Cytomegalovirus Infection: Monitoring and Treatment in Allogeneic Bone Marrow and Peripheral Blood S

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Cytomegalovirus Infection Monitoring and
Treatment in Allogeneic Bone Marrow and
Peripheral Blood Stem Cell Transplant Patients at
Washington University Medical Center
2
Cytomegalovirus

• Member of the herpes virus family (EBV,
  varicella-zoster, herpes simplex)
• Worldwide seroprevalence 30-100
• Found in body fluids
• Blood, saliva, urine, breast milk

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Types of CMV Infection

• Primary infection
  (asymptomatic to mononucleosis like syndrome
  in immune competent individuals)
• Latent infection
  (presence of viral genome in mononuclear
  leukocytes, endothelial cells, and organs in
  the absence of active replication of infectious
  virus)
• Reactivation
• Reinfection
  (new strain of CMV)

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Sequence of Infections After Organ Transplant
Fishman, J. A. et al. N Engl J Med
19983381741-1751
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Detection of CMV Infection

• Immune status serology (IgG)
• Active infection (viremia)
• Histology
• Viral culture
• Shell vial culture
• Antigenemia assay
• CMV PCR (qualitative/quantitative)

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CMV Infection in BMT Patients

• Patients at risk for CMV reactivation patient
  or donor seropositive for CMV pre-transplant
• CMV reactivation can lead to CMV disease in
  untreated patients (30-45)
• Manifestation of CMV disease in transplant
  patients
• Pneumonitis
• Hepatitis
• Enteritis
• Retinitis
• Myelosuppression

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Treatment of CMV Infection in Allogeneic Bone
Marrow Transplant Patients

• Ganciclovir/Foscarnet
• Two major treatment approaches
• Prophylactic treatment treat all patients at
  engraftment
• Pre-emptive treatment monitor patients for
  viremia and treat when infection detected
• Goal prevent CMV disease

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CMV Monitoring

• Patients monitored every 1-2 weeks for CMV
  viremia
• Shell vial cultures
• Antigenemia assays
• CMV PCR
• Incidence of CMV viremia may vary depending on
  monitoring strategy

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Reported Incidence of CMV Viremia
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PCR Based Screening Methods

• PCR is more sensitive than shell vial or
  antigenemia assays
• Some patients may be pre-emptively treated
  unnecessarily using PCR strategies
• Quantitative PCR may be more sensitive than
  qualitative PCR
• No criteria for standard treatment threshold
  exist for quantitative CMV PCR

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Reported Quantitative CMV PCR Viral Load with CMV
Disease
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Quantitative CMV PCR at Washington University

• Shell vial culture negative at lt15,000 copies/ml
• Half of qualitative CMV PCR negative at lt4,000
  copies/ml
• Detection limit 200 copies/ml
• Quantitation limit 2000 copies/ml

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CMV Monitoring /Treatment Strategy
Treat with once daily ganciclovir (5mg/kg/day)
CMV PCR gt10,000 copies/ml
Quantitative CMV PCR (weekly)
Monitor
CMV PCR lt10,000 copies/ml
Patients treated for 21 days Dose escalation to
BID ganciclovir (5mg/kg/BID) for increasing CMV
PCR on once daily ganciclovir Successful
treatment defined as CMV PCR lt2000 copies/ml
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Results

• Retrospective review of patients treated with
  this strategy from April 15, 2003 to March 30,
  2004

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Patient Characteristics

• Number of Patients 98 (allogeneic
  transplant)
• Mean age in years 46.5 (20-67)
• Median follow-up in days 318 (120-478)
• Allogeneic Transplants
• Related donor 44
• Unrelated donor 54
• Patients at risk for CMV Disease 69
• (donor or recipient CMV seropositive)

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CMV Viremia

• Patients at risk for CMV 69
• CMV viremia (gt200 copies/ml) 48/69 (70)
• Viral load never increased to gt10,000 copies/ml
  5/48 (10)
• Viral load increased to gt10,000 copies/ml 20/48
  (42)
• Initial viral load gt10,000 copies/ml 23/48
  (48)
• Onset of viremia post transplant (days)
• CMV PCR gt200 copies/ml 37 (19-62)
• CMV PCR gt10,000 copies/ml 52 (27-196)

