1. CMV infection in HSCT recipients; Current trends and perspectives Prof
CMV infection in HSCT recipients; Current trends and perspectives Prof. Per Ljungman Center for Allogeneic Stem Cell Transplantation Karolinska University Hospital and Karolinska Institutet Stockholm, Sweden

2. Disclosures Advisory boards: AiCuris; Merck, Oxford Immunotech
Investigator: Merck, Astellas, Oxford Immunotech
DSMB/DRC: Shire

3. Timing of management options
Viral load
Viral disease
Time
Diagnosis of viral infection
Treatment of established disease
Pre-emptive therapy
Prophylaxis

4. Treat established CMV disease
A failure of strategy
Associated with significant mortality in the most severely immunosuppressed patients

5. What is the risk for CMV disease today?
Placeboarms in prospective randomized studies
Author
Journal
Year N
Incidence
Marty et al
Lancet ID
2011
227
2.4%
N Engl J Med
2013 59
3.0%
Chemaly et al
2014 33 0%
2017
170
1.8%

6. Patients in and outside of clinical trials

7. Real life probability of CMV disease
Green et al: Lancet Haematol 2016

8. CMV Following Hematopoietic Cell Transplantation Current Strategies
Infection
Universal prophylaxis
‘Risk-adapted’ prophylaxis
Pre-emptive
Therapy
To prevent CMV
infection/reactivation
To prevent CMV
infection/reactivation
in high-risk subgroups
(A)symptomatic CMV
infection detected by
a screening assay
CMV disease
Disease
J.Maertens 2018

9. The fight!
Preemptive
therapy
Prophylaxis

10. CMV replication is associated with mortality!
Retrospective analysis of seropositive patients monitored by qPCR. Effect of detection of any level of viremia Multivariate Cox model Day 0 – 60 Day 61 – 365 All cause mortality 2.6 (1.4 – 5.0) 1.7 (1.2 – 2.4) Non-relapse mortality 1.3 (0.9 – 2.0) 1.8 (1.2 – 2.6) Green et al Lancet Haematol 2016

11. Prophylaxis – previous studies
Aciclovir/valaciclovir are not effective enough
Ganciclovir and foscarnet are effective but toxic in HSCT
Valganciclovir effective in SOT
Resistance / intolerance remains as problems
Immune globulin is not effective in HSCT
Failure of phase III studies for maribavir, brincidofovir, and CMV DNA vaccine

12. Letermovir (AIC246)
- Belongs to a new class of compounds (a 3,4-dihydro-quinazoline-4-yl-acetic acid derivative)
Inhibits CMV through a novel mechanism involving the viral terminase complex
Potent CMV activity in vitro & in vivo
No effect on other herpesviruses
No cross-resistance with drugs currently used in treatment of CMV

14. Clinical Significant CMV Infection (%)
Time to Clinically Significant CMV Infection
Primary Efficacy Population; Patients without Detectable CMV DNA at Randomization 60 50 40 30 20 10
Letermovir vs. Placebo
Stratified log-rank test,
Two-sided p=0.0005
Placebo
Clinical Significant CMV Infection (%)
Cumulative Rate of
Letermovir 2 6 10 14 18 24
Post-Transplant Week
Letermovir
325
320
299
279
270
254
212
Placebo
170
169
135 96 85 77 70
Subjects at risk

15. Clinical Significant CMV Infection (%)
Time to Clinically Significant CMV Infection
Primary Efficacy Population; Patients without Detectable CMV DNA at Randomization
High Risk Stratum
Low Risk Stratum 60 50 40 30 20 10
Log-rank two-sided p<0.0001 60 50 40 30 20 10
Log-rank two-sided p<0.0001
Placebo
Placebo
Clinical Significant CMV Infection (%)
Cumulative Rate of
Letermovir
Letermovir 2 4 10 12 14 16 18 20 22 24 6 8 2 4 10 12 14 16 18 20 22 24 6 8
Post-Transplant Week

17. All-cause mortality through w.24
Letermovir
Placebo
Patients with CS-CMVi
17.7%
29.5%
Patients without CS-CMVi
19.7%
18.3%
Letermovir neutralizes the negative effect of significant CMV replication

18. Real life experience
Implemented at some centers at all seropositive patients.
Some centers have been using it in ”high risk” patients only
Some resistance is developing.
Break-throughs with disease have been seen
Secondary prophylaxis have also been used (off label)

