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Cytomegalovirus in Adult Allogeneic Blood and Marrow Transplant Patients Before or Around the Period of Neutrophil Recovery: A Single-Center, Retrospective, Descriptive Study

Cytomegalovirus in Adult Allogeneic Blood and Marrow Transplant Patients Before or Around the... Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 applyparastyle “fig//caption/p[1]” parastyle “FigCapt” Open Forum Infectious Diseases MAJOR ARTICLE Cytomegalovirus in Adult Allogeneic Blood and Marrow Transplant Patients Before or Around the Period of Neutrophil Recovery: A Single-Center, Retrospective, Descriptive Study 1,2 2 3 3 3 4, Isabella Martin, Alexandra Valsamakis, Douglas Gladstone, Richard Jones, Richard Ambinder, and Robin K. Avery 1 2 3 Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA, Division of Infectious Diseases, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA  Background. Few reports exist on pre-engraftment cytomegalovirus (CMV) DNAemia in allogeneic blood or marrow trans- plant (allo BMT) recipients. We describe this clinical entity, its management, and the potential effect of 3 different quantitative CMV deoxyribonucleic acid (DNA) tests used during the 6-year study period.  Methods. We performed a retrospective, single-center study of allo BMT recipients from 2010 to 2015 who developed CMV DNAemia before neutrophil recovery (absolute neutrophil count [ANC] <1000 cells/mm , “pre-engraftment CMV”) or who became neutropenic concomitant with detectable CMV DNA (“peri-engraftment CMV”). Clinical data were collected from the electronic medical record. Results. Among 1151 adult allo BMT patients, 73 developed CMV DNAemia before engraftment or while neutropenic aer ft in- itial engraftment. Most patients were eventually treated (valganciclovir or ganciclovir, N = 68; foscarnet, N = 1); 4 were not treated. First CMV detection occurred at median day +12 (range, 0–48), but treatment was not started until median day +33 (range, 4–105) at median ANC of 760 cells/mm . Six patients had peak viral loads >5000 IU/mL; none had tissue-invasive disease. One developed ganciclovir resistance. No significant differences were observed upon stratification by quantitative CMV DNA test.  Conclusions. Cytomegalovirus DNA was detected in 6.3% of pre- and peri-engraftment allo-HSCT patients. Ganciclovir deriva- tives were commonly used for treatment despite risk of neutropenia. Treatment was typically deferred until CMV DNA and ANC rose. With rare exceptions, this treatment strategy did not appear to have adverse clinical consequences with respect to acute CMV. Different CMV DNA quantification tests used performed similarly from a clinical perspective despite different analytical perfor - mance characteristics. Keywords. bone marrow transplant; CMV; pre-engraftment. Cytomegalovirus (CMV) disease remains a significant infec- have continued the strategy of serial monitoring of CMV de- tious cause of morbidity and mortality in patients undergoing oxyribonucleic acid (DNA) in blood and preemptive therapy, in allogeneic blood or marrow transplant (allo BMT) despite ad- which infection is treated before disease onset. With preemptive vances in monitoring and treatment [1, 2]. Cytomegalovirus therapy, postengraftment CMV DNA detection in blood (CMV replication and disease are well recognized complications DNAemia) of asymptomatic patients is far more common than postengraftment, when the newly acquired immune system CMV disease [3]. However, progressive, tissue-invasive infec- becomes functional [3]. Prophylaxis with valganciclovir or tion of the gastrointestinal tract, lungs, liver, central nervous letermovir has been demonstrated to be effective in preventing system, retina, or other sites can occur occasionally. postengraftment CMV disease [4, 5]; however, many centers In contrast to postengraftment CMV infection, less is un- derstood about CMV detection early aer t ft ransplantation, from the period before engraftment to around the time neu- Received 22 January 2020; editorial decision 24 February 2020; accepted 4 March 2020. trophil recovery. One study noted that CMV disease before Correspondence: Robin Avery, MD, 1830 E. Monument Street, #449, Baltimore, MD 