Abstract
Background
A systematic review and meta-analysis of real-world observational studies was conducted to summarize the impact of letermovir cytomegalovirus (CMV) primary prophylaxis (PP) among adult allogeneic hematopoietic cell transplant (allo-HCT) recipients.
Methods
Systematic searches in Medline/PubMed, Embase, and conferences (from database inception to October 2021) were conducted to identify studies for inclusion. Random-effects models were used to derive pooled estimates on the relative effectiveness of letermovir PP compared to controls.
Results
Forty-eight unique studies (N = 7104 patients) were included, most of which were comparative, single-center, and conducted in the United States. Letermovir PP was associated with statistically significant reduction in odds of CMV reactivation (pooled odds ratio [pOR], 0.13 and 0.24; P < .05), clinically significant CMV infection (pOR, 0.09 and 0.19; P < .05), and CMV disease (pOR, 0.31 and 0.35; P < .05) by day +100 and day +200 after allo-HCT, respectively. Letermovir PP was associated with significantly lower odds of all-cause (pOR, 0.73; P < .01) and nonrelapse mortality (pOR, 0.65; P = .01) beyond day 200 after allo-HCT.
Conclusions
Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.
Keywords: allogeneic hematopoietic cell transplantation, cytomegalovirus, letermovir, meta-analysis
We summarized and analyzed real-world effectiveness of letermovir primary prophylaxis (PP) for cytomegalovirus (CMV) reactivation, clinically significant CMV infection, CMV disease, and mortality among adult allogeneic hematopoietic cell transplant recipients. Letermovir PP reduced the risk of CMV-related complications overall, including mortality beyond day 200.
INTRODUCTION
Cytomegalovirus (CMV) reactivation is common after allogeneic hematopoietic cell transplantation (allo-HCT) and can lead to serious complications [1, 2]. If left untreated, it can result in tissue-invasive CMV disease [3–6] and can have damaging effects including increased risk of other infections, graft failure, and death [7]. Historically, preemptive therapy (PET) for CMV infection and disease with ganciclovir, valganciclovir, or foscarnet has been utilized to avoid prolonged medication exposure, thereby limiting undesirable myelosuppressive or nephrotoxicity associated with these agents [8–12]. However, PET has shown to increase the risk of neutropenia and acute kidney injury [13], which ultimately increases the risk of mortality [14] and healthcare resource utilization [15–17].
Letermovir was approved by the United States (US) Food and Drug Administration in November 2017 and the European Medicines Agency in January 2018 for the prophylaxis of CMV infection and disease in adult CMV-seropositive (R+) allo-HCT recipients. A phase 3 trial showed that letermovir primary prophylaxis (PP) reduced clinically significant CMV infection (cs-CMVi) at 24 weeks post-HCT compared to placebo [18]. Additional analysis of the phase 3 dataset showed that patients who received letermovir had lower all-cause mortality at week 24 (10.2% vs 15.9%, P = .03) and numerically lower mortality at week 48 (P > .05) compared to those who received placebo [19].
Several site-specific real-world studies have been published to evaluate the real-world effectiveness of letermovir PP in allo-HCT recipients, many of which have smaller sample sizes. A comprehensive systematic literature review and meta-analysis of all real-world studies published till recently is yet not available. Such a systematic review and meta-analysis will help better understand the effectiveness of letermovir PP in a larger representative patient sample across multiple study sites. Therefore, we conducted a systematic review and meta-analysis of real-world observational studies focusing on the incidence of CMV reactivation (CMVr), cs-CMVi, and CMV disease (CMVd), other clinical outcomes including mortality, and healthcare resource utilization following PP with letermovir among adult allo-HCT recipients.
METHODS
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [20–22].
Inclusion Criteria for the Systematic Review
Studies eligible for inclusion were prospective or retrospective observational studies published in English language and with no geographical restrictions. We included prospective or retrospective observational studies that used either case-control or cohort design. We included studies with a population of adults undergoing allo-HCT, received letermovir PP for the intervention group, and had no comparator (single-arm study) or had a control group with no letermovir PP (with or without PET). We excluded studies where letermovir was utilized as a secondary prophylaxis or for treatment of CMV infection.
Systematic Literature Search
A comprehensive systematic search of real-world evidence was conducted in Embase and PubMed using a combination of keywords that included “letermovir,” “cytomegalovirus or CMV or cytomegaloviral,” or “transplant or transplantation” as text words, title/abstract, or exploded terms, from their inception through October 2021. We also searched conference proceedings indexed in Embase as well as specifically searched abstracts and retrieved posters presented at Transplant Cellular Therapy meetings, European Blood and Marrow Transplantation meetings, European Hematology Association Meetings, American Society of Clinical Oncology meetings, and IDWeek meetings using the conference portal and contacting authors for access to full posters. References of the included studies and relevant systematic reviews were also searched for additional studies.
Study Selection, Data Extraction, and Study Quality Assessment
Titles and abstracts of studies were reviewed by 1 of the co-authors (A. V.) to determine eligibility for the full text review based on the predefined criteria. Then, 2 reviewers (A. V. and S. K.) independently examined the full text reports of all the articles that were deemed eligible. Disagreements were resolved through discussion.
Data from all studies that met the eligibility criteria were extracted by 1 reviewer (S. K.) and validated by a second one (A. V.). Data on specific characteristics of the studies, interventions, patients, and outcomes were extracted. For outcomes, data on CMV outcomes (including presence of CMVr, cs-CMVi, and CMVd), indirect outcomes (including graft-vs-host disease [GVHD], all-cause mortality, and nonrelapse mortality) and healthcare resource use and costs (including CMV-related hospitalization) were extracted when available at different time points from allo-HCT (D+100: follow-up of 100 days or 14 weeks; D+200: follow-up of 200 days or 24 weeks; and beyond D+200: follow-up of ≥200 days or ≥24 weeks). Any discrepancies were resolved through discussion and by a third reviewer (K. L.).
Two independent reviewers appraised methodological quality of the eligible real-world observational studies using the Newcastle-Ottawa Scale [23]. Studies with scores ≥7, 4–6, and <4 were considered high, moderate, and low quality, respectively.
Data Synthesis and Statistical Analysis
The feasibility of performing meta-analysis for each outcome was assessed. Any substantial variations in the disease characteristics, time period within which outcomes occurred, and the type of publication were assessed. Based on heterogeneity across studies, we pooled the data from the relevant studies for meta-analysis on each outcome of interest using the random-effects model. Pooled odds ratios (pORs) and the corresponding 95% confidence intervals (CIs) and P values for each outcome were determined. Heterogeneity between studies was examined using I2 statistics and Cochrane χ2 statistics. Subgroup analyses by country of study (US/non-US), full publication versus abstracts/presentations, studies with R+-only patients versus R+ and other risk factors, studies that included cord-blood recipients only, and high-CMV-risk patients only were performed for certain outcomes as we found moderate (30%–60%) to substantial (50%–90%) heterogeneity in the meta-analyses. Publication bias was assessed for cs-CMVi, CMVd, CMVr, and all-cause mortality (outcomes for which >10 studies were available) using Egger method. Additionally, contour-enhanced funnel plots were used to identify publication bias by examining the plot symmetry. Statistical software R was used to perform meta-analyses.
RESULTS
Of 576 retrieved citations identified, 60 citations representing 48 unique studies (see Supplementary Appendix 1 for the list of citations and unique studies) met the inclusion criteria (Figure 1).
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram for study selection. Abbreviations: CMV, cytomegalovirus; RCT, randomized controlled trial.
Study and Patients’ Characteristics
Most of the studies were comparative retrospective cohort studies (n = 40 [83.3%]), were single-center studies (n = 43 [89.6%]), and were conducted in the US (n = 28 [58.3%]), Italy (n = 7 [14.6%]), or Japan (n = 5 [10.4%]) (Table 1). Twenty-two studies (45.8%) were full publications whereas 26 studies (54.2%) were conference proceedings. The patient sample size ranged from 12 to 204 patients in the letermovir arm and 18 to 637 patients in the control arm. Table 2 lists the CMV serostatus and inclusion–exclusion criteria of patients in each included study. Of the 40 comparative studies, 21 studies had PET historical group as a comparator, 13 had nonletermovir historical group as a comparator, 4 had CMV prophylaxis historical group as a comparator, and 2 had matched historical group as a comparator.
Table 1.
