1. Clinical Impact of New Data on Managing Cytomegalovirus Infection Post-BMT
CCO Independent Conference Coverage* of Hematology 2016; December 3-6, 2016; San Diego, California, and the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
BMT, bone marrow transplant.
Roy F. Chemaly, MD:
In this Expert Analysis, Guenther Koehne, MD, PhD, and I discuss key studies on post–bone marrow transplantation (BMT) cytomegalovirus (CMV) infection presented at the recent Hematology and BMT Tandem meetings.
We review 11 of the most exciting studies presented at these meetings, highlighting potentially practice-changing data. These studies addressed a range of topics, including risk, prophylaxis, and treatment of CMV infection in post-BMT patients.
This program is supported by an educational grant from Merck

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Slide credit: clinicaloptions.com
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3. Faculty
Roy F. Chemaly, MD Professor of Medicine Department of Infectious Diseases, Infection Control, and Employee Health University of Texas M. D. Anderson Cancer Center Houston, Texas
Guenther Koehne, MD, PhD Attending Physician Adult Bone Marrow Transplant Service Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York

4. Faculty Disclosures
Roy F. Chemaly, MD, has disclosed that he has received consulting fees from Astellas, Chimerix, Merck, and Oxford Immunotec and funds for research support from Chimerix, Merck, and Novartis. Guenther Koehne, MD, PhD, has no real or apparent conflicts of interest to disclose.

5. CMV Prophylaxis and Preemptive Therapy
CMV, cytomegalovirus.

6. MK-8228-001: Letermovir for Post-HSCT CMV Prophylaxis
Randomized, multicenter, double-blind, placebo-controlled phase III trial
Primary endpoint: pts with clinically significant CMV infection* through post-HSCT Wk 24 (full analysis set†)
Letermovir: inhibits CMV terminase complex via UL56 binding; terminase complex important in CMV DNA cleavage and packaging
Post-HSCT Wk 14
CMV-seropositive, adult allogeneic HSCT recipients with no CMV viremia
or acute liver injury and GFR ≥ 10 mL/min
(N = 570)
Letermovir 480 mg‡ QD PO or IV (n = 376)
Pts assessed through
post-HSCT Wk 48;
preemptive treatment
given per study
center guidelines
CMV, cytomegalovirus; GFR, glomerular filtration rate; HSCT, hematopoietic stem cell transplantation.
Pts were stratified by study center and risk of clinically significant CMV infection (high vs low). High risk was defined by haploidentical or cord blood HSCT; HSCT from a related donor with ≥ 1 mismatch for HLA-A, -B, or -DR; HSCT from an unrelated donor with ≥ 1 mismatch for HLA-A, -B, -C, or -DRB1; ex vivo T-cell depletion; or current prednisone ≥ 1 mg/kg/day (or equivalent) for acute graft-vs-host disease. Low risk was defined as any patient that did not meet high risk criteria.
Roy F. Chemaly, MD:
CMV is a significant viral infection following BMT. Numerous trials have sought to identify a prophylactic strategy to prevent the occurrence of CMV infection in this setting. Letermovir is an inhibitor of the CMV terminase complex, binding UL56 and interfering with CMV DNA cleavage and packaging.[1,2] This agent was previously assessed as CMV prophylaxis in a dose-finding phase II trial in CMV-seropositive HSCT patients.[3] This study demonstrated a significantly decreased risk of all-cause prophylaxis failure with letermovir vs placebo.
MK was a multicenter, double-blind phase III trial in which CMV-seropositive, adult allogeneic HSCT recipients were randomized 2:1 to receive either daily letermovir or placebo for 14 weeks (N = 570).[4] Letermovir was given at 480 mg, which is double the highest dose in the phase II trial, with reduction to 240 mg if the patient was concomitantly receiving cyclosporine. Although treatment stopped at post-HSCT Week 14, the primary endpoint measured clinically significant CMV infection up to post-HSCT Week 24.
For more information on this study, please see the associated Capsule Summary:
Placebo (n = 194)
Pts required to begin treatment before post-HSCT Day 28.
*Clinically significant CMV infection defined as CMV disease occurrence or treatment with anti-CMV preemptive therapy (which occurred if confirmed CMV viremia and CMV disease risk). †Full analysis set included pts with undetectable CMV DNA at baseline. ‡240 mg if concomitantly taking cyclosporine.
Slide credit: clinicaloptions.com
Marty FM, et al. BMT Tandem Abstract LBA2.

7. MK-8228-001: Clinically Significant CMV Infection and Mortality Through Wk 24
Outcome at Wk 24,* %
Letermovir (n = 325)
Placebo (n = 170)
Failure of therapy
37.5
60.6
Clinically significant CMV
17.5†
41.8
Started preemptive therapy
16.0
37.6
CMV disease
1.5
1.8
All-cause mortality
9.8‡
15.9
Nonrelapse mortality
6.5
10.6
CMV, cytomegalovirus.
Roy F. Chemaly, MD:
The results were impressive. At post-HSCT Week 24, even after stopping therapy for 10 weeks, letermovir failed in only 37.5% of patients vs 60.6% who failed on placebo. In adjusted analysis, clinically significant CMV infection was reduced in patients receiving letermovir vs placebo (17.5% vs 41.8%, respectively; P < .0001). Although the rate of CMV disease was comparable between arms, all-cause mortality was significantly lower with letermovir vs placebo (9.8% vs 15.9%, respectively; P = .0317).
For more information on this study, please see the associated Capsule Summary:
*Full analysis set. †Adjusted treatment difference: -23.5% (95% CI: to -14.6; P < .0001). ‡P = vs placebo.
In pts with undetectable CMV DNA at baseline, letermovir associated with significant benefit in terms of time to clinically significant CMV infection and all-cause mortality vs placebo through Wk 24
For all subgroups assessed, letermovir associated with less clinically significant CMV infection through Wk 14 vs placebo
Slide credit: clinicaloptions.com
Marty FM, et al. BMT Tandem Abstract LBA2.

8. MK : Safety
GVHD was the most common AE of any severity (39% in both groups)
Diarrhea, nausea, fever, and rash also occurred in > 20% of pts in both groups with similar frequency
Safety Outcome During Treatment Phase, %
Letermovir
(n = 373)
Placebo
(n = 192)
Any AE
97.9
100
Drug-related AE
16.9
12.0
Serious AE
44.2
46.9
Infection
20.6
18.8
GVHD
9.9
10.4
Relapse of AML
4.0
4.7
Acute kidney injury
1.3
Diarrhea
0.5
2.6
Atrial arrhythmia
Discontinuation due to AE
19.3
51.0
CMV treatment
6.2
39.1
Other
13.1
AE, adverse event; AML, acute myeloid leukemia; CMV, cytomegalovirus; GVHD, graft-vs-host disease.
Roy F. Chemaly, MD:
AEs, including serious AEs, arose at similar rates between arms during the treatment phase, with the expected any-grade AEs of diarrhea, nausea, fever, and rash occurring in more than 20% of patients. The most common AE was graft-vs-host disease, which 39% of patients developed in each arm. Ultimately, letermovir did not raise any real safety signals in causing major AEs when compared with placebo. In fact, far more patients discontinued for AEs while receiving placebo vs letermovir (51.0% vs 19.3%, respectively).
Overall, prophylactic letermovir effectively and safely prevented CMV reactivation vs placebo through post-HSCT Week 24, with no major AEs that commonly occur with other drugs, such as nephrotoxicity or myelosuppression. These outcomes make MK a landmark study, as safety has been a major concern with prescribing currently available agents for CMV prophylaxis after HSCT.
Guenther Koehne, MD, PhD:
I agree that this appears to be the first drug with the capacity to prevent CMV reactivation in the absence of additional AEs. Prior to his study, other drugs were tested but either did not prevent CMV reactivation or had to be discontinued secondary to significant AEs. Thus, letermovir seems like a promising agent for CMV prophylaxis.
For more information on this study, please see the associated Capsule Summary:
Slide credit: clinicaloptions.com
Marty FM, et al. BMT Tandem Abstract LBA2.