21205 engraftment was uncommon, occurring in approximately 1% (ravery4@jhmi.edu). of allo BMT recipients, but was associated with a high mor- Open Forum Infectious Diseases © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases tality rate [6]. A  subsequent study demonstrated that CMV Society of America. This is an Open Access article distributed under the terms of the Creative DNAemia was identified in a greater proportion of patients Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any with CMV disease and at higher levels compared with controls medium, provided the original work is not altered or transformed in any way, and that the [7]. Cytomegalovirus DNAemia was also detectable approxi- work is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofaa081 mately 2 weeks before disease, suggesting that monitoring CMV Cytomegalovirus in Adult Allogeneic Blood • ofid • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 DNA in plasma might help identify patients at risk of this pre- neutrophil recovery (defined as ANC <1000 cells/mm , n = 60) engraftment complication [7]. and a second, smaller group with peri-engraftment neutropenia Extension of monitoring for CMV DNA into the pre- (n = 13) who developed recurrent neutropenia after neutrophil engraftment period has been facilitated by the ready availability recovery, with their first episode of CMV DNAemia detectable of quantitative nucleic acid amplification tests for CMV DNA after recurrent neutrophil decline. These latter patients were in- measurement (CMV qNAATs), which are now routine compo- cluded because the treatment dilemma in this group was similar nents of test menus at centers performing allo BMT. However to that in patients with pre-engraftment CMV. Patients who had many questions remain regarding pre-engraftment CMV undergone a prior allo BMT were excluded. DNAemia including its prevalence when monitoring is initi- Data collected from retrospective medical record review in- ated immediately aer a ft llo BMT, its clinical characteristics, the cluded age, gender, underlying disease, allograft type, donor/re- risk of progression to tissue-invasive disease, and whether pre- cipient CMV serostatus, conditioning regimen, CMV qNAAT engraftment CMV DNAemia should be treated and when. In results, ANCs at specific time points (at time CMV DNA was addition, it is unclear which antivirals should be used in these detectable, at time CMV DNA was greater than assay’s lower medically tenuous patients, given the myelosuppressive poten- limit of quantification [LLOQ], and at time of treatment initi- tial of first-line therapy (ganciclovir, valganciclovir) and neph- ation), CMV treatment (what antiviral agent was used, if any, rotoxicity of second-line drugs (foscarnet and cidofovir). and treatment duration), CMV disease within 100 days of allo At our center, post-allo BMT monitoring includes weekly BMT, and death within 6 months of allo BMT. This study was CMV qNAAT from plasma starting at day 0 (day of receipt of the approved by the Johns Hopkins Medicine Institutional Review allo BMT). This practice allowed us to perform a retrospective, Board. descriptive study of CMV DNAemia in neutropenic patients Cytomegalovirus Management in Allogeneic Blood or Marrow Transplant before engraftment and among those who became neutro- Post-allo BMT CMV DNA monitoring at this center in- penic again aer en ft graftment (peri-engraftment neutropenia). cludes weekly CMV qNAAT from plasma, starting from day e m Th ain aims of this study were to determine the prevalence 0 (date of allo BMT). In the electronic medical record, CMV of CMV DNAemia during pre- and peri-engraftment neutro- DNA ≥LLOQ was flagged as an abnormal result. Once this penia, define its clinical characteristics, and describe thera- occurred, management was per clinician choice and included peutic practices such as whether CMV DNAemia was treated, decisions such as CMV DNA monitoring frequency (could clinical parameters at treatment initiation (CMV DNA level and increase to twice weekly), initiation of preemptive treatment, absolute neutrophil count [ANC]), and treatment regimens. CMV antiviral drug selection, duration of preemptive treat- Furthermore, we