A Modified Intensive Strategy to Prevent Cytomegalovirus Disease in Seropositive Umbilical Cord Blood Transplantation Recipients

Abstract

We previously demonstrated a lower rate of cytomegalovirus (CMV) reactivation and disease among seropositive umbilical cord blood transplantation (CBT) recipients receiving an intensive prophylaxis strategy consisting of ganciclovir on days –8 to –2 pretransplantation, high-dose valacyclovir post-transplantation, and twice-weekly serum CMV polymerase chain reaction testing. We hypothesized that a modified intensive strategy excluding pre-transplantation ganciclovir would be similarly effective. We compared the risk of CMV reactivation, occurrence of CMV disease, and duration of anti-CMV therapy by day 100 post-CBT in patients receiving the modified intensive and intensive strategies. Forty patients received the modified intensive strategy, and 43 received the intensive strategy. There was no difference in the hazard for CMV reactivation (hazard ratio, 1.1; P = .77). No patients in the modified intensive cohort, but 2 patients in the intensive cohort, developed CMV disease (P = .53). There was no difference in the hazard for early (c30 days post-CBT; P = .76) or high-level (>1000 IU/mL; P = .37) CMV reactivation. Patients in the modified intensive cohort had marginally higher CMV viral loads and percentage of days of CMV detection and treatment, although the contribution of pretransplantation ganciclovir to these differences is unclear. The overall percentage of treatment days was 32% in both cohorts after accounting for pretransplantation ganciclovir. In conclusion, exclusion of prophylactic ganciclovir before CBT did not impact the risk of CMV reactivation or disease, although CMV kinetics appeared to differ by prevention strategy. Best practices for CMV prevention will need further study as new prophylactic strategies become available.

INTRODUCTION

In cytomegalovirus (CMV)-seropositive umbilical cord blood transplantation (CBT) recipients, CMV reactivation occurs in in up to 100% of patients within 100 days after transplantation [1–3]. CMV disease develops in up to 28% of CBT recipients, with a CMV-attributable mortality as high as 11% by 1 year [1,2,4]. CBT recipients with CMV reactivation require substantial anti-CMV treatment, with a median duration of therapy of 70% of the first 100 days after transplantation, contributing to additional cost and toxicities [2,5,6]. Despite the high risk for infectious complications after CBT [7], CBT remains an important therapy for patients without an HLA- matched donor, particularly those with minimal residual disease, given the potential for improved overall survival and lower relapse compared with HLA-mismatched unrelated donor transplantation [8].

Effective strategies to limit CMV complications in this patient population are critical. We previously demonstrated a lower rate of CMV reactivation and disease after CBT with the implementation of an intensive prophylaxis strategy consisting of ganciclovir on days 8 to 2 followed by high-dose valacyclovir on days 0 to 365, biweekly serum CMV polymerase chain reaction (PCR) testing, and preemptive therapy at any level of CMV PCR positivity [2]. This approach resulted in significantly lower CMV reactivation and disease rates, as well as fewer days on anti-CMV therapy in patients with CMV reactivation. Similar strategies have been adopted for use in high-risk CBT recipients at other centers [1,9,10]. We subsequently instituted a modified intensive strategy that excluded pretransplantation ganciclovir given the potential for additional side effects, logistical barriers, and cost, with unclear benefit in the context of additional aspects of the prevention strategy. Given this change, here we report a comparison of CMV outcomes in CBT recipients receiving the modified intensive and intensive CMV prevention strategies.

METHODS

Patients

Patients who underwent CBT at the Fred Hutchinson Cancer Research Center (FHCRC) between April 2006 and January 2017 and who were CMV seropositive were eligible for this study. Patients were excluded who had undergone previous CBT, had died within 14 days of transplantation, or had participated in CMV prevention trials. Patients who were receiving anti-CMV therapy at the time of CBT for pretransplantation CMV reactivation were also excluded.

