DONOR: If there is more than one donor with the least amount of HVG allele mismatches, the following prioritization will be used: (will always minimize HVG mismatch as highest priority)\r\n* ABO compatibility (in order of priority)\r\n** Compatible or minor ABO incompatibility\r\n** Major ABO incompatibility\r\n* Cytomegalovirus (CMV) status\r\n** The CMV status of the pair donor-recipient is frequently employed to select a potential donor; this is a controversial issue and the data available is somewhat limited; the following guidelines are recommended:\r\n*** For a CMV seronegative recipient, use a CMV seronegative donor\r\n*** For a CMV seropositive recipient, use a CMV seropositive donor\r\n* In CMV- patients with CMV+ stem-cell donors, primary CMV infection/reactivation develops in about 30%; data from the European Registry shows the following: seropositive patients receiving grafts from CMV+ HLA-identical sibling donors had the same survival as patients grafted from CMV- donors; however, matched unrelated donor (MUD) recipients receiving grafts from CMV+ donors had an improved 5-year survival, an improved event-free survival, and a reduced transplant-related mortality; there was no influence on the relapse incidence; the effects of donor CMV status remained in multivariate analyses; the effect of donor status was different among different disease categories; in patients with chronic myelogenous leukemia, T-cell depletion abrogated the beneficial effect of donor status, suggesting that the effect is mediated through transfer of donor immunity; these data suggest that donor CMV status influences outcome of unrelated stem cell transplant (SCT)
DONOR: The cytomegalovirus (CMV) status of the pair donor-recipient is frequently employed to select a potential donor; the following guidelines are recommended:\r\n* For a CMV seronegative recipient, use a CMV seronegative donor\r\n* For a CMV seropositive recipient, use a CMV seropositive donor
Patients must be CMV seropositive
Have a documented asymptomatic CMV infection, with a screening value of CMV DNA >=2730 IU/mL to less than or equal to (<=) 273000 IU/mL in whole blood or >=910 IU/mL to <=91000 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. Both samples should be taken within 14 days prior to randomization with second sample obtained within 5 days prior to randomization. Same laboratory and same sample type (whole blood or plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection that does not present with tissue invasive CMV disease, as assessed by the investigator.
Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or reactivation.
Have CMV tissue invasive disease as assessed by the investigator at the time of screening and randomization at Visit 2/Day 0.
Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, foscarnet, or cidofovir based on documented evidence.
Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a subject who had at least one previously documented episode of CMV infection posttransplant, and who has had at least 2 weeks of undetectable CMV DNA between the episodes (during active surveillance, based on same local laboratory and same sample type). The subject must also have been off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection may be considered continuation of the prior infection.
Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus [HSV] coinfection requiring use of any of these agents after the randomization) or would need a co-administration with maribavir for CMV infection.
Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet or cidofovir) for the current CMV infection for longer than 72 hours. Note: A subject who is receiving these anti-CMV agents must discontinue their use before the first dose of study treatment. A subjects who may be receiving cidofovir must discontinue this antiviral at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Note: Subjects who were administered these anti-CMV agents for prophylaxis, should have these treatments completed at least 2 weeks prior to the study entry or start of the treatment for current infection, whichever comes first and have undetectable CMV DNA (based on local laboratory) for at least two weeks between the completion of this treatment and onset of the current infection.
Patients must be CMV seropositive
CMV seropositive
CMV seronegative
Persistent CMV infection despite optimum anti-viral therapy\r\n* Patients with CMV disease: defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) or the detection of CMV by culture or direct fluorescent antibody stain in bronchoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates; OR \r\n* Failure of antiviral therapy: defined as the continued presence of deoxyribonucleic acid (DNA)emia (defined as >= 137 copies/ml by polymerase chain reaction [PCR]) for at least 2 weeks of CMV antiviral therapy; OR \r\n** Optimum therapy is defined as at least 14 days of therapy with ganciclovir, foscarnet, cidofovir, or valganciclovir for patients with disease or CMV viremia\r\n** Relapse while on CMV antiviral therapy defined as recurrence of DNAemia while being on at least 2 weeks of antiviral therapy OR\r\n* Patients who cannot tolerate standard anti-viral therapy and cannot continue anti-viral treatment due to side effect profile will be eligible independent of anti-viral therapy duration
CMV seropositive
STEP 2: Eligibility at time of generating and infusing CMV-specific cytotoxic T cells (adoptive immunotherapy): CMV reactivation defined as CMV DNA present in the blood (DNAemia) >= 137 copies/ml
CMV seronegative
STEP 2: Eligibility at time of generating and infusing CMV-specific cytotoxic T cells (adoptive immunotherapy): documented CMV end-organ disease
The patient must have a clinically documented condition associated with CMV (e.g. interstitial pneumonia, hepatitis, retinitis, colitis) Or
The patient must have microbiological evidence of CMV viremia or tissue invasion as attested by viral culture, or detection of levels of CMV DNA in the blood or body fluids consistent with CMV infection.