sought to assess whether clinicians’ decisions ment (until CMV qNAATs results were either <LLOQ or to treat (or to wait), depending on the viral load and ANC, had undetectable), and duration of CMV DNA monitoring after any adverse effects in terms of development of tissue-invasive treatment cessation. CMV disease or high peak viral loads. Finally, CMV DNA quantitative testing evolved during the 6-year study period to Cytomegalovirus Quantitative Nucleic Acid Amplification Tests exploit the diagnostic gains ao ff rded by improved automation Three different qNAATs were used sequentially during the and by the adoption of a US Food and Drug Administration- 6-year study period (Table  1) [10]. Testing eras 1 and 2 were approved assay that incorporated a new international standard reported in copies/mL, whereas era 3 was calibrated according for CMV qNAAT calibration [8, 9]. The utilization of different to the CMV WHO International Standard and reported in IU/ assays at our center allowed us to compare clinical features mL [9]. Validation studies performed before test implementa- and treatment characteristics of pre-/peri-engraftment CMV tion demonstrated a mean difference in CMV DNA measure- DNAemia in 3 sequential eras during the study period when 3 ment of −0.12 log for era 2 qNAAT versus era 1 (era 2 qNAAT CMV qNAATs with varying performance characteristics were values were on average 0.12 log , or 1.3-fold, greater than era 1 in use, in order to discern the clinical impact of deploying as- qNAAT) and 0.31 log for era 3 qNAAT versus era 2 qNAAT says with slightly different functionality. (era 3 qNAAT values were on average 0.31 log , or 2-fold, less than era 2 qNAAT). METHODS Clinical Record Review Statistical Analysis Subjects who underwent allo BMT between January 2010 and Descriptive statistics (means, medians) were analyzed with December 2015 were identified through 2 databases of adult Stata version 14. Associations between discrete variables allo BMT recipients at the Sidney Kimmel Comprehensive (such as assay era) and continuous variables (such as the day Cancer Center at the Johns Hopkins Hospital. Two groups posttransplant when CMV DNA was first detectable) were of first-time allo BMT patients were selected for inclusion, tested using one-way analysis of variance. P < .05 was con- one group with detectable CMV DNAemia occurring before sidered significant. 2 • ofid • Martin et al Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Table 1. Clinical CMV qNAATs During Study Period Era 1 Era 2 Era 3 Dates January 1, 2010 (study start)–May 1, 2012 May 2, 2012–April 2, 2013 April 3, 2013–December 31, 2015 (study end) Test Laboratory developed test Laboratory developed test (7) COBAS AmpliPrep (extraction)/ COBAS TaqMan (real-time PCR) • Extraction BioRobot M48 (QIAGEN) QIASymphony (QIAGEN) CMV (Roche Molecular Diagnos- • Amplification SDS 7500 (Applied Biosystems) RGQ (Rotorgene, QIAGEN) tics) Test system approved by • Real-time PCR reagents Artus (QIAGEN) Artus (QIAGEN) the US Food and Drug Admin- istration LLOQ 300 copies/mL 100 copies/mL 137 IU/mL LOD 100 copies/mL 50 copies/mL 91 IU/mL Abbreviations: CMV, cytomegalovirus; LLOQ, lower limit of quantification; LOD, limit of detection; PCR, polymerase chain reaction; qNAAT, quantitative nucleic acid amplification tests  Conversion from copies to IU between tests used in era 2 and era 3, 1.09 copy/IU as per era 3 validation studies using clinical plasma samples. A sensitivity analysis was performed, either including or in the total 1151 patient cohort; most patients with pre- or excluding patients (n  =  13) who initially engrae ft d then again peri-engraftment CMV DNA had received nonmyeloablative became neutropenic by the time their CMV DNAemia was de- conditioning regimens (78%) and haploidentical allografts tected. The analysis that excluded these patients included only using posttransplant cyclophosphamide (PTCy) (82%). those who had detectable CMV DNAemia before initial neutro- Cytomegalovirus serologic status was documented for all re- phil recovery (n = 60). cipients and for 70 of 73 (96%) of donors (Table  2). Most re- cipients were CMV immunoglobulin (Ig)G seropositive (R+, 68 RESULTS of 73, 93%). Donor CMV IgG