9. Maribavir for Treating Ganciclovir/Foscarnet-Resistant/Refractory CMV in US Transplant Pts
Randomized, multicenter, dose-ranging phase II study[1]
Primary endpoint: undetectable plasma CMV DNA within 6 wks of treatment
Maribavir: oral-dosed inhibitor of CMV UL97 kinase; in vitro activity vs CMV resistant to current therapeutics[2]
Wk 3 ‡
Wk 6 ‡
Maribavir 400 mg BID PO (n = 40)
Stem cell or solid organ transplant recipients ≥ 12 years of age;
refractory* or resistant† CMV infection
(N = 120)
Treatment up to Wk 24
allowed to reach/maintain
undetectable CMV DNA; follow-up 12 wks post treatment
Maribavir 800 mg BID PO (n = 40)
CMV, cytomegalovirus.
Roy F. Chemaly, MD:
Maribavir is an orally dosed inhibitor of CMV UL97 kinase, with in vitro activity against CMV resistant to current therapeutics.[5] A previous phase II trial demonstrated that prophylactic maribavir could prevent CMV infection after transplant vs placebo, but a subsequent phase III trial failed to show a significant difference associated with maribavir vs placebo in CMV disease post engraftment.[6,7] Despite this, many clinicians believe that maribavir could have a role in CMV treatment if the correct dose can be ascertained.
This randomized, multicenter, dose-ranging phase II study compared blinded, twice-daily doses of 400-mg, 800-mg, or 1200-mg maribavir as treatment for 120 US stem cell (39%) or solid organ (61%) transplantation recipients with relapsed/refractory CMV infection.[8] Refractory patients had not achieved ≥ 1 log reduction in CMV DNA with ≥ 14 days of previous ganciclovir/valganciclovir and/or foscarnet treatment and had ≥ 1000 CMV DNA copies/mL at screening. Resistant patients met these criteria but also harbored resistance mutations in UL97 and/or UL54. Treatment was allowed for up to 24 weeks to reach or maintain undetectable CMV DNA, and patients were assessed at Weeks 3 and 6 to determine eligibility to continue maribavir. The primary endpoint was undetectable CMV DNA within 6 weeks of treatment.
Maribavir 1200 mg BID PO (n = 40)
*Did not achieve ≥ 1 log reduction in CMV DNA with ≥ 14 days of previous treatment; ≥ 1000 CMV DNA copies/mL at screening. †Resistance mutations in UL97 and/or UL54; meets refractory criteria. ‡Requirements to continue treatment: past Wk 3, any decline in CMV DNA at Wk 2; past Wk 6, ≥ 2 log reduction or undetectable CMV DNA at Wk 5.
39% of pts received stem cell transplant
Slide credit: clinicaloptions.com
1. Papanicolaou G, et al. BMT Tandem Abstract Drew WL, et al. J Clin Virol. 2006;37:

10. Maribavir for Resistant/Refractory CMV: Key Results
Outcome
Maribavir
400 mg
(n = 40)
800 mg
1200 mg
All Doses
(n = 120)
Undetectable CMV DNA within 6 wks, %
70.0
62.5
67.5
66.7
CMV recurrence, % (n/N)*
During treatment
24.1 (7/29)
40.7 (11/27)
40.0 (12/30)
34.9 (30/86)
After treatment
3.4 (1/29)
7.4 (2/27)
6.7 (2/30)
5.8 (5/86)
Discontinuation for AEs, %
27.5
42.5
32.5
34.2
TEAEs, %
100
Dysgeusia
60.0
72.5
65.0
CMV, cytomegalovirus; TEAE, treatment-emergent adverse event.
Roy F. Chemaly, MD:
Historically, CMV infection that is resistant to standard agents has been associated with poor response to alternative agents and high mortality.[9] Here, even the lowest maribavir dose (twice-daily 400 mg) resulted in 70% of patients achieving undetectable CMV DNA within 6 weeks; at higher doses, this rate ranged from 63% to 68%. What is especially notable is that recurrent CMV infection, which is common, arose in 24% of patients receiving maribavir 400 mg and approximately 40% of patients receiving maribavir 800 mg and 1200 mg while on treatment. After treatment, CMV recurrence emerged in 3% to 7% of patients. This can happen in the absence of maintenance therapy and/or a potent CMV-specific immune response.
Approximately one third of patients discontinued for AEs, but no major unexpected AEs occurred during maribavir treatment. Dysgeusia was the most common AE, arising in 65% of all patients. Although more pronounced here, this taste disturbance was documented with prophylactic maribavir in phase II/III trials.[6,7] No myelosuppression or nephrotoxicity signals were observed.
Thus, this study effectively showed that patients with resistant or refractory CMV infection following transplantation may respond to maribavir. Based on these data, a confirmatory phase III trial of the twice-daily 400-mg maribavir dose is currently recruiting additional patients in this population.[10] To lessen the recurrence rate, patients will receive maribavir for 8 weeks.
Guenther Koehne, MD, PhD:
I agree that maribavir demonstrated the capacity to induce remission or undetectable CMV within 6 weeks of treatment in this resistant/refractory population. The limitation, as Dr. Chemaly also pointed out, was the relatively high rate of on-treatment recurrence. It would be interesting to know if these patients had other drugs that could be administered subsequently, or if they were already maxed out with antiviral treatments. Furthermore, is this a patient population that should be considered for the T-cell therapies that we will discuss shortly?
Yes, good point. Extensive unmet need remains in this area of CMV treatment.
*In pts with confirmed undetectable CMV DNA.
Dysgeusia most common TEAE; others included nausea (all doses, 34.2%), vomiting (all doses, 29.2%)
n = 1 death possibly related to maribavir treatment (multiorgan failure) in 800-mg arm
Slide credit: clinicaloptions.com
Papanicolaou G, et al. BMT Tandem Abstract 45.

11. Follow-up 12 wks post treatment
Maribavir for Primary Preemptive CMV Treatment in European Transplant Pts
Randomized, multicenter, dose-ranging, active-controlled phase II study[1]
Primary endpoint: undetectable plasma CMV DNA (< 200 copies/mL) within 3 or 6 wks of treatment
Wk 12
Maribavir 400 mg BID PO (n = 40)
Stem cell or solid organ transplant recipients 18 yrs of age or older;
CMV DNA ,000 copies/mL; no CMV organ disease
(N = 159)
Maribavir 800 mg BID PO (n = 40)
Follow-up 12 wks post treatment
Maribavir 1200 mg BID PO (n = 39)
CMV, cytomegalovirus.
Roy F. Chemaly, MD:
This next study was a multicenter, dose-ranging, active-controlled phase II study of primary preemptive CMV treatment in 159 stem cell (52%) or solid organ (48%) transplantation recipients in Europe.[11] Patients with ,000 copies/mL CMV DNA and no CMV organ disease were randomized to one of 4 arms: twice-daily 400-mg, 800-mg, or 1200-mg maribavir vs twice-daily 900-mg valganciclovir. After Week 3, valganciclovir recipients switched to once-daily maintenance dosing. Whereas valganciclovir treatment was open label, investigators and maribavir recipients were blinded to the maribavir dose. The primary endpoint was undetectable plasma CMV DNA (ie, < 200 copies/mL) within 3 or 6 weeks of treatment.
Valganciclovir 900 mg* PO (n = 40)
Pts receiving maribavir knew they were receiving this drug but we blinded to dose; valganciclovir treatment open label. *BID Wks 1-3, then QD; adjusted for renal function.
52% of pts received stem cell transplant
Slide credit: clinicaloptions.com
Maertens JA, et al. BMT Tandem Abstract 229.