Transplantation Practices

Patients received myeloablative preparative regimens with either high-dose total body irradiation (TBI)-based conditioning consisting of 1320 cGy TBI, fludarabine 75 mg/m², and cyclophosphamide 120 mg/kg, or low-dose TBI-based conditioning with 200 cGy TBI, treosulfan 42 mg/m², and fludarabine 150 mg/m². Nonmyeloablative regimens consisted of fludarabine 200 mg/m², cyclophosphamide 50 mg/kg, and TBI in a single fraction of 200 or 300 cGy. No patients received serotherapy with antithymoglobulin or alemtuzumab. All patients received cyclosporine plus mycophenolate mofetil for prevention of acute graft-versus-host disease (GVHD). Granulocyte colony-stimulating factor (G-CSF) was given post-transplantation until stable absolute neutrophil count (ANC) recovery to > 2.5 × 10⁹/L and then as needed to maintain an ANC >1.0 × 10⁹/L. Patients received a double CBT if a suitable single cord blood graft could not be found, as determined by institutional criteria [8]. Underlying disease was categorized as standard or high risk based on previously described criteria [11].

Antiviral Prevention Strategies

We used three different antiviral prevention strategies for consecutive periods of time since 2006. Our initial “standard” strategy consisted of acyclovir 800 mg or valacyclovir 500 mg twice daily (or acyclovir 250 mg/m² intravenously every 12 hours until tolerating oral medications) for varicella zoster virus and herpes simplex virus prophylaxis. Patients were started on anti-CMV therapy if weekly serum pp65 antigenemia testing was positive at any level or polymerase chain reaction (PCR) for CMV DNA was c125 international units (IU)/mL. In patients receiving ≥ 1 mg/kg of steroids, preemptive therapy was started in patients with a CMV viral load ≥ 25 IU/ml. After day 100, weekly PCR surveillance was performed and preemptive therapy with valganciclovir (900 mg twice daily) was started for patients with 250 IU/mL CMV DNA. An “intensive” strategy for CMV prevention was implemented in June 2008 that consisted of pre-transplant intravenous ganciclovir of 5 mg/kg daily from day –8 to day –2 during conditioning, followed by high-dose acyclovir (2 g of valacyclovir every 8 hours or 500 mg/m² acyclovir intravenously every 8 hours until tolerating oral medications) for the first 100 days. We tested serum for CMV biweekly with PCR, and any detection prompted pre-emptive therapy. After day 100, we recommended that patients with prior CMV reactivation take valganciclovir 900 mg once daily through day 365; patients who could not tolerate valganciclovir continued high-dose acyclovir. Weekly PCR surveillance was continued and preemptive therapy with valganciclovir (900 mg twice daily) was started for patients with ≥ 250 IU/mL CMV DNA. A “modified intensive” strategy for CMV prevention was implemented in November 2014 that excluded pre-transplant intravenous ganciclovir of 5 mg/kg daily from day 8 to day 2 but was otherwise identical to the intensive strategy. Pre-transplant CMV testing within 2 weeks prior to conditioning was recommended for all patients receiving the intensive and modified intensive strategies.

Preemptive therapy consists of ganciclovir 5 mg/kg or foscarnet 90 mg/kg intravenously twice daily for 7–14 days as induction therapy, followed by maintenance therapy with once-daily dosing until routine surveillance testing was negative. Patients are given foscarnet if they are intolerant to ganciclovir or if preemptive therapy starts pre-engraftment. Patients who do not respond after the second week of induction therapy continue on twice-daily dosing until CMV PCR levels decrease. Patients who rapidly clear their CMV receive a minimum of 1 week of induction and 1 week of maintenance therapy. Decisions regarding transitioning from induction to maintenance therapy outside of standard practice guidelines, resistance testing, and therapy changes were at the discretion of health care providers. Doses of prophylactic and treatment regimens were adjusted as necessary for patients with renal insufficiency as per package insert or weight <40 kg. Patients resumed the recommended antiviral prophylaxis regimens after completing CMV treatment.