serology was positive in 43 of 73 (D+, 59%) and negative in 27 of 73 (37%). The greatest propor- Patients tion of patients were D+/R+ (55%) (Table 2). During the study period, 73 of 1151 (6.3%) adult patients who underwent allo BMT met the case definitions of CMV DNA de- Clinical Features of Pre-/Peri-Engraftment Cytomegalovirus Among All tection in plasma with ANC <1000 (pre- or peri-engraftment). Case Patients and Stratified by Testing Era Demographic information and basic clinical characteristics To better understand the clinical entity of pre-/peri-engraftment were retrieved (Table  2). The conditioning regimen type and CMV, clinical features related to plasma CMV DNA detection donor and graft types in these 73 patients mirrored that seen were characterized. Overall, CMV DNAemia was first detect- able at a median of 12  days posttransplant (range, 0–48  days) and rose to levels above the LLOQ at a median of 28  days Table 2. Patient Demographic and Clinical Characteristics (n = 73) posttransplant (range, 0–49  days). The median ANC at which Median age (years) 52 (23–76) CMV DNA became detectable and measurable (>LLOQ) was Gender less than 500 cells/mm . The median peak CMV DNA of the Male 39 (53%) pre-/peri-engraftment episode was <1000 copies/mL, but it Female 34 (47%) ranged considerably (790–84  300 copies or IU/mL). Only 6 Donor/Recipient CMV Serology Recipient seropositive (total) 68 (93%) patients (8%) had peak CMV DNA  >5000 (data not shown). Recipient seronegative (total) 5 (7%) Stratified analysis according to test era to determine the effect Donor seropositive (total) 43 (59%) of qNAAT demonstrated no significant difference between the Donor seronegative (total) 27 (37%) 3 testing eras for the following parameters: day posttransplant Donor serology missing 3 (4%) and ANC at which CMV DNA was first detectable, day D+/R+ 40 (55%) posttransplant and ANC at which CMV DNA was first above D-/R+ 25 (34%) D+/R− 3 (4%) the LLOQ, or peak CMV DNA of the episode (Table 3). In ad- D−/R− 2 (3%) dition, a sensitivity analysis demonstrated no significant differ- Induction Regimen ence in these results when excluding the group of 13 patients Myeloablative 16 (22%) who had initially engrafted and then had become neutropenic Nonmyeloablative 57 (78%) again by the time that CMV DNA was detected. Allograft Type Matched related 7 (9%) Haploidentical 60 (82%) Treatment of Pre-/Peri-Engraftment Cytomegalovirus Among All Case Patients and Stratified by Testing Era Unrelated donor 5 (7%) Cord blood 1 (1%) Most patients with CMV DNAemia in the pre- and peri- Abbreviations: CMV, cytomegalovirus; D, donor, R, recipient. engraftment period were eventually treated with antiviral drugs Cytomegalovirus in Adult Allogeneic Blood • ofid • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Table 3. Clinical Features of CMV Among All Patients and Stratified by Testing Era All Patients Era 1 Patients (n = 20) Era 2 Patients (n = 14) Era 3 Patients (n = 39) (n = 73) (<300 copies/mL) (<100 copies/mL) (<137 IU/mL) Median (Range) Median (Range) Median (Range) Median (Range) P Value Day posttransplant when 12 (0–48) 10 (2–48) 13 (3–38) 12 (0–34) .72 CMV first detectable Day posttransplant when 28 (0–49) 28 (9–48) 28 (3–45) 30 (0–49) .79 CMV > LLOQ ANC when CMV first de- 110 (20–4030) 76 (50–1647) 90 (20–1340) 125 (20–4030) .99 tectable (cells/mm ) ANC when CMV 423 (20–2560) 416 (50–1632) 610 (20–2560) 350 (20–1660) .76 first > LLOQ Peak CMV DNA of ep- 790 (137–84 300) 1127 (300–22 122) 449 (211–2489) 829 (137–84 300) .46 isode (copies/mL or IU/mL) Abbreviations: ANC, absolute neutrophil count; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; LLOQ, lower limit of quantification.  