Characteristics of the Included Real-World Studiesa of Letermovir Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients
| Study IDb | Country | LET Identification Period | Control Identification Period | Historic Control vs Parallel Control | Total Sample Size, No. | LET, No. | Comparator, No. |
|---|---|---|---|---|---|---|---|
| Comparative retrospective cohort studies | |||||||
| Anderson, 2020 | US | Mar 2018–Jan 2019 | Sep 2012–May 2016 | Historic | 131 | 25 | 106 |
| Derigs, 2021 | Germany | Mar 2018–Mar 2019 | Jan 2017–Mar 2018 | Historic | 160 | 80 | 80 |
| Sassine, 2021 | US | Mar 2016–Feb 2018 | Mar 2018–Oct 2018 | Historic | 537 | 123 | 414 |
| Hill, 2021 | US | Oct 2018–Dec 2019 | 2014–2017 | Historic | 61 | 21 | 40 |
| Hosoi, 2020 | Japan | Oct 2018–Mar 2020 | Oct 2016–Mar 2018 | Historic | 44 | 22 | 22 |
| Johnsrud, 2020 | US | Jan 2018–Dec 2019 | Jan 2013–May 2019 | Historic | 745 | 108 | 637 |
| Zavras, 2019 | US | Dec 2017–2018 | 2017 | Historic | 193 | 98 | 95 |
| Lin, 2020 | US | Jan 2018–2019 | 2014–2017 | Historic | 64 | 32 | 32 |
| Malagola, 2020 | Italy | Dec 2018–Apr 2020 | Nov 2017–Nov 2018 | Historic | 86 | 45 | 41 |
| Marzolini, 2021c | UK | Jul 2019–Aug 2020 | Jan 2006–Feb 2017 | Historic | 344 | 110 | 234 |
| Mori, 2021c | Japan | Jan 2015–Mar 2019d | … | Historic | 685 | 114 | 571 |
| Royston, 2021 | Switzerland | May 2019–May 2020 | Jan 2015–May 2019 | Historic | 78 | 26 | 52 |
| Serio, 2021 | Italy | Feb 2012–Sep 2020d | … | Historic | 35 | 13 | 22 |
| Sperotto, 2021 | Italy | Jan 2016–Mar 2020d | … | Historic | 110 | 55 | 55 |
| Studer, 2020 | Switzerland | 2019–2020 | 2010–2018 | Historic | 381 | 28 | 353 |
| Sharma, 2020 | US | 2018 | Dec 2009–Dec 2018 | Historic | 133 | 32 | 101 |
| Terao, 2021 | Japan | 2018–Aug 2020 | Jan 2014–2018 | Historic | 48 | 25 | 23 |
| Wolfe, 2021 | US | Jul 2018–Jun 2020 | Jun 2016–Jul 2018 | Historic | 262 | 119 | 143 |
| Archambeau, 2019 | US | Mar 2018–Feb 2019 | Mar 2017–Feb 2018 | Historic | 109 | 42 | 67 |
| Bradshaw, 2021 | US | NR | NR | Historic | 91 | 28 | 63 |
| Cutini, 2021 | Italy | 2019–2020 | 2016–2018 | Historic | 121 | 31 | 90 |
| Dadwal, 2019 | US | Feb 2018–Jun 2018 | Jan 2017–Feb 2018 | Historic | 338 | 59 | 279 |
| Desnica, 2021 | Croatia | Jun 2019–Jun 2020d | NR | Historic | NR | 90 | NR |
| Dwabe, 2020 | US | 2018–2020d | NR | NR | 116 | 71 | 45 |
| Faraci, 2021 | Italy | 2019–Apr 2020 | Jan 2015–2019 | Historic | 93 | 19 | 74 |
| Freyer, 2021 | US | Feb 2019–May 2020 | Feb 2013–Jan 2019 | Historic | 37 | 19 | 18 |
| Hedvat, 2019 | US | Nov 2017–Mar 2019 | Jul 2016–Nov 2017 | Historic | 150 | 50 | 100 |
| Jinnouchi, 2020 | Japan | NR | After 2008 | Historic | 62 | 31 | 31 |
| Karam, 2019 | US | 2017–2019d | … | Historic | 104 | 63 | 41 |
| Koch, 2021 | Germany | Jan 2017–Aug 2020d | … | Historic | 48 | 27 | 21 |
| Lau, 2020 | US | Dec 2017–Jun 2019 | Mar 2013–Dec 2017 | Historic | 82 | 20 | 62 |
| Loecher, 2020 | US | Jun 2018–Jun 2019 | Jun 2017–Jun 2018 | Historic | 67 | 31 | 36 |
| Markowski, 2019 | US | Jan 2014–Dec 2018d | … | Historic | 85 | 15 | 70 |
| Merchant, 2019 | US | Dec 2017–Aug 2018 | NR | Historic | 65 | 30 | 35 |
| Muhsen, 2021 | US | Jan 2016–Jun 2020d | … | Historic | 79 | 24 | 55 |
| Myers, 2021 | US | NR | NR | Historic | 192 | 38 | 154 |
| Ngyuen, 2020 | Germany | 2018+ | 2013–2017 | Historic | 347 | 12 | 335 |
| Satake, 2020 | Japan | May 2018–Aug 2019 | Jan 2009–Apr 2018 | Historic | NR | 27 | NR |
| Shahan, 2021 | US | Jul 2019–Oct 2020 | Mar 2018–Jun 2019 | Historic | 59 | 26 | 33 |
| Smith, 2021c | UK | Jul 2019–Oct 2020e | Jan 2004–Feb 2014 | Historic | 184 | 60 | 124 |
| Single-arm retrospective cohort studies | |||||||
| Abidi, 2021f | US | NR | … | NA | 26 | 26 | … |
| Bansal, 2021 | US | Jan 2018–Jan 2020 | … | NA | 20 | 20 | … |
| Cassaniti, 2021c | Italy | NR | … | NA | 75 | 75 | … |
| Chen, 2021 | US | Nov 2017–Dec 2019 | … | NA | 60 | 60 | … |
| Ferrari, 2019 | US | Jan 2018–Sep 2018 | … | NA | 25 | 25 | … |
| Kodiyanplakkal, 2019 | US | Jan 2018–Jan 2019 | … | NA | 31 | 31 | … |
| Paviglianiti, 2021c | Italy | Jan 2019–Jun 2020 | … | NA | 204 | 204 | … |
| Patel, 2020 | US | May 2018–Dec 2019 | … | NA | 20 | 20 | … |
| Total sample size | … | … | … | … | 7104 | 2350 | 4754 |
Abbreviations: LET, letermovir; NA, not applicable; NR, not reported; UK, United Kingdom; US, United States.
Full publication studies: Anderson 2020, Bansal 2020, Cassaniti 2021, Chen 2021, Derigs 2020, Sassine 2021, Hill 2021, Hosoi 2020, Johnsrud 2020, Zavras 2019, Lin 2020, Malagola 2020, Marzolini 221, Mori 2020, Paviglianiti 2021, Royston 2021, Serio 2021, Sperotto 2021, Studer 2020, Sharma 2020, Terao 2021, Wolfe 2021. Abstract/poster studies: Abidi 2021, Archambeau 2019, Bradshaw 2021, Cutini 2021, Dadwal 2019, Desnica 2021, Dwabe 2020, Faraci 2021, Ferrari 2019, Freyer 2021, Hedvat 2019, Jinnouchi 2020, Karam 2019, Koch 2021, Kodiyanplakkal 2019, Lau 2020, Loecher 2020, Markowski 2019, Muhsen 2021, Myers 2021, Ngyuen 2020, Patel 2020, Satake 2020, Shahan 2021, Smith 2021.
Citations of all the included studies are found in Supplementary Appendix 1.
Multicenter study.
Identification period for both letermovir and comparator groups.
Study focused on adult patients, but LET group included patients in the age range 16–74 years.
Prospective cohort study.
Table 2.
