Efficacy and safety of letermovir prophylaxis for cytomegalovirus infection after hematopoietic stem cell transplantation

Wen-Wen Li; Yong-Mei Zhang; Meng-Zhu Shen; Xiao-Dong Mo

doi:10.1097/BS9.0000000000000178

. 2024 Jan 10;6(1):e00178. doi: 10.1097/BS9.0000000000000178

Efficacy and safety of letermovir prophylaxis for cytomegalovirus infection after hematopoietic stem cell transplantation

Wen-Wen Li ^a,^b, Yong-Mei Zhang ^a,^c, Meng-Zhu Shen ^a,^*, Xiao-Dong Mo ^a,^d,^*

PMCID: PMC10781138 PMID: 38213825

Abstract

Letermovir is a specific inhibitor of cytomegalovirus (CMV) terminase complex. Several studies have reported that letermovir can effectively prevent CMV activation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the efficacy and safety of letermovir prophylaxis for CMV infection after allo-HSCT with a systemic review and meta-analysis. A literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. PubMed and Embase databases were searched. A total of 28 studies were included. The incidence of CMV activation at 14 weeks after HSCT was 0.10 (95% confidence interval [CI], 0.06–0.18), which was 0.10 (95% CI, 0.04–0.21) and 0% in adult and children (2 studies were included and both of them were 0%). In addition, the incidence of CMV activation at 14 weeks after allo-HSCT was 0.11 (95% CI, 0.06–0.21) and 0.07 (only 1 study included), respectively, in retrospective and prospective studies. The incidence of CMV activation at 100 and 200 days after HSCT was 0.23 (95% CI, 0.16–0.33) and 0.49 (95% CI, 0.32–0.67), respectively. The incidence of CMV disease at 14 weeks and at 6 months after HSCT was 0.01 (95% CI, 0.01–0.02) and 0.03 (95% CI, 0.01–0.09), respectively. Thus, our systemic review and meta-analysis suggested that letermovir prophylaxis was safe and effective for CMV activation after allo-HSCT.

Keywords: Allogeneic hematopoietic stem cell transplantation, Cytomegalovirus, Letermovir, Prophylaxis

1. INTRODUCTION

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most important treatments for patients with hematological malignancies and non-malignant hematologic disorder.¹ Infections are the most common and significant cause of mortality and morbidity after allo-HSCT.² Viruses contribute to nearly one-third of infection-related mortality,³ and cytomegalovirus (CMV) is the most common viral infection after allo-HSCT. The 1-year cumulative incidence of CMV activation was 55.0% after allo-HSCT, which is 23.5% to 48%,^4–6 42% to 66%,^7–9 and 54% to 87%,^10–12 respectively, in identical sibling donor (ISD), haploidentical-related donor (HID), and unrelated donor (URD) HSCT recipients. In addition, nearly 50% of these patients may experience refractory/recurrent CMV infection which significantly increases the risk of CMV disease and non-relapse mortality (NRM) after allo-HSCT.¹³

Although most of the allo-HSCT recipients receive acyclovir for herpes simplex virus prevention, it cannot prevent CMV activation. There are several anti-CMV agents, such as ganciclovir, foscarnet, and cidofovir; however, most of them are not suitable for CMV prophylaxis because of their toxicities. For example, ganciclovir can cause severe myelosuppression, and foscarnet and cidofovir can cause severe or even irreversible nephrotoxicity.^14–17 Thus, how to prevent CMV activation safely and effectively is important to improve the clinical outcomes of allo-HSCT recipients.

Letermovir is a 3,4-dihydro-quinazoline-4-yl-acetic acid derivative that inhibits viral terminase complex inhibitor^18,19 Several studies observe that letermovir can prevent CMV activation after allo-HSCT.^20–22 However, most of them were retrospective studies and the efficacy of CMV prophylaxis was inconsistent among these studies.

Thus, we aimed to further identify the efficacy and safety of letermovir prophylaxis for CMV infection after allo-HSCT through a systemic review and meta-analysis.

2. METHODS

2.1. Inclusion criteria

The inclusion criteria were as follows: patients of any race, any sex, and all ages; those diagnosed with CMV infection after allo-HSCT; and those using letermovir for CMV infection after allo-HSCT. Reviews, case reports, duplicates, and conference abstracts were excluded.

