1. Sesión monográfica, 6 Nov 2008
Prophylaxis with oral valganciclovir or intravenous ganciclovir to prevent cytomegalovirus infection and disease after umbilical cord blood transplantation
Pau Montesinos, Jaime Sanz, Susana Cantero, Ignacio Lorenzo, Guillermo Martín, Silvana Saavedra, Javier Palau, Mónica Romero, Alberto Montava, Leonor Senent, Jesús Martínez, Isidro Jarque, Miguel Salavert, Juan Córdoba, Lola Gómez, Shirley Weiss, Federico Moscardó, Javier de la Rubia, Luis Larrea, Miguel A. Sanz and Guillermo F. Sanz
Good afternoon. I will talk about the Central Nervous System Relapse in Patients with Acute Promyelocytic Leukemia Treated with All-trans Retinoic Acid and Reinforced Anthracycline Monochemotherapy
Sesión monográfica, 6 Nov 2008

2. Backgound (1) CMV = major cause of therapeutic failure after allo-SCT.
Major advances in the prevention and treatment of CMV disease after allo-SCT:
Ganciclovir, a potent anti-cytomegalovirus (CMV) agent.
Rapid initiation of treatment based on detection assays, such as DNA polymerase chain reaction (PCR) or pp65 antigenemia (pp65 Ag)
However, CMV infection and disease remain a significant cause of morbidity and mortality.
UCBT = subset with a high risk of CMV infection and disease  poor immune reconstitution
The incidence and outcome of, and risk factors for, CMV infection and disease after UCBT have been scarcely addressed
Central nervous system relapse can complicate the course of patients with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA) and chemotherapy. The incidence of these complication is not established, varying from 0.6% to 5%. It has been said that treatment with ATRA may have increased the risk of CNS relapse, but this relationship has not been proved. More over, this can be a false impression due to an increased risk exposure to CNS relapse, which in turn is due to prolonged survival of patients receiving ATRA-containing therapies. Concerning the risk factors for CNS relapse, few studies have addressed this issue. In the study of de Botton, patients with high WBC at diagnosis (10x109/L), age under 45 years and those with BCR3 pml/rarA isoform had more probabilities of extramedullary relapse. However, the WBC was the only independent prognostic factor in multivariate analysis. Other two studies have found an association with BCR3 isoform, and in one study the development of differentiation syndrome was significantly associated with extramedullary involvement at relapse. Some authors have speculated on the role of adhesion molecules in CNS or other extramedullary relapses. 2

3. Backgound (2)
Risk factors for CMV = patient’s and donor’s CMV serological status, unrelated donor, GVHD, T cell depletion  allowing risk-adapted strategies.
Strategies in high-risk patients include:
Preemptive therapy with IV ganciclovir as soon as CMV+ in the blood;
IV ganciclovir prophylaxis initiated (form engraftment until day +100.
Randomized study comparing both preventive strategies:
a lower incidence of CMV infection and a similar incidence of disease and survival
a higher incidence of neutropenia and fungal and bacterial infections in patients under prophylaxis
Preemptive therapy with ganciclovir = most frequently used after allo-SCT. Prophylaxis in patients with a very high risk? (such as CMV-seropositive UCBT). 3

4. Backgound (3)
Valganciclovir = oral prodrug of ganciclovir with excellent bioavailability
Similar efficacy to IV ganciclovir for prophylaxis of CMV infection in organ-solid transplant recipients.
Early studies also showed a similar efficacy to IV ganciclovir as preemptive therapy in allo-SCT
Oral valganciclovir  potential to replace IV ganciclovir:
making outpatient care possible, which should provide more comfort for the patient and reduce the use of hospital resources.
especially valuable when prophylaxis for CMV infection and disease is considered.
No information on the efficacy and safety of valganciclovir as prophylaxis after allo-SCT. 4

5. Objectives
Evaluate and compare the efficacy, toxicity, and hospital resource use of prophylaxis of CMV infection and disease with IV ganciclovir or oral valganciclovir in two consecutive cohorts of CMV-seropositive adult patients undergoing UCBT at a single center.
Assess the rates of CMV infection and disease in the group of CMV-seronegative patients, in whom prophylaxis comprised low-dose acyclovir.
Analyze the characteristics, outcome, and risk factors for CMV infection and disease.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 5

6. Patients and Transplant Charactheristics
From May 1997 to January 2008, 143 adults UCBT
Median age and weight were 31 years (range, 15–62 years) and 70 kg (range, 34–112), respectively.
Underlying diseases: ALL (33%), AML (31%), others.
Early disease stages in 65% of patients.
HLA matching: 6/6 in 9 patients, 5/6 in 53, and 4/6 in 81.
Median number of nucleated, CD34+, and CD3+ cells infused were: 2.26  107/kg recipient’s body weight, 1.18  105/kg, and 0.55  107/kg.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 6

7. Preparative regimens and GVHD prophylaxis
BUCYTT and ATG in 72 patients (50%) (29 horse ATG (Lymphoglobulin®) and 40 rabbit ATG (Thymoglobulin®).
BUFLUTT and Thymoglobulin in 61 other patients (43%).
A reduced-intensity conditioning regimen was used in the remaining 10 patients (FLU, CY, and Thymoglobulin with or without TT in nine patients, and FLU, TT and Lymphoglobulin in one patient).
Acute GVHD prophylaxis = CsA+PDN (87%) and CsA+MMF (13%).
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 7

8. Risk stratification
CMV serology from the mother or cord blood unit (CBU) and the recipient were assessed before UCBT.
None of the CBU or mothers was positive for IgM antibody to CMV.
The CBU was considered CMV seronegative regardless of the serostatus of the mother.
 risk stratification for CMV infection and disease was based only on the patient’s CMV serostatus.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 8