Definitions

CMV reactivation was defined as any detection of CMV DNA in serum, and CMV disease was defined by standardized criteria [12]. High-viral load was defined as any CMV detection 1000 IU/mL. The conversion factor for our laboratory-developed CMV PCR assay [13] to the WHO standard is 4 copies = 1 IU. We calculated the percentage of days of CMV detection and anti-CMV treatment in the first 100 days by dividing the number of days of CMV detection or treatment by the total days alive in the first 100 days. The percentage of days of induction anti-CMV therapy was calculated for the period during which patients received an equivalent of twice-daily dosing of anti- CMV therapy. We defined early reactivation as any serum CMV DNA detection 30 days after transplantation. Neutrophil engraftment was defined as the first of 3 consecutive days with an ANC .5 10⁹/L. Grade 3 and grade 4 neutropenia were defined as an ANC <1.0 10⁹/L and an ANC <.5 10⁹/L, respectively, according to the Common Terminology Criteria for Adverse Events, version 4.03. Acute kidney injury (AKI) was assessed for up to 100 days post-CBT and was categorized as a serum creatinine concentration 2 times (moderate) or 3 times (severe) greater than the baseline value [14].

Statistical Methods

Analyses were focused on comparisons between recipients of the modified intensive and intensive strategies. We compared patient, transplantation, and CMV characteristics using the Fisher exact test or Wilcoxon rank-sum test, as applicable. We estimated the probability of CMV reactivation for each prevention strategy with cumulative incidence curves with death as a competing risk. We used Cox proportional hazards models to evaluate the impact of the modified intensive versus intensive strategies on CMV reactivation incidence and timing. Linear regression models were used to compare percentages of days of CMV detection and treatment. Baseline variables included the prevention strategy, age, sex, number of donors, HLA disparity, conditioning regimen, total nucleated cell dose, use of an expanded cellular product [15], underlying disease, and disease risk; acute GVHD was incorporated into Cox models as a time-dependent variable. Any variables with a P value <.10 was considered for adjusted analyses and was retained in final models if the P value was <.10 or if its inclusion modified the effect of the primary predictor of interest by >10%. All P values were 2-sided, and values <.05 were considered significant. The study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board, and all participants provided written informed consent according to the principles of the Declaration of Helsinki.

RESULTS

Patient Characteristics

A total of 112 CMV seropositive CBT recipients were included in this study (Table 1). Forty consecutive patients received the new modified intensive strategy and were compared with historical cohorts of 43 patients receiving the intensive strategy and 29 patients receiving the standard strategy [2]. Eleven patients were excluded due to receipt of a second CBT (n = 1), enrollment in a CMV prevention trial (n = 1), death within 14 days of CBT (n = 2), or use of anti-CMV therapy at the time of transplantation (n = 3 in the intensive strategy cohort and n = 4 in the modified intensive strategy cohort). There were some differences in demographic and transplantation characteristics between patients receiving the modified intensive strategy and those receiving the intensive strategy, including a higher percentage of patients in the modified intensive cohort with a single donor, 4/6 HLA disparity, and myeloablative conditioning (Table 1).

Table 1.

Characteristics of CMV-Seropositive Patients Undergoing CBT by CMV Prevention Strategy