2.2. Search strategy

A literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.²³ The PubMed and Embase databases were searched, published from January 2017 to December 2022, with the search strategy following the Population (allo-HSCT recipients), Intervention (letermovir for prevention of CMV infection), Outcomes (CMV infection, CMV disease, adverse events, overall survival [OS]), and Study framework (retrospective, prospective non-randomized, and randomized trials).²⁴

2.3. Data extraction and outcomes

Information on the following was extracted: study characteristics (eg, study framework, first author, publish year), patients (eg, age, number, and diagnosis), and outcome parameters during the follow-up period. CMV infection at 14 weeks after allo-HSCT was chosen as the primary end point. CMV infection at other time points (ie, 100 days, 6 months, 200 days, and at any time) after HSCT, CMV disease after allo-HSCT, adverse event, and OS were chosen as secondary end points. Missing data were documented as “not available (NA).” All data were extracted according to the Cochrane Handbook for Systematic Reviews of Interventions.²⁵

2.4. Statistical analysis

The “meta” package version 4.16-2²⁶ was used to perform the meta-analysis (R Project for Statistical Computing, version 4.0.5). Statistical heterogeneity among studies was assessed using the I² statistics and Cochran Q-test. The random effects model was adopted, with the heterogeneity test showing I² > 50% and P < .10. The subgroup comparison of adults and children was also conducted. The null hypothesis was set to no difference. A P value <.05 was considered statistically significant to reject the null hypothesis. The results were analyzed by the boxplot using “ggplot2” package version 3.3.5.²⁷

3. RESULTS

3.1. Included studies

A total of 28 studies with 2389 patients were included in this meta-analysis (Tables 1 and 2, Fig. 1; Supplementary Table 1, http://links.lww.com/BS/A76).

Table 1.

Main characteristics of 28 included studies.

Studies	Study design	N	CMV infection					CMV disease
Studies	Study design	N	At 100 d	At 14 wk	At 6 mo	At 200 d	At any time	At 14 wk	At 6 mo	At 200 d	At any time
Marty et al 2017³²	Prospective	373	NA	25	57	NA	NA	1	5	NA	NA
Lin et al 2019⁴⁸	Retrospective	53	NA	NA	NA	NA	2	NA	NA	NA	NA
Malagola et al 2020³⁰	Retrospective	60	NA	6	11	NA	NA	1	1	NA	NA
Anderson et al 2020⁴⁶	Retrospective	25	NA	NA	NA	10	NA	NA	NA	0	0
Johnsrud et al 2020³⁷	Retrospective	114	49	NA	NA	NA	NA	NA	NA	NA	NA
Sharma et al 2020⁴¹	Retrospective	32	7	NA	NA	NA	NA	NA	NA	NA	NA
Chen et al 2021⁴²	Retrospective	60	NA	NA	12	NA	1	NA	NA	NA	NA
Mori et al 2021⁴³	Retrospective	114	NA	NA	47	NA	NA	NA	NA	NA	NA
Royston et al 2021⁴⁴	Retrospective	26	NA	NA	9	NA	NA	NA	NA	NA	NA
Wolfe et al. 2021⁴⁷	Retrospective	119	NA	NA	NA	76	NA	NA	NA	NA	NA
Martino et al 2021³¹	Retrospective	204	NA	20	61	NA	NA	5	7	NA	NA
Derigs et al 2021³⁵	Retrospective	80	11	NA	NA	NA	NA	NA	NA	NA	NA
Cassaniti et al 2021²⁸	Retrospective	77	NA	26	NA	NA	NA	NA	NA	NA	NA
Serio et al 2021⁴⁰	Retrospective	13	1	NA	NA	NA	NA	NA	NA	NA	NA
Sassine et al 2021³⁹	Retrospective	123	19	NA	NA	NA	21	NA	NA	NA	NA
Hiraishi et al 2021²⁹	Retrospective	460	NA	79	140	NA	NA	6	11	NA	NA
Beauvais et al 2022²⁰	Retrospective	96	NA	15	NA	NA	NA	0	NA	NA	NA
Politikos et al 2022³³	Retrospective	28	NA	0	NA	NA	NA	NA	NA	NA	NA
Gabanti et al 2022³⁶	Retrospective	30	10	NA	NA	NA	NA	NA	NA	NA	NA
Daukshus et al 2022⁴⁹	Retrospective	10	NA	NA	NA	NA	2	NA	NA	NA	NA
Richert-Przygonska et al 2022³⁴	Retrospective	13	NA	0	NA	NA	NA	0	NA	NA	NA
Cheng et al. 2022²¹	Retrospective	4	NA	0	NA	NA	NA	NA	NA	NA	NA
Freyer et al 2022²²	Retrospective	19	NA	NA	NA	4	NA	NA	NA	NA	NA
Yoshimura et al 2022⁴⁵	Retrospective	38	NA	NA	1	NA	NA	NA	1	NA	NA
Mizuno et al 2022³⁸	Retrospective	43	13	NA	NA	28	NA	NA	NA	NA	NA
Łojko et al 2022⁵²	Retrospective	53	NA	NA	NA	NA	NA	NA	15	NA	NA
Robin et al 2020⁵⁰	Prospective	80	NA	NA	NA	NA	4	NA	NA	NA	3
Studer et al 2020⁵¹	Retrospective	42	NA	NA	NA	NA	5	NA	NA	NA	NA

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CMV = cytomegalovirus, NA = not available.