19. Prophylaxis in allogeneic HCT; Antiviral drugs ECIL 2017
Grading
References
Comment
Aciclovir CI
Prentice, Lancet 1994
Milano, Blood 2011
Less efficient than valaciclovir
Valaciclovir BI
Ljungman, Blood 2002
Winston CID 2003
Association with preemptive strategy
Ganciclovir/
Valganciclovir
CIIh
Winston, Ann Intern Med 1993
Goodrich , Ann Intern Med 1993
Montesinos, BBMT 2009
Cord blood SCT
Foscarnet
DIIu
Ordemann, Ann hematol 2000
Bregante et al, Bone Marrow Transplant 2000
Letermovir AI
Marty et al, NEJM 2017 .
Ljungman et al; Lancet Infect Dis; in press 2019

20. How far have we come?
So, early intervention should be the goal

21. What is the rationale for monitoring and preemptive treatment
A sensitive diagnostic test is available
CORRECT – Many studies
A positive result is predictive for development of disease
Partly CORRECT – Not for all types of disease
Early intervention can prevent disease
CORRECT
An effective (and safe) antiviral drug is available
YES AND NO

22. Testing issues All PCRs are not created equal!! Starting materials
DNA extraction methods
Primer/probe selection
Variability
International standard!!

23. The variability in CMV DNA results reported on individual samples samples have been reduced by the international standard, but ongoing clinically relevant variability persists, preventing meaningful interassay result comparison
CID 2017

24. CMV viral load cut-off values
There is major variability between patients
There is still variability between assays
It is therefore not possible (or meaningful) to give a standard cut-off reocmmendation to be used at different centers (outside clinical trials)

25. First line preemptive therapy – ECIL 2017
The only data available for preemptive therapy of asymptomatic patients exists in allogeneic HSCT recipients.
Preemptive antiviral therapy based on detection of CMV nucleic acid (or antigen) is effective for prevention of CMV disease (AI)
Either iv ganciclovir or foscarnet can be used for first line preemptive therapy (AI)
Valganciclovir can be used in place of iv ganciclovir or foscarnet (except in patients with severe GI GVHD); AIIu)
The combination foscarnet+ ganciclovir is not recommended (DIII)
The choice of drug depends on time after HSCT, risk of toxicity, and previous antiviral drug exposure
Ljungman et al; Lancet Infect Dis; in press 2019

26. Repeated CMV reactivations
Common in high risk patients
Frequently poor activity/tolerability of existing antiviral drugs
Associated with poor T-cell control of CMV
Increased risk for resistant strains

27. Second and third line preemptive therapy
The alternate drug of ganciclovir/valganciclovir or foscarnet can be considered for second line pre-emptive therapy (AIIu)
Cidofovir can be considered for second/third line pre-emptive therapy (3-5 mg/kg/week) but careful monitoring of the renal function is required (BIIu).
The combination of ganciclovir and foscarnet might be considered for second/third line pre-emptive therapy (CIIu)
Reduce immunosuppression if possible (BIII)
No recommendation can be given for the antiviral drugs in development
Leflunomide or artesunate can be considered in patients resistant/refractory to available antiviral drugs (CIII)
Addition of iv immune globulin for preemptive therapy is not recommended (DIII)
EXPAND THIS DISCUSSION ALSO TO TREATMENT OF DISEASE
Ljungman et al; Lancet Infect Dis; in press 2019

28. How common is antiviral resistance in HSC recipients?
Varies between patient populations
Ganciclovir resistance
0% in a prospective randomized study (Boeckh et al Ann Intern Med 2015)
0% in auto and allo SCT non-haplo recipients in a large prospective cohort study
9.6% in haploidentical allo SCT recipients (Shmueli et al JID 2013

29. CMV genes and antiviral drugs

30. Most “resistance” is clinical!

31. Causes for “clinical” resistance
If you give oral therapy, does the patient take the drug?
Vomiting?
Does the patient absorb the oral drug?
What are the drug levels? TDM for ganciclovir
Viral replication kinetics
Poor T-cell function

32. Response to antiviral therapy takes some time!
Mattes et al JID 2005

33. When to Suspect Drug Resistance
High risk clinical setting (severe T-cell immunodeficiency)
Prolonged drug exposure (usually > 6 weeks)
Rising viral load or persistent culture positive >2 weeks after full dose therapy (GCV/VGV)
Progressive disease after prolonged therapy

34. Treatment of resistant/refractory patients
Increase dose of ganciclovir/TDM
Foscarnet
Cidofovir
Maribavir
Letermovir/
Brincidofovir
T-cells
Leflunomide
Artesunate