Patient Characteristics of the Included Real-World Studies of Letermovir Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients
| Study IDa | Included CMV Serostatus | Inclusion Criteria | Exclusion Criteria |
|---|---|---|---|
| Comparative retrospective cohort studies | |||
| Anderson, 2020 | R+ | Allo-HCT + (HAPLO/UCB/MMURD/prednisone for acute GVHD) | Died within 30 days post-HCT or had active CMV DNAemia at the time of LET initiation or <100 days follow-up |
| Derigs, 2021 | R+ | Allo-HCT | … |
| Sassine, 2021 | R+ | Allo-HCT | R– recipients |
| Hill, 2021 | R+ | Allo-HCT + UCB | Received CMV treatment at index HCT |
| Hosoi, 2020 | NR | Allo-HCT | Engraftment failure, died, or relapsed within 60 days post-HCT |
| Johnsrud, 2020 | R+ or D+ | Allo-HCT + (HAPLO/UCB/MMURD/ATG/CD34+ selected graft/considered at high risk by the provider) | Previous transplant; no CMV measurements; participated in RCT |
| Zavras, 2019 | R+ | Allo-HCT + (PB/BM) | UCB recipients |
| Lin, 2020 | R+ | Allo-HCT + (PB/BM) + (HAPLO/HLA MMURD) + PTCy | UCB recipients |
| Malagola, 2020 | R+ or D+ | Allo-HCT | … |
| Marzolini, 2021 | R+ | Allo-HCT + (alemtuzumab) | … |
| Mori, 2021 | D+/− or R+/− | Allo-HCT | Received other prophylactic agent for CMV reactivation, graft failure, or died before engraftment |
| Royston, 2021 | R+ | Allo-HCT | … |
| Serio, 2021 | R+ or D+ | Allo-HCT | … |
| Sperotto, 2021 | R+ | Allo-HCT + (HAPLO/MMURD/MUD/ATG regimen and/or prednisone treatment) | Died within 29 days post-HCT |
| Studer, 2020 | R+ | Allo-HCT | Survived at least until day +180 without LET prophylaxis |
| Sharma, 2020 | R+ | Allo-HCT + (HAPLO/UCB) | Baseline CMV reactivation, graft failure, death, or relapse before day 100, or participated in CMV prophylaxis trial |
| Terao, 2021 | R+ or D+ | Allo-HCT + HAPLO + PTCy + PB; Allo-HCT + MRD + PB | … |
| Wolfe, 2021 | R+ | Allo-HCT + acute GVHD | … |
| Archambeau, 2019 | R+ or D+ | Allo-HCT | CrCl <10 mL/min; severe liver impairment; foscarnet/ganciclovir use within 90 days posttransplant |
| Bradshaw, 2021 | R+ | Allo-HCT | R– recipients, LET missed/held for ≥5 doses, CMV reactivation prior to LET PP |
| Cutini, 2021 | R+ | Allo-HCT + hematologic malignancies | … |
| Dadwal, 2019 | R+ | Allo-HCT | … |
| Desnica, 2021 | R+/− | Allo-HCT | … |
| Dwabe, 2020 | R+/− | Allo-HCT | … |
| Faraci, 2021 | R+/D− | Allo-HCT | Not able to take oral therapy at day +7 posttransplant or those with major pharmacokinetic interactions |
| Freyer, 2021 | R+ | Allo-HCT + HAPLO + PTCy | … |
| Hedvat, 2019 | R+ | Allo-HCT | … |
| Jinnouchi, 2020 | NR | Allo-HCT | … |
| Karam, 2019 | R+ | Allo-HCT + (HAPLO/UCB/MUD/ATG) | … |
| Koch, 2021 | R+ | Allo-HCT | … |
| Lau, 2020 | R+ | Allo-HCT + CB | … |
| Loecher, 2020 | R+ | Allo-HCT | … |
| Markowski, 2019 | NR | Allo-HCT + (HAPLO/ MUD/MRD) + PTCy | … |
| Merchant, 2019 | R+ or D+ | Allo-HCT + (HAPLO/UCB/MUD with ATG/ruxolitinib use/prednisone use) | Active CMV reactivation prior to LET initiation or anti-CMV treatment posttransplant |
| Muhsen, 2021 | R+ | Allo-HCT + unrelated donor + alemtuzumab | … |
| Myers, 2021 | D+/− or R+/− | Allo-HCT | … |
| Ngyuen, 2020 | NR | Allo-HCT | … |
| Satake, 2020 | NR | Allo-HCT | … |
| Shahan, 2021 | R+ | Allo-HCT | … |
| Smith, 2021 | R+ | Allo-HCT | … |
| Single-arm retrospective cohort studies | |||
| Abidi, 2021 | R+ | Allo-HCT + (HAPLO/UCB/pre-HCT CMV cell-mediated immunity) | <180 days follow-up posttransplant |
| Bansal, 2021 | R+ | Allo-HCT + (acute/chronic GVHD) | Those without GVHD within 100 days after LET PP |
| Cassaniti, 2021 | R+ | Allo-HCT | Baseline CMV viremia with D0–D5 post-HCT or received CMV treatment at index transplant |
| Chen, 2021 | R+ | Allo-HCT + (HAPLO/MMRD/MMURD/UCB/GVHD prophylaxis) | Use of secondary prophylaxis; quantifiable CMV DNAemia prior to LET initiation; R– with high-risk HCT procedure; participation in RCT; <10 days LET PP |
| Ferrari, 2019 | R+ or D+ | Allo-HCT | Pediatric patients |
| Kodiyanplakkal, 2019 | R+ | Allo-HCT + (rATG/alemtuzumab) | CMV DNA prior to PP |
| Paviglianiti, 2021 | R+ | Allo-HCT | Incomplete data |
| Patel, 2020 | R+ | Allo-HCT + HAPLO | CMV end-organ disease within 6 mo of HCT, history of viremia at any point prior to transplant, received PET within 7 days of transplant |
Abbreviations: –, negative; +, positive; Allo-HCT, allogeneic hematopoietic stem cell transplantation; ATG, antithymocyte globulin; BM, bone marrow; CB, cord blood; CMV, cytomegalovirus; CrCl, creatinine clearance; D, donor; GVHD, graft-versus-host disease; HAPLO, haploidentical; HCT, hematopoietic stem cell transplant; HLA, human leukocyte antigen; LET, letermovir; MMURD, mismatched unrelated donor; MRD, matched related donor; MUD, matched unrelated donor; NR, not reported; PB, peripheral blood; PET, preemeptive therapy; PP, primary prophylaxis; PTCy, posttransplant cyclophosphamide; R, recipient; rATG, rabbit antithymocyte globulin; RCT, randomized controlled trial; UCB, umbilical cord blood.
Citations of all the included studies are found in Supplementary Appendix 1.
Twenty-seven studies included any type of allo-HCT (56.3%), 3 studies included cord-blood transplant recipients only (6.3%), and 18 studies (37.5%) included haploidentical, cord-blood, or unrelated donor cell recipients, with GVHD, and/or in the setting of posttransplant GVHD prophylaxis or T-cell depletion therapy. Of the 48 studies, 22 (45.8%) included patients who were at high risk of CMV infection and/or disease as per the authors of these studies (Table 3). The median days for initiation of letermovir PP was in the range of 0–42 days posttransplant, while the duration of letermovir prophylaxis ranged between 79 and 191 days.
Table 3.
