A classic case of loosing options…Hans H Hirsch

Transplantation & Clinical VirologyDepartment Biomedicine (Haus Petersplatz)

Division Infection DiagnosticsDepartment Biomedicine (Haus Petersplatz)University of Basel

Infectious Diseases & Hospital EpidemiologyUniversity Hospital Basel

Switzerland

Cases in TIDCases in TIDCancun, MexicoCancun, Mexico13.10.201513.10.2015

Case 1Case 1

2

Male, 50-years-old, follicular lymphoma in 2002, CMV IgG + Matched unrelated HSCT in 2011 Donor CMV IgG – GvHD prophylaxis standard low-dose CsA – MTX - MPred Asymptomatic CMV replication 561 IU/mL in weekly surveillance at 3

weeks posttransplant, coincident with engraftment Would your treat with antivirals ?

Case 1 (cont’d 2)Case 1 (cont’d 2)

3

Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT Matched unrelated HSCT in 2011 Donor CMV IgG – GvHD prophylaxis standard low-dose CsA – Methotrexate Asymptomatic CMV replication 561 IU/mL in weekly surveillance at 3 weeks posttransplant, coincident with engraftment

– Valganciclovir 900mg bd (GFR corrected), for 3 weeks– CMV <137 IU/mL after 2 weeks

Day 52: Symptomatic CMV replication 73’00 IU/mL Valganciclovir 900mg bd (GFR corrected), for 6 weeks

– CMV <137 IU/mL after 4 weeks

Day 152: Recurrence CMV 85’000 IU/mL Valganciclovir 900mg bd (GFR corrected), for 6 weeks

– CMV remains detectable after 4 weeks, re-increasing

Some QuestionsSome Questions

4

Why is this so difficult ?

– Is this a patient problem?– Is this a donor problem?– Is this a drug problem?

Ganciclovir resistance testing– UL97 phopshotransferase mutation

Case 1 (cont’d 3)Case 1 (cont’d 3)

5

Male, 50yrs, follicular lymphoma 2002, CMV IgG + 1. HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV Month 8: CMV 1.400’000 IU/mL, Foscarvir 60 mg/kg x12h

Case 1 (cont’d 4)Case 1 (cont’d 4)

6

Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV

– clinical FOS failure, Cidofovir 5 mg/kg/wk+probenicid

Case 1 (cont’d 5)Case 1 (cont’d 5)

7

Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV

– clinical FOS failure, Cidofovir response, CMV rebound

Case 1 (cont’d 6)Case 1 (cont’d 6)

8

Male, 50yrs, follicular lymphoma in 2002, CMV IgG + 1.HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV

– GCV UL97®, FOS failure?, Cidofovir response, CMV rebound– FOS UL54®, Leflunomide failure, lymphopenia

Case 1 (cont’d 7)Case 1 (cont’d 7)

9

Male, 50yrs, follicular lymphoma 2002, CMV IgG + 1. HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV

– GCV UL97®, FOS UL54®; LEF failure, graft failure 2. HSCT 2013 (MUD CMV IgG+); Artes tox, Maribavir + pp65+CMV T-cells

Case 1 (cont’d 8)Case 1 (cont’d 8)

10

Male, 50yrs, follicular lymphoma 2002, CMV IgG + 1. HSCT 2011 (MUD CMV IgG –), cGvHD; recurrent CMV

– GCV UL97®, FOS UL54®; LEF failure, graft failure 2. HSCT 2013 (MUD CMV IgG+); Artes tox, Maribavir + pp65+CMV T-cells

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Key pointsKey points

High-risk for recurrent CMV replication– HSCT CMV D-/R+– SOT CMV D+/R-

High-risk for CMV resistance– Insufficient antiviral drug levels (dosing, adherence, GFR)– Outpatient, oral administration, high viral loads

CMV non-response, resistance– Virological, genotypic, clinical– Limited fitness costs in CMV-T-cell deficiency

Experimental drugs– Cave dosing, toxicity

Adopitve T-cell transfer– Availability timing, immunopathology (CMV retinitis, IRIS)

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Evidence level: Dramatic results from single casesEvidence level: Dramatic results from single cases

http://onlinelibrary.wiley.com/doi/10.1111/tid.12435/abstract

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Risk factors of viral complications posttransplantRisk factors of viral complications posttransplant

Insufficient immune control– Naïve (no memory)– Depleted (anti-lymphocyte globulins, -pheresis)– Immunosuppressed (maintenance, anti-rejection)

Allogenic constellation between virus-infected cells and the T-cell effectors– Virus with tropism for organ transplant– Allogeneic HSCT

Pathology– Virus determinants– Host determinants– Cytopathology– Immunopathology (including IRIS)

Some QuestionsSome Questions

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How does your laboratory determine CMV – CMV pp65 Antigenemia ? – Quantitative Nucleic Acid Testing (NAT) e.g. PCR

How is your CMV quantification reported ?– Antigenemia per 200’000 Leukocytes ?– CMV loads in copies/mL, Geq/mL, or IU/ml?

What is the Lower Limit of Detection (LOD) used at your center ?– 2 AG /200’000 cells?– 137 IU/mL ?– Other ?

What is the threshold of starting antiviral therapy ?– Any CMV detection in blood in 3 months screening posttransplant?– Any confirmed CMV detection– 500 IU/mL; 1500 IU/mL; 3000 IU/mL