Upper end of range is >1000 because the cohort includes peri-engraftment patients with recovered ANCs who again became neutropenic after plasma CMV was detected. duration, there was a trend toward significance between era 2, (69 of 73, 95%) (Table  4). Most patients (69 of 73, 95%) were when a qNAAT with the lowest LLOQ and limit of detection started on CMV treatment on the basis of preemptive CMV PCR (LOD) was in use, and eras 1 and 3 (<300 copies/mL and <137, monitoring (Table 4), but treatment initiation was deferred until respectively). The median duration of treatment in era 2 was after engraftment (median 33  days posttransplant) (Table  5) 36 days, compared with 31 and 34 days for era 1 and era 3, re- relative to initial detection (median 12  days posttransplant) spectively (P = .04) (Table 5). (Table  3). Valganciclovir (41 of 69, 59% of treated patients; 41 of 73, 56% of all case patients) and intravenous (IV) ganciclovir Acute Cytomegalovirus-Related Outcomes (27 of 69, 39% of treated patients; 27 of 73, 37% of all case pa- No patients in this cohort developed biopsy-proven tissue- tients) were used most commonly. Only one patient received invasive CMV disease within the first 100 days posttransplant. foscarnet initially. Cytomegalovirus Ig was used at some point in Fifty-nine (80%) patients were alive at 6  months. Stratified the course of treatment in 6 (8%) patients. Four patients (4 of 73, analysis according to test era demonstrated that there was no 5%) were managed with continued monitoring and no antiviral significant association between survival at 6  months and the therapy. At initiation of therapy, the median CMV DNA level day posttransplant on which treatment was started (P  =  .17). was 656 copies or IU/mL and the median ANC was 760 cells/ In addition, there was no significant association between sur- 3 3 mm (compared with median 110 cells/mm at initial detection vival at 6 months and the ANC at which treatment was started of CMV). The median treatment duration was 34 days (Table 5). (P = .62). Stratified analysis according to test era to determine the effect er Th e was no significant association between the ANC at of qNAAT on treatment of pre-/peri-engraftment CMV dem- start of treatment and the time from transplant until neutro- onstrated no significant differences in the 3 testing eras for the phil engraftment (ANC >500; P = 1.0), nor was there a signif- following parameters: day posttransplant when treatment was icant association between treatment/no treatment and time to started, CMV DNA level when treatment was started, and ANC engraftment (P = .9). However, all but 4 patients in this cohort on the day treatment was started (Table  5). There was also no were treated for CMV. significant association between the peak CMV DNA level and One patient developed ganciclovir-resistant CMV during a the day posttransplant on which treatment was started (P = .99) recrudescence of CMV DNAemia, approximately 3  months or the peak CMV DNA level and the ANC at which treatment into the course of CMV treatment. This patient’s CMV DNA was started (P = .56, data not shown). However, for treatment level peaked at 53  900 IU/mL during initial treatment with valganciclovir, fell to a level that was detectable but not quanti- Table 4. Patient Treatment Information (n = 73) fiable (<137 IU/mL) while on IV ganciclovir, and rose again in the setting of graft-versus-host disease (GVHD) and oncologic Initial Agent Used to Treat CMV DNAemia Number (%) relapse. Cytomegalovirus DNAemia persisted in the 3000–4000 Valganciclovir 41 (56%) IU/mL range, and foscarnet treatment was required due to the Ganciclovir 27 (36%) development of ganciclovir resistance, with UL97 mutations Foscarnet 1 (1%) M460V and A594V detected by direct sequencing. Four addi- No treatment 4 (6%) tional patients were tested for antiviral resistance and were not Abbreviations: CMV, cytomegalovirus. CMV immunoglobulin was used at some point of treatment in 6 (8%) patients. found to have UL97 resistance mutations. 4 • ofid • Martin et al Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Table 5. CMV Treatment Among All Patients and Stratified by Testing Era Era 1 (<300 copies/mL) Era 2 (<100 copies/mL) Era 3 (<137 IU/mL) Total (n = 20) (n = 14) (n = 39) (n = 73) Median (Range) Median (Range) Median (Range) P Value Median (Range) Day posttransplant when treatment initiated 29 (10–50) 29 (4–48) 36 (4–105) .23 33 (4–105) CMV DNA level at treatment initiation 1127 (428–4262) 439 (175–1660) 736 (159–22 900) .46 656 (159–22 900) (copies/mL or IU/mL) ANC at treatment initiation (cells/mm ) 492 (28–1590) 890 (60–5840) 1070 (50–9680) .11 760 (28–9680) Treatment duration (days) 31 (9–66) 36 (25–392) 34 (11–243) .04 34 (9–392) Days of