12. Maribavir for Preemptive CMV Treatment: Key Results
Outcome
Maribavir 400 mg
(n = 40)
Maribavir 800 mg
Maribavir mg
(n = 39)
Maribavir All Doses
(n = 119)
VGC
Undetectable CMV DNA within 3 wks, %
65.0
57.5
59.0
60.5
55.0
P value vs VGC
.28
.72
.64
.41 --
Undetectable CMV DNA within 6 wks, %
77.5
82.5
71.8
77.3
.17
.06
.45
.08
CMV recurrence, % (n/N)*
Within 6 wks
5.9 (2/34)
2.0 (2/98)
During study period
30.3 (10/33)
23.5 (8/34)
12.9 (4/31)
22.4 (22/98)
17.9 (5/28)
Discontinuation for AEs, %†
30.0/12.5
12.5/10.0
25.6/17.9
22.7/13.4
TEAEs, %†
97.5/62.5
95.0/62.5
100/76.9
97.5/67.2
85.0/22.5
Serious TEAEs, %†
40.0/7.5
42.5/2.5
48.7/20.5
43.7/10.1
32.5/2.5
Death, %†
5.0/0
2.5/0
7.7/0
7.5/0
AE, adverse event; CMV, cytomegalovirus; TEAE, treatment-emergent adverse event; tx, treatment; VGC, valganciclovir.
Roy F. Chemaly, MD:
Within 3 weeks of treatment, between 57.5% and 65.0% of patients receiving maribavir had undetectable CMV DNA vs 55.0% of patients receiving valganciclovir. When treatment was continued to Week 6, rates of undetectable CMV DNA increased up to 82.5% with the maribavir 800-mg dose, which trended toward a significant difference vs the 65.0% achieved by valganciclovir recipients (P = .06). Similar to the previous maribavir study discussed, recurrence during treatment occurred in numerous patients: 12.9% to 30.3% of those receiving maribavir vs 17.9% of those receiving valganciclovir. This will need to be addressed in any ensuing phase III trial.
Few drug-related serious AEs arose with maribavir treatment. Treatment-emergent dysgeusia and gastrointestinal AEs such as diarrhea, nausea, and vomiting were reported more frequently with maribavir treatment, whereas valganciclovir recipients experienced more treatment-emergent neutropenia.
These data show that maribavir is effective for preemptive CMV therapy, offering possible improvements over valganciclovir because of its increased safety. A phase III trial of preemptive CMV therapy with twice-daily 400-mg maribavir vs valganciclovir in HSCT recipients is currently recruiting participants.[12] Here, again, patients will receive 8 weeks of treatment to mitigate the potential for CMV recurrence.
Guenther Koehne, MD, PhD:
The maribavir responses here were impressive and essentially comparable to valganciclovir. With extended use, valganciclovir often must be discontinued secondary to myelosuppressive AEs.[13] Moving forward, long-term safety considerations such as this may ultimately determine which drug to use in the preemptive strategy.
I agree. Using valganciclovir for up to 8 weeks in a phase III trial will likely lead to frequent discontinuation for myelosuppression, and this could be a decisive factor in selecting an optimal preemptive therapy.
*In pts with ≥ 2 undetectable CMV DNA results, only 1 of which had to precede post-tx follow-up. †Overall/drug related.
Slide credit: clinicaloptions.com
Maertens JA, et al. BMT Tandem Abstract 229.

13. Outcomes Associated With Drug-Resistant CMV Infection in HSCT Pts
Single-site retrospective analysis assessing outcomes for HSCT recipients infected with CMV with suspected antiviral resistance* who had available genotypic analysis (N = 26)
Mutation spectrum: UL97, n = 7; UL54, n = 3; none, n = 16
Outcome
Mutation
(n = 10)
No Mutation
(n = 16)
CMV mortality, % 30 13
Response to alternative therapy, % 10 56
CMV disease, % 19
Mean peak CMV antigenemia, cells/million WBCs
2247
1440
Previous CMV therapy, %
100
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; WBC, white blood cell.
Roy F. Chemaly, MD:
This small, single-site retrospective analysis assessed outcomes in 26 HSCT recipients infected with CMV that was resistant to antiviral therapy.[14] Genotypic examination revealed that only 10 of these 26 patients had UL97 or UL54 resistance mutations and 16 patients had no mutations, although they had refractory infections.
When patients with and without resistance mutations were compared, the presence of mutations was associated with higher mortality and lower response to alternative therapy vs the absence of mutations. The refractory status of patients without mutations could be secondary to a host factor or another CMV-specific factor such as viral fitness.
The rate of CMV disease and mean peak CMV antigenemia were also higher in patients with demonstrated mutations. Although data are still being collected from additional patients, these early results show a difference in outcomes between patients with resistant CMV who have documented genetic resistance and those who do not.
Guenther Koehne, MD, PhD:
I agree. The fact that mutated forms of CMV induced higher CMV mortality came as no surprise because antiviral options are limited for this patient population. This is a population where immunotherapeutics can potentially provide additional treatment options.
*No improvement of CMV antigenemia with 2 wks of antiviral therapy and/or CMV end-organ disease despite antiviral therapy > 6 wks—including 2 wks of full-dose therapy—with risk factors and CMV resistance as determined by genotypic analysis.
Slide credit: clinicaloptions.com
El Chaer F, et al. BMT Tandem Abstract 223.

14. CMV Reactivation and Treatment Efficacy in CMV-Seropositive Cord Blood Transplant Pts
Single-site retrospective analysis of CMV infection and therapeutic efficacy and toxicity in CMV-seropositive cord blood transplant pts (N = 42)
Pts received ganciclovir 5 mg/kg/day IV prophylaxis on transplant Days -7 to -2
Preemptive treatment started when first or second PCR positivity observed
CMV response: 3 consecutive negative PCR findings; no CMV disease
CMV incidence and severity in 100 days following cord blood transplant
CMV reactivation: 83% (35/42)
Median viremia onset: 33 days
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; PCR, polymerase chain reaction.
Guenther Koehne, MD, PhD:
This single-site retrospective analysis investigated the toxicity and efficacy of sequential prophylactic and early preemptive therapies in 42 CMV-seropositive umbilical cord blood transplantation recipients.[15] Despite pretransplantation ganciclovir, 35 of 42 (83%) patients reactivated CMV within the first 100 days of transplantation with a median viremia onset of 33 days. Foscarnet, ganciclovir, or valganciclovir preemptive treatment, with either induction or maintenance dosing, was initiated after the detection of CMV viremia.
Slide credit: clinicaloptions.com
Lau C, et al. BMT Tandem Abstract 228.

