Idelalisib and Progressive Mul2focal Leukoencephalopathy. ISoP Annual Mee-ng 2016 R.E.Chandler and P. Caduff- Janosa

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1 Idelalisib and Progressive Mul2focal Leukoencephalopathy ISoP Annual Mee-ng 2016 R.E.Chandler and P. Caduff- Janosa

2 Idelalisib Reversible, highly selec2ve lipid kinase inhibitor interfering with B- cell receptor signalling, resul2ng in increased apoptosis and inhibited prolifera2on of malignant B- cells.

3 Idelalisib approval: US- FDA (July 2014) The approval for CLL was based on the results of a pivotal interna2onal, mul2- center, randomized (1:1), placebo- controlled trial of 220 pa2ents comparing idelalisib 150 mg twice daily in combina2on with rituximab to placebo in combina2on with rituximab. Accelerated approval for relapsed follicular B- cell non- Hodgkin lymphoma (FL) and relapsed small lymphocy2c lymphoma (SLL) was based on the results of a mul2- center, single arm, open- label trial enrolling 123 pa2ents hvp://

4 Idelalisib approval: EMA (September 2014) CLL in combina2on with rituximab and relapsed follicular lymphoma as monotherapy Same dataset as US- FDA Total number of pa2ents in clinical safety database at 2me of approval: 752 hvp:// _Public_assessment_report/human/003843/ WC pdf

5 Progressive mul2focal leukoencephalopathy (PML) JC virus infec2on in the brain (white maver) leading to demyelina2on JC virus infec2on very common, PML typically seen only in pa2ents with severely depressed cell- mediated immunity HIV/AIDS Malignancies (CLL) Medica-on (monoclonal AB, immunosuppressants)

6 PML Clinically, PML presents with Cogni-ve deficits Language problems Personality changes Motor dysfunc-on Visual changes Headaches Seizures and shows characteris2c lesions on MRI JCV DNA can be detected in CSF and brain 2ssue

7 PML Unmanaged, PML is reported to have a fatal outcome in 30-50% of pa2ents within a few months of diagnosis Treatment is suppor2ve, permanent neurological sequelae are very frequent

8 Case series in VigiBase As per 1 September 2016: 7 reports on PML under idelalisib therapy Received June 2015 to July 2016 USA (2), Germany, Spain, Portugal, Switzerland, and UK 3 spontaneous reports and 4 from studies 5/7 JC virus PCR posi-ve

9 56 to 80 yrs (median 73) 5 men, 2 women 6 reports with co- suspected rituximab 1 report 5 addi-onal suspect agents 1 report with co- suspected obinutuzumab but no men2on of rituximab

10 TTO: 11 d to 7 months (median 3 months) TTO unknown in one case Outcome: 3 fatal 1 recovered 1 recovering 1 not recovered 1 unknown

11 Recovered/recovering Recovered: 56 yr old lady, CLL stage 3, idelalisib/obinutuzumab TTO 2 weeks, no narra2ve Recovering 73 yr old man, progressive CLL, rituximab+idelalisib, TTO 7 months, both drugs discon2nued, therapy with immunoglobulins, mirtazapine, and mefloquin

12 Discussion CLL and rituximab as confounders Es2mated incidences of PML CLL 11.1/ person- years ( ) Rituximab in SLE 2/8000, in RA 1/ No es-mates for CLL+rituximab Amend KL, Turnbull B, FoskeV N, Napalkov P, Kurth T, Seeger J. Incidence of progressive mul2focal leukoencephalopathy in pa2ents without HIV. Neurology Oct 12;75(15): doi: /WNL.0b013e3181f Kavanaugh A, MaVeson E. Hotline: Rituximab and Progressive Mul2focal Leukoencephalopathy. [Accessed March 2, 2009];American College of Rheumatology hvp:// Clifford DB, Ances B, Costello C, Rosen- Schmidt S, et al. Rituximab- Associated Progressive Mul2focal Leukoencephalopathy in Rheumatoid Arthri2s. Arch Neurol Sep; 68(9):

13 No post marke2ng exposure data publicly available 7 case reports reported within approx 2 years, with 2 cases without rituximab at 2me of diagnosis and one case with no history of rituximab therapy call for inves2ga2on, whether there might be an addi2ve risk for CLL pa2ents treated with idelalisib and rituximab

14 Raisch DW, Rafi JA, Chen C, BenneV CL. Detec2on of cases of progressive mul2focal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA's adverse event repor2ng system. Expert Opin Drug Saf Aug;15(8): PML reports with cancer therapeu2cs used in combina2on with other agents associated with PML, stand out dispropor2onally (PRR) brentuximab 24.5, (CI: ) ofatumumab 16.3, (CI: ) alemtuzumab 9.9, (CI: ) obinutuzumab 7.4, (CI: ) ibru2nib 5.6 (CI: ) belimumab 4.5 (CI: ) idelalisib 4.1, (CI: )

15 Conclusions Need for More research to clarify the risk of PML in CLL pa-ents under idelalisib + rituximab Addi-onal risk minimiza-on measures for early recogni-on and treatment of PML

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17 A WHO Collabora2ng Centre One goal In our role as a WHO Collabora-ng Centre, we adhere to WHO policies and work in close liaison with WHO headquarters. We provide scien-fic leadership and opera-onal support to the WHO Programme for Interna-onal Drug Monitoring. We share the WHO s goal of beder health for all, but are organisa-onally and professionally dis-nct from the WHO itself.