Table 2.

Other characteristics of 28 included studies.

Studies	Median age/year (range)	HLA matching (n)				Diagnosis (n)
Studies	Median age/year (range)	MRD	mMRD	MUD	mMUD	AML	ALL	AL	MDS	CLL	CML	MM	Lymphoma	AA/SAA/VSAA	MPN	Other
Marty et al 2017³²	53 (18–75)	121	63	138	51	142	35	NA	63	NA	NA	NA	47	NA	NA	86
Lin et al 2019 (group 1)⁴⁸	59 (20–74)	9	2	16	3	12	NA	3	13	NA	NA	2	5	NA	NA	4
Lin et al 2019 (group 2)⁴⁸	54 (28–72)	2	0	8	1	4	NA	1	2	NA	NA	3	2	NA	NA	2
Malagola et al 2020³⁰	52 (21–71)	11	NA	32	NA	NA	NA	32	NA	NA	NA	8	7	2	NA	9
Anderson et al 2020⁴⁶	60 (NA)	0	NA	4	14	NA	NA	12	NA	NA	NA	NA	3	NA	4	3
Johnsrud et al 2020³⁷	55.5 (22–77)	29	NA	NA	67	43	15	NA	28	NA	2	NA	14	7	NA	5
Sharma et al 2020⁴¹	50 (22–74)	NA	NA	NA	NA	15	10	NA	3	0	0	NA	1	NA	2	1
Chen et al 2021⁴²	61 (19–73)	4	NA	16	10	17	7	NA	9	NA	NA	NA	9	NA	5	13
Mori et al 2021⁴³	57 (15–75)	21	37	22	34	52	20	NA	NA	NA	NA	2	34	2	2	2
Royston et al 2021⁴⁴	55.8 (NA)	4	NA	15	NA	18	8	NA	NA	NA	NA	NA	NA	NA	NA	NA
Wolfe et al 2021⁴⁷	56 (21–74)	24	NA	62	9	44	20	NA	23	6	2	5	12	NA	NA	7
Martino et al 2021³¹	52 (18–75)	66	68	56	14	109	28	NA	19	NA	NA	NA	15	NA	NA	33
Derigs et al 2021³⁵	58.5 (18–75)	21	1	45	10	31	NA	NA	23	NA	NA	NA	15	NA	NA	11
Cassaniti et al 2021²⁸	58 (48–64)	11	NA	NA	41	NA	NA	47	16	NA	NA	2	6	NA	NA	4
Serio et al 2021⁴⁰	43 (22–71)	NA	NA	NA	NA	9	2	NA	1	NA	NA	1	0	NA	NA	NA
Sassine et al 2021³⁹	57 (18–93)	37	NA	58	NA	52	16	NA	14	NA	NA	NA	NA	NA	10	31
Hiraishi et al 2021²⁹	53 (4–73)	164	295	NA	236	186	73	NA	63	NA	NA	NA	65	NA	NA	73
Beauvais et al 2022²⁰	56 (NA)	NA	56	NA	NA	45	16	NA	9	1	1	1	12	0	4	7
Politikos et al 2022³³	47 (26–65)	NA	NA	NA	NA	13	7	21	5	NA	NA	NA	2	NA	NA	0
Gabanti et al 2022³⁶	59 (45–62)	NA	NA	NA	NA	13	3	NA	6	NA	0	2	0	NA	2	4
Daukshus et al 2022⁴⁹	15.2 (10–17.6)	2	NA	3	5	3	5	NA	NA	NA	1	NA	NA	1	NA	NA
Richert-Przygonska et al 2022³⁴	13.2 (7.1–16.9)	NA	NA	8	NA	NA	NA	8	NA	NA	NA	NA	2	3	NA	0
Cheng et al 2022²¹	16.1 (9.2–17.8)	NA	NA	1	1	1	2	NA	NA	NA	NA	NA	0	1	NA	NA
Freyer et al 2022²²	64 (37–74)	NA	NA	NA	NA	9	NA	NA	NA	NA	NA	NA	NA	NA	NA	10
Yoshimura et al 2022⁴⁵	49 (18–68)	5	NA	18	8	15	13	NA	4	NA	1	NA	2	NA	NA	3
Mizuno et al 2022³⁸	52 (18–65)	6	0	16	2	16	8	NA	7	NA	NA	NA	6	NA	NA	6
Łojko et al 2022⁵²	38 (5–70)	NA	NA	NA	NA	20	12	NA	4	NA	NA	NA	7	2	2	4
Robin et al 2020⁵⁰	57 (19–72)	NA	NA	NA	NA	31	13	NA	16	NA	1	NA	NA	NA	4	10
Studer et al 2020⁵¹	43 (22–65)	NA	NA	NA	NA	14	4	NA	7	NA	3	NA	11	NA	NA	3

