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PROPOSALS: Worldwide Phase III aHSCT study, challenges

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  • PROPOSALS: Worldwide Phase III aHSCT study, challenges

    Autologous hamatopoietic stem cell transplantation in multiple sclerosis – Current state and outline of a phase III trial

    R. Martin, S. Schippling, D. Farge-Bancel, M.P. Sormani, P.A. Muraro, G. Mancardi, R. Saccardi (Zurich, CH; Hamburg, DE; Paris, FR; Genoa, IT; London, UK; Florence, IT)

    Autologous hematopoietic stem cell transplantation (aHSCT) has been explored during the last two decades as a treatment option for rapidly worsening relapsing-remitting- (RR-MS) and secondary progressive multiple sclerosis (SP-MS). When compared to already approved and upcoming immunomodulatory therapies aHSCT appears highly efficient in RR-MS. The characteristics of MS patients, who will benefit most from aHSCT, its risks, the preferred conditioning regimen and important mechanistic aspects have been established. However, a phase III clinical trial that establishes comparable or superior efficacy over best approved/available therapy is still lacking.

    To initiate such a phase III trial, investigators from Europe and North America have been discussing its cornerstones with respect to: patient enrolment criteria (highly active RR-MS under 45 years of age and disease duration of 5 years from initiation of DMD or less, failure of one or two lines of treatment), mobilization with Cyc 4 g/sqm + G-CSF, unmanipulated graft, conditioning regimen (BEAM-ATG), primary and secondary outcomes (time to failure and proportion of patients meeting failure criteria), sample size estimates, treatment comparators (best approved and available treatments), biosamples acquisition and accompanying mechanistic studies. The existing European experience from more than 400 aHSCT in MS and from several trials that have been performed during the last decade serve as a basis for the planned phase III trial and will be presented together with the design of the trial.


    Autologous haematopoetic stem cell therapy (aHSCT) in highly active relapsing-remitting multiple sclerosis. Endpoint and sample size considerations for a phase III trial comparing aHSCT versus best available treatment

    J.-P. Stellmann, E. Vettorazzi, M.P. Sormani, R. Martin, S. Schippling (Hamburg, DE; Genoa, IT; Zurich, CH)

    Objective: Autologous haematopetic stem cell therapy (aHSCT) has been investigated since the mid 1990s as ultimate treatment for patients with severe forms of relapsing and progressive Multiple Sclerosis (MS). Young (< 40 years) and highly active relapsing remitting MS (RRMS) patients unresponsive to standard treatment seem to have the most favourable benefit to risk ratio. Since a first randomized controlled phase IIb/III trial, comparing aHSCT to immunosuppression with mitoxantrone had to be terminated prematurely due to recruitment problems, a new phase III with “best available therapy“ as a comparative treatment is currently being planned. The design of such a trial faces four main challenges: (1) Difficulties in properly sizing the trial due to the lack of data on the efficacy of escalation treatment regimens in a cohort eligible for aHSCT, (2) the sample size restrictions in an investigator initiated trial, (3) conventional clinical outcomes do not appear suitable in case of a treatment with relatively high risks such as aHSCT and (4) patients should have the chance of receiving aHSCT in case of ongoing disease activity in the control group.

    Method: We performed a systematic literature research to estimate the range of disease activity that might theoretically be expected in an active but heterogeneous control group treated with available/approved compounds for escalation therapy. In addition, we estimated the efficacy of aHSCT in a cohort of highly active RRMS patients based on the available data and performed sample size and power calculations. Finally we analysed the feasibility of a newly identified endpoint “time to failure”.

    Results: Clinical data derived from trials with escalation regimens are scarce and limited in most cases to a maximum prospective follow up of 1 year. One-year follow up data for aHSCT were available for 38 patients. Event rates of a combined endpoint ”time to failure” differ according to the inclusion of clinical and MRI outcomes. In case of sensible definition “Time to failure” outcomes have the following advantages: 1. Patients in the control arm can be transplanted after reaching the endpoint 2. The validity of the trial is preserved 3. Standard survival techniques are available for the analysis.

    Conclusion: A precise estimation of efficacy of best available/approved treatment is difficult due to limited available data. A “time to failure” outcome seems promising, but a careful definition of “failure” is warranted.
    Dave Bexfield