The patient's CMV infection is clinically progressing or CMV viremia is persistent or increasing (as evidenced by quantitation of CMV DNA in the blood) despite two weeks induction therapy with antiviral drugs. Or
The patient has developed CMV viremia as attested by viral culture, or detection of levels of CMV DNA in blood or body fluids while receiving prophylactic doses of antiviral drugs to prevent CMV infection post transplant. Or
The patient's HCT donor, if seropositive, is either not available or not willing to provide leukocytes for generation of CMV-specific T-cells.
CMV: Treatment of persistent or relapsed CMV disease or infection after standard therapy; for CMV infection, standard therapy is defined as antiviral therapy with ganciclovir, foscarnet or cidofovir\r\n* CMV disease: defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) or the detection of CMV by culture or direct fluorescent antibody stain in broncheoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates or changes consistent with CMV retinitis on ophthalmologic examination\r\n* CMV infection: defined as the presence of CMV positivity as detected by polymerase chain reaction (PCR) or pp65 antigenemia or culture from ONE site such as stool or blood or urine or nasopharynx\r\n* Failure of antiviral therapy: defined as a rise or a fall of less than 50% in viral load in peripheral blood or any site of disease as measured by PCR or pp65 antigenemia after 7 days of antiviral therapy
DONOR: In the event that two or more eligible donors are identified, the following order of priority will be used to determine the preferred donor:\r\n* Medically and psychologically fit and willing to donate\r\n* Killer immunoglobulin receptor (KIR) haplotype B donor\r\n* Red blood-cell compatibility (in order of preference)\r\n** Red blood cell (RBC) cross-match compatible\r\n** Minor ABO incompatibility\r\n** Major ABO incompatibility\r\n* For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor; for CMV seropositive recipients, a CMV seropositive donor is preferred\r\n* When possible, HLA-mismatched donors will be prioritized over HLA-matched to maximize an allogeneic benefit
DONOR: If patient is cytomegalovirus (CMV)-negative, donors who are CMV-negative will be preferred; CMV serology of the donor will be tested prior to the allogeneic cell donation; donations from CMV-positive donors to CMV-negative recipients will be given if no CMV negative donor is available, and CMV surveillance and pre-emptive treatment given
Subjects with active cytomegalovirus (CMV) (positive serology for anti-CMV IgM antibody and negative for anti-CMV IgG antibody and positive CMV PCR with clinical manifestations consistent with active CMV infection) and requiring therapy will be excluded from participation in the study; carriers will be monitored per institutional guidelines
If patient is cytomegalovirus (CMV)-negative, donors who are CMV-negative will be preferred; CMV serology of the donor will be tested prior to the allogeneic cell donation; donations from CMV-positive donors to CMV-negative recipients will be given if no CMV negative donor is available, and CMV surveillance and pre-emptive treatment given as per guidelines below
The subject must have a current CMV infection refractory or resistant to treatment. Refractory is defined as documented failure to achieve greater than (>) 1 log10 (common logarithm to base 10) decrease in CMV DNA level in whole blood or plasma after 2 or more weeks of continuous treatment with intravenous (IV) ganciclovir, oral valganciclovir, IV foscarnet, or IV cidofovir. This definition applies to the current CMV infection and the most recently administered anti-CMV agent. Resistant is defined as documented failure to achieve > 1 log10 (common logarithm to base 10) decrease in CMV DNA level in whole blood or plasma after 2 or more weeks of continuous treatment with IV ganciclovir, oral valganciclovir, IV foscarnet, or IV cidofovir. This definition applies to the current CMV infection and the most recently administered anti-CMV agent. AND Documentation of 1 or more CMV genetic mutations associated with resistance to ganciclovir, valganciclovir, foscarnet, or cidofovir.
