Drugs Xagena
Genzyme Europe BV has informed Healthcare Professional of six infection-related deaths, reported from a trial ( CALGB10101 ) in which previously untreated, symptomatic B-cell chronic lymphocytic leukemia patients were treated with Fludarabine and Rituximab followed by Alemtuzumab for remission consolidation.
MabCampath is approved for the treatment of patients with B-cell chronic lymphocytic leukaemia ( B-CLL ) for whom Fludarabine combination chemotherapy is not appropriate and should not be used as consolidation therapy following induction with Fludarabine + Rituximab outside of a clinical trial.
Fludarabine, Rituximab and MabCampath all have known immunosuppressive properties, and it is possible that the fatal infectious complications which occurred in this trial are the result of a prolonged period of immunosuppression resulting from the sequencing of these drugs without sufficient time for recovery, as well as other factors specific to this trial.
Further information on the safety concern
The five fatal infections were reported as: viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus ( CMV ) infection and Pneumocystis jiroveci pneumonia ( PCP ), all in patients who achieved a complete response ( CR ) after induction therapy. In addition, a case of fatal EBV associated lymphoproliferative disorder was reported in a patient who achieved a partial response ( PR ) after induction therapy.
Genzyme has subsequently been informed of an additional non-infection related fatality believed to be related to Transfusion Associated Graft Versus Host Disease ( TAGVHD ) in a patient who had received non-irradiated blood products.
The above fatalities were presented in an abstract submitted for the 2007 American Society of Hematology ( ASH ) Annual Meeting on the first 51 patients who received all three agents ( induction with Fludarabine + Rituximab and consolidation with Alemtuzumab ).
The induction regimen in this study consisted of Fludarabine 25 mg/m2 IV on days 1-5; Rituximab escalated from 50 mg/m2 on day 1 to 325 mg/m2 on day 3, to 375 mg/m2 on day 5 ( cycle 1 ) and then 375 mg/m2 IV on day 1 of cycles 2-6; every 28 days for up to 6 cycles. Approximately four months after the last dose of Fludarabine, patients with stable or responsive disease were to receive consolidation therapy with Alemtuzumab escalated to 30 mg SC on days 1, 2 and 3 of Week 1, and 30 mg three times weekly thereafter for 6 weeks.
Based on the toxicity in complete response patients, the clinical trial was amended to restrict consolidation therapy with MabCampath to patients who experienced a PR, with close monitoring for infectious and other toxicities.
The Authors conclude that MabCampath cannot be safely administered as consolidation therapy to patients who achieve a complete response following induction chemotherapy and that administration of MabCampath consolidation for patients in partial response following Fludarabine + Rituximab induction should not be pursued outside of a clinical trial due to concerns about serious infectious morbidity and mortality.
The use of MabCampath consolidation in chronic lymphocytic leukemia is an area of active investigation. Moreover, the design of the CALGB10101 study did not allow for a direct assessment of the relative contribution of any one of the agents in this regimen ( including Alemtuzumab ). Fludarabine, Rituximab, and Alentuzumab all have known immunosuppressive properties, and it is possible that the infectious complications which occurred in this trial are the result of a prolonged period of immunosuppression resulting from the sequencing ( i.e. the interval between induction and consolidation ) of these drugs without sufficient time for recovery, but the risk may also be influenced by the induction regimen and/or dose or schedule of the agents used.
The protocol described in the highlighted ASH abstract employs MabCampath for use as consolidation therapy, which is not approved in the current EU SPC/labelling for MabCampath. The benefit/risk profile of MabCampath is unchanged when it is used, as approved, for the treatment of patients with B-CLL for whom Fludarabine combination chemotherapy is not appropriate. MabCampath should not be used as consolidation therapy outside of a clinical trial.
Source: Medicines and Healthcare product Regulatory Agency MHRA, 2008
XagenaMedicine_2008