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AA = aplastic anemia, AL = acute leukemia, ALL = acute lymphoblastic leukemia, AML = acute myeloid leukemia, CLL = chronic lymphocytic leukemia, CML = chronic myelogenous leukemia, HLA = human leukocyte antigen, MDS = myelodysplastic syndromes, mMRD = mismatched related donor, mMUD = mismatched unrelated donor, MM = multiple myeloma, MPN = myeloproliferative neoplasms, MRD = matched related donor, MUD = matched unrelated donor, NA = not available, SAA = severe aplastic anemia, VSAA = very severe aplastic anemia.

Figure 1. — Selection scheme of studies. CMV = cytomegalovirus, GVHD = graft-versus-host disease.

3.2. CMV infection after allo-HSCT

Nine studies^{20,21,28–34} including 1315 patients reported CMV activation at 14 weeks after allo-HSCT. The incidence of CMV activation at 14 weeks after HSCT was 10% (95% confidence interval [CI], 6%–18%) (Fig. 2A). In the subgroup analysis, 5 and 2 studies, respectively, reported the CMV activation at 14 weeks after allo-HSCT in adults and children. The incidence of CMV activation at 14 weeks after allo-HSCT in adults was 10% (95% CI, 4%–21%), which was comparable with that in children (0.0%, Fig. 2B). In addition, one of them was prospective study and the others were retrospective studies. In retrospective studies, the incidence of CMV activation at 14 weeks after allo-HSCT was 11% (95% CI, 6%–21%, Fig. 2C), which was 7% in prospective study.

Figure 2. — The incidence of CMV activation (A) at 14 wk after allo-HSCT in all the studies; (B) at 14 wk after allo-HSCT in adults and children; (C) at 14 wk after allo-HSCT in retrospective studies; (D) at 100 d after allo-HSCT in adults. allo-HSCT = allogeneic hematopoietic stem cell transplantation, CI = confidence interval, CMV = cytomegalovirus.

Seven studies^35–41 including 435 patients reported the CMV activation at 100 days after allo-HSCT. Only adults were enrolled in this analysis and the incidence of CMV activation at 100 days after allo-HSCT was 23% (95% CI, 16%–33%, Fig. 2D).

Eight studies^{29–32,42–45} including 1335 patients reported the CMV activation at 6 months after allo-HSCT. The incidence of CMV activation at 6 months after allo-HSCT was 23% (95% CI, 16%–32%, Fig. 3A). One of them was prospective study and the others were retrospective studies. The incidence of CMV activation at 6 months after allo-HSCT was 24% (95% CI, 16%–35%, Fig. 3B) and 15%, respectively, for retrospective studies and the prospective study.

Figure 3. — The incidence of CMV activation (A) at 6 mo after allo-HSCT in all the studies; (B) at 6 mo after allo-HSCT in retrospective studies; (C) at 200 d after allo-HSCT; (D) at any time after allo-HSCT; (E) at any time after allo-HSCT in adults and children. allo-HSCT = allogeneic hematopoietic stem cell transplantation, CI = confidence interval, CMV = cytomegalovirus.

Four retrospective studies^22,38,46,47 including 206 patients reported the CMV activation at 200 days after HSCT. The incidence of CMV activation at 200 days after allo-HSCT was 49% (95% CI, 32%–67%, Fig. 3C).

Six studies^{39,42,48–51} including 368 patients reported the CMV activation at any time after allo-HSCT. The incidence of CMV activation at any time was 7% (95% CI, 4%–14%, Fig. 3D). Five and 1 studies,⁵² respectively, were included for the analysis of CMV infection at any time after HSCT in adults and children, and the incidence of CMV infection at any time was 6% (95% CI, 3%–13%) in adults, which was comparable with that in children (20%, Fig. 3E).

3.3. CMV disease

Six studies^{20,29–32,34} including 1206 patients reported the incidence of CMV disease at 14 weeks after allo-HSCT. The incidence of CMV disease at 14 weeks after allo-HSCT was 1% (95% CI, 1%–2%) (Fig. 4A). In retrospective studies, the incidence of CMV disease at 14 weeks after allo-HSCT was 1% (95% CI, 1%–3%, Fig. 4B). One prospective study was included in this analysis³² and the incidence was 0.3%. In addition, 3 and 1 studies, respectively, were included for the analysis of CMV disease at 14 weeks after allo-HSCT in adults and children. The incidence of CMV disease at 14 weeks after allo-HSCT was comparable between adults (1%, 95% CI, 0%–3%) and children (0%, Fig. 4C).