The Investigator must be willing to treat the subject with at least one of the available anti-CMV drugs (ganciclovir, valganciclovir, foscarnet, or cidofovir). Note: Combination therapy with foscarnet and cidofovir is not permitted in the investigator-assigned anti-CMV treatment (IAT) arm due to the potential for serious nephrotoxicity.
The subject must be willing to provide necessary samples (example [e.g,] biopsy) for the diagnosis of tissue invasive CMV disease at baseline as determined by the Investigator.
Have a current CMV infection that is considered refractory or resistant due to inadequate adherence to prior anti-CMV treatment, to the best knowledge of the Investigator.
Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus (HSV) coinfection requiring use of any of these agents after the randomization) or would need a coadministration with maribavir for CMV infection. NOTE: A subject who is not continuing with the same anti-CMV drug(s) (ganciclovir, valganciclovir or foscarnet) for the study treatment (if randomized to the investigator assigned anti-CMV treatment arm), must discontinue their use before the first dose of study drug. If subject is currently being treated with cidofovir and is assigned another anti-CMV therapy by the investigator, the subject must discontinue its use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment.
Have tissue invasive CMV disease with central nervous system involvement including the retina (example, CMV retinitis).
DONOR: The following criteria, in order of importance, should also be used for donor selection:\r\n* Medically and psychologically fit and willing to donate\r\n* The patient must lack antibodies against donor HLA molecules potentially clinically significant\r\n* ABO compatibility (in order of priority)\r\n** Compatible or minor ABO incompatibility\r\n** Major ABO incompatibility\r\n* Cytomegalovirus (CMV) status\r\n** For a CMV seronegative recipient, use a CMV seronegative donor\r\n** For a CMV seropositive recipient, use a CMV seropositive donor
Donors will be prioritized in the following order:\r\n* Fit to donate\r\n* HLA-matched prioritized over HLA-mismatched\r\n* Lack of major ABO incompatibility\r\n** In order of priority:\r\n*** Compatible\r\n*** Minor incompatibility\r\n*** Major incompatibility\r\n* Cytomegalovirus (CMV) serostatus: CMV negative donor preferred, if the patient is CMV negative; CMV positive donor preferred, if the patient is CMV is positive\r\n* Avoidance of female donor for male recipient
Ongoing infection with, or treatment or prophylaxis for, CMV within the past 28 days.
Dual refractory CMV reactivation to foscarnet and ganciclovir or evidence of CMV disease
CMV PCR > 500 copies/mL or evidence of end-organ damage due to CMV
Subjects will be adult allogeneic HSCT recipients aged ? 18 years-old (or as applicable, per local law) who were CMV seropositive before transplantation and are CMV viremia negative posttransplant.
Subjects who have a positive CMV viremia test at any time between transplant and the First Dose Day (FDD).
Subjects must be CMV seropositive prior to transplant by CMV immune screen or CMV immunoglobulin G (IgG) or develop detectable disease by polymerase chain reaction (PCR) in the post-transplant setting
DONOR: Adult donors must be CMV seropositive prior to transplant by CMV immune screen or CMV IgG positive
Patients must have documented opportunistic CMV infection, or reactivation; the criteria include (both of the following criteria must be met)\r\n* Patients may have asymptomatic viremia (> 1000 copies/ml) OR presence of symptoms secondary to CMV infection, AND\r\n* Patients must have ONE OF THE NEXT FOUR CRITERIA:\r\n** Absence of an improvement of viral load after >= 14 days of antiviral therapy with ganciclovir, valganciclovir or foscarnet (decrease by at least 1 log, i.e. 10-fold) or \r\n** New, persistent and/or worsening CMV-related symptoms, signs and/or markers of end organ compromise while on antiviral therapy with ganciclovir, valganciclovir or foscarnet, or\r\n** Have contraindications or experience adverse effects of antiviral therapy with ganciclovir, valganciclovir or foscarnet\r\n** Second recurrence of CMV viremia, CMV-related symptoms, signs and/or markers of end organ compromise
Must have evidence of a serologic response (i.e. be seropositive) against CMV
DONOR: donors will be prioritized in the following order:\r\n* Fit to donate\r\n* HLA-matched prioritized over HLA-mismatched prioritized over unrelated\r\n* Lack of major blood group antigens (ABO) incompatibility; in order of priority:\r\n** Compatible\r\n** Minor incompatibility\r\n** Major incompatibility\r\n* Cytomegalovirus (CMV) serostatus; CMV negative donor preferred, if the patient is CMV negative; CMV positive donor preferred, if the patient is CMV is positive\r\n* Avoidance of female donor for male recipient
