in common with germinal-centre derived B-cell NHL than classical HL. Management of NLPHL remains controversial. In a 14-year multi-centre series, 69 cases were analysed; median follow-up was 53 months (range 11-165.) B symptoms were present in only 4.3% of patients. 81.1% of patients had stage I/II disease. Treatment was with radiotherapy (53.6 %), chemotherapy (21.7%), combined modality (17.4%) and observation (7.2%.) 10.1% of patients relapsed and 2.9% of patients developed high-grade transformation to DLBCL. All relapses and transformations were salvageable. No patient died of their disease. The 5 yr relapse-free survival was 96.7%, transformation-free survival 98.4% and overall survival 100%. We conclude that NLPHL behaves as a distinct clinical entity, often presenting at early stage without risk factors. It has an excellent outcome. It may be possible to reduce intensity of therapy in NLPHL without affecting OS.
Thrombosis is a well-recognized complication of asparaginase therapy for acute lymphoblastic leukemia (ALL), associated with the depletion of antithrombin (AT). Following a high incidence of thrombotic episodes during induction therapy for ALL in our tertiary referral center, we prospectively instituted a protocol of AT replacement. Forty-five consecutive adolescents and adults with ALL treated with asparaginase-containing phase I induction protocols were included in this observational study. Fifteen received standard therapy with no replacement; the subsequent 30 were managed with the protocol described. One or more low AT levels (<70 iu/dl) were recorded in 76% of patients in the cohort managed using the protocol, resulting them in receiving an AT replacement. There was a significant reduction in the incidence of thrombosis with this strategy (0/30 vs. 5/15, p < 0.001). We suggest that such a strategy should be studied in a prospective randomized sub-study within the context of a national ALL trial.
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