Figure 4. — The incidence of CMV disease (A) at 14 wk after allo-HSCT; (B) at 14 wk after allo-HSCT in retrospective studies; (C) at 14 wk after allo-HSCT in adults and children; (D) at 6 mo after allo-HSCT; (E) at 6 mo after allo-HSCT in retrospective studies. allo-HSCT = allogeneic hematopoietic stem cell transplantation, CI = confidence interval, CMV = cytomegalovirus.

Six studies including 1188 patients reported the incidence of CMV disease at 6 months after allo-HSCT.^{29–32,45,52} The incidence of CMV disease at 6 months after allo-HSCT was 3% (95% CI, 1%–9%, Fig. 4D). In the 5 retrospective studies, the incidence of CMV disease at 6 months after allo-HSCT was 4% (95% CI, 1%–12%) (Fig. 4E). One prospective study was included,³² and the incidence of CMV disease at 6 months after allo-HSCT was 1%.

Only 1 retrospective study including 25 patients reported the incidence of CMV disease at 200 days after allo-HSCT.⁴⁶ The incidence of CMV disease at 200 days after allo-HSCT was 0%.

Only 1 prospective study⁵⁰ including 80 patients reported the incidence of CMV disease at any time after allo-HSCT. The incidence of CMV disease at any time after allo-HSCT was 4%.

3.4. Adverse events

Six studies reported the adverse events after letermovir prophylaxis (Supplementary Table 2, http://links.lww.com/BS/A77), and 4, 3, 3, 2, 2, 2, 2, 1, 2, 1, 2, 1, 1, 3, 1, 1, 1, and 2 studies showed the occurrence of graft-versus-host disease (GVHD), diarrhea, nausea, fever, rash, vomiting, cough, peripheral edema, fatigue, mucosal inflammation, headache, abdominal pain, ascites, acute kidney injury, hepatic function abnormal, decreased appetite, hypertension, and constipation after treatment (Table 3). Most studies^32,34,40,45 show that no myelotoxicity of letermovir was found, which is particularly important in the context of the toxicity of other anti-CMV drugs.⁵²

Table 3.

The incidence of adverse events.

Adverse events	Incidence (cases per person)
Graft-versus-host disease	0.24–0.53
Diarrhea	0.01–0.75
Nausea	0.02–1.25
Fever	0.21–1.25
Rash	0.20–1.25
Vomiting	0.18–0.75
Cough	0.14–0.75
Peripheral edema	0.14
Fatigue	0.13–1.75
Mucosal inflammation	0.12
Headache	0.00–0.14
Abdominal pain	0.12
Ascites	0.01
Acute kidney injury	0.02–0.10
Hepatic function abnormal	0.01
Decreased appetite	0.10
Hypertension	0.08
Constipation	0.07–1.00

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3.5. Overall survival

Two studies were included in the analysis of OS.^35,43 The probability of OS at 6 months and at 1 year after allo-HSCT was 80.4% and 84%, respectively.

4. DISCUSSION

We observed that the incidence of CMV activation at 14 weeks and at any time was 10% and 7%, respectively. In addition, the incidence of CMV disease at 14 weeks and at any time was 1% and 4%, respectively. This is the first systematic review and meta-analysis identifying the efficacy and safety of letermovir prophylaxis for CMV activation after allo-HSCT.

Drugs currently used for CMV treatment, such as ganciclovir, and foscarnet, cannot be routinely used for CMV prophylaxis because of myelosuppression and nephrotoxicity. According to the published articles, the rate of acute kidney injury was only 2% to 10% cases per person and no myelosuppression event was observed after letermovir prophylaxis. These are the most important adverse events in CMV prophylaxis after allo-HSCT particularly for those receiving HID HSCT who have a higher risk of poor graft function and renal injury.^{20,21,29,32,39,41} In addition, most side effect of letermovir is mild which suggested that letermovir is suitable for CMV prophylaxis after allo-HSCT.

CMV disease was one of the most important risk factors for NRM, and the incidence was 23.5% to 48%, 54% to 87%, and 42% to 66%, respectively, for those receiving ISD,^4–6 URD,^10–12 and HID HSCT.^7–9 We observed that the incidence of CMV disease was only 4% at any time after allo-HSCT, which was significantly decreased by letermovir prophylaxis.

CMV reactivation rate at 14 weeks after HSCT was only 10% after letermovir prophylaxis for CMV activation after allo-HSCT, which suggested that letermovir could effectively prevent CMV activation within 3 months after allo-HSCT. However, we observed that the incidence of CMV activation increasing beyond 3 months after allo-HSCT, and the incidence of CMV activation at 200 days after HSCT could achieve as high as 49%. Some authors reported that frequent delayed-onset CMV infections may be associated with letermovir discontinuation.⁵³ In addition, late-clinically significant CMV infection may be correlated with HLA-mismatched donors or CMV-IgG–negative donors.⁵⁴ However, some authors reported that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure.⁵⁵ Thus, how to prevent the late-onset CMV infection should be further identified.