Each patient must satisfy at least one of the following criteria:\r\n* The patient must have a clinically documented condition associated with CMV (e.g. interstitial pneumonia, hepatitis, retinitis, colitis) Or\r\n* The patient must have microbiological evidence of CMV viremia or tissue invasion as attested by viral culture, or detection of levels of CMV DNA in the blood or body fluids consistent with CMV infection
Patient must also satisfy at least one of the following criteria:\r\n* The patient's CMV infection is clinically progressing or CMV viremia is persistent or increasing (as evidenced by quantitation of CMV DNA in the blood) despite two weeks induction therapy with antiviral drugs; or\r\n* The patient has developed CMV viremia as attested by viral culture, or detection of levels of CMV DNA in blood or body fluids while receiving prophylactic doses of antiviral drugs to prevent CMV infection post-transplant; or\r\n* The patient is unable to sustain treatment with antiviral drugs due to drug associated toxicities (e.g. myelosuppression [absolute neutrophil count (ANC) < 1000 ul/ml without filgrastim (GCSF) support] or nephrotoxicity [corrected creatinine clearance =< 60 ml/min/1.73 m^2 or serum creatinine > 2 mg/dl])
DONOR: Donors who are known CMV seronegative
CMV seropositive (recipient)
Experimental anti-CMV chemotherapy in the last 6 months
Antiviral medications with known therapeutic effects on CMV such as ganciclovir/valganciclovir (GCV/VAL), foscarnet (FOS), Cidofovir, CMX-001, maribavir; acyclovir has no known therapeutic efficacy against CMV and is allowable as standard of care to prevent herpes simplex virus (HSV)
Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment
CMV seropositive (recipient)
Experimental anti-CMV chemotherapy in the last 6 months
Planned medications from the time of HCT to day 70 post-HCT:\r\n* Live attenuated vaccines\r\n* Medically indicated subunit (Engerix-B for HBV; Gardasil for human papilloma virus [HPV]) or killed vaccines (e.g. influenza, pneumococcal, or allergy treatment with antigen injections)\r\n* Allergy treatment with antigens injections\r\n* Alemtuzumab or any equivalent in vivo T-cell depleting agent; this includes anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide\r\n* Antiviral medications with known therapeutic effects against CMV such as ganciclovir (GCV)/valine (VAL), foscarnet (FOS), cidofovir, hexadecyloxypropyl-cidofovir (CMX-001) and maribavir; acyclovir has no therapeutic efficacy against CMV and is allowable as standard of care to prevent herpes simplex virus (HSV)\r\n* Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment\r\n* Other investigational product - concurrent enrollment in other clinical trials using an investigational product is prohibited\r\n* Other medications that might interfere with the evaluation of the investigational product
CMV seropositive (recipient)
Experimental anti-CMV chemotherapy in the last 6 months
Antiviral medications with known therapeutic effects on CMV such as ganciclovir (GCV)/valganciclovir (VAL), foscarnet (FOS), Cidofovir, CMX-001, maribavir; acyclovir has no known therapeutic efficacy against CMV and is allowable as standard of care to prevent herpes simplex virus (HSV)
Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment
Prophylaxis for patients at risk of CMV, adenovirus, EBV, BK virus, or HHV6 infection
RECIPIENT: CMV seropositive
RECIPIENT: Experimental anti?CMV chemotherapy in the last 6 months
RECIPIENT: Antiviral medications with known therapeutic effects on CMV such as ganciclovir (GCV)/valganciclovir (VAL), FOS, Cidofovir, CMX?001, maribavir. Acyclovir has no known therapeutic efficacy against CMV and is allowable as standard of care to prevent Herpes simplex virus (HSV)
RECIPIENT: Prophylactic therapy with CMV immunoglobulin or prophylactic antiviral CMV treatment (Letermovir is permitted)
Patients who have HIV, Hepatitis A, B or C or CMV reactivation
Subject is a CMV-seropositive HCT recipient
Subject has active CMV disease or infection or has received treatment for active CMV disease or infection within 3 months (90 days) prior to transplant
History of CMV end-organ disease within 6 months before randomization
Received the following within 30 days before screening or plan to receive during the study: cidofovir, CMV hyper-immune globulin, any investigational CMV antiviral agent or biological therapy