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Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplant (allo-HSCT) is mainly due to an increase of latent viremia in previously exposed patients. Furthermore, CMV reactivation in this setting has a significant impact on patient survival. Traditional approach to CMV reactivation post allo-HSCT was a pre-emptive treatment with antivirals in the case of increased viremia. A new antiviral compound, letermovir, has been introduced in clinical practice and is deeply changing the common CMV approach. The toxicity profile of letermovir allowed its use in prophylaxes in patients at high risk of CMV reactivation.
- allogeneic hematopoietic stem cell transplant
- CMV
- letermovir
1. Introduction
Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1,2]. CMV replication occurs in 50–60% of these patients either as a reactivation of a latent viremia or as a new infection. Without any prophylaxis or pre-emptive therapy (PET), 20% to 30% of them may develop end-organ disease [3]. Furthermore, CMV infection predisposes patients to several indirect effects, such as Graft-Versus-Host-Disease (GVHD) [4], myelosuppression and invasive bacterial and fungal infection [5,6], leading to increased non-relapse mortality (NRM) [7,8,9,10,11]. However, several studies have suggested that CMV replication could enhance leukemia-specific T cells, eventually reducing the risk of relapse [12].
2. Letermovir
LTV is a new anti-CMV agent targeting the viral terminase subunits pUL56 and pUL51, which are components of the terminase complex involved in DNA cleavage and packaging of the viral progeny [40,41]. LTV is available as oral tablets and as an intravenous solution. The oral bioavailability is 94%; however, in HSCT, recipients can drop down to 35%. LTV elimination is mainly biliary, involving the hepatic active transport transporters OATP1B1/3 and the UGT1A1/3 for glucuronidation.
LTV is a weak-to-moderate inhibitor of CYP3A4, resulting in increased levels of sirolimus and tacrolimus; a weak-to-moderate inducer of CYP2C9/19 potentially resulting in increased levels of voriconazole; and an inhibitor of OATP1B1/3. The LTV recommended dose is 480 mg once a day. Co-administration with OATP1B1/3 inhibitors may result in increased plasma concentrations of LTV; in this respect, when LTV is co-administered with cyclosporine, a potent OATP1B1/3 inhibitor, the LTV dose should be halved (240 mg once daily) [28,42]. Another frequently used drug that inhibits OATP1B is rifampin.
Overall, LTV is generally well tolerated, with gastrointestinal symptoms, including nausea and diarrhea, as the most common adverse events. Other main side effects reported are cough, headache and fatigue. Nephrotoxicity and myelotoxicity, the most common adverse effects of other anti-CMV drugs, were not observed in patients receiving LTV and included in the phase III clinical trial [28]. The excellent safety profile of LTV is probably due to the lack of a mammalian counterpart to the viral terminase complex.
No dose adjustment of LTV is necessary in the presence of mild (Child–Pugh class A) or moderate (Child–Pugh class B) hepatic impairment, while LTV is not recommended in patients with severe hepatic impairment. Similarly, dose adjustment of LTV is not required in patients with mild, moderate or severe renal impairment [43].
CMV genotyping in patients with clinically significant CMV infection (CS-CMV-i) during LTV therapy, revealed mainly UL56 gene mutations associated with reduced susceptibility to LTV, in particular V236M and C325W mutant during LTV prophylaxis and E237G and R369T mutant after its discontinuation; in these cases, patients were rescued by ganciclovir [44].
3. CMV Reactivation after Letermovir Prophylaxis
Although many studies demonstrated that LTV is highly effective for the prevention of CS-CMV-i after allo-HSCT, delayed-onset infections after LTV discontinuation are frequently reported, suggesting a potential role for the extension of LTV prophylaxis beyond day 100 [60,61,62,63,64].
In a retrospective analysis, Sperotto et al. [56] showed that CMV reactivation occurred more frequently within 100 days after HSCT in the PET group (87% vs. 9%, p < 0.01), while, in the LTV prophylactic group, reactivations were observed mainly after drug discontinuation (13% vs. 91%, p < 0.01). However, there was a statically significant difference in the peak of DNAemia with a lower copy number in the LTV group versus PET group.