treatment until 2 consecutive unde- 33 (20–80) 34 (17–228) 37 (12–341) .38 34 (12–341) tectable CMV qNAAT results Abbreviations: ANC, absolute neutrophil count; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; qNAAT, quantitative nucleic acid amplification test. DISCUSSION Pre-engraftment CMV was first described in the premolecular era [6], and it was noted to be associated with significant dis- In this descriptive study, pre- or peri-engraftment CMV ease and mortality. There is a paucity of published data on pre- DNAemia occurred in 6.3% of adult allo BMT recipients. engraftment CMV in the current era, in which CMV DNA is Treatment of this entity is not protocolized at our center; monitored routinely with sensitive quantification assays. Our therefore, this study offered the opportunity to document ap- findings along with a recent report by Solano et al [15] clarify proaches to its management. Studies of postengraftment CMV some aspects of pre-engraftment CMV in the current clinical infection have suggested treatment initiation at levels ranging era. Unlike the original report [6], CMV disease seems to be from 135 IU/mL to 1000 copies/mL or based on the doubling uncommon among individuals with detectable CMV DNA in time of DNA levels [11–14]. However, there is still a lack of this setting. We observed no CMV end-organ disease before en- consensus on treatment thresholds in the pre-engraftment pop- graftment among 73 patients with pre-engraftment DNAemia. ulation. Although the biology of those with pre- versus peri- Likewise, Solano et  al [15] found only 1 patient among 29 engraftment CMV DNAemia may be distinct, we chose to with pre-engraftment CMV with nonfatal CMV esophagitis include both groups in this study because the clinical manage- before engraftment (day 18 aer t ft ransplant). In addition, pre- ment dilemma is similar in these 2 populations. The sensitivity engraftment CMV DNAemia occurs more commonly among analysis performed, excluding the smaller peri-engraftment CMV-seropositive than CMV-seronegative recipients. In our group, did not change the overall analysis of results. study, 68 patients (93%) were CMV-seropositive recipients Our study demonstrated that most providers at our center among 73 patients with pre/peri-engraftment CMV. Likewise, elected preemptive treatment. However, therapy was typically in a univariate analysis, Solano et  al [15] found that recipient deferred approximately 3 weeks, suggesting that clinicians seropositivity had the greatest odds ratio (4.6; 95% confidence waited for the CMV DNA level and/or ANC to rise before interval, 0.59–35.58) among pretransplant variables associ- initiating treatment. It appeared that treatment was deferred ated with pre-engraftment CMV and trended as a risk factor until there was evidence that CMV might become clinically (P  =  .14). These findings suggest that pre-engraftment CMV problematic and/or that the bone marrow had recovered suffi- reactivation is more likely to be recipient-derived rather than ciently to potentially withstand the adverse effects of ganciclovir donor-transmitted. and valganciclovir, which were used in almost all patients despite Other aspects of pre-engram ft ent CMV remain unclear, as the potential for bone marrow toxicity. This deferred treatment highlighted by differences in findings between our study and the strategy did not appear to adversely ae ff ct short-term outcomes report by Solano et al [15]. Prevalence appears to be variable; in relating to acute CMV infection, because only 8% of patients de- our study, it was lower than in the previous report (~6.5% versus veloped viral loads over 5000 copies or IU/mL, and no patient ~15%). Whether this relates to differences in patients or trans- developed biopsy-proven tissue-invasive CMV. e Th relative lack plant approaches (for example, virtually all of our patients receive of high-viral-load CMV and end-organ involvement suggests PTCy as GVHD prophylaxis) is unknown. Moreover, Solano that CMV DNAemia remained manageable even when treat- et al [15] showed that in a subset of patients, CMV DNAemia de- ment was deferred until aer t ft he ANC rose, to avoid hemato- velops much earlier than previously recognized; approximately