Characteristic	Standard Strategy (n = 29)	Intensive Strategy (n = 43)	Modified Intensive Strategy (n = 40)	P Value*
Age, yr, median (IQR)	21.4 (10.1–41.9)	31.7 (16.0–51.0)	25.8 (9.8–37.6)	.06
Sex, n (%)
Female	16 (55)	22 (51)	26 (65)	.27
Male	13 (45)	21 (49)	14 (35)
Transplantation year, range	2006–2008	2008–2010	2014–2017	<.001
Number of donors, n (%)
1	5 (17)	5 (12)	16 (40)	.005
2	24 (83)	38 (88)	24 (60)
HLA disparity, n (%)†
4/6	15 (52)	25 (58)	32 (80)	.12
5/6	14 (48)	13 (30)	6 (15)
6/6	0	5 (12)	2 (5)
Conditioning regimen, n (%)
Myeloablative	23 (79)	34 (79)	39 (98)	.02
Nonmyeloablative	6 (21)	9 (21)	1 (3)
Total nucleated cell dose (x 107/kg), median (IQR)	5.3 (4.1–9.2)	4.9 (4.1–7.7)	7.2 (5.4–10.9)	.02
Expanded cellular product, n (%)‡
Yes	6 (21)	6 (14)	10 (25)	.27
No	23 (79)	37 (86)	30 (75)
Diagnosis, n (%)
Acute lymphoblastic leukemia	7 (24)	12 (28)	21 (53)	.06
Acute myelogenous leukemia	17 (59)	21 (49)	13 (33)
Chronic myelogenous leukemia	3 (10)	3 (7)	0
Other	2 (7)	7 (16)	6 (15)
Disease risk, n (%)§
Standard	21 (72)	17 (40)	25 (63)	.02
High	8 (28)	21 (49)	15 (38)
Missing	0 (0)	5 (12)	0
Acute GVHD, n (%)
Grades 0–1	4 (14)	15 (35)	10 (25)	.35
Grades 2–4	25 (86)	28 (65)	30 (75)

^*P values for comparisons between the intensive and modified intensive cohorts.

^†For recipients of 2 cord blood units, HLA matching reflects the unit with the lowest match.

^‡The expanded cellular product consisted of non-HLA-matched ex vivo expanded cord blood progenitor cells [15].

^§Standard refers to aplastic anemia, chronic myelogenous leukemia in chronic phase, myelodysplastic syndromes without excess blasts, and leukemia and lymphoma in remission. High refers to all other hematologic malignancies [11].

Incidence and Features of CMV Reactivation and Treatment

The cumulative incidence of CMV reactivation in the modified intensive and intensive strategy cohorts were similar and significantly lower than that in the standard strategy cohort (Figure 1). The median time to first CMV detection in the modified intensive strategy cohort was 17 days (range, 0 to 78 days), which was not significantly different from that in the intensive strategy cohort (27 days; range, 3 to 77 days; P = .18). In univariable Cox models, there were no differences in the hazards for any CMV reactivation, early CMV reactivation, or high-level CMV reactivation between the modified intensive strategy and intensive strategy cohorts (Table 2).

Figure 1.

Cumulative incidence of CMV reactivation by day 100, stratified by prevention strategy, in seropositive CBT recipients. The modified intensive prevention strategy cohort comprised 40 patients, the intensive strategy cohort comprised 43 patients, and the standard strategy comprised 29 patients. Competing risks for CMV reactivation considered retransplantation or death.

Table 2.

CMV Outcomes within 100 Days of CBT in CMV Seropositive Recipients Receiving a Modified Intensive Versus Intensive Prevention Strategy

Outcome	Intensive (n = 43)	Modified Intensive (n = 40)	HR (95% CI)*	Mean Difference (95% CI)†	P Value
CMV reactivation, n (%)	26 (60.0)	26 (65.0)	1.1 (.6–1.9)		.77
Early CMV reactivation, n (%)‡	16 (37.0)	16 (40.0)	1.1 (.6–2.2)		.76
High-level viremia, n (%)§	1 (2.3)	3 (7.5)	2.84 (.3–27.3)		.37
CMV duration, % days, median (IQR)	17.0 (8.0–29.0)	36.0 (26.0–47.0)		8.9 (.2–17.7)	.05
CMV therapy, % days, median (IQR)	42.0 (21.0–57.0)	52.5 (43.0–64.0)		8.7 (−3.1 to 20.5)	.15
CMV disease, n (%)	2 (4.7)	0			.53║

^*Cox proportional hazards models using the intensive strategy as the reference group. These models were not adjusted, given that the primary predictor variables did not meet criteria for inclusion in a multivariable model.

^†Linear regression models using the intensive strategy as the reference group. These models were not adjusted, given that no other variables met criteria for inclusion in a multivariable model.

^‡Early CMV reactivation was defined as CMV detection ≤30 days after CBT.

^§High-level viremia was defined as a CMV DNA PCR value ≥ 1000 IU/mL.