Details of Letermovir Primary Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients
| Study IDa | Inst. Protocol for LET | Time to Initiate LET, days, Median (Range)/[IQR] | Duration of LET, days, Median, (Range)/[IQR] | Preparative/Conditioning Regimen Type | GVHD Prophylaxis | High Risk of CMV | Protocol on Time of Initiation | PET Protocol/Threshold | Comparator Type | Definition of Comparator |
|---|---|---|---|---|---|---|---|---|---|---|
| Comparative retrospective cohort studies | ||||||||||
| Anderson, 2020 | … | 10 [10–10] | 89 [56–93] | MAC, RIC, or NMA | NR | HAPLO, MMURD, UCB, acute GVHD requiring prednisone | D10–D100 | CMV VL ≥200 IU/mL on 2 consecutive tests | HC: PET | PET treatment as per local protocol |
| Derigs, 2021 | R+ | 19 | NR | MAC or RIC | Cyc + MTX; Cyc + MMF; TAC + MTX; TAC + MMF | … | D0–D100 | CMV VL >3200 IU/mL | HC: PET | VAL, GAN, FOS |
| Sassine, 2021 | R+ | NR | NR | MAC or RIC or NMA | TAC/MTX; ATG/TAC/MTX; PTCy/TAC; PTCy/TAC/MMF; TAC/MMF; ATG/TAC/MMF | … | D5–D100+ | CMV monitoring twice weekly by PCR in plasma | HC: PET | VAL, GAN, FOS |
| Hill, 2021 | … | NR | 97 [88–98] | MAC or NMA | NR | CB | D1–D100 | CMV VL ≥150 IU/mL between days D1–D98 and ≥500 IU/mL thereafter | HC: CMV prophylaxis | High-dose VAL; patients who could not tolerate VAL continued on high-dose VALA |
| Hosoi, 2020 | … | NR | NR | MAC or RIC | TAC + MTX; TAC + MMF; Cyc + MTX; Cyc + MMF | … | NR | … | HC: non-LET | … |
| Johnsrud, 2020 | (R+/D+ or R+/D− or R−D+) and (HAPLO/UCB/ATG/CD34+/MMRD/MMURD) | NR | 100 (3–347) | MAC or RIC or NMA | CNI; CNI + MMF; CNI + MTX; SIRO | HAPLO, CB, ATG regimen, CD34+ selected graft, MMRD/MMURD | D1–D100 | CMV VL >400 IU/mL | HC: PET | VAL, GAN, FOS |
| Zavras 2019 | … | NR | NR | MAC or RIC | NR | HAPLO, mismatched, T-cell–depleted graft | D7–D100+ | >2 consecutive values of CMV VL >300 IU/mL | HC: PET | VAL, GAN, FOS |
| Lin, 2020 | … | 7 (5–12) | 191 (16–796) | MAC, RIC, or NMA | PTCy | (HAPLO or HLA MMURD) + PTCy | D7–D180 | 2 consecutive values of CMV VL >300 IU/mL or a single CMV VL >1000 IU/mL | HC: PET | VAL, FOS |
| Malagola, 2020 | R+ or (R+/D−, mismatch donor, GVHD) | NR | 100 [40–100] | MAC or RIC | Local guidelines and protocols | R+, R+/D−, mismatched donor, GVHD | D0–D100+ | 2 consecutive tests with CMV VL >1000 copies/mL | HC: PET | VAL, GAN, FOS |
| Marzolini, 2021 | … | NR | NR | MAC or RIC | Alemtuzumab | … | D0–D100 | … | HC: non-LET | Alemtuzumab-based T-cell–depleted and no LET |
| Mori, 2021 | Physician's choice guided by stem cell course, HLA parity, or CMV serostatus | 0 (0–35) | 92 (5–108) | MAC or RIC | Cyc/TAC; MTX; MMF; mPSL; ATG; PTCy | HAPLO, HLA Mismatched, CB, grade ≥2 GVHD requiring corticosteroid | D0–D100+ | ≥2 CMV antigen-positive cells per 50 000 WBCs detected | HC: PET | IV GAN, FOS, oral VAL |
| Royston, 2021 | (R+/D−) or (R+ with early grade 2+ GVHD requiring prednisone treatment) | NR | 98b (4–258) | MAC or RIC | NR | D−/R+, R+ with early grade ≥2 GVHD requiring corticosteroids | D1–D100 | CMV VL >150 IU/mL and/or evidence of CMV syndrome/disease | Matched HC: PET | VAL, GAN, FOS |
| Serio, 2021 | … | 7 (3–10) | NR | MAC or RIC | Cyc; Cyc + MTX; Cyc + MMF + Cys; ATG | R+ | D7–D100 | … | HC: PET | VAL |
| Sperotto, 2021 | … | NR (1–8) | NR | MAC or RIC | Cyc + MTX + ATG; TAC + MTX + ATG;TAC + MMF + Cys | R+, HAPLO, MMURD, ATG regimen, prednisone treatment | D3–D100 | CMV VL >150 copies/mL for high risk; >300 copies/mL for low-risk CMVr and CMVd | HC: PET | VAL, GAN, FOS |
| Studer, 2020 | … | NR | 98 (5–153) | MAC or NMA | MAC + Cyc + MTX; MAC + Cyc + MTX + ATG; Flu + Bu + Cyc + MTX + ATG; FluTBI + Cyc + MMF | … | D0–D100 | CMV DNAemia >1000 copies/mL determined twice | HC: PET | VAL, GAN, FOS |
| Sharma, 2020 | R+ with CBT | NR | NR | MAC or NMA | Cyc + MMF | R+ (HAPLO, CB) | D0–D100 | CMV DNAemia > 10 000 IU/mL whole blood, any repeat PCR value >5000 IU/mL following an initial positive, or evidence of end-organ involvement | HC: CMV prophylaxis | VALA; prior to Nov 2016, GAN |
| Terao, 2021 | … | NR | 95 | MAC or RIC | MTX + CNI, MMF + CNI; high-dose PTCy + TAC + MMF | … | … | … | HC: non-LET | … |
| Wolfe, 2021 | Allo-HCT | NR | 97 | MAC or RIC | TAC + MTX; TAC + SIRO; TAC + MMF; PTCy | GVHD | NR | As used in Marty et al RCT | HC: PET | VAL, GAN, FOS |
| Archambeau, 2019 | … | NR | NR | … | NR | R+ or D+ | NR | … | HC: non-LET | … |
| Bradshaw, 2021 | R+ | NR | NR | MAC or RIC | NR | … | NR | … | HC: PET | VAL, GAN, FOS |
| Cutini, 2021 | … | NR | NR | … | NR | … | D2–D100 | … | HC: non-LET | … |
| Dadwal, 2019 | … | 13 (4–26) | NR | MAC or NMA | Cellcept, MTX, TAC/SIRO | HAPLO, CB, ATG use, GVHD onset prior to CMV infection and LET | NR | CMV VL >1250 IU/mL in high-risk and >3750 IU/mL in low-risk HCT | HC: PET | GAN, FOS |
| Desnica, 2021 | … | 9 (5–28) | NR | RIC or others | … | … | NR | … | HC: PET | Not specified |
| Dwabe, 2020 | … | NR | NR | MAC or RIC | NR | CMV positive, T-cell–depleting therapies (PTCy and/or ATG), a related donor with at least 1 mismatch at 1 of the specified 3 HLA gene loci (HLA-A, -B, or -DR), an unrelated donor with at least 1 mismatch at 1 of the specified 4 HLA gene loci (HLA-A, -B, -C, and -DRB1), HAPLO, CB, grade ≥2 GVHD | NR | … | Non-LET | … |
| Faraci, 2021 | … | 11 (5–27) | 89 (40–113) | … | NR | R+/D− | NR | … | HC: PET | Not specified |
| Freyer, 2021 | … | NR | NR | RIC or others | TAC, MMF, PTCy | HAPLO + PTCy | D10–D100 | CMV VL ≥137 IU/mLc | HC: CMV prophylaxis | High-dose VALA |
| Hedvat, 2019 | … | 2b (−6–24) | NR | MAC or others | TAC/MTX; TAC/MMF/Cys | … | NR | … | HC: PET | Not specified |
| Jinnouchi, 2020 | … | NR | NR | MAC or RIC | TAC + MTX; TAC + MTX + ATG | … | NR | At least 1 pp65 antigen-positive cell per 50 000 leukocytesc | Matched HC: non-LET | … |
| Karam, 2019 | … | NR | NR | … | NR | HAPLO, MUD, CB, or ATG use | NR | … | HC: PET | Not specified |
| Koch, 2021 | … | NR | NR | … | NR | … | NR | CMV copies >1250 IU/mL in PBc | HC: non-LET | … |
| Lau, 2020 | … | NR | IV: 15 (0–35) Oral: 79 (0–94) | … | Cys/Flu/Thio/TBI + Cyc/MMF, tocilizumab (LET group only) | CB | D7–D100 | … | HC: PET | VAL, GAN, FOS |
| Loecher, 2020 | … | NR | 96 [66–116] | MAC or RIC | NR | … | D10–D100 | … | HC: non-LET | … |
| Markowski, 2019 | … | NR | NR | … | PTCy | … | NR | … | HC: non-LET | … |
| Merchant, 2019 | … | 32 (5–40) | NR | … | NR | (HAPLO, CB, MUD recipient with thymoglobulin administration, ruxolitinib initiation, prednisone equivalent) | NR | CMV VL >500 IU/mLc | HC: CMV prophylaxis | High-dose VALA |
| Muhsen, 2021 | … | 15 (12–41) | 124 (43–270) | … | NR | MMURD/MUD + T-cell depletion with alemtuzumab | NR | … | HC: PET | Not specified |