However, there were some questions that could not be resolved by our study. Most of the published studies did not compare the clinical outcomes of letermovir prophylaxis among different donor types, and we could not further identify its efficacy and safety in particular allo-HSCT recipients (eg, HID HSCT recipients). In addition, the information about letermovir prophylaxis among different underlying disease, disease status, and comorbidities burden before HSCT was also rare. To draw a more significant conclusion, we listed odds ratios/hazard ratios in Supplementary Table 3, http://links.lww.com/BS/A78. Lastly, few post-engraftment variables were available in these articles and most of the studies were retrospective, which were the limitations of this paper.

5. CONCLUSION

In summary, our systemic review and meta-analysis suggested that letermovir prophylaxis was safe and effective for CMV activation after allo-HSCT.

ACKNOWLEDGMENTS

National Key Research and Development Program of China (grant no. 2022YFC2502606), Tongzhou District Distinguished Young Scholars (grant no. JCQN2023009), the National Natural Science Foundation of China (grant nos. 82170208, 82200239), and CAMS Innovation Fund for Medical Sciences (grant nos. 2019-I2M-5-034, 2022-I2M-C&T-B-121). Thanks for the support from Yinzhu Jin in terms of data collection and analysis.

Supplementary Material

bs9-6-e00178-s001.pdf^{(248.3KB, pdf)}

bs9-6-e00178-s002.pdf^{(242.2KB, pdf)}

bs9-6-e00178-s003.pdf^{(331.1KB, pdf)}

Footnotes

W.-W.L. and Y.-M.Z. contributed equally to this manuscript.

Conflict of interest: The authors declare that they have no conflict of interest.