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Treatment of CMV Viremia

• Initiated treatment 43
• BID ganciclovir or foscarnet 15
• Once daily ganciclovir 28
• Once Daily Ganciclovir
• Viral load at time of initiation of therapy
  (copies/ml) 11,324-53,000
• Completed once daily therapy 17/28 (61)
• Changed to BID ganciclovir 10/28 (36)
• Change to foscarnet 1/28 (4)
• (neutropenia ANClt500/ml)

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Clearance of CMV Viremia on Once Daily Ganciclovir
All patients initiated on once daily ganciclovir
(n28)
Patients completing once daily ganciclovir (n17)
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Recurrent CMV Viremia / CMV Disease

• Recurrent Viremia 12/28 (43)
  (54-247 days)
• CMV Disease
• Overall 4/69 (6)
• Deaths 2
• Patients initiated on once daily
• ganciclovir 2/28 (7)
• Deaths 0

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Summary At risk patients

• 70 had one or more episodes of CMV viremia
• 62 received treatment for CMV viremia
• 6 developed CMV disease

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Summary patients treated with once daily
ganciclovir

• 36 had dose of ganciclovir increased to BID
• 93 cleared CMV viremia at 5 weeks
• 2 patients developed CMV disease no deaths
• 1 case of neutropenia (ANC lt500/ml)

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• Randomized Trial of Pre-emptive Treatment with
  Oral Valganciclovir compared with IV Ganciclovir
  for CMV Infection after Bone Marrow or Peripheral
  Blood Stem Cell Transplant

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Valganciclovir

• Oral prodrug of ganciclovir which is converted to
  ganciclovir in the intestinal wall and liver
• Oral bioavailability 60
• Dose of 900mg BID has been shown to effectively
  treat CMV retinitis in AIDS patients

Martin, D.F., et al, NEJM, 346(15), (2002), 1119
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See next
IV Ganciclovir BID x 7 days
CMV PCR Viral Load gt index
IV Ganciclovir qday x 14 days (28 days of
treatment)
Group A IV Ganciclovir BID x 7 days Followed
by qday x 7 days

• CMV PCR
• gt 5,000 and
• lt index

CMV PCR day 14
IV Ganciclovir qday x 7 days and stop (21 days of
treatment)
CMV PCR lt5,000
Randomization
Transplant
See next
CMV PCR Viral Load gt index
PO Valganciclovir BID x 7 days
Screening CMV PCR gt10,000 x 1 gt5000 x 2
CMV PCR day 14
PO Valganciclovir qday x 14 days (28 days of
treatment)
CMV PCR gt5,000 and ltindex
Group B PO Valganciclovir BID x 7 days Followed
by qday x 7 days
PO Valganciclovir qday x 7 days and stop (21
days of treatment)
CMV PCR lt 5,000
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Increase in CMV viral load
Off study
CMV PCR after 7 days
Decrease in CMV viral load
IV ganciclovir BID x 7 days (28 days tx.)
Increease in CMV viral load
Off study
CMV PCR after 7 days
Decrease in CMV viral load
Valganciclovir BID x 7 days (28 days tx.)
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Inclusion/Exclusion Criteria

• Eligibility Criteria
• Allogeneic transplant at Washington University
• ANC gt 1000
• Creatinine clearance gt10 ml/min
• Bilirubin gt3.0
• Exclusion Criteria
• GI GVHD grade 3-4
• Evidence of CMV disease
• Uncontrolled emesis or diarrhea (gt4 episodes/day)

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Status

• 17 patients consented
• 4 not transplanted or newly transplanted
• 3 died without evidence of CMV infection
• 10 patients remaining
• 3 have turned CMV positive
• 2 removed from study for emesis/diarrhea
  (presumed GI GVHD)
• 1 randomized
• PO Valganciclovir
• Cleared viremia in 1 week
• Initial viral load lt2000, treatment viral load
  8964

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Conclusions

• Not all patients with positive CMV PCR require
  treatment for CMV viremia
• Optimum treatment threshold for initiation of
  treatment / clearance of viremia not defined
• Clinical trial currently underway to determine if
  oral valganciclovir can be an effective treatment
  for bone marrow transplant patients with CMV
  viremia

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Acknowledgments

• Ravi Vij
• John Dipersio