| Myers, 2021 | … | NR | NR | MAC or others | NR | … | NR | … | HC: non-LET | … |
| Ngyuen, 2020 | … | NR | NR | … | NR | R+/D− and/or HLA mismatch | NR | CMV VL >10 copies/µg DNA in 2 consecutive PCRsc | HC: PET | Not specified |
| Satake, 2020 | … | NR | NR | RIC | NR | Related HLA 1 loci mismatch (HLA-A, -B, -DRB1), HAPLO, unrelated HLA 1 loci mismatch (HLA-A, -B, -DRB1), UBC, ex-vivo T-cell–depleted graft, grade ≥2 GVHD with prednisone use | Starting on D0 | … | HC: non-LET | … |
| Shahan, 2021 | … | NR | NR | … | NR | … | NR | … | HC: non-LET | … |
| Smith, 2021 | … | NR | NR | MAC or RIC | NR | … | NR | … | HC: non-LET | … |
| Single-Arm Retrospective Studies | ||||||||||
| Abidi, 2021 | R+ | … | NR | … | Cyc + MMF | R+ (Haplocord, Dualcord) | Through D100 | … | NA | … |
| Bansal, 2021d | R+ | NR | 182 (107–576+) | MAC or RIC | TAC/MTX; TAC/MMF/PTCy; alemtuzumab; TAC/MMF | Acute GVHD or Chronic GVHD | D5–D100+ | Within 100 days post-HCT: CMV VL ≥500 IU/mL or for 2 consecutive values of ≥137 IU/mL + physician judgment; past 100 days HCT: CMV VL ≥137 IU/mL for 2 consecutive values or for a single value ≥1000 IU/mL + physician judgment | NA | … |
| Cassaniti, 2021 | … | 4 [1–14] | 105 [101–114] | MAC or RIC | Cyc + MXT; Cyc + MXT + MMF/ATG; Cyc + PTCy + MMF; PTCy + SIRO | … | D0/28–D100 | CMV VL >10 000 copies/mL whole blood | NA | … |
| Chen, 2021 | R+ at high risk of CMVr based on graft source, conditioning regimen, GVHD prophylaxis | 8 (0–43) | 92 (10–504) | MAC or RIC | PTCy + TAC + MMF; TAC + MTX; MTX + TAC + SIRO; TAC + MMF; TAC + MMF + MTX; PTCy; TAC + SIRO; PTCy + MMF + SIRO | Based on Marty et al RCT | D7–D100+ | CMV VL >137 IU/mL (151 copies/mL) | NA | … |
| Ferrari, 2019 | R+ or R−/D+ | 5 (0–20) | 79 (20–110) | MAC or others | TAC or Cyc, MTX, MMF | … | Through D100 | … | NA | … |
| Kodiyanplakkal, 2019 | R+ | … | NR | MAC or RIC | Alemtuzumab | T-cell depletion with alemtuzumab for related and HLA-identical unrelated transplant recipients; ATG for UCB transplant recipients | NR | … | NA | … |
| Paviglianiti, 2021 | R+ | … | 93 (5–100) | MAC or RIC | Cyc + MTX; Cyc; Cyc + MMF; TAC | HAPLO, CB, HLA-related donor with at least 1 mismatch at HLA-A, -B, or -DR loci, unrelated donor with at least 1 mismatch at HLA-A, -B, -C. or -DRB, ex-vivo T-cell–depleted grafts, ≥2 grade GVHD requiring corticosteroids | D0–D100 | 2 consecutive values of CMV DNAemia level >1000 copies/mL in plasma or 10 000 copies/mL in whole blood | NA | … |
| Patel, 2020 | … | … | NR | MAC or RIC | TAC + MMF + PTCy | HAPLO | D16–D100 | … | NA | … |
Abbreviations: allo-HCT, allogeneic hematopoietic stem cell transplant; ATG, antithymocyte globulin; Bu, busulfan; CB, cord blood; CBT, cord blood transplantation; CMV, cytomegalovirus; CMVd, cytomegalovirus disease; CMVr, cytomegalovirus reactivation; CNI, calcineurin inhibitor; Cyc, cyclosporine A; Cys, cyclophosphamide; D, donor; Flu, fludarabine; FluTBI, fludarabine with total body irradiation; FOS, foscarnet; GAN, ganciclovir; GVHD, graft-versus-host disease; HAPLO, haploidentical donor; HC, historical cohort; HCT, hematopoietic stem cell transplant; HLA, human leukocyte antigen; Inst, institution; IQR, interquartile range; IV, intravenous; LET, letermovir; MAC, myeloablative conditioning; MMF, mycophenolate mofetil; MMRD, mismatched related donor; MMURD, mismatched unrelated donor; mPSL, methylprednisolone; MTX, methotrexate; MUD, matched unrelated donor; NMA, nonmyeloablative conditioning; NR, not reported; PB, peripheral blood; PCR, polymerase chain reaction; PET, preemeptive therapy; PTCy, posttransplant cyclophosphamide; R, recipient; RCT, randomized controlled trial; RIC, reduced-intensity conditioning; SIRO, sirolimus; TAC, tacrolimus; TBI, total body irradiation; Thio, Thiotepa; UCB, umbilical cord blood; VAL, valganciclovir; VALA, valacyclovir; VL, viral load; WBC, white blood cell.
Citations of all the included studies are found in Supplementary Appendix 1.
Mean value.
CMV viremia/CMV reactivation.
All studies with LET use for primary prophylaxis except the Bansal 2020 study focused on letermovir use for extended primary prophylaxis.
The median age of patients ranged from 42 to 65 years in the letermovir arm and from 26 to 65 years in the comparator arm (Supplementary Appendix 2). Overall, most of the studies had a higher proportion of patients at high risk of CMVr or CMVd in the letermovir arm compared to the control arm (see footnote of Supplementary Appendix 2).
Quality Assessment of Included Studies
Of all of the studies included in this systematic review, 12 studies (25.0%) were high-quality studies, while 4 studies (8.3%) were low-quality studies and the remaining 32 studies (66.7%) were of moderate quality (Supplementary Appendix 3).
CMV-Related Outcomes
CMV-related outcomes included CMVr, cs-CMVi, and CMVd. In the individual studies that provided a definition of CMVr, CMVr was defined as any DNAemia or viremia in 20 studies, CMV antigenemia in 2 studies, CMV viral load of >500 IU/mL in 1 study, and polymerase chain reaction (PCR) >137 DNA IU/mL in 1 study. In the individual studies that provided a definition of cs-CMVi, cs-CMVi was defined as CMV viremia requiring PET or CMV disease in 30 studies, or CMV viral load >1250 IU/mL in peripheral blood in 1 study. Last, in the individual studies that provided a definition of CMVd, CMVd was defined as CMV end-organ disease in 8 studies, CMV tissue-invasive disease or dysfunction in 2 studies, or presence of appropriate clinical signs and symptoms and/or radiographic findings in an appropriate risk patient plus detection of CMV by rapid culture, direct fluorescent antibody tests, cytology, or detection of CMV by PCR in 1 study.
Table 4 and Figures 2–4 show the pORs for clinical outcomes comparing letermovir PP to the control group among allo-HCT recipients. Letermovir PP was associated with 87% (pOR, 0.13 [95% CI, .08–.22]; I2 = 74%), 76% (pOR, 0.24 [95% CI, .18–.32]; I2 = 0%), and 78% (pOR, 0.22 [95% CI, .15–.32]; I2 = 55%) decreased odds of CMVr at D+100, D+200, and beyond D+200, respectively (P < .01; Table 4 and Figure 2). Regarding cs-CMVi, letermovir PP was associated with a 91% (pOR, 0.09 [95% CI, .05–.14]; I2 = 76%) and 81% (pOR, 0.19 [95% CI, .14–.25]; I2 = 47%) decreased odds in the random-effects model at D+100 and D+200, respectively (P < .01; Figure 3). For CMVd, letermovir PP was associated with a 69% (pOR, 0.31 [95% CI, .12–.77]; I2 = 0%) and 65% (pOR, 0.35 [95% CI, .16–.78]; I2 = 0%) decreased odds in the random-effects model at D+100 and D+200, respectively (Figure 4). The findings from the subgroup analyses are available in Table 5.
Table 4.