Liu et al. [65] compared the LTV and PET strategy in a group of 333 patients, showing that the initial improvement observed in the first 3 months in the LTV group disappears afterwards. The multivariate analyses demonstrated that the use of LTV was associated with improved OS and reduced NRM and CMV-related mortality from day 0 to day 99 (HR 0.43, p 0.004; HR 0.50, p 0.03; HR 0.40, p 0.04, respectively) but worse CMV-related mortality afterwards (at day 364, HR 3.19, p 0.01) with a trend toward worse OS and NRM (at day 364, HR 1.28 and 1.68, respectively, p ns). An increased risk of CMV reactivation was associated with serum IgG levels <400 mg/dL at day 100, high-risk HSCT (p 0.004), the use of post-transplantation cyclophosphamide (PTCy; p 0.001) and mismatched-unrelated donors (MMUD; p = 0.02).
In a similar study, the prophylactic approach reduced the 180-day cumulative incidence of CS-CMV-i (44.7 vs. 72.4%, p < 0.001) and improved the OS rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower NRM (8.9 vs. 14.9%, p 0.052) [51]. In another retrospective study, a lower incidence of CS-CMV-i was also observed in the LTV group in time-to-event analyses censored at day 200 (20% vs. 59%, p 0.0003), although CS-CMV-i doubled in the LTV group between day +100 and +200 post-HSCT, after discontinuation of LTV, hence, raising the importance for continued CMV monitoring until day +200 post-HCT [49].
The optimal duration of LTV prophylaxis remains an unanswered question, especially in high-risk allo-HSCT recipients. Scattered studies reported that late CS-CMV-i was rare if LTV prophylaxis was continued beyond 14 weeks. Based on this rationale, an ongoing phase III randomized double-blind placebo-controlled clinical trial is exploring the efficacy and safety of LTV administrated for 200 days post-transplant in CMV-seropositive allotransplant recipients (Clinicaltrials.gov: NCT03930615). Preliminary results showed a strongly lower CS-CMV-i in these patients (2.8% in LTV group vs. 18.9% in placebo group), confirmed at a longer follow-up until 48 weeks (14.6% in LTV group vs. 20.3% in placebo group), recommending LTV continuation until day 200.
4. Letermovir as Secondary Prophylaxis
Given the efficacy of LTV as primary prophylaxis, the drug has been studied as secondary prophylaxis (SP) in patients who experienced at least one CMV episode after allo-HSCT [66]. Regrettably, to date, there are only few data published so far, with scattered case reports [67,68,69,70,71].
In a retrospective study conducted by EBMT [71], LTV as SP was used in 40 patients: 10.1% breakthrough CS-CMV-i were reported; however, all of them were successfully rescued with other antivirals and OS at 120 days was 81.9% (95% CI = 65.7–90.9; 7/40 events). A French compassionate program reported the results of 80 CMV-seropositive patients who received LTV as SP [70]. Four patients developed CMV breakthrough infections (n = 1) or disease (n = 3) after the initiation of LTV, and three of these patients carried CMV UL56 mutation C325Y or W, conferring the high-level LTV resistance. Six deaths were reported, but only two were related to CMV infection among other causes.
Based on these data, LTV warrants further investigations as a potential tool for SP.
5. Letermovir as Therapy
LTV has also been studied as a treatment in non-responders to standard anti-CMV treatment, and some case reports support the potential efficacy in clearing CMV-DNA and treating CMV disease [71,72]. Interestingly, LTV showed efficacy in UL54 mutant CMV, which is a recurrent mutation found in patients resistant to foscarnet, ganciclovir and cidofovir [73,74].
Schubert et al. [75] studied the effect of LTV in patients refractory to ganciclovir or foscarnet. Nine patients received LTV for CMV-i after allo-HSCT, and all but two responded. The median duration of LTV treatment was 31 (8–127) days. The median treatment duration to achieve a decrease of viral load <200 IU/mL was 23 (8–83) days. All patients received LTV as a monotherapy. The treatment was generally well tolerated, and no adverse events were reported.