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[13].Liu J, Kong J, Chang YJ, et al. Patients with refractory cytomegalovirus (CMV) infection following allogeneic haematopoietic stem cell transplantation are at high risk for CMV disease and non-relapse mortality. Clin Microbiol Infect 2015;21(12):1121.e9–1121.15. [DOI] [PubMed] [Google Scholar]
[14].Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996;88(10):4063–4071. [PubMed] [Google Scholar]
[15].Bregante S, Bertilson S, Tedone E, et al. Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study. Bone Marrow Transplant 2000;26(1):23–29. [DOI] [PubMed] [Google Scholar]
[16].Ljungman P, Deliliers GL, Platzbecker U, et al. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 2001;97(2):388–392. [DOI] [PubMed] [Google Scholar]
[17].Winston DJ, Yeager AM, Chandrasekar PH, Snydman DR, Petersen FB, Territo MC. Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation. Clin Infect Dis 2003;36(6):749–758. [DOI] [PubMed] [Google Scholar]
[18].Lischka P, Hewlett G, Wunberg T, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother 2010;54(3):1290–1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
[19].Borst EM, Kleine-Albers J, Gabaev I, et al. The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. J Virol 2013;87(3):1720–1732. [DOI] [PMC free article] [PubMed] [Google Scholar]
[20].Beauvais D, Robin C, Thiebaut A, et al. Effective letermovir prophylaxis of CMV infection post allogeneic hematopoietic cell transplantation: results from the French temporary authorization of use compassionate program. J Clin Virol 2022;148:105106. [DOI] [PubMed] [Google Scholar]
[21].Cheng C, Li S, Yeh Y, Shen C, Chen J. Letermovir prophylaxis for cytomegalovirus reactivation in children who underwent hematopoietic stem cell transplantation: a single-institute experience in Taiwan. J Microbiol Immunol Infect 2022;55(2):323–327. [DOI] [PubMed] [Google Scholar]
[22].Freyer CW, Carulli A, Gier S, et al. Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide. Leukemia Lymphoma 2022;63(8):1925–1933. [DOI] [PubMed] [Google Scholar]
[23].Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151(4):264–9, W64. [DOI] [PubMed] [Google Scholar]
[24].Miller SA, Forrest JL. Enhancing your practice through evidence-based decision making: PICO, learning how to ask good questions. J Evid Base Dent Pract 2001;1(2):136–141. [Google Scholar]
[25].Higgins JPT, Green S. eds. Cochrane Handbook for Systematic Reviews of Interventions. United States: John Wiley & Sons, Ltd; 2011. [Google Scholar]
[26].Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health 2019;22(4):153–160. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[29].Hiraishi I, Ueno R, Watanabe A, Maekawa S. Safety and effectiveness of letermovir in allogenic hematopoietic stem cell transplantation recipients: interim report of post-marketing surveillance in Japan. Clin Drug Investig 2021;41(12):1075–1086. [DOI] [PMC free article] [PubMed] [Google Scholar]
[30].Malagola M, Pollara C, Polverelli N, et al. Advances in CMV management: a single center real-life experience. Front Cell Dev Biol 2020;8:534268. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[32].Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377(25):2433–2444. [DOI] [PubMed] [Google Scholar]
[33].Politikos I, Lau C, Devlin SM, et al. Extended-duration letermovir prophylaxis for cytomegalovirus infection after cord blood transplantation in adults. Blood Adv 2022;6(24):6291–6300. [DOI] [PMC free article] [PubMed] [Google Scholar]
[34].Richert-Przygonska M, Jaremek K, Debski R, et al. Letermovir prophylaxis for cytomegalovirus infection in children after hematopoietic cell transplantation. Anticancer Res 2022;42(7):3607–3612. [DOI] [PubMed] [Google Scholar]
[35].Derigs P, Radujkovic A, Schubert M, et al. Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data. Ann Hematol 2021;100(8):2087–2093. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[38].Mizuno K, Sakurai M, Kato J, et al. Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2022;24(6):e13904. [DOI] [PubMed] [Google Scholar]
[39].Sassine J, Khawaja F, Shigle TL, et al. Refractory and resistant cytomegalovirus after hematopoietic cell transplant in the letermovir primary prophylaxis era. Clin Infect Dis 2021;73(8):1346–1354. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[41].Sharma P, Gakhar N, MacDonald J, et al. Letermovir prophylaxis through day 100 post transplant is safe and effective compared with alternative CMV prophylaxis strategies following adult cord blood and haploidentical cord blood transplantation. Bone Marrow Transplant 2020;55(4):780–786. [DOI] [PubMed] [Google Scholar]
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[43].Mori Y, Jinnouchi F, Takenaka K, et al. Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data. Bone Marrow Transplant 2021;56(4):853–862. [DOI] [PubMed] [Google Scholar]
[44].Royston L, Royston E, Masouridi-Levrat S, et al. Letermovir primary prophylaxis in high-risk hematopoietic cell transplant recipients: a matched cohort study. Vaccines 2021;9(4):372. [DOI] [PMC free article] [PubMed] [Google Scholar]
[45].Yoshimura H, Satake A, Ishii Y, et al. Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: a single-center retrospective analysis. J Infect Chemother 2022;28(9):1317–1323. [DOI] [PubMed] [Google Scholar]
[46].Anderson A, Raja M, Vazquez N, Morris M, Komanduri K, Camargo J. Clinical “real-world” experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Clin Transplant 2020;34(7):e13866. [DOI] [PubMed] [Google Scholar]
[47].Wolfe D, Zhao Q, Siegel E, et al. Letermovir prophylaxis and cytomegalovirus reactivation in adult hematopoietic cell transplant recipients with and without acute graft versus host disease. Cancers 2021;13(21):5572. [DOI] [PMC free article] [PubMed] [Google Scholar]
[48].Lin A, Maloy M, Su Y, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: real-world experience. Transpl Infect Dis 2019;21(6):e13187. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[50].Robin C, Thiebaut A, Alain S, et al. Letermovir for secondary prophylaxis of cytomegalovirus infection and disease after allogeneic hematopoietic cell transplantation: results from the French compassionate program. Biol Blood Marrow Transplant 2020;26(5):978–984. [DOI] [PubMed] [Google Scholar]
[51].Studer U, Khanna N, Leuzinger K, et al. Incidence of CMV replication and the role of letermovir primary/ndary prophylaxis in the early phase after allogeneic hematopoietic stem cell transplantation—a single centre study. Anticancer Res 2020;40(10):5909–5917. [DOI] [PubMed] [Google Scholar]
[52].Łojko A, Styczynski J, Nasilowska-Adamska B, et al. Real-life experiences of letermovir prophylaxis for cytomegalovirus infection in patients after hematopoietic stem cell transplantation: Polish Acute Leukemia Group (PALG) analysis. Acta Haematol Pol 2022;53:350–354. [Google Scholar]
[53].Hill JA, Zamora D, Xie H, et al. Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients. Blood Adv 2021;5(16):3113–3119. [DOI] [PMC free article] [PubMed] [Google Scholar]
[54].Mori Y, Harada T, Yoshimoto G, et al. Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis. Int J Hematol 2022;116(2):258–265. [DOI] [PubMed] [Google Scholar]
[55].Zamora D, Duke ER, Xie H, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood 2021;138(1):34–43. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

bs9-6-e00178-s001.pdf^{(248.3KB, pdf)}

bs9-6-e00178-s002.pdf^{(242.2KB, pdf)}

bs9-6-e00178-s003.pdf^{(331.1KB, pdf)}

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[R35] [35].Derigs P, Radujkovic A, Schubert M, et al. Letermovir prophylaxis is effective in preventing cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: single-center real-world data. Ann Hematol 2021;100(8):2087–2093. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R37] [37].Johnsrud JJ, Nguyen IT, Domingo W, Narasimhan B, Efron B, Brown JW. Letermovir prophylaxis decreases burden of cytomegalovirus (CMV) in patients at high risk for CMV disease following hematopoietic cell transplant. Biol Blood Marrow Transplant 2020;26(10):1963–1970. [DOI] [PubMed] [Google Scholar]

