Shoud CMV infection post ao SCT be treated by ce-based therapy? CMV Prof. Per Ljungman Department of Hematoogy Karoinska University Hospita Stockhom, Sweden
The fight! Antivira drugs Ce therapy
How can we manage CMV infections in HSCT recipients? Prevent a patient from becoming infected Prevent an infected patient from deveoping disease Treat an estabished vira disease
Timing of management options Treatment of estabished disease Vira repication Prophyaxis Pre-emptive therapy vira disease Diagnosis of vira infection Time Grafting Aain, ILTS 2008
Treat estabished vira disease A faiure of strategy! Associated with significant mortaity in the most immunosuppressed patients such as HSCT recipients
Prevention Measure Safe bood products Seect the right donor (HSCT) What can we prevent? Infection Infection, disease Eary diagnosis, monitoring/preemptive therapy Antivira propyaxis Vaccination Disease Infection, disease Infection, disease
Prevention Measure Safe bood products Seect the right donor (HSCT) What can we prevent? Infection Infection, disease Eary diagnosis, monitoring/preemptive therapy Antivira propyaxis Vaccination T-ce therapy Disease Infection, disease Infection, disease Infection, disease
Safe bood products Products from CMV seronegative donors Leukocyte depeted/fitered products Pathogen inactivated products
Donor infuence in CMV pos patients Negative donors: Higher transpant reated mortaity 39% CMV + donor p = 0.006 52% CMV donor More patients have repeated CMV reactivations More courses of antivira therapy required More CMV disease
What is the rationa for monitoring and preemptive treatment A sensitive diagnostic test shoud be avaiabe A positive resut is predictive for deveopment of disease Eary intervention can prevent disease An effective (and safe) antivira drug is avaiabe
Strategic study Design: Patients: Randomized study of diagnostic strategy 71 aogeneic SCT patients PCR Rapid cuture CMV disease 5% P=0.02 23% CMV assoc. death 0% P=0.02 14% Einsee et a 1995
CMV monitoring strategies M Boeckh and P Ljungman; Bood 2009
Antivira drugs with efficacy against CMV Low potency Acicovir Vaacicovir (Famcicovir) High potency Gancicovir Vagancicovir Foscarnet Cidofovir Undetermined potency Artesunate Lefunomide
With what drug sha we treat? 1.0 0.8 Foscarnet Gancicovir 0.6 0.4 0.2 0.0 0 20 40 60 80 100 120 140 160 180 Days after randomization Reusser et a
Randomized study of preemptive treatment of CMV DNAemia 101 SCT patients Induction treatment for 14 days iv-gancicovir 5 mg/kg x2/day po-vagancicovir 900 mg x2/day Maintenance treatment for 14 days gancicovir 6 mg/kg x1/day vagancicovir 900 mg x1/day Proportion p=0.257 po n = 50 n = 51 iv Duration of treatment (days) Voin et a EBMT 2008
Anti-CMV agents in deveopment Maribavir AIC 246 CMX 001 CMV vaccines gb TransVax
Maribavir - In vitro efficacy against : CMV and EBV - Two phase III prophyaxis studies (HSCT and iver tx - both were negative - Efficacy in refractory patients (Avery et a) - Low rate of significant side effects
Treatment of refractory patients 6 treated patients 6 CMV disease Median 4 prev. agents 4 proven resistant 4 ceared virus 5 survived 1 deveoped resist. Avery et a; TID 2010
AIC246 - Beongs to a new cass of compounds ( a 3,4-dihydro-quinazoine-4-y-acetic acid derivative) - A pure CMV antivira - CMV terminase inhibitor - A phase II prophyactic study is ongoing - Shown efficacy in refractory/intoerant patients - Shown imited toxicity so far
CMX 001 - Lipid conjugate of cidofovir - CMX001 is significanty more active in vitro than cidofovir against orthopoxviruses (varioa, monkeypox, vaccinia, cowpox) herpes viruses (CMV, HSV -1,-2, HHV-6, VZV, EBV poyomaviruses, and mutipe adenovirus subtypes)
Repeated CMV reactivations Common in high risk patients Frequenty poor activity/toerabiity of existing antivira drugs Associated with poor T-ce contro of CMV
Adoptive T-ce therapy In deveopment for > 20 years Major advances in technoogy have been achieved over the ast few years However, sti far away from routine therapy in most centers
Probems with T-ce therapy Loss of activity over time? Loss of activity during steroid therapy Need for a CMV positive donor (3:d party?) (Takes time to produce enough T-ces) Avaiabe at ony a few centers Cost???
The numbers game
The numbers game, Karoinska 80 patients/year 15 are seroneg with seroneg donors no CMV infection Remains 65/year 30% of the rest do not reactivate CMV no CMV infection Remains 44/year 50% reactivate once and respond rapidy no CMV disease Remains 22/year
The numbers game, Karoinska 22 patients/year 50% reactivate twice but respond easiy - no CMV disease Remains 11/year Of these patients 3-4 require repeated/proonged antivira courses for DNAemia but recover without major probems 2-3 deveop CMV disease 3-4 deveop resistance or significant toxicity.
The numbers game, Karoinska 22 patients/year 50% reactivate twice but respond - no CMV disease Remains 11/year Of these patients 3-4 require repeated/proonged antivira courses for DNAemia but recover without major probems 2-3 deveop CMV disease 3-4 deveop resistance or significant toxicity.
Indications for ce therapy; Karoinska Approx 8-10% of the patients need ceuar therapy What is the response rate of ceuar therapy in this high risk cohort? Other benefits??
And the winner is!!!!! 2011 antvira therapy
Can we stimuate the immune system another way? Possiby with a CMV vaccine!
Vica CMV DNA vaccine - phase II study in HSCT recipients Singe-via formuation Two pasmids: gb + pp65 (5 mg tota DNA in 1-mL dose) Competed Phase 1 & Phase 2 in HCT Successfuy dose-escaated up to 5 mg DNA/dose Induces T-ce and antibody responses Safe and we-toerated
Freedom from viremia
Shoud CMV be treated with ceuar therapy? Maybe! In a subgroup of patients if you have the technoogy avaiabe. How do we go on from here? A randomized study based on intention to treat comparing an antivira drug strategy with a ce therapy strategy anayzing feasibiity, efficacy, toxicity, and cost
Thank you for your attention!