Pooled Absolute Event Ratesa and Odds Ratios for Clinical Outcomes Comparing Letermovir With Controls Among Allogeneic Hematopoietic Cell Transplant Recipients
| Outcome | Absolute Effect—Letermovir | Absolute Effect—Control | Random-Effects Model | Publication Bias | |||||
|---|---|---|---|---|---|---|---|---|---|
| No. of Studies/Sample Size | Pooled % (95% CI) |
No. of Studies/Sample Size | Pooled %(95% CI) | No. of Studies/Sample Size | Pooled OR (95% CI) |
P Value | NNT(95% CI) | EggerTest | |
| CMV reactivation | … | ||||||||
| D+100 | 25/1204 | 24% (19%–28%)** | 18/2221 | 62% (52%–71%)** | 18/3054 | 0.13 (.08–.22)** | <.01 | 2.29 (2.00–2.85) | Significantb |
| D+200 | 15/806 | 32% (24%–37%)** | 5/942 | 69% (62%–75%)** | 5/1297 | 0.24 (.18–.32) | <.01 | 2.92 (2.49–3.60) | NA |
| Beyond D+200 | 17/849 | 32% (36%–36%)** | 8/1601 | 69% (57%–79%)** | 8/2109 | 0.22 (.15–.32)* | <.01 | 2.75 (2.28–3.61) | NS |
| Clinically significant CMV infection | … | ||||||||
| D+100 | 27/1548 | 11% (9%–12%)* | 21/2857 | 57% (48%–65%)** | 21/3993 | 0.09 (.05–.14)** | < .01 | 2.16 (2.00–2.45) | NS |
| D+200 | 19/1165 | 23% (17%–28%)** | 14/1951 | 64% (52%–74%)** | 14/2771 | 0.19 (.14–.25)* | <.01 | 2.56 (2.26–3.02) | NS |
| CMV disease | |||||||||
| D+100 | 16/894 | 1% (0%–3%) | 12/1272 | 5% (3%–7%) | 10/1838 | 0.31 (.12–.77) | .0125 | 38.92 (30.52–121.89) | NS |
| D+200 | 12/674 | 2% (1%–5%) | 7/938 | 9% (7%–11%)* | 7/1261 | 0.35 (.16–.78) | .01 | 22.00 (16.67–68.01) | NA |
| All-cause mortality | |||||||||
| D+100 | 9/757 | 10% (7%–17%)* | 5/1337 | 12% (9%–16%)** | 5/1723 | 0.70 (.46–1.07) | .1 | 30.52 (–133.60 to 16) | NA |
| Beyond D+200 | 17/1060 | 22% (18%–27%)** | 15/1845 | 30% (22%–39%)** | 15/2685 | 0.73 (.60–.90) | <.01 | 15.99 (10.11–44.78) | NS |
| Nonrelapse mortality | |||||||||
| D+100 | 5/449 | 7% (4%–13%)* | 4/640 | 10% (6%–18%)** | 3/889 | 0.70 (.39–1.25) | .23 | 40.20 (–51.20 to 19.37) | NA |
| Beyond D+200 | 8/708 | 11% (8%–14%)* | 6/1341 | 18% (12%–26%)** | 6/1829 | 0.65 (.47–.90) | .01 | 17.04 (10.79–64.21) | NA |
| Grade ≥2 GVHD | |||||||||
| D+100 | 6/199 | 18% (10%–30%)** | 6/272 | 30% (16%–48%)** | 6/471 | 0.52 (.32–.85) | <.01 | 8.23 (5.34–30.43) | NA |
| D+200 | 3/354 | 20% (0%–10%)** | 2/179 | 50% (38%–62%)* | 2/329 | 1.03 (.67–1.61) | >.05 | –116.21 (–8.51 to 10.10) | NA |
| CMV-related hospitalization | |||||||||
| D+100 | 3/238 | 0% (0%–3%) | 3/817 | 8% (3%–21%)* | 3/1055 | 0.08 (.02–.36) | <.01 | 12.72 (11.81–18.57) | NA |
| D+200 | 2/81 | 2% (0%–10%) | 2/136 | 6% (0%–39%)** | 2/217 | 0.22 (.04–1.31) | >.05 | 14.10 (–39.66 to 11.18) | NA |
Heterogeneity was examined as I2 statistic along with other parameter as per the Cochrane Handbook for systematic reviews: *30%–60% may represent moderate heterogeneity; **50%–90%, substantial heterogeneity; 75%–100%, considerable heterogeneity. CMV reactivation indicates any CMV DNAemia or viremia; clinically significant CMV infection indicates CMV DNAemia or viremia requiring preemptive therapy. Follow-up periods were as follows: D+100, follow-up of 100 days or 14 weeks; D+200, follow-up of 200 days or 24 weeks; beyond D+100, follow-up of ≥100 days or ≥14 weeks; beyond D+200, follow-up of ≥200 days or ≥24 weeks.
Abbreviations: CI, confidence interval; CMV, cytomegalovirus; GVHD, graft vs host disease; NA, not applicable; NNT, number needed to treat; NS, not significant; OR, odds ratio.
Event rate indicates number of patients with outcome over the sample size in each treatment group.
A trim and fill analysis eliminated publication bias (P = .67).
Figure 2.
Cytomegalovirus reactivation at D+100 follow-up (A), D+200 follow-up (B), and beyond D+200 follow-up (C). Abbreviations: CI, confidence interval; OR, odds ratio.
Figure 3.
Clinically significant cytomegalovirus infection at D+100 follow-up (A) and D+200 follow-up (B). Abbreviations: CI, confidence interval; OR, odds ratio.
Figure 4.
Cytomegalovirus disease at D+100 follow-up (A) and D+200 follow-up (B). Abbreviations: CI, confidence interval; OR, odds ratio.
Table 5.
Pooled Odds Ratios on Clinical Outcomes Comparing Letermovir With the Control Group in Different Subgroups of Allogeneic Hemopoietic Cell Transplant Recipients
| Outcome | Durationa | Subgroups | Relative Effect (RE Model) | ||||
|---|---|---|---|---|---|---|---|
| No. of Studies | No. of Patients | Pooled OR (95% CI) | P Value | I 2 | |||
| CMV reactivation | D+100 | 18 | 3054 | 0.13 (.08–.22) | <.01 | 74% | |
| Full publication | 10 | 2083 | 0.19 (.12–.32) | <.01 | 60% | ||
| Abstracts | 8 | 971 | 0.09 (.03–.22) | <.01 | 80% | ||
| US-based studies | 11 | 1988 | 0.27 (.20–.36) | <.05 | 27% | ||
| Non-US-based studies | 7 | 1066 | 0.05 (.02–.14) | <.01 | 77% | ||
| R+-only studies | 9 | 1670 | 0.11 (.04–.29) | <.01 | 85% | ||
| Studies with R+ and others | 9 | 1384 | 0.17 (.11–.27) | <.01 | 44% | ||
| High-risk population | 8 | 1361 | 0.15 (.08–.26) | <.01 | 58% | ||
| Cord blood only (100% cord blood) | 2 | 194 | 0.24 (.08–.69) | <.05 | 46% | ||
| Posttransplant cyclophosphamide | 3 | 155 | 0.09 (.02–.43) | <.05 | 57% | ||
| D+200 | 5 | 1297 | 0.24 (.18–.32) | <.01 | 0% | ||
| Full publication | 3 | 926 | 0.28 (.20–.39) | <.01 | 0% | ||
| Abstracts | 2 | 371 | 0.16 (.07–.35) | <.01 | 43% | ||
| US-based studies | 3 | 502 | 0.20 (.13–.30) | <.01 | 11% | ||
| Non-US-based studies | 2 | 795 | 0.28 (.19–.40) | <.01 | 0% | ||
| R+-only studies | 3 | 904 | 0.25 (.18–.36) | <.01 | 42% | ||
| Studies with R+ and others | 2 | 393 | 0.22 (.14–.35) | <.01 | 0% | ||
| High-risk population | 2 | 241 | 0.28 (.16–.51) | <.05 | 0% | ||
| Beyond D+200 | 8 | 2109 | 0.22 (.15–.32) | <.01 | 55% | ||
| Full publication | 4 | 1270 | 0.22 (.14–.35) | <.01 | 53% | ||
| Abstracts | 4 | 839 | 0.22 (.09–.54) | <.05 | 68% | ||
| US-based studies | 3 | 502 | 0.20 (.13–.30) | <.01 | 11% | ||
| Non-US-based studies | 5 | 1607 | 0.24 (.13–.45) | <.05 | 70% | ||
| R+-only studies | 5 | 1372 | 0.25 (.13–.47) | <.05 | 59% | ||
| Studies with R+ and others | 3 | 737 | 0.18 (.11–.28) | <.01 | 37% | ||
| High-risk population | 2 | 241 | 0.28 (.16–.51) | <.05 | 0% | ||
| Clinically significant CMV infection | D+100 | 21 | 3993 | 0.09 (.05–.14) | < .01 | 76% | |
| Full publication | 11 | 3139 | 0.08 (.05–.14) | <.01 | 69% | ||
| Abstracts | 10 | 854 | 0.08 (.03–.22) | <.01 | 81% | ||
| US-based studies | 14 | 2523 | 0.11 (.06–.20) | <.01 | 72% | ||
| Non-US-based studies | 7 | 1490 | 0.06 (.02–.13) | <.01 | 79% | ||
| R+-only studies | 10 | 2127 | 0.11 (.05–.25) | <.01 | 81% | ||
| Studies with R+ and others | 11 | 1866 | 0.06 (.04–.11) | <.01 | 56% | ||
