ALBERT

Description: Actimid™ (CC-4047[Celgene]) is a thalidomide derivative that induces apoptosis, disrupts myeloma-stromal cell adhesion, reduces cytokine secretion, is anti-angiogenic and stimulates anti-myeloma NK cell proliferation. In vivo T-cell and NK cell stimulatory cytokines are enhanced. We have reported a phase I study of daily Actimid with a MTD of 2 mg daily and have carried out a further phase I study using alternate day dosing. Methods: Patients (pts) with relapsed/refractory myeloma who had received at least one prior line of therapy were eligible.This was a dose escalation study designed to define the maximum tolerated alternate day (a/d) dose (1mg, 2mg, 5mg, 10mg). Pts discontinued therapy after 4 weeks if grade 3/4 non-haematological toxicity developed, grade 4 haematological toxicity had not resolved or there was progressive disease. Pts who relapsed following response were eligible to receive dexamethasone (20 mg od for 4 days alternate weeks). Results: 20 pts were treated with median age 58 years (range 34 – 75) and a median of 4 (range 1 – 7) prior lines of chemotherapy (including HDT(65%) and/or thalidomide (85%)). 3/20 pts developed grade 4 neutropaenia within 4 weeks of treatment. All were receiving 10mg a/d. This resolved in all pts within 5 weeks without recourse to growth factors and therapy was restarted at a lower dose. There were no dose limiting grade 3/4 non-haematological toxicities. The maximum tolerated dose was identified as 5 mg a/d. One patient was withdrawn from treatment following the development of relapsing /remitting fevers of unknown origin. He had previously had similar symptoms following treatment with bortezomib. One patient was withdrawn following the development of transverse myelitis and one patient withdrew consent within two weeks of commencing treatment. No pts withdrew due to recurrent neutropaenia. The median duration of exposure to single agent actimid is 5 months (1 – 14) and the overall median duration of therapy is 10 months (1 – 21). All 20 pts are evaluable for response. With a median follow-up of 12 months 12(60%) achieved at least a 25% paraprotein reduction. 19 achieved a best response of stable disease(SD) or better. 1/20 pts progressed within 4 weeks of starting therapy. 2/20 pts attained a complete response, 8/20 pts achieved at least 75% paraprotein reduction (VGPR+CR), 10/20 pts achieved a 〉 50% paraprotein reduction and a further 2/20 pts achieved a 25 – 50% paraprotein reduction. 6/20 pts had dexamethasone added. Two pts achieved a best response after the addition of dexamethasone (both had relapsed following PR and SD respectively and both achieved VGPR). Additionally 1/6 pts achieved MR and 3/6 pts achieved SD. In the group overall the median time to achieve maximum response was 4 months (1 – 17). 8/20 progressed on treatment with a median time to progression of 10 months (1 – 21). 5/20 pts have subsequently died due to progressive disease. There have been no treatment related deaths. Conclusions: Actimid is a well tolerated oral agent with activity in myeloma. The maximum tolerated dose was 5mg a/d. No grade 3/4 non-haematological toxicity was observed and the neutropaenia resolved rapidly. Responses were excellent with 50% patients achieving at least a 50% reduction in paraprotein. Dexamethasone improved response in 2/6 patients. This study indicates that Actimid has good anti-myeloma activity either as a single agent or in combination with dexamethasone and further clinical studies are justified.

Description: In the UK there is a paucity of epidemiological data on the chronic myeloproliferative disorders (CMPDs) and myelodysplastic syndromes (MDS). In contrast data on acute myeloid leukaemia is consistently collected, but morphological subtypes are rarely defined. We present the incidence and outcome of myeloid malignancies in an unselected population from the South Thames area, which comprises 5.4 million adult inhabitants. A consensus registration form was designed in which haemato-oncologists from 27 Acute National Health Service Trusts prospectively identified and confirmed cases of myeloid malignancies between 1999 and 2000. The French, American and British classification system was used to define acute leukaemia and MDS (Eikelboom et al., 1996, Bennett et al., 1976, 1991). PT was defined according to the MRC PT1 criteria and diagnostic criteria for PV and IMF as defined by Pearson et al., (1996). Twice a year contributing haematologists validated their cases to ensure complete ascertainment of cases. Additional myeloid malignancies diagnosed outside haematology were ascertained and validated by the Thames Cancer registry (TCR) data collection officers. Registration forms were forwarded to the TCR for processing. Deaths from myeloid malignancies were identified by the Office of National Statistics, which records all cases nationally. Statistical analyses: the direct method was used to calculate the age standardized incidence rate using the European standard population (ESP) as defined by Jensen et al., (1991). Kaplan-Meier survival curves were compared using log-rank tests. Between 1999 and 2000 a total of 2,112 myeloid malignancies were registered of which 24% of cases were AML, 37% MDS and 39% CMPDs. Morphological subtypes were unspecified in 46.3% cases of AML, 27% cases of MDS and 17% of CMPDs. The median age was 〉70 years for all subtypes of myeloid malignancies with the exception of idiopathic myelofibrosis (median age 69 years) and chronic myeloid leukaemia (median age 51 years). The European age standardised incidence rate for AML was 3.00/100,000, MDS 3.47/100,000, chronic myelomonocytic leukaemia (CMML) 0.46/100,000, IMF 0.37/100,000, polycythamia vera 1.08/100,000, PT 1.65/100,000 and for CML 1.09/100,000. There was a significant male predominance for AML, CMML and MDS. Three year estimated overall survival (OS) for AML was 15%, MDS 45% (survival advantage observed for females), CMML 29%, IMF 48%, PV 60% and CML 50%. Three year survival was significantly different in patients aged less than 65 years compared to those aged 65 years or greater for AML (37% vs. 2%), MDS (66% vs.40%) and CML (74% vs. 17%) p

Description: GCS-100 is a galectin-3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance. In the present study, the mechanisms of action of GCS-100 are elucidated in myeloma cell lines and primary tumor cells. GCS-100 induced inhibition of proliferation, accumulation of cells in sub-G1 and G1 phases, and apoptosis with activation of both caspase-8 and -9 pathways. Dose- and time-dependent decreases in MCL-1 and BCL-XL levels also occurred, accompanied by a rapid induction of NOXA protein, whereas BCL-2, BAX, BAK, BIM, BAD, BID, and PUMA remained unchanged. The cell-cycle inhibitor p21Cip1 was up-regulated by GCS-100, whereas the procycling proteins CYCLIN E2, CYCLIN D2, and CDK6 were all reduced. Reduction in signal transduction was associated with lower levels of activated IκBα, IκB kinase, and AKT as well as lack of IκBα and AKT activation after appropriate cytokine stimulation (insulin-like growth factor-1, tumor necrosis factor-α). Primary myeloma cells showed a direct reduction in proliferation and viability. These data demonstrate that the novel therapeutic molecule, GCS-100, is a potent modifier of myeloma cell biology targeting apoptosis, cell cycle, and intracellular signaling and has potential for myeloma therapy.