^║This was calculated with the Fisher exact test.

The median first and median maximum CMV viral loads in patients with CMV reactivation in the modified intensive strategy were 1.6 log₁₀ copies/mL (interquartile range [IQR], 1.3–1.8 log₁₀ copies/mL) and 2.1 log₁₀ copies/mL (IQR 1.9–2.5 log₁₀ copies/mL), respectively. These were within a half log₁₀ of corresponding measurements in patients receiving the intensive strategy: 1.3 log₁₀ copies/mL (IQR, 1.2–1.5 log₁₀ copies/mL) and 1.6 log₁₀ copies/mL (IQR, 1.3–1.9 log₁₀ copies/mL), respectively. The mean CMV viral load in the modified intensive strategy cohort was similar to that in the intensive strategy cohort in every week except week 7 (P = .013) and was significantly lower than the standard strategy cohort in every week except week 1 (Figure 2).

Figure 2.

Mean CMV viral load during the first 100 days after CBT, stratified by prevention strategy. Whiskers indicate the 95% CI for the weekly mean CMV DNA PCR value, in IU/mL.

The median percentage of days of CMV detection within the first 100 days post-CBT among patients with CMV reactivation in the modified intensive strategy cohort was 36% (IQR, 26%- 47%), which was higher than that in the intensive strategy cohort (median, 17%; IQR, 8%−29%; P = .003). There remained a significantly increased mean difference of 9% of days CMV detection in the modified intensive strategy cohort in a linear regression model (Table 2). Patients in the modified intensive strategy cohort with CMV reactivation received anti-CMV therapy for a median of 53% of the days (IQR, 43%−64%), exceeding the value in the intensive strategy cohort (median, 42% of days; IQR, 21%−57%; P = .05). There remained an increased mean difference of 9% of days, which was not statistically significant in a linear regression model (Table 2). There was no difference in the median percentage of days of induction of anti-CMV therapy between the 2 cohorts (modified intensive strategy, 22% of days [IQR, 11%−8%] versus intensive strategy, 15% of days [IQR, 8%−24%]; P = .22).

Given that all patients in the intensive strategy cohort received 7 additional days of pretransplantation ganciclovir, we calculated the overall percentage of days of anti-CMV therapy for each prevention strategy based on the number of days of antiviral use divided by the number of days alive (including an additional 7 days pretransplantation either on or off ganciclovir per group). After accounting for pretransplantation ganciclovir use, the percentage of days of anti-CMV therapy was 32% in both the modified intensive and intensive strategy cohorts.

CMV Disease and Other Outcomes

The increased duration of CMV detection and corresponding use of post-transplantation anti-CMV therapy among patients with CMV reactivation in the modified intensive strategy cohort did not appear to increase adverse events compared with the intensive strategy cohort. No CMV disease occurred by day 100 in the modified intensive cohort, but 2 cases of CMV disease occurred by day 100 in the intensive cohort (Table 2). Two cases of CMV disease occurred between days 100 and 365 in the modified intensive cohort (both gastrointestinal disease), and there were no late cases of CMV disease in the intensive cohort. There were no CMV-attributable deaths in either cohort.

The median time to neutrophil engraftment was significantly shorter in the modified intensive cohort (median, 17 days; range, 9–33 days) compared with the intensive cohort (median, 20 days; range, 7–89 days; P = .04) (Table 3). Among patients treated for CMV, more patients in the modified intensive cohort developed post-engraftment grade 3 neutropenia (76.9% versus 55.6%), but not grade 4 neutropenia, and more patients required G-CSF (58% versus 43%) for a longer duration (median, 4 days versus 2 days); however, these differences were not statistically significant (Table 3). There was no significant difference in the incidence of moderate AKI in the modified intensive and intensive strategy cohorts (42.3% versus 51.9%) but a significantly higher incidence of severe AKI in the intensive cohort (3.8% versus 25.9%; P = .03) (Table 3). A similar proportion of patients in the modified intensive and intensive strategy cohorts received foscarnet within the first 100 days after CBT (40% and 49%). No patients with CMV reactivation deviated from the recommended prophylaxis strategies in either cohort.