| High-risk population | 11 | 1638 | 0.10 (.05–.22) | <.01 | 73% | ||
| Cord blood only (100% cord blood) | 3 | 276 | 0.05 (.01–.32) | <.01 | 48% | ||
| Posttransplant cyclophosphamide | 2 | 101 | 0.07 (.02–.21) | <.01 | 0% | ||
| D+200 | 14 | 2771 | 0.19 (.14–.25) | <.01 | 47% | ||
| Full publication | 8 | 1986 | 0.17 (.11–.27) | <.01 | 65% | ||
| Abstracts | 6 | 785 | 0.21 (.15–.30) | <.01 | 0% | ||
| US-based studies | 9 | 1485 | 0.20 (.16–.27) | <.01 | 21% | ||
| Non-US-based studies | 5 | 1286 | 0.16 (.09–.28) | <.01 | 70% | ||
| R+-only studies | 6 | 1641 | 0.22 (.17–.29) | <.01 | 0% | ||
| Studies with R+ and others | 8 | 1130 | 0.16 (.10–.27) | <.01 | 60% | ||
| High-risk population | 6 | 524 | 0.17 (.09–.33) | <.01 | 55% | ||
| CMV disease | D+100 | 10 | 1838 | 0.31 (.12–.77) | .0125 | 0% | |
| Full publication | 7 | 1507 | 0.22 (.07–.65) | <.05 | 0% | ||
| Abstracts | 3 | 331 | 0.75 (.11–5.37) | >.05 | 17% | ||
| US-based studies | 6 | 1405 | 0.37 (.11–1.26) | >.05 | 0% | ||
| Non-US-based studies | 4 | 433 | 0.23 (.06–.98) | <.05 | 0% | ||
| R+-only studies | 5 | 675 | 0.49 (.13–1.84) | >.05 | 0% | ||
| Studies with R+ and others | 5 | 1163 | 0.19 (.05–.71) | <.05 | 0% | ||
| High-risk population | 6 | 1258 | 0.23 (.07–.75) | <.05 | 0% | ||
| Cord blood only (100% cord blood) | 2 | 143 | 0.30 (.04–2.51) | >.05 | 0% | ||
| D+200 | 7 | 1261 | 0.35 (.16–.78) | .0105 | 0% | ||
| Full publication | 5 | 1044 | 0.31 (.13–.75) | <.05 | 0% | ||
| Abstracts | 2 | 217 | 0.91 (.03–24.37) | >.05 | 65% | ||
| US-based studies | 4 | 412 | 0.69 (.17–2.77) | >.05 | 0% | ||
| Non-US-based studies | 3 | 849 | 0.25 (.09–.67) | <.05 | 0% | ||
| R+-only studies | 3 | 902 | 0.35 (.13–.94) | <.05 | 41% | ||
| Studies with R+ and others | 4 | 359 | 0.36 (.10–1.38) | >.05 | 0% | ||
| High-risk population | 4 | 359 | 0.36 (.10–1.38) | >.05 | 0% | ||
| All-cause mortality | D+100 | 5 | 1723 | 0.70 (.46–1.07) | .10 | 0% | |
| Full publication | 4 | 1573 | 0.61 (.38–.95) | <.05 | 0% | ||
| Abstracts | 1 | 150 | 1.81 (.57–5.71) | .31 | NA | ||
| US-based studies | 4 | 1563 | 0.73 (.46–1.17) | .3 | 19% | ||
| Non-US-based studies | 1 | 160 | 0.55 (.15–1.95) | >.05 | NA | ||
| R+-only studies | 3 | 847 | 0.78 (.38–1.61) | .21 | 35% | ||
| Studies with R+ and others | 2 | 876 | 0.66 (.34–1.25) | .4 | 0% | ||
| High-risk population | 2 | 876 | 0.66 (.34–1.25) | .4 | 0% | ||
| Beyond D+200 | 15 | 2685 | 0.73 (.60–.90) | <.01 | 0% | ||
| Full publication | 9 | 1933 | 0.72 (.57–.92) | <.05 | 0% | ||
| Abstracts | 6 | 752 | 0.81 (.48–1.39) | .12 | 43% | ||
| US-based studies | 9 | 1569 | 0.83 (.65–1.07) | .43 | 1% | ||
| Non-US-based studies | 6 | 1116 | 0.59 (.42–.82) | <.05 | 0% | ||
| R+-only studies | 10 | 2017 | 0.75 (.59–.96) | <.05 | 14% | ||
| Studies with R+ and others | 5 | 668 | 0.70 (.49–1.00) | <.05 | 0% | ||
| High-risk population | 6 | 632 | 0.79 (.54–1.17) | .67 | 0% | ||
| Nonrelapse mortality | D+100 | 3 | 889 | 0.70 (.39–1.25) | .23 | 0% | |
| US-based studies | 2 | 729 | 0.72 (.38–1.38) | .31 | 3% | ||
| Non-US-based studies | 1 | 160 | 0.58 (.13–2.53) | >.05 | NA | ||
| R+-only studies | 2 | 697 | 0.57 (.29–1.14) | .58 | 0% | ||
| Studies with R+ and others | 1 | 192 | 1.14 (.38–3.43) | .49 | NA | ||
| High-risk population | 1 | 192 | 1.14 (.38–3.43) | .49 | NA | ||
| Beyond D+200 | 6 | 1829 | 0.65 (.47–.90) | .01 | 0% | ||
| Full publication | 4 | 1513 | 0.62 (.43–.90) | <.05 | 0% | ||
| Abstracts | 2 | 316 | 0.77 (.37–1.60) | >.05 | 0% | ||
| US-based studies | 3 | 930 | 0.69 (.46–1.05) | >.05 | 0% | ||
| Non-US-based studies | 3 | 899 | 0.59 (.35–1.00) | <.05 | 0% | ||
| R+-only studies | 4 | 1436 | 0.61 (.42–.89) | <.05 | 0% | ||
| Studies with R+ and others | 2 | 393 | 0.78 (.41–1.47) | >.05 | 0% | ||
| High-risk population | 1 | 131 | 0.70 (.27–1.82) | >.05 | NA | ||
| Grade ≥2 GVHD | D+100 | 6 | 471 | 0.52 (.32–.86) | .0098 | 0% | |
| Full publication | 2 | 177 | 0.34 (.11–1.08) | >.05 | 50% | ||
| Abstracts | 4 | 294 | 0.66 (.34–1.30) | >.05 | 0% | ||
| US-based studies | 4 | 365 | 0.69 (.39–1.23) | >.05 | 0% | ||
| Non-US-based studies | 2 | 106 | 0.25 (.10–.65) | <.05 | 0% | ||
| R+-only studies | 3 | 222 | 0.33 (.15–.77) | <.05 | 11% | ||
| Studies with R+ and others | 3 | 249 | 0.66 (.36–1.23) | >.05 | 0% | ||
| High-risk population | 4 | 365 | 0.69 (.39–1.23) | >.05 | 0% | ||
Heterogeneity was examined as I2 statistic along with other parameter as per the Cochrane Handbook for systematic reviews: 30%–60% may represent moderate heterogeneity; 50%–90%, substantial heterogeneity; 75%–100%, considerable heterogeneity. CMV reactivation indicates any CMV DNAemia or viremia; clinically significant CMV infection indicates CMV DNAemia or viremia requiring preemptive therapy.
Abbreviations: CI, confidence interval; CMV, cytomegalovirus; GVHD, graft-versus-host disease; NA, not applicable; OR, odds ratio; RE, random effects; US, United States.
Durations: D+100, follow-up of 100 days or 14 weeks; D+200, follow-up of 200 days or 24 weeks; beyond D+200, follow-up of ≥200 days or ≥24 weeks.
Time to CMV Reactivation and Duration of CMV Viremia
At D+100, time to CMVr in the letermovir group ranged from a median of 10 days (interquartile range [IQR], 5–38 days) [24] to 38 days (IQR was not reported in these 2 studies) [25, 26]. At D+200, time to any detectable CMV viremia ranged from a median of 19 days (IQR, 14–67 days) [27] to 67 days (IQR, 32–100 days) [28]. At D+100, duration of CMVr was lower in the letermovir group compared to the control group in several studies that reported the data and ranged from a median of 3 days (IQR, 1–24 days) [29] to 29 days (IQR, 26–38 days) [30] in the letermovir group compared to a range of 27 days (IQR, 3–99 days) [29] to 42 days (IQR, 31–54 days) in the control group [30]. The findings remained consistent for the D+200 follow-up as well.
Graft-Versus-Host Disease and Mortality Outcomes
The odds of grade ≥2 GVHD was significantly lower in patients who received letermovir PP compared to those who did not (control group) at D+100 (pOR, 0.52 [95% CI, .32–.86]; I2 = 0%) (Table 4); however, this finding was not significant for D+200 (pOR, 1.03 [95% CI, .67–1.61]). Letermovir was associated with 30% reduced odds of all-cause mortality at D+100 (pOR, 0.70 [95% CI, .46–1.07]; P = .1, I2 = 0%) (Table 4 and Figure 5). Beyond D+200, letermovir was associated with a significant 27% decreased odds of all-cause mortality (pOR, 0.73 [95% CI, .60–.90]; P < .01, I2 = 0%). The findings remained consistent for nonrelapse mortality (pOR, 0.70, P = .23 for D+100, and pOR, 0.65, P = .01 for beyond D+200) (Table 4 and Figure 6).