15. Continued Induction (n = 11)
CMV-Seropositive Cord Blood Transplant Pts: Treatment Efficacy and Toxicity
Finding at Post-CBT Day 100
Induction Dosing
(n = 11)
Maintenance Dosing
(n = 24)
Median CMV DNA at therapy start, copies/mL (range)
< 137 (< )
< 137 (< )
Median post-CBT therapy initiation timing, Day (range)
47 (19-74)
29 (9-75)
Therapy type: foscarnet/ganciclovir/valganciclovir, %
27/0/73
75/17/8
Switched to Induction, n (%)
Continued Induction (n = 11)
Induction (n = 12)
Maintenance (n = 12)
Cleared viremia
6 (55)
5 (42)
10 (83)
Controlled viremia
5 (45)
4 (33)
1 (8)
Death
3 (25)*
CBT, cord blood transplant; CMV, cytomegalovirus; G-CSF, granulocyte-colony stimulating factor.
Guenther Koehne, MD, PhD:
Although pretransplantation administration of ganciclovir was not shown to be effective, continuing with early monitoring and preemptive therapy after transplantation reduced CMV viremia and the occurrence of CMV disease. All preemptive treatments were initiated at a median CMV DNA level of < 137 copies/mL. With induction dosing, 6 of 11 (55%) patients cleared viremia, 5 of 11 (45%) controlled viremia, and none developed disease. In the 24 patients who initiated maintenance dosing, 11 cleared or controlled viremia and 1 died; 12 required therapeutic switch to induction dosing because of lack of response or CMV pneumonia.
Roy F. Chemaly, MD:
This study reinforces both the very high degree of CMV reactivation after cord blood transplantation and the significant AEs associated with available drugs. For instance, one third of patients receiving foscarnet developed nephrotoxicity that necessitated dose reduction or a therapeutic switch. In addition, 61% of patients receiving either ganciclovir or valganciclovir required granulocyte-colony stimulating factor treatment. Although it is not surprising to observe worsening on-treatment AEs in this very sick patient population, future management may warrant outright prevention of CMV reactivation with a safe intervention.
I agree; this is a high-risk population. It is hoped that some of the newer drugs will reduce CMV reactivation if administered preemptively, as in this trial. Assessing prophylactic use of novel agents may be another next step, along with the evaluation of early CMV-specific T-cell administration.
*CMV pneumonia, n = 2; on therapy, n = 1.
Foscarnet: 32% (8/25) developed nephrotoxicity necessitating dose reduction or therapy switch
Ganciclovir or valganciclovir: 61% (19/31) required G-CSF treatment
Slide credit: clinicaloptions.com
Lau C, et al. BMT Tandem Abstract 228.

16. T-Cell Therapy

17. Additional Baseline Characteristics, %
Third-Party CMV-Specific T Cells for Treating Pts With Resistant CMV Post-HSCT
Single-arm, single-site exploratory study in which HSCT recipients with CMV viremia/ disease resistant* to standard antivirals treated with in vitro–expanded, third-party, previously characterized CMV pp65-specific CTLs from investigative site bank (N = 15)
CTLs matched for ≥ 2 of 8 HLA alleles and restricted by ≥ 1 HLA allele shared with recipient
1 cycle comprised 5-min IV infusions of 106 CTLs/kg each at Wks 1-3; pts lacking dose-related toxicity could receive additional cycles, with intervening 3-wk breaks
Baseline Antiviral Resistance, %
Pts (N = 15)
Additional Baseline Characteristics, %
Ganciclovir and/or valganciclovir
100
Presence of UL97 mutation 53
Foscarnet 67
Presence of UL54 mutation 73
Cidofovir and/or brincidofovir 40
CMV viremia
All 3 lines of therapy 33
CMV disease 27
CMV, cytomegalovirus; CTL, cytotoxic T lymphocyte; HSCT, hematopoietic stem cell transplantation.
Guenther Koehne, MD, PhD:
HSCT patients with antiviral-resistant CMV infection have few therapeutic options.[9] Post-HSCT infusion of donor-derived cytotoxic T lymphocytes (CTLs) attempts to overcome CMV resistance with an immunotherapeutic approach: T-cells from the blood of a CMV-seropositive stem cell donor are purified and made specific for CMV viral antigens, such as pp65. They are then reinfused back into the HSCT patient. This approach has met with success in several pilot studies in treating CMV viremia or disease in patients with resistance virus.[16,17]
There are several caveats to using donor-derived CTLs. Expansion of these cells can require up to 8 weeks and does not guarantee the generation of highly effective cells. In addition, donors may not always be available. To address these issues, a strategy has been devised in which CTLs from multiple third-party donors can be characterized and stored in banks for more rapid use. This strategy has been shown to be effective as CMV treatment in the post-HSCT setting.[18,19]
In this single-arm, single-site exploratory study, 15 HSCT recipients with CMV viremia (73%) or disease (27%) resistant to standard antivirals were treated with in vitro–expanded, third-party CMV pp65-specific CTLs from an investigative site bank.[20] These CTLs were matched for 2 or more HLA alleles, restricted by 1 or more HLA alleles shared with the recipient, and given cycles comprising 3 doses of 106 cells/kg. At baseline, 100% of patients were resistant to ganciclovir and/or valganciclovir, 67% to foscarnet, 40% cidofovir and/or brincidofovir, and 33% to all 3 lines of therapy; UL97 and UL54 mutations were prevalent.
For more information on this study, please see the associated Capsule Summary:
*Genetic resistance: presence of mutations in genes encoding CMV UL54 or UL97 proteins.
Slide credit: clinicaloptions.com
Prockop S, et al. ASH Abstract 61.

18. Third-Party CMV-Specific T-Cells for Resistant CMV: Key Results
Overall Survival by T-Cell Response
Outcome, % (n/N)
Pts
(N = 15)
Response
CR + PR*
73 (11/15) CR
40 (6/15)
SD + PD
27 (4/15)
6-mo overall survival
Responder (CR + PR)
73 (8/11)
Nonresponder (SD + PD)
25 (1/4)
Responder (CR + PR) (n = 11)
Nonresponder (SD + PD) (n = 4)
100 80 60
Survival (%) 40 20
P = .04 2 4 6
Mos
AE, adverse event; CMV, cytomegalovirus; CR, complete response; CTL, cytotoxic T lymphocyte; GVHD, graft-vs-host disease; PD, progressive disease; PR, partial response; SD, stable disease.
Guenther Koehne, MD, PhD:
In total, 11 of 15 (73%) patients achieved either a CR or a PR to CMV CTLs. Of critical importance, responders experienced significantly improved OS vs nonresponders (73% vs 25%, respectively) and exhibited in vivo CMV CTL expansion. In addition, no serious AEs probably or definitely related to treatment occurred. These outcomes support the clinical application of third-party CTLs in HSCT recipients infected with antiviral-resistant CMV.
Roy F. Chemaly, MD:
I completely agree. The achievement of high response rates in patients with demonstrated antiviral resistance is very encouraging, but these findings need to be validated with a larger sample size. In the future, this alternative therapy, given alone or in combination with newer drugs, could improve survival after HSCT in this population.
It should be noted that because these cells have now been licensed, additional institutions will soon be able to administer third-party CMV CTLs. In this way, significantly more patients can be recruited and treated, bolstering the outcomes readout from this protocol.
For more information on this study, please see the associated Capsule Summary:
*CR = no CMV viremia, biopsy-proven resolution of disease; PR = 2 log10 decline in CMV viremia, resolution of symptoms.
In vivo expansion of CMV CTLs evident in responders, absent in nonresponders
In all pts receiving CMV CTLs at investigative site (N = 66), no serious AEs probably/definitely related to treatment; n = 1 GVHD possibly related to treatment
Slide credit: clinicaloptions.com
Prockop S, et al. ASH Abstract 61. Reproduced with permission.