9. Monitoring and diagnosis of CMV
In CMV-seronegative (low-risk) patients: no CMV monitoring.
In CMV-seropositive (high-risk) patients: PB samples twice weekly from +7 to +100, every 15 days until +180, monthly until +365, and weekly for patients taking more than 15 mg daily of prednisone for chronic GVHD.
pp65 Ag in PB leukocytes in the first 63 CMV-seropositive patients (56%), and plasma quantitative LC-PCR in the next 49 patients (44%).
Diagnosis of CMV infection = pp65 Ag assay (> 1 infected cell of 50,000 cells) or PCR (> 500 CMV DNA copies).
Diagnosis of CMV disease = standard clinical and microbiological criteria.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 9

10. Prophylaxis of CMV infection and disease
31 CMV-seronegative patients (22%)  IV acyclovir (250 mg/m2 twice daily) from–5 until +30, followed by oral acyclovir (400 mg three times daily) until +100.
CMV-seropositive patients  intravenous ganciclovir (first cohort) or oral valganciclovir (second cohort).
First cohort of 38 CMV-seropositive patients (27%) IV acyclovir (500 mg/m2 three times daily) from day –5 until engraftment, followed until day +100 by IV ganciclovir (5 mg/kg daily from Monday to Friday) and oral acyclovir (800 mg three times daily on weekend).
From October 2003, the second cohort of 74 CMV-seropositive patients (52%)  prophylaxis with IV acyclovir followed by oral valganciclovir (900 mg once daily) until day
G-CSF to maintain neutrophil count above 1.2  109/L.
All patients IgIV (0.5 g/kg weekly through day +100 and then monthly until +365).
All transfused products were irradiated and depleted of leukocytes but were not tested for CMV.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 10

11. Treatment of CMV infection and disease
IV ganciclovir 5 mg/kg twice daily or oral valganciclovir 900 mg twice daily.
Foscarnet 90 mg/kg twice daily was used if severe neutropenia.
For 14–21 days after the first of two consecutive negative tests of PB.
Maintenance (every 24 hours) for 14–21 days or until the completion of the originally scheduled prophylaxis.
When CMV disease (suspected or diagnosed)  IgIV (every 48 hours) until resolution of symptoms.
Ganciclovir and valganciclovir were discontinued temporarily and substituted with foscarnet in patients with a neutrophil count < 0.5–1  109/L despite the administration of G-CSF.
If renal failure, ganciclovir and valganciclovir were reduced to 50% (clearance < 70 mL/min) or to 25% (clearance < 50 mL/min).
Second-line with foscarnet was generally started in case of persistence of CMV positive tests in PB after 3-4 weeks of first-line antiviral therapy, or in case of non-responding/progressing CMV disease.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 11

12. Incidence and time of diagnosis of CMV infection and disease
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy.
CMV infection occurred at a median of 45 days (range, 14–239).
CMV disease occurred at a median of 183 days (range, 65–355).
Second recurrent CMV infection at a median of 156 days (range, 64–338). 12

13. CMV-seropositive recipients
CMV-seronegative recipients 13

14. Sites of CMV disease
13 CMV disease: 7 under ganciclovir prophylaxis, 4 patients under valganciclovir prophylaxis, and 2 CMV-seronegative under acyclovir prophylaxis.
Gastrointestinal in 6 patients, pneumonia in 5, retinitis in 1, and pancytopenia and fever in 1.
2 gastrointestinal disease without detectable CMV PCR or pp65 Ag in PB.
5 recurrent CMV disease: 3 pneumonia, 1 gastrointestinal, 1 retinitis.
2 patients died from CMV disease (pneumonia).
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 14

15. Prognostic factors and efficacy of prophylaxis
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 15

16. Prognostic factors and efficacy of prophylaxis
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 16

17. Intravenous ganciclovir
P = 0.52
Intravenous ganciclovir
Oral valganciclovir 17

18. Multivariate analyses
CMV infection and disease in the entire cohort:
CMV serostatus of the recipient for infection (hazard ratio [HR], 6.26;P < 0.001).
No factor was associated clearly with CMV disease.
CMV infection and disease in CMV-seropositive:
Grade III–IV acute GVHD for infection (HR, 2.45;P = 0.02).
CMV monitoring by pp65 Ag for CMV disease (HR, 8.35; P = 0.008).
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 18

19. Toxicity
Less frequent in the group of ganciclovir compared with valganciclovir, but not significant (3% vs 8%, P = 0.48).
Ganciclovir group, one patient required dose adjustment due to renal toxicity.
Valganciclovir group, six patients switched to foscarnet because of neutropenia. 5 patients (7%) switched to ganciclovir prophylaxis because of the impossibility of oral intake.
None developed secondary graft failure after starting valganciclovir or ganciclovir.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 19

20. Efficacy of preemptive therapy
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 20

21. Use of hospital resources
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 21

22. CMV-seropositive recipients
CMV-seronegative recipients 22

23. Intravenous ganciclovir
P = 0.46
Intravenous ganciclovir
Oral valganciclovir 23

24. Conclusions
Prophylaxis with oral valganciclovir is as effective as intravenous ganciclovir for reducing the incidence of CMV infection and disease in CMV-seropositive recipients of UCBT.
Oral valganciclovir has an acceptable toxicity profile and leads to a significant reduction of the use of hospital resources when compared with intravenous ganciclovir.
While ATRA and anthracyclines do not cross the cerebrospinal barrier, some trials for APL includes the use of intrathecal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. 24