Figure 5.
All-cause mortality at D+100 follow-up (A) and beyond D+200 follow-up (B). Abbreviations: CI, confidence interval; OR, odds ratio.
Figure 6.
Nonrelapse mortality at D+100 follow-up (A) and beyond D+200 follow-up (B). Abbreviations: CI, confidence interval; OR, odds ratio.
Healthcare Utilization and Costs
The odds of CMV-related hospitalization were significantly lower with letermovir PP at D+100 (pOR, 0.08 [95% CI, .02–.36]; P < .01; Table 4); however, the finding was nonsignificant for D+200 follow-up. The duration of CMV-related hospitalization was 35 days in the letermovir group compared to 20 days in the comparator group as reported in 1 study [25]. One US-based study reported letermovir costs of $38 461 for up to D+200 follow-up [31], whereas another US-based study reported letermovir costs of $21 686 for the letermovir group compared to PET costs of $22 466 for the comparator group at D+100 [32].
DISCUSSION
This systematic review aimed to understand the current and real-world effectiveness of letermovir use as primary prophylaxis for CMV infection and disease in adult allo-HCT recipients, using data from real-world observational studies since the approval of letermovir. Our systematic review identified several noteworthy findings. Real-world use of letermovir demonstrated significant decline in CMVr, cs-CMVi, and CMVd at D+100 and D+200, compared to any control group, usually the historical control group. In addition, letermovir PP significantly reduced the odds of all-cause and nonrelapse mortality beyond D+200 compared to historical controls.
Patients on letermovir PP had significantly lower odds of experiencing CMVr at D+100, and beyond. Our study findings for D+100 is consistent with a published summary of reported data of 19 real-world studies which described that letermovir PP was associated with significantly lower CMVr [33]; however, the latter study did not perform meta-analysis of the CMV-related outcomes. Importantly, our findings underscore the prolonged and sustained positive impact of letermovir even after its discontinuation, which was consistent with that reported in the phase 3 study [18]. Due to differences in characteristics of the included studies, we found moderate to substantial heterogeneity for the CMVr finding. To assess the source of heterogeneity, subgroup analyses by publication type, location of studies, and CMV risk of populations were conducted. At D+100, it was found that studies presented at conferences or meetings (80% vs 60% heterogeneity for presentations vs full publications), and non-US studies (77% for non-US studies vs 27% for the US-based studies) contributed substantially to the high heterogeneity. However, there was consistency in the effectiveness of letermovir PP in the subgroup analyses. Similar findings about sources of heterogeneity were found for D+200 and beyond as well. Variation in methods, patient characteristics, and initiation of PET to define CMVr in the included studies may have contributed to this heterogeneity in our meta-analysis findings. Another important finding was that letermovir PP also had a relatively stronger positive effect on patients at high risk of CMV infection and who received posttransplant cyclophosphamide with comparatively lower heterogeneity than that reported for the overall analyses. This finding about effectiveness of letermovir in high-risk patients is consistent with the phase 3 trial by Marty et al [18]. and highlights the importance of effectiveness beyond 100 days posttransplantation with letermovir [18].
Letermovir PP was also associated with significant reduction in the incidence of cs-CMVi compared to control groups arms, at D+100 and D+200 showcasing again sustained effectiveness post–letermovir discontinuation. Our findings are consistent with the results of the phase 3 clinical trial [18] that reported lower incidence of cs-CMVi by week 24 posttransplantation for patients who received letermovir PP. The proportion of patients with cs-CMVi in the letermovir group was 11% at D+100 follow-up in the studies that reported the data. This proportion increased to 23% in the D+200 period, which indicates that some patients may experience late CMV infections following letermovir cessation. Despite this finding, letermovir was found to significantly reduce cs-CMVi at D+200 compared to the control group. The odds ratio estimates were not significantly different when subgroup analysis was performed only for the high-risk population. The heterogeneity was substantial for D+100 follow-up (76%) whereas moderate heterogeneity was found for D+200 follow-up period (47%). In subgroup analyses, conference presentations and non-US studies contributed substantially to the high heterogeneity. An important observation in our meta-analysis was that at D+100, letermovir had a significantly stronger effect for cord-blood recipients only, those who received cyclophosphamide posttransplantation, or those who were at the high-risk of CMV. Lau et al included CMV-seropositive cord-blood transplant recipients and found significantly lower incidence of cs-CMVi at D+100 in the letermovir group compared to the historical control group (0% vs 82%, P < .0001) [32].
Overall, letermovir use was also associated with significantly reduced risk of CMVd at both D+100 and D+200 follow-up periods, with no heterogeneity in the pooled results. In the studies included in the meta-analysis, patients who received letermovir PP had lower rates of CMVd that ranged from 0% to 6%. Surprisingly, in the subgroup analyses, conference presentations and US-based studies showed a nonsignificant effect of letermovir PP on CMVd at both D+100 and D+200 follow-up. A likely explanation of these findings is inclusion of relatively smaller number of studies with comparatively lower sample sizes in these subgroups.
Letermovir PP was associated with a significant decrease in all-cause mortality and nonrelapse mortality beyond D+200, with no heterogeneity reported between the included studies. Our findings are different than that reported in the phase 3 trial for letermovir PP at D+200, although a trend was observed [18]. By combining studies and increasing the sample size, we identified enough number of outcome events, thereby resulting in significant outcomes beyond D+200 . Additionally, immune reconstitution following allo-HCT improves over time. The reduction or delay in CMVr may allow the reconstituted immune system to control the deleterious outcomes of CMVr [10, 34]. Hence, letermovir PP may bestow mortality benefit compared to the control group by reducing the risk of or delaying CMVr. Furthermore, letermovir PP may reduce, shorten duration, or delay PET with antiviral agents that are associated with serious toxicities, thereby providing observed mortality benefit for the letermovir PP group. Our findings for the mortality outcomes remained consistent in many subgroups: Abstracts reported nonsignificant findings for all-cause mortality and nonrelapse mortality, while full publications demonstrated significant findings in favor of letermovir use. Overall, US-based studies showed that letermovir PP was not significantly associated with lower all-cause and non-relapse mortality, in contrast with the non-US studies. This finding could be explained by the inclusion of high-risk allo-HCT population in many of the US-based studies compared to the non-US studies. In fact, 4 of 9 US studies that reported all-cause mortality beyond D+200 had a slightly higher mortality rate in the letermovir group compared to the control group. Furthermore, all-cause and nonrelapse mortality among high-risk allo-HCT recipients was not statistically significant between the letermovir PP and control groups.
To the best of our knowledge, this is the first comprehensive systematic review and meta-analysis of all of the published real-world studies that summarized the role of letermovir PP for CMV-related outcomes among adult allo-HCT recipients. Our review provides real-world evidence that is consistent with 1 of the pivotal trial studies on letermovir PP among adult CMV-seropositive allo-HCT recipients [18]. This review includes studies conducted in several countries, predominantly in the US, Italy, and Japan. Importantly, we summarized findings in this systematic review by several subgroup analyses including publication type, location of studies, and high-risk population. This systematic review focused on real-world studies, some with limited sample sizes and shorter follow-up period. The studies also varied in terms of patient characteristics. We have addressed these limitations by exploring these differences through statistical analysis in random-effects model and subgroup analysis/meta-regression.
In summary, our systematic review of real-world studies among adult allo-HCT recipients supports that compared to the control group, letermovir use for CMV PP was effective in reducing the risk of CMV-related complications including CMVr, cs-CMVi, CMVd, all-cause and nonrelapse mortality, and CMV-related hospitalization at different time points post–allo-HCT. Finally, the use of letermovir for CMV PP reduced the incidence of CMV-related complications, the use of PET with anti-CMV agents that are associated with severe adverse events and may have prevented the direct and indirect effects of CMV infections that most probably led to improved clinical outcomes in adult allo-HCT recipients.
Supplementary Material
Contributor Information
Ami Vyas, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
Amit D Raval, Center for Observational and Real-World Evidence, Merck & Co., Inc., Rahway, New Jersey, USA.
Shweta Kamat, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
Kerry LaPlante, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
Yuexin Tang, Center for Observational and Real-World Evidence, Merck & Co., Inc., Rahway, New Jersey, USA.
Roy F Chemaly, Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Notes
Author contributions. All authors contributed substantially to the reviewing and editing of the manuscript.
Patient consent. As our study is a systematic review and meta-analyses of published studies, it does not include factors necessitating patient consent.
Disclaimer. The funders played no role in the writing of the first draft of the manuscript.
Financial support. This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
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