19. CHARMS: Third-Party Multivirus-Specific T-Cells for Treating Refractory Infections Post-HSCT
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
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)‡
AdV, adenovirus; BKV, BK virus; CMV, cytomegalovirus; CTL, cytotoxic T lymphocyte; CR, complete response; EBV, Epstein-Barr virus; GVHD, graft-vs-host disease; HHV, human herpesvirus; HSCT, hematopoietic stem cell transplantation; PR, partial response.
Guenther Koehne, MD, PhD:
CHARMS, a single-arm phase II study, treated 38 post-HSCT patients infected with 1 or 2 refractory viral infections with closely HLA-matched, third-party, multivirus-specific donor CTLs from an investigative site bank.[21] In the previous study, CTLs were generated against overlapping CMV-specific peptides. Here, CTLs targeted antigens on several viruses, including CMV, Epstein-Barr virus (EBV), adenovirus, BK virus, and HHV-6. Patients initially received a single dose of 2 x 107 CTLs/m2, but partial responders could receive additional doses every 2 weeks thereafter.
Overall, a CR or PR was achieved for 91% of viral infections. For patients infected with 2 viruses, a CR or PR was achieved for all viral infections. Response rates varied by virus type. For example, 100% of patients with EBV achieved CR (n = 2). From there, this rate decreased to 71% for adenovirus (n = 7), 65% for CMV (n = 17), 33% for BK virus (n = 15), and 0% for HHV-6 (n = 2). Indeed, HHV-6 is very difficult to treat.
Another key feature of this study was that AEs were absent or very limited. For these reasons, simultaneous treatment of multiple viruses with a single, banked CTL line is an interesting and promising alternative strategy for patients with refractory viral infections.
Roy F. Chemaly, MD:
With such data supporting multivirus-specific CTL treatment of refractory, post-HSCT viral infections, I wonder if a similar approach could be employed preventively in high-risk transplantation patients—such as cord blood or haploidentical recipients—where multiple viral reactivations can occur at a higher frequency. There would not be as large a volume of patients in this setting, but using this therapeutic option to prevent viral reactivation could be interesting.
I agree. The problem with treating several viruses with 1 CTL line is as follows: A donor-derived, virus-specific T-cell only recognizes its cognate epitope or peptide in the context of the appropriate HLA. Thus, the T-cells are said to be HLA restricted. If, for example, a CMV pp65-derived epitope is recognized in the context of HLA-A*0201, this restriction may not necessarily apply to EBV or adenovirus or BK virus at the same time, which means that T-cell would only recognize CMV. Therefore, the cell line may really be able to target all of the viruses in the same clinical setting or with the same HLA restriction pattern.
Good point. This is more a patient-targeted approach vs a general approach for every recipient.
Yes. That is the hypothesis at this point, but if each viral epitope and corresponding HLA restriction were identified, the appropriate CTL lines could be used in theory. That needs to be tested. The results, as presented here, validate that at least 2 viruses can simultaneously respond to a CTL line, and that is clearly impressive.
Safety: grade 1 skin GVHD, n = 1 (resolved); chronic skin GVHD flare, n = 3 (immunosuppression discontinued); transient fever, n = 2
*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.
Slide credit: clinicaloptions.com
Tzannou I, et al. ASH Abstract 501.

20. Predicting CMV Reactivation Risk and Therapeutic Response
CMV, cytomegalovirus.

21. REACT: Immune Response as a Predictor of CMV Reactivation in CMV-Seropositive HSCT Pts
Multicenter, prospective, observational study in which the immune responses of CMV-seropositive allogeneic HSCT pts (N = 244) were assessed to determine ability to predict CMV reactivation
Enzyme-linked immunospot (ELISPOT) assay used to assess IFN-γ production in PBMCs after ex vivo stimulation with CMV antigens IE1 and pp65
Serial blood draws assessed prior to and every 2 wks after transplant until Wk 26
Immune responses related to occurrence of posttransplant CMV events/disease*
HSCT donor most commonly matched unrelated (46%) or matched related (36%)
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; IFN, interferon; PBMC, peripheral blood mononuclear cell.
Roy F. Chemaly, MD:
REACT was a multicenter, prospective, observational study assessing the value of T-cell–mediated immune responses in predicting post-HSCT CMV reactivation/disease.[22] Responses were evaluated via enzyme-linked immunospot (ELISpot) assay in 244 CMV-seropositive allogeneic HSCT patients. Peripheral blood mononuclear cells were isolated from blood collected every 2 weeks up to Week 26 post HSCT and stimulated in vitro with CMV antigens IE-1 and pp65 to determine interferon-γ production.
For more information on this study, please see the associated Capsule Summary:
*CMV event = first episode of CMV reactivation requiring anti-CMV treatment; CMV disease = first evidence of end-organ disease.
Slide credit: clinicaloptions.com
Ariza-Heredia EJ, et al. BMT Tandem Abstract 38.

22. REACT: Time to Post-HSCT CMV Event per Immune Response
Time to CMV Event by Immune Response to pp65 CMV Antigen 60
Low response (pp65 ≤ 100 spot counts) 50 40
P < .0001
Significant CMV Event/Reactivation (%) 30 20
High response (pp65 > 100 spot counts) 10
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation.
Roy F. Chemaly, MD:
ELISpot response cutoffs were established for each of the CMV antigens tested. For pp65, spot counts of > 100 were considered a high response, whereas for IE-1, a high response started at > 50 spot counts. With each of these antigens, significantly longer times from HSCT to CMV events were observed in patients with high vs low T-cell responses.
This is an interesting study—it suggests that high immune response to CMV antigens may be predictive of not only the risk of reactivation but protection against CMV reactivation. This could be helpful in the future to predict who will need CMV preventive therapy and who will not.
For more information on this study, please see the associated Capsule Summary: 20 40 60 80
100
120
140
Days to Post-HSCT CMV Reactivation
Similar difference in time to CMV event observed with high vs low immune response to CMV antigen IE-1 (P < .0001)
Slide credit: clinicaloptions.com
Ariza-Heredia EJ, et al. BMT Tandem Abstract 38. Reproduced with permission.