Table 3.

Other Outcomes within 100 Days in CBT Recipients by Prevention Strategy

Outcome	Intensive (n = 43)	Modified Intensive (n = 40)	P Value*
Time to engraftment, d, median (range)†	20 (7–89)	17 (9–33)	.04
Expanded cellular product	19 (17–26)	20 (9–27)	1
No expanded cellular product	20 (7–89)	16 (12–33)	.04
Neutropenia, n (%)‡,§
Grade 3	15 (55.6)	20 (76.9)	.18
Grade 4	2 (7.4)	2 (7.7)	1
G-CSF use║
Patients, n (%)	9 (43)	15 (58)	.47
Days, median (range)	2 (1–12)	4 (1–7)	.39
AKI, n (%)§
≥2 times baseline creatinine	14 (51.9)	11 (42.3)	.67
≥3 times baseline creatinine	7 (25.9)	1 (3.8)	.03

^*P values were calculated with the Fisher exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables.

^†Determined only for patients who engrafted.

^‡For neutropenia occurring after engraftment, grade 3 was defined as an ANC <1.0 × 109/L, and grade 4 was defined as an ANC <.5 × 109/L. The patients in the grade 4 category are included in the grade 3 category, except for 1 patient who never achieved an ANC c1.0 × 109/L.

^§Among patients who received anti-CMV therapy.

^║Among patients who engrafted, were receiving anti-CMV therapy, and required G-CSF after starting antiviral therapy (n = 21 for the intensive strategy and n = 26 for the modified strategy cohorts).

Patients in the modified intensive cohort had a significantly higher percentage of days alive and out of the hospital within the first 100 days after CBT compared with those in the intensive cohort (median, 64.5% of days [IQR, 52%−72%] versus 48% of days [IQR, 15%−68%]; P = .009) (Figure 3).

Figure 3.

Percentage of days alive and out of the hospital by prevention strategy. Total percentage was determined by dividing the total number of days alive and out of the hospital for patients on each prevention strategy by the total number of days alive in the first 100 days after CBT. The horizontal line represents the median, the box represents the first and third quartiles, and the whiskers indicate the 10th to 90th percentiles.

DISCUSSION

CMV reactivation and disease cause substantial morbidity and mortality in CMV seropositive CBT recipients [9]. With implementation of an intensified prevention strategy, these complications are significantly reduced [1,9,10,16]. Prophylactic use of ganciclovir in the immediate pretransplantation period has been incorporated into some strategies that demonstrate reduced CMV reactivation and disease [6,17,18], but it is unclear whether this approach adds benefit in the context of additional post-transplantation prevention methods. In this study, we showed that CMV seropositive CBT recipients receiving a modified intensive CMV prevention strategy that excluded prophylactic pretransplantation ganciclovir had a similar cumulative incidence of CMV reactivation and rate of CMV disease compared with patients receiving an intensive strategy including pretransplantation ganciclovir. There were no CMV-attributable deaths in either cohort. Patients in the modified intensive cohort had marginally higher CMV viral loads and percentages of days of CMV detection and treatment, although the contribution of pretransplantation ganciclovir to these changes is unclear, owing to limitations of the study design. The overall percentage of treatment days was 32% in both cohorts after accounting for pretransplantation ganciclovir.

Ganciclovir administered before transplantation has been shown to decrease CMV complications in other hematopoietic cell transplantation recipient populations and is hypothesized to decrease the risk of early post-transplantation CMV reactivation [6,17,18]. Our previous study comparing the intensive strategy with a standard strategy without pretransplantation ganciclovir also demonstrated fewer early reactivation events without evidence of delayed engraftment or more AKI [2]. In this study, there was no significant difference in the occurrence of early CMV reactivation between the modified intensive and intensive strategy cohorts in the context of other preventive measures. Patients receiving the modified intensive strategy had an earlier median time to engraftment. It is unclear whether this may be related to myelotoxicity of pre-transplantation ganciclovir or to other differences in the patient cohorts, such as total nucleated cell dose, and further study of this finding is warranted.