35. Foscarnet/cidofovir Standard second line therapies
Most ganciclovir resistant patients can be managed
Multidrug resistance is rare
However, toxicity problems are common (renal toxicity, electrolyte disturbances, cystitis)

36. Maribavir Sucessful phase II study for prophylaxis
Failed phase III studies for prophylaxis
Case series on refractory patients.
Phase II study of refractory patients finalized.
Phase III studies ongoing

37. Maribavir for Treatment of CMV Resistant or Refractory to Ganciclovir or Foscarnet: A Phase 2 Trial
MBV 400 mg twice daily
Weeks 1-3
Weeks 3-6
Weeks 6-24
MBV 1200 mg twice daily
MBV doses blinded
Randomization
• HCT or SOT recipient • R/R CMV
• ≥1,000 CMV DNA copies/mL
At week 3 and week 6 visits, minimum virologic responses are required for study drug treatment to continue
PCR CMV testing
Day 1, weekly to week 6
Study evaluations/PCR CMV testing
Every 2 weeks to week 12; weeks 16, 20, and 24
Week 4
Week 8
Week 12
MBV 800 mg twice daily
Screening
Study drug administration (maximum 24 weeks)
Follow-up (post-treatment weeks 1-12)
Week 1
a Did not achieve ≥1 log reduction in CMV DNA with ≥14 d of previous treatment; ≥1,000 CMV DNA copies/mL at screening. b Resistance mutations in UL97 and/or UL54; meets refractory criteria. c Requirements to continue treatment: past week 3, any decline in CMV DNA at week 2; past week 6, ≥2 log reduction or undetectable CMV DNA at week 5.
Papanicolaou G, et al. BMT Tandem Abstract 45.
ClinicalTrials.gov identifier: NCT
G. Papanicolaou 2018

38. Time to Undetectable Plasma CMV DNA was Similar Across all Maribavir Doses
Median estimated time to confirmed undetectable plasma CMV DNA at any time (days [95% CI]) were similar: 24 (15, 31), 28 (15, 38), 22 (19, 30), and 23 (21, 29) for MBV 400 mg, 800 mg, 1,200 mg (twice daily), and MBV all doses, respectively
Papanicolaou G, et al. BMT Tandem Abstract 45.
ClinicalTrials.gov identifier: NCT
G. Papanicolaou 2018

39. Letermovir No data in children
Likely to be tested in refractory/resistant situations (off label)
Dose not determined.
Very limited published data
Resistance found in vitro and in vivo.
Unclear clinical relevance as of today

40. Adoptive T-cell therapy
In develpment for 30 years
Major advances in technology have been achieved over time
Most (almost all) data are from phase I – II type studies
In practice, it is still far away from routine therapy/ available for most centers

41. Effect of CTL
Uhlin et al CID 2012

42. Response, % (n/N)
CMV
EBV
AdV
BKV
HHV-6
CR + PR
94 (16/17)
100 (2/2)
71 (5/7)
93 (14/15)
100 (2/2)‡ CR
65 (11/17)
33 (5/15)
0 (0/2)‡
Single-arm phase II study in which post-HSCT pts infected with refractory* CMV, EBV, AdV, BKV, and/or HHV-6 were treated with closely HLA-matched, third-party, multivirus-specific donor CTLs from investigative site bank (N = 38)
Pts received 2 x 107 CTLs/m2; partial responders could receive additional infusions every 2 wks
Efficacy: overall, CR or PR† achieved for 91% of viral infections; all pts infected with 2 viruses (n = 6) achieved CR or PR for both viruses
Intolerance to or 14-day failure of standard antiviral treatment. †CR: return of viral load to normal and clinical signs/symptoms resolution; PR: viral load decrease of ≥ 50% and/or improvement of clinical signs/symptoms. ‡n = 1 additional pt not evaluable.
Small single-center studies have shown feasibility and effectiveness
CMV or multivirus specificities
No major safety concerns
Randomized trials are needed
Safety: grade 1 skin GVHD, n = 1 (resolved); chronic skin GVHD flare, n = 3 (immunosuppression discontinued); transient fever, n = 2
Tzannou I, et al. J Clin Oncol. 2017;35(31):

43. How do I treat very difficult CMV problems? The numbers game
In real life, this is quite rare
1-2 patients/year at my center
Individual management based on transplant history, GVHD, tolerability of drugs, possibility to use immune therapy.

44. One size doesn’t fit all

45. A look into the situation in 2022
Or………………

46. Since transplanters are innovative
"The person who takes medicine must recover twice, once from the disease and once from the medicine."
- William Osler, M.D.