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Effectiveness of letermovir prophylaxis for CMV infection in patients with or without acute GvHD

Jan 6, 2022
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Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) commonly develop graft-versus-host disease (GvHD).1 The risk of infection is increased in this population due to suppression of the immune system caused by treatment of acute GvHD (aGvHD) with high dose corticosteroids. Progression of GvHD is also associated with increased incidence of cytomegalovirus (CMV) reactivation. The incidence of CMV primary infection or reactivation is highest in CMV-seropositive patients undergoing allo-HSCT, particularly in those receiving stem cells from CMV-seronegative donors. Letermovir, an oral antiviral agent inhibiting the CMV terminase complex thereby preventing CMV, has demonstrated effectiveness in reducing CMV infection with a tolerable safety profile in patients with GvHD, but these studies had a relatively small sample size and only a small number of patients received letermovir.1 Therefore, there is limited evidence on prophylactic treatments for patients developing aGvHD.

Here, we summarize the key findings from a retrospective study published by Wolfe et al.1 in Cancers, assessing the effectiveness of letermovir prophylaxis for CMV infection in patients at high risk for CMV reactivation.

Study design

This was a single-center, retrospective, cohort study comparing letermovir prophylaxis in patients who had undergone allo-HSCT to a historical control group. Eligible patients had undergone allo-HSCT at the Ohio State University Comprehensive Cancer Center between June 2016 and June 2020, were aged ≥18 years, and were CMV seropositive. Ohio State University incorporated letermovir into institutional prophylaxis guidelines in July 2018; therefore, patients receiving allo-HSCT between July 2018 and June 2020 comprised the letermovir group and those receiving allo-HSCT between June 2016 and July 2018 comprised the control group.

  • The primary outcome was the incidence of clinically significant CMV infection (CS-CMVi) within the first 200 days post-allo-HSCT.
    • CS-CMVi was defined as CMV disease or CMV viremia leading to preventative treatment with ganciclovir, valganciclovir, or foscarnet.
  • Secondary outcomes included incidence of CS-CMVi in all patients, incidence of CMV viremia, duration of letermovir therapy, mortality, non-relapse mortality (NRM), overall survival (OS), and analysis of risk factors for the development of CS-CMVi.
    • OS was defined as date of transplant to date of death.
    • NRM was defined as date of transplant to date of death due to reasons other than relapse.

Results

Baseline characteristics

A total of 119 and 143 allo-HSCT events were included in the letermovir and control groups, respectively. Four patients included had two allo-HSCT events during the study and each transplant event was assessed separately. There were significant differences between the groups for age, gender, GvHD prophylaxis, and the use of anti-thymocyte globulin or a T cell-depleted graft (Table 1).

Table 1. Baseline characteristics*

Characteristics, % (unless stated otherwise)

Letermovir
(n = 119)

Control
(n = 143)

p value

Median age, years (range)

56 (2174)

60 (1876)

0.010

Sex, male

47.9

60.1

0.048

Diagnosis

 

 

0.380

              AML

37.0

40.6

 

              ALL

16.8

10.5

 

              NHL and HL

10.1

13.3

 

              MM

4.2

1.4

 

              MDS/MPN

19.3

25.9

 

              CML

1.7

1.4

 

              CLL

5.0

4.2

 

Donor positive CMV serostatus

43.7

53.1

0.128

GvHD prophylaxis

 

 

0.003

              Tac + MTX

56.3

65.7

 

              Tac + sirolimus

0.8

6.3

 

              Tac + mycophenolate

2.5

0.7

 

              PTCy

40.3

25.2

 

Use of ATG or T cell-depleted graft

21.0

37.7

0.004

aGvHD grade

 

 

0.86

              01

42.0

45.5

 

              2

40.3

37.8

 

              34

17.7

16.8

 

aGvHD, acute graft-versus-host disease; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATG, anti-thymocyte globulin; BM, bone marrow; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMV, cytomegalovirus; HL, Hodgkin lymphoma; HLA, human leukocyte antigen; MDS, myelodysplastic syndromes; MM, multiple myeloma; MPN; myeloproliferative neoplasms; MTX, methotrexate; NHL, non-Hodgkin lymphoma; PTCy, post-transplantation cyclophosphamide; Tac, tacrolimus.
*Adapted from Wolfe et al.1
Values in bold are statistically significant.

Primary and secondary outcomes

  • Treatment for CS-CMVi was initiated in 29 and 81 patients in the letermovir and control groups, respectively.
    • Patients with aGvHD Grade ≥2 in the letermovir group showed a significant reduction in the incidence of CS-CMVi (hazard ratio, [HR], 0.08; 95% confidence interval [CI], 0.030.27; p < 0.001) (Table 2).
    • Similarly, CS-CMVi was also significantly reduced in all patients within 200 days post-allo-HSCT (HR, 0.18; 95% CI, 0.100.32; p < 0.001).
    • Patients in the letermovir group showed a lower incidence of CMV viremia compared with the control group (39.5% vs 75.5%; p < 0.01) (Table 2).
    • A reduced risk of developing CS-CMVi with letermovir was observed in multivariate analysis among all patients, while the development of aGvHD and PTCy prophylaxis increased the risk of CS-CMVi.
  • Compared with the control group, the letermovir group showed improved OS (HR, 0.46; 95% CI, 0.230.95; p = 0.035) and NRM (HR, 0.41; 95% CI, 0.180.96; p = 0.04).
  • With regards to risk factors, age and aGvHD were associated with increased risk of death (HR, 1.03; p < 0.001; and HR, 2.05; p = 0.001, respectively) and increased risk of NRM (HR, 1.03; p = 0.012; and HR, 3.59; p < 0.001, respectively).
  • Median duration of letermovir therapy was 95 days, and nine patients continued letermovir prophylaxis for recurrent CMV viremia.

Table 2. Primary and secondary outcomes*

Outcomes, % (unless stated otherwise)

Letermovir
(n = 119)

Control
(n = 143)

p value

CS-CMVi

24.4

56.6

<0.001

CMV viremia

39.5

75.5

<0.01

Median CMV viremia, IU/mL (range)

770 (5118,178)

1,003 (5181,300)

0.03

Mortality

31.9

43.4

0.06

Cause of death

 

 

 

              Treatment-related

12.6

14.6

0.65

              Non-relapse

8.4

9.7

 

              Disease-related

10.9

18.8

 

CMV, cytomegalovirus; CS-CMVi, clinically significant CMV infection.
*Adapted from Wolfe et al.1
Values in bold are statistically significant.

Conclusion

This single-center, retrospective, cohort study demonstrated that the risk of CS-CMVi was significantly reduced in patients with aGvHD undergoing allo-HSCT. CS-CMVi and CMV viremia were also significantly reduced in all patients receiving letermovir prophylaxis. The strengths of the current study compared with previous studies included additional analysis of patients who developed aGvHD post-transplantation, relatively few exclusion criteria improving external validity, an extended duration of letermovir use post-transplantation to Day +200, and inclusion of patients at high risk of aGvHD. However, the study also had certain limitations; it was a retrospective single-center study and included a historical cohort, meaning the study may have been influenced by changes in clinical practice over time. Therefore, further prospective trials are warranted to determine the beneficial extent of letermovir for CMV prophylaxis in patients who develop GvHD.

  1. 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 (Basel). 2021;13(21):5572. DOI: 3390/cancers13215572

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