[R38] [38].Mizuno K, Sakurai M, Kato J, et al. Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2022;24(6):e13904. [DOI] [PubMed] [Google Scholar]

[R39] [39].Sassine J, Khawaja F, Shigle TL, et al. Refractory and resistant cytomegalovirus after hematopoietic cell transplant in the letermovir primary prophylaxis era. Clin Infect Dis 2021;73(8):1346–1354. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] [40].Serio B, Giudice V, Guariglia R, et al. Prophylactic letermovir decreases cytomegalovirus reactivation after stem cell transplantation: a single-center real-world evidence study. Infez Med 2021;29(1):102–113. [PubMed] [Google Scholar]

[R41] [41].Sharma P, Gakhar N, MacDonald J, et al. Letermovir prophylaxis through day 100 post transplant is safe and effective compared with alternative CMV prophylaxis strategies following adult cord blood and haploidentical cord blood transplantation. Bone Marrow Transplant 2020;55(4):780–786. [DOI] [PubMed] [Google Scholar]

[R42] [42].Chen K, Arbona Haddad E, Cheng MP, et al. Cytomegalovirus events in high-risk allogeneic hematopoietic-cell transplantation patients who received letermovir prophylaxis. Transpl Infect Dis 2021;23(4):e13619. [DOI] [PubMed] [Google Scholar]

[R43] [43].Mori Y, Jinnouchi F, Takenaka K, et al. Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data. Bone Marrow Transplant 2021;56(4):853–862. [DOI] [PubMed] [Google Scholar]

[R44] [44].Royston L, Royston E, Masouridi-Levrat S, et al. Letermovir primary prophylaxis in high-risk hematopoietic cell transplant recipients: a matched cohort study. Vaccines 2021;9(4):372. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R45] [45].Yoshimura H, Satake A, Ishii Y, et al. Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: a single-center retrospective analysis. J Infect Chemother 2022;28(9):1317–1323. [DOI] [PubMed] [Google Scholar]

[R46] [46].Anderson A, Raja M, Vazquez N, Morris M, Komanduri K, Camargo J. Clinical “real-world” experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Clin Transplant 2020;34(7):e13866. [DOI] [PubMed] [Google Scholar]

[R47] [47].Wolfe D, Zhao Q, Siegel E, et al. Letermovir prophylaxis and cytomegalovirus reactivation in adult hematopoietic cell transplant recipients with and without acute graft versus host disease. Cancers 2021;13(21):5572. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R48] [48].Lin A, Maloy M, Su Y, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: real-world experience. Transpl Infect Dis 2019;21(6):e13187. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R49] [49].Daukshus NP, Cirincione A, Siver M, et al. Letermovir for cytomegalovirus prevention in adolescent patients following hematopoietic cell transplantation. J Pediat Inf Dis Soc 2022;11(7):337–340. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R50] [50].Robin C, Thiebaut A, Alain S, et al. Letermovir for secondary prophylaxis of cytomegalovirus infection and disease after allogeneic hematopoietic cell transplantation: results from the French compassionate program. Biol Blood Marrow Transplant 2020;26(5):978–984. [DOI] [PubMed] [Google Scholar]

[R51] [51].Studer U, Khanna N, Leuzinger K, et al. Incidence of CMV replication and the role of letermovir primary/ndary prophylaxis in the early phase after allogeneic hematopoietic stem cell transplantation—a single centre study. Anticancer Res 2020;40(10):5909–5917. [DOI] [PubMed] [Google Scholar]

[R52] [52].Łojko A, Styczynski J, Nasilowska-Adamska B, et al. Real-life experiences of letermovir prophylaxis for cytomegalovirus infection in patients after hematopoietic stem cell transplantation: Polish Acute Leukemia Group (PALG) analysis. Acta Haematol Pol 2022;53:350–354. [Google Scholar]

[R53] [53].Hill JA, Zamora D, Xie H, et al. Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients. Blood Adv 2021;5(16):3113–3119. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R54] [54].Mori Y, Harada T, Yoshimoto G, et al. Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis. Int J Hematol 2022;116(2):258–265. [DOI] [PubMed] [Google Scholar]

[R55] [55].Zamora D, Duke ER, Xie H, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood 2021;138(1):34–43. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Efficacy and safety of letermovir prophylaxis for cytomegalovirus infection after hematopoietic stem cell transplantation

Wen-Wen Li

Yong-Mei Zhang

Meng-Zhu Shen

Xiao-Dong Mo

Abstract

1. INTRODUCTION