23. REACT: Immune Response as a Predictor of CMV Reactivation
Multivariate Cox Regression Analysis: Likelihood of CMV Events
Outcome by CMV Immune Response
CMV Event by Antigen Response Level
IE-1
pp65
High response,* % (n/N)
8.9 (10/112)
8.1 (11/136)
Low response,* % (n/N)
40.8 (51/125)
49.5 (50/101)
Sensitivity, %
83.6
82.0
Specificity, %
58.0
71.0
PPV, %
40.8
49.5
NPV, %
91.1
91.9
Likelihood of CMV Events by Variable
P Value
HR (95% CI)
Maximum pp65 > 100 spot counts
< .0001
0.133 ( )
Recipient age
.9998
1.000 ( )
GVHD
.9668
0.988 ( )
Cord blood transplant
.9295
1.097 ( )
Haploidentical transplant
.1722
1.773 ( )
Matched or mismatched unrelated donor
.5144
1.231 ( )
Steroid use
.0064
5.364 ( )
Donor CMV seropositivity
.0694
1.685 ( )
CMV, cytomegalovirus; GVHD, graft-vs-host disease; PPV, positive predictive value; NPV, negative predictive value.
Roy F. Chemaly, MD:
The left-hand table on this slide shows CMV events according to CMV immune response level. Only 8.1% to 8.9% of patients demonstrating high antigen response experienced CMV reactivation, and 40.8% to 49.5% of patients exhibiting low response experienced CMV reactivation.
The negative predictive values of 91.1% for IE-1 and 91.9% for pp65 signified the percentage of patients with high antigen response who were protected from CMV reactivation. In the future, this type of measurement could be helpful in identifying which patients will require preventive CMV therapy after HSCT.
The right-hand table evaluates the likelihood of CMV events by multivariate Cox regression. Of the metrics listed, high response to pp65 was identified as an independent predictor of protection from CMV reactivation, and steroid use was a predictor of reactivation. Thus, even after controlling for multiple risk factors, these 2 variables significantly affected the probability of CMV reactivation.
For more information on this study, please see the associated Capsule Summary:
*High/low response levels: IE-1, > 50 vs ≤ 50 spot counts; pp65, > 100 vs ≤ 100 spot counts.
Slide credit: clinicaloptions.com
Ariza-Heredia EJ, et al. BMT Tandem Abstract 38.

24. pp65 > 100 and IE-1 > 50 Spot Counts
REACT: Immune Response at Post-HSCT Wk 2 as a Predictor of CMV Reactivation
Outcome by Antigen Response at Wk 2, % (n/n)
pp65 > 100 Spot Counts
pp65 > 100 and IE-1 > 50 Spot Counts
Any CMV Event
CMV Event by Wk 6
Sensitivity
96.7 (58/60)
96.1 (49/51)
98.3 (59/60)
98.0 (50/51)
Specificity
13.2 (23/174)
12.6 (23/183)
6.9 (12/174)
6.6 (12/183)
PPV
27.8 (58/209)
23.4 (49/209)
26.7 (59/221)
22.6 (50/221)
NPV
92.0 (23/25)
92.3 (12/13)
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; PPV, positive predictive value; NPV, negative predictive value.
Roy F. Chemaly, MD:
An associated study assessed ELISpot-detected antigen response at post-HSCT Week 2 to determine if responses at this early time point could predict CMV reactivation.[23] The negative predictive values for development of any CMV event or a CMV event by Week 6 in patients with high IE-1 and/or pp65 responses were consistently 92% across subgroups. Thus, a high T-cell response at post-HSCT Week 2 correlated with protection against CMV reactivation 92% of the time, at least through Week 6. A final analysis is awaited, where additional time points will be examined for predictive capacity, and risk factors potentially predisposing high responders to reactivation will be determined.
Guenther Koehne, MD, PhD:
In general, ELISpot assays are relatively easy to perform and tend to be quite reproducible. Although the patient population recognized as having high CMV T-cell responses in the REACT study was small, a protection against CMV reactivation was clear. I wonder, however, why patients at this early time point (Week 2) had such high T-cell responses. Around post-HSCT Week 2, very few T-cells and very little anti-CMV immunity would be expected. Are the observed high responder T-cells derived from the host at this early stage rather than the donor? This phenomenon, where host T-cells reoccur to prevent CMV, was previously described in the T-cell–depleted transplantation setting.[24]
Great point. Considerations of donor vs recipient T-cells are salient, especially early on after transplantation. Further analysis will try to control for variables such as the conditioning regimen, type of transplantation, and donor CMV serostatus.
Slide credit: clinicaloptions.com
Ariza-Heredia EJ, et al. BMT Tandem Abstract 39.

25. CMV Viremia and Preemptive Therapy Outcomes
CMV Viremia as a Predictor of CMV Clearance and Preemptive Therapy Response
Single-center retrospective analysis of CMV infection and preemptive therapy outcomes in allogeneic HSCT pts (N = 174)
Pts monitored for CMV viremia twice weekly for 100 days; viremia clearance defined as 2 negative PCR values ≥ 1 wk apart; preemptive therapy started at treating physician’s discretion
CMV Viremia and Preemptive Therapy Outcomes
Allogeneic HSCT (N = 174)
CMV viremia (n = 109; 63%)
No CMV viremia (n = 65; 37%)
Spontaneous clearance (n = 30; 28%)
Received antiviral therapy (n = 79; 72%)
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; NRM, nonrelapse mortality; PCR, polymerase chain reaction.
Roy F. Chemaly, MD:
This single-center retrospective analysis from the University of Miami investigated the relationship between CMV viremia and preemptive therapy outcomes in 174 allogeneic HSCT patients.[25] Participants were monitored for CMV viremia twice weekly for 100 days. Preemptive therapy was started at the discretion of the treating physician.
Overall, 109 of 174 patients (63%) reactivated their CMV. Within this subset, 30 patients (28%) spontaneously cleared viremia, and the remaining 79 patients (72%) met criteria to receive preemptive therapy. Just more than one half of these patients undergoing treatment cleared their viremia within 35 days; none of these patients experienced therapeutic failure. By contrast, in those who did not clear their viremia within 35 days of initiating preemptive therapy, the failure rate was 32%. One-year all-cause and nonrelapse mortality were lower in patients who did vs did not clear their CMV viremia within 35 days.
The considerable percentage of patients achieving spontaneous clearance is notable. As clinicians, we do sometimes overtreat these patients, beginning therapy before a patient may autonomously resolve viremia.
Failed therapy
(n = 0)
Cleared within 35 days
(n = 41; 53%)
Did not clear within 35 days
(n = 37; 47%)
Failed therapy
(n = 12; 32%)
1-Yr Mortality
All-cause: 9/41 (22%)
NRM: 5/34 (15%)
1-Yr Mortality
All-cause: 18/37 (49%)
NRM: 13/31 (42%)
Slide credit: clinicaloptions.com
Camargo JF, et al. BMT Tandem Abstract 221. Reproduced with permission.

26. CMV Viremia as a Predictor of CMV Clearance
Peak CMV viremia > 150 IU/mL associated with failure to attain spontaneous CMV clearance (univariate/multivariate risk ratios of 0.16/0.26, both P < .0001)
Spontaneous CMV Clearance by Peak CMV Viremia
100 80 60
Pts (%) 40
CMV, cytomegalovirus.
Roy F. Chemaly, MD:
By univariate and multivariate analyses, a peak CMV viremia of > 150 IU/mL was associated with a decreased probability of achieving spontaneous CMV clearance. Indeed, the rate of clearance decreased in a stepwise fashion as peak viremia thresholds increased. For instance, 25% of patients with peak viremia > 100 IU/mL demonstrated spontaneous CMV clearance vs 1% of patients with peak viremia > 500 IU/mL. Thus, in this study, reaching 200 IU/mL and above drastically reduced the chance of spontaneous CMV clearance. Even in high-risk patients, it may be advantageous to withhold treatment until a patient reaches a certain threshold of viremia. This would prevent the administration of unneeded therapy and avoid numerous AEs in this patient population. 20
25%
14% 4% 3% 1%
> 100
> 150
> 200
> 350
> 500
> 1000
Peak CMV Viremia (IU/mL)
Spontaneous clearance
Required treatment
Slide credit: clinicaloptions.com
Camargo JF, et al. BMT Tandem Abstract 221. Reproduced with permission.