In the EBMT study [71], only two patients received LTV to treat CMV pneumonia and CMV colitis, both healed the disease after 35 and 91 days, respectively. However, no antiviral effect was documented in patients treated with LTV as PET (n = 5).
Therefore, LTV may be considered in patients with multidrug-resistant CMV disease or in those intolerant or resistant to current therapies, owing to its favorable side-effect profile with less bone marrow toxicity compared with valganciclovir and ganciclovir and less nephrotoxicity compared with cidofovir and foscarnet.
6. Letermovir and Immune Reconstitution
Immune reconstitution after allo-HSCT depends on the use of high-dose steroids, lymphopenia, chronic GVHD and the stem cell source, but it is also deeply influenced by CMV serostatus and CMV replication [76,77,78]. Decreased CMV-specific cellular immunity at 3 months after allo-HSCT is associated with increased late CMV reactivation and mortality [79]. Ganciclovir prophylaxis, leading to decreased CMV reactivation and reduced antigen exposure, has been shown to play a key role in delayed immune reconstitution [80]. Similarly, decreased CMV reactivation on LTV prophylaxis provides a potential mechanism for the observed increase of CS-CMV-i after LTV discontinuation.
Zamora et al. studied CMV-specific T cell responses at 3 months after allo-HSCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens with thirteen-color flow cytometry. The study showed that LTV prophylaxis appeared to be associated with delayed polyfunctional CMV-specific cellular immune reconstitution at 3 months compared with PET, and polyfunctional T cell response remained diminished also after adjustment for donor CMV serostatus, absolute lymphocyte count and steroid use.
Among LTV recipients, greater peaks of CMV-DNA and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1 [64]. A different study evaluated the number of absolute numbers of CD4+ and CD8+ T cells in two groups of patients receiving PET or prophylactic LTV. No difference was observed between PET versus LTV in CD4+ and CD8+ T cell recovery at early timepoints. However, a statistically significant difference was detected at day +60 (CD4+: median 270/mL vs. 130/mL, p = 0.04; CD8+: median 260/mL vs. 100/mL, p 0.03) and at day +90 (CD4+: median 430/mL vs. 190/mL, p 0.03; CD8+: median 410/mL vs. 270/mL, p 0.04).
After day +180, a progressive increase of immune recovery was observed in the LTV group but the difference between the two groups disappeared at 1 year from transplant only (PET vs. LTV group: CD4: median 650/mL vs. 510/mL, p 0.5; CD8: median 310/mL vs. 290/mL, p 0.4) [56]. The analysis of CMV-specific immunity by intracellular cytokine staining (ICS) and ELISPOT assays in PET and LTV groups, showed a delayed recovery in the latter group (ICS assay: median, 177 days for PET vs. 275 days for LTV; p 0.001; ELISPOT assay: 183 days vs. 307 days; p 0.002) [62].
The same study reported other two interesting observations: (1) time to recovery of CMV-specific immunity was not influenced by the occurrence of abortive infection during LTV prophylaxis; and (2) in both groups, no CS-CMV-i was observed, once protective immunity was achieved, especially if detected by ELISPOT assay [62].
A standardized method to measure post-allotransplant CMV-specific immune recovery might be of great benefit to help a patient tailored management of LTV prophylaxis. In the kidney transplant setting quantiferon CMV positive at day +100 is strongly associated with protection from CS-CMV-i after this time. In allo-HSCT setting, a landmark analysis demonstrated that IgG level <400 mg/dL at day +100 was associated with significantly increased incidence of CS-CMV-i, suggesting that such patients may require LTV extended beyond day +100 [65].
Several CMV-specific immune monitoring assays have been described in allo-HSCT setting, some not constantly reliable or difficult to replicate, whereas other are more standardized [56,62,81,82,83,84], all showing capability to predict recurrent and/or late CMV reactivation. However, a prospective study applying a risk stratification models based on the monitoring of CMV-specific cell-mediated immunity to LTV prophylaxis is still lacking.
This entry is adapted from the peer-reviewed paper 10.3390/hemato4020013
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