Additional notable findings of this study include higher median first and maximum viral loads, as well as higher percentages of days of CMV detection and treatment, in patients in the modified intensive strategy cohort. Although these data indicate differences in viral kinetics, the contribution of with-holding pretransplantation ganciclovir versus other changes in practice over time are unclear. Importantly, the differences in viral kinetics did not appear to have clinical significance. This was supported by the findings that patients receiving the modified intensive strategy had no CMV disease within the first 100 days and no significant increase in the time to neutrophil engraftment, incidence of postengraftment grade 3 or 4 neutropenia, use of postengraftment G-CSF, or incidence of AKI. After accounting for the use of pretransplantation ganciclovir in all patients receiving the intensive strategy, the overall percentage of days of anti-CMV therapy was the same in both cohorts. In addition, the percentage of days alive and out of the hospital was higher in the modified intensive cohort. Although this was likely driven by multiple changes in practice over time, it provides an additional indirect metric to support that finding of no increase in post-transplantation health care utilization in the modified intensive cohort. Thus, the modified intensive approach focuses on anti-CMV therapy use in patients with CMV reactivation and avoids the potential logistical barriers, costs, and toxicities of pretransplantation prophylactic ganciclovir in CMV seropositive CBT recipients without increasing the risk of CMV complications.

Despite extensive efforts to mitigate CMV reactivation and its complications, the majority of CBT recipients continue to experience CMV reactivation necessitating prolonged treatment. Letermovir for CMV prophylaxis in CMV seropositive allogeneic hematopoietic cell transplantation recipients was recently approved by the US Food and Drug Administration. However, only 12 patients (3.2%) who received letermovir in the phase III trial were CBT recipients, and 38% of all patients developed clinically significant CMV infection or were considered failures [19]. Biweekly testing and early treatment in patients with breakthrough CMV viremia after CBT remains important until additional data are available in this setting. Optimal testing and treatment strategies will need continued refinement as new prophylactic approaches are implemented.

Strengths of this study include systematic approaches to supportive care and sequential changes in CMV prevention strategies over time. All patients underwent CBT as part of a clinical trial and had prospectively collected data, but the analyses were retrospective with limitations, including an imbalance in patient characteristics by prevention strategy. Changes in practice over time may have contributed to differences in CMV detection and treatment between the modified intensive and intensive cohorts, but the variables that we tested were not associated with CMV endpoints in regression models. Lack of adherence to high-dose valacyclovir prophylaxis could contribute to differences in CMV reactivation kinetics [16], but all patients with CMV reactivation received the recommended prophylaxis through day 100. The relatively small sample size of our comparator groups limited the power and precision of our analyses. Based on the sample size and incidence of CMV reactivation in the modified intensive and intensive strategy cohorts, the minimal detectable HR that we could detect for a difference in CMV reactivation was 2.18 with 80% power and 5% 2-sided type I error. Our ability to demonstrate significant differences in outcomes with fewer events was further limited. Prospective randomized trials incorporating different CMV prevention strategies after CBT will be important to establish the relative importance of each component and determine how to combine these approaches with new prophylactic treatments.

In conclusion, CMV seropositive CBT recipients receiving a modified intensive strategy that excluded pretransplantation ganciclovir had similar CMV reactivation and disease rates in the first 100 days after CBT as patients receiving an intensive strategy. Although patients in the modified intensive strategy cohort had an increased duration of CMV detection and treatment, this was not associated with increased adverse events, and it is unclear whether the elimination of pretransplantation ganciclovir played a role. The overall percentage of days of anti-CMV therapy administration was similar in the 2 prevention strategy cohorts after accounting for pretransplantation ganciclovir use in all patients receiving the intensive strategy. Pretransplantation ganciclovir might not be needed as part of a CMV prophylaxis regimen in CBT, and best practices for CMV prevention in high-risk patients will need reevaluation in larger prospective cohorts as new prophylactic strategies become available.