27. CMV Viremia as a Predictor of CMV Treatment Response
NRM by Response to Therapy at Day 35
NRM by Overall Response to Therapy
1.0
1.0
0.8
0.8
CMV clearance (n = 54)
Persistent viremia (n = 11)
0.6
0.6
P < .01
Survival Probability
Survival Probability
0.4
0.4
P < .0001
Unresolved viremia by treatment Day 35 (n = 31)
Cleared viremia by treatment Day 35 (n = 34)
0.2
0.2
100
200
300
400
100
200
300
400
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; NRM, nonrelapse mortality.
Roy F. Chemaly, MD:
The left-hand graph and first bullet point on this slide recapitulate what was previously mentioned, in that unresolved or uncontrolled viremia at Day 35 translated to significantly poorer outcomes: higher all-cause and nonrelapse mortality. Hence, ongoing viremia approximately 1 month after transplantation predicted lower survival. The right-hand graph demonstrates that persistent viremia in the first year post transplantation was also associated with lower survival probability vs CMV clearance.
Guenther Koehne, MD, PhD:
Determining when to initiate CMV treatment is clearly a difficult clinical decision when viremia is detected at a low level such as 100 IU/mL or 150 IU/mL. In some settings, such as cord blood transplantation, it has been demonstrated that the sooner treatment is started, the better the clearance.[15] Even here, starting treatment at lower levels of CMV viremia was associated with a shorter median time to CMV clearance.
In total, 25% of patients with low peak viremia spontaneously cleared their CMV, but that means that 75% did not. As a clinician, I need to know if a patient falls within the 25% or the 75%, and it would be interesting to know why as well. As an example, did the patient develop host-derived CMV-specific T-cells that helped to clear the reactivation spontaneously? A predictive assay such as the one assessed in the REACT study could offer some insight here and provide rationale as to whether a patient should be treated immediately or not.
That is a great point. Unnecessarily delaying therapy in patients who need to be treated could lead to the worsened outcomes that can occur with persistent viremia.
Fusing data with the ELISpot assay from REACT and the results from this current study could provide the appropriate predictive power.
Yes, absolutely. Going forward, the data will hopefully be validated in multi-institution trials.
Days Post Transplant
Days Post Transplant
All-cause mortality higher for those with longer CMV clearance times (< 35 vs ≥ 35 days, 22% vs 49%, P = .01)
Starting treatment at lower levels of CMV viremia was associated with shorter median time to CMV clearance (< 350 IU/mL vs ≥ 350 IU/mL, 19 vs 33 days; P = .02)
Slide credit: clinicaloptions.com
Camargo JF, et al. BMT Tandem Abstract 221. Reproduced with permission.

28. Additional Studies

29. CMV Reactivation and Risk of Post-HSCT GVHD, Disease Relapse, and Infection
Single-center retrospective analysis of CMV reactivation and the risk of GVHD, disease relapse, and infection post–allogeneic HSCT (N = 324 consecutive pts)
CMV reactivation: CMV DNA ≥ 1000 copies/mL and antiviral therapy initiated
Baseline Characteristic
Pts (N = 324)
Recipient
Median age range, yrs
51-60
Male, % 56
Karnofsky score ≥ 90, % 68
AML/ALL/MDS, %
61/21/17
Disease status (CR1/active), %
56/24
Donor
31-40
Donor/recipient CMV serostatus (-/-, +/+, +/-, -/+), %
31, 28, 14, 28
Donor/recipient HLA match (8-8 match/7-8 match/haploidentical), %
83/14/3
Transplant type (PB/UCB/BM), %
78/12/10
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; CMV, cytomegalovirus; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndromes; PB, peripheral blood; UCB, umbilical cord blood.
Roy F. Chemaly, MD:
This single-center retrospective analysis evaluated post–allogeneic HSCT CMV reactivation and its effect on the risk of graft-vs-host disease (GVHD), malignant disease relapse, or infection in 324 consecutive patients.[26]
Slide credit: clinicaloptions.com
Auletta JJ, et al. ASH Abstract 3409.

30. Impact of CMV Reactivation on GVHD, Infection, and Relapse Post-HSCT
Outcome Risk by Factor
HR (P Value)
Risk of CMV reactivation†
Acute GVHD grade 1*
1.84 (.073)
Acute GVHD grade 2*
1.93 (.013)
Acute GVHD grade 3/4*
3.36 (< .001)
Recipient CMV seropositive
18.33 (< .001)
Risk of acute GVHD during CMV reactivation†
0.93 (.825)
Risk of any infection during CMV reactivation†
1.64 (.342)
Risk of disease relapse during CMV reactivation†
0.20 (.131)
1.0
First CMV Reactivation, Cumulative Incidence
0.8
0.6
Probability
0.4
0.2 50
100
150
200
Days Post-HSCT
1.0
Acute GVHD, Cumulative Incidence
0.8
Grade 1 (n = 44)
Grade 2 (n = 115)
Grade 3 (n = 40)
Grade 4 (n = 9)
CMV, cytomegalovirus; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation.
Risk of CMV reactivation adjusted for CMV serostatus, ANC engraftment, and related donors/recipients. Risk of acute GVHD during CMV reactivation adjusted for graft type, donor/recipient gender, ANC engraftment, and TBI conditioning. Risk of any infection during CMV reactivation adjusted for conditioning intensity, growth factor, and number of CD3+ cells infused. Risk of disease relapse during CMV reactivation adjusted for recipient disease, donor/recipient CMV serostatus, GVHD prophylaxis, disease risk classification, infection, and Karnofsky score.
Roy F. Chemaly, MD:
Not surprisingly, patients who developed acute GVHD grades 2-4 or with CMV seropositivity were at significantly increased risk for subsequent CMV reactivation. What was especially interesting in this study, however, was that CMV reactivation did not trigger an increased risk of GVHD. There was no increased risk of infection or relapse during reactivation either.
0.6
Probability
0.4
0.2
Proportional subdistribution hazard model. *vs no acute GVHD. †Adjusted for several factors; see slidenotes. 50
100
150
200
Days Post-HSCT
Slide credit: clinicaloptions.com
Auletta JJ, et al. ASH Abstract Reproduced with permission.

31. Impact of CMV Reactivation and GVHD on Survival Outcomes Post-HSCT
1.00
Overall Survival
0.6
Nonrelapse Mortality
0.6
Infection-Related Mortality
0.6
Disease-Related Mortality
0.5
0.5
0.5
0.75
0.4
0.4
0.4
0.50
0.3
0.3
0.3
0.2
0.2
0.2
0.25
0.1
0.1
0.1
500
1000
1500
2000
500
1000
1500
2000
500
1000
1500
2000
500
1000
1500
2000
Days Post-HSCT
Days Post-HSCT
Days Post-HSCT
Days Post-HSCT
Landmark Analysis: Impact of CMV Reactivation and Acute GVHD on Post-HSCT Survival/Mortality
CMVr Status No
Yes
aGVHD Status
Post-HSCT Day 100 Risk, HR (P Value) OS
NRM
IRM
DRM
No CMVr/no aGVHD
1 (--)
CMVr/no aGVHD
0.41 (.037)
1.43 (.557)
1.54 (.571)
0.41 (.091)
No CMVr/aGVHD
0.58 (.015)
1.39 (.434)
1.24 (.685)
0.46 (.005)
CMVr/aGVHD
0.77 (.33)
2.85 (.014)
3.65 (.008)
0.52 (.04)
Recipient CMV seropositive
1.61 (.029) NR
aGVHD, acute graft-vs-host disease; CMV, cytomegalovirus; CMVr, cytomegalovirus reactivation; DRM, disease-related mortality; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; IRM, infection-related mortality; NR, not reported; NRM, nonrelapse mortality; OS, overall survival.
Roy F. Chemaly, MD:
In patients with acute GVHD, OS was significantly improved when CMV reactivation did not occur in the first 100 post-HSCT days.
Guenther Koehne, MD, PhD:
There were several important aspects of this study. First, it came as no surprise that the presence of GVHD promoted CMV reactivation, as treatment of GVHD with immunosuppressive steroids can increase reactivation risk. But CMV reactivation did not appear to influence the development of GVHD. Other data have previously supported this bidirectional correlation.[27,28]
The other important takeaway message from this study was that CMV reactivation does not affect the risk of malignant disease relapse. More and more evidence, now including this study, confirms that this is the case.
Slide credit: clinicaloptions.com
Auletta JJ, et al. ASH Abstract Reproduced with permission.

32. KIR Ligand Donor/Recipient Matching to Prevent CMV Reactivation Post Transplant
Prospective study in which haploidentical, T-cell–replete HSCT recipients and donors were KIR- and/or HLA-typed to determine if KIR ligand matching could prevent CMV reactivation (N = 180)[1]
Killer immunoglobulin-like receptors: present on NK cells and specific for HLA-I ligands; ligand binding promotes licensing and anti-CMV activity of NK cells[2]
CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; KIR, killer immunoglobulin-like receptor; NK, natural killer.
Slide credit: clinicaloptions.com
1. Zhao XY, et al. ASH Abstract Di Bona D, et al. J Infect Dis. 2014;210:

33. KIR Ligand Donor/Recipient Matching: Key Results
CMV Viremia
1.0
1.0
CMV Infection
0.8
0.8
0.6
0.6
Cumulative Incidence of CMV Viremia
Cumulative Incidence of Refractory CMV Viremia
0.4
0.4
0.2
0.2
P = .012
P = .004 20 40 60 80
100 20 40 60 80
100
Days Post Transplant
Days Post Transplant
1.0
CMV Disease
Donor and recipient L-L mismatch (n = 89)
0.8
Donor and recipient L-L match (n = 91)
CMV, cytomegalovirus; KIR, killer immunoglobulin-like receptor.
0.6
Cumulative Incidence of CMV Disease
0.4
P = .02
0.2 20 40 60 80
100
Days Post Transplant
Slide credit: clinicaloptions.com
Zhao XY, et al. ASH Abstract Reproduced with permission.

34. Go Online for More CCO Coverage of CMV!
Capsule Summaries of the most clinically relevant new data on CMV infection in BMT recipients from the Hematology 2016 and BMT Tandem 2017 meetings CME-certified Expert Analysis with expert commentary on the studies in these slides CME-certified video and downloadable slides in which expert faculty discuss key aspects and best practices in managing post-BMT CMV infection
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Chemaly RF, Ullmann AJ, Stoelben S, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014;370:
Marty FM, Ljungman PT, Chemaly RF, et al. A phase III randomized, double-blind, placebo-controlled trial of letermovir (LET) for prevention of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract LBA2.
Drew WL, Miner RC, Marousek GI, et al. Maribavir sensitivity of cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet. J Clin Virol. 2006;37:
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Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011;11:
Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for treatment of cytomegalovirus infections resistant or refractory to ganciclovir or foscarnet in hematopoietic stem cell transplant or solid organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract 45.
Avery RK, Arav-Boger R, Marr KA, et al. Outcomes in transplant recipients treated with foscarnet for ganciclovir-resistant or refractory cytomegalovirus infection. Transplantation. 2016;100:e74-e80.
ClinicalTrials.gov. A phase 3, multicenter, randomized, open-label, active-controlled study to assess the efficacy and safety of maribavir treatment compared to investigator-assigned treatment in transplant recipients with cytomegalovirus (CMV) infections that are refractory or resistant to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir. Available at: Accessed April 6, 2017.
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ClinicalTrials.gov. A phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study to assess the efficacy and safety of maribavir compared to valganciclovir for the treatment of cytomegalovirus (CMV) infection in hematopoietic stem cell transplant recipients. Available at: Accessed April 6, 2017.
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Lau C, Bhatt V, Dahi P, et al. Incidence, severity, day 100 treatment efficacy and therapy toxicity of cytomegalovirus (CMV) infections with early pre-emptive therapy in adult cord blood (CS) transplant recipients. Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract 228.
Koehne G, Hasan A, Doubrovina E, et al. Immunotherapy with donor T Cells sensitized with overlapping pentadecapeptides for treatment of persistent cytomegalovirus infection or viremia. Biol Blood Marrow Transplant. 2015;21:
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Gupta MP, Coombs P, Prockop SE, et al. Treatment of cytomegalovirus retinitis with cytomegalovirus-specific T-lymphocyte infusion. Ophthalmic Surg Lasers Imaging Retina. 2015;46:80-82.
O’Reilly RJ, Prockop S, Hasan AN, et al. Virus-specific T-cell banks for “off the shelf” adoptive therapy of refractory infections. Bone Marrow Transplant. 2016;51:
Prockop S, Doubrovina E, Hasan AN, et al. Third party CMV-specific cytotoxic T cells for treatment of antiviral resistant CMV infection after hematopoietic stem cell transplant. Program and abstracts of the 58th American Society of Hematology Annual Meeting and Exposition; December 3-6, 2016; San Diego, California. Abstract 61.
Tzannou I, Papadopoulou A, Watanabe A, et al. Administration of most closely HLA-matched multivirus-specific T cells for the treatment of EBV, CMV, AdV, HHV6, and BKV post allogeneic hematopoietic stem cell transplant. Program and abstracts of the 58th American Society of Hematology Annual Meeting and Exposition; December 3-6, 2016; San Diego, California. Abstract 501.
Ariza-Heredia EJ, Shah DP, Winston DJ, et al. A prospective observational study to evaluate a cytomegalovirus (CMV)-specific enzyme-linked immunospot (ELISPOT) assay in allogeneic hematopoietic cell transplant (allo-HCT) recipients: the REACT study. Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract 38.
Ariza-Heredia EJ, Shah DP, Winston DJ, et al. The impact of pre- and week 4 post-transplant CMV-specific ELISPOT assay on CMV reactivation and survival in CMV-seropositive allogeneic hematopoietic cell transplant (allo-HCT) recipients. Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract 39.
Sellar RS, Vargas FA, Henry JY, et al. CMV promotes recipient T-cell immunity following reduced-intensity T-cell-depleted HSCT, significantly modulating chimerism status. Blood. 2015;125:
Camargo JF, Shimose L, Bueno MX, et al. Impact of cytomegalovirus (CMV) viral load on probability of spontaneous clearance and efficacy of pre-emptive therapy among CMV seropositive allogeneic stem cell transplant recipients. Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract 221.
Auletta JJ, Ardura MI, Vasu S, et al. Cytomegalovirus reactivation does not increase subsequent risk for acute graft-versus-host disease, malignant disease relapse, or infection following allogeneic hematopoietic cell transplantation. Program and abstracts of the 58th American Society of Hematology Annual Meeting and Exposition; December 3-6, 2016; San Diego, California. Abstract 3409.
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Hall CE, Koparde VN, Jameson-Lee M, et al. Cytomegalovirus antigenic mimicry of human alloreactive peptides: exploring cross-reactivity as a potential trigger for graft versus host disease. Program and abstracts of the 2017 BMT Tandem Meetings; February 22-26, 2017; Orlando, Florida. Abstract 93.
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