logic toxicity. In addition, the timing of treatment did not appear one quarter of all pre-engraftment episodes initiated before in- to ae ff ct the time to engraftment. Despite these findings, careful fusion. We were unable to study this further because CMV DNA management of these patients is still warranted, because occa- monitoring is initiated at the time of bone marrow or peripheral sional patients can develop complex CMV syndromes including blood-derived stem cell infusion at our center. ganciclovir resistance, as seen in 1 patient in our cohort. Cytomegalovirus in Adult Allogeneic Blood • ofid • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Cytomegalovirus qNAATs have been demonstrated to tissue-invasive disease, because no biopsy-proven invasive dis- perform variably, demonstrating quantitative bias, varying ease occurred in this cohort. However, the occasional experience quantification ranges, and differences in sensitivity [16]. The of individual patients with complex courses means that pre- introduction of an international biological standard prepa- engraftment CMV is not always clinically mild, and it should not ration of CMV intended for use as a global calibrator has im- be viewed as inconsequential. Furthermore, because most pa- proved quantitative agreement. However, interassay differences tients in this cohort did eventually get treated, these data should in quantification persist [17, 18], suggesting that the interna- not be interpreted to mean that treatment is not necessary. tional standard’s goal of harmonization has not been achieved Additional prospective studies are necessary to further define yet. Interassay differences could ae ff ct the clinical description appropriate thresholds for treatment of pre-engraftment CMV. and management of any CMV-mediated syndrome. A  pre- vious study demonstrated that a shift from an unstandardized Acknowledgments Author contributions. I.  M.  contributed to design of the project, data laboratory-developed qNAAT to a more sensitive commercial collection and analysis, and writing and revision of the manuscript. R.  K. test that reports results in international units per milliliter had A.  contributed to design of the project, data collection and analysis, and minimal clinical impact [19]. Our study oer ff ed the unique op- revision of the manuscript. D. G. contributed to data collection and anal- portunity to describe clinical aspects and management prac- ysis and critical review and revision of the manuscript. R. J. contributed to critical review and revision of the manuscript. R. A. contributed to critical tices of pre-engraftment CMV over 3 eras during which assays review and revision of the manuscript. A.  V.  contributed to design of the with small differences in LOD and LLOQ were used. We ob- project and critical review and revision of the manuscript. served no significant differences in the clinical features of pre- Financial support. This work was funded by National Institutes of Health, National Cancer Institute Grants PO1 CA015396 (to R.  J.) and engraftment CMV stratified by testing era. The lone difference P30CA06973 (W. N.). Dr William Nelson is the head of the Johns Hopkins in CMV treatment parameters was a predictable one—slightly Sidney Kimmel Cancer Center. longer median duration of treatment in era 2, when a qNAAT Potential coni fl cts of interest. R. K. A. received study/grant support on studies related to cytomegalovirus and other viruses from AiCuris, Astellas, with the lowest LOD and LLOQ was in use. The small number Chimerix, Merck, Oxford Immunotec, QIAGEN, and Shire/Takeda. A. V. is of pre-engraftment CMV cases during each era precludes defin- now employed by Roche Molecular Systems. All authors have submitted the itive conclusions regarding the clinical impact of different tests. ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that However, the data are somewhat reassuring in that they suggest the editors consider relevant to the content of the manuscript have been disclosed. that the clinical performance of the 3 assays was fairly similar, which is consistent with previous findings [19]. References This study has several limitations, the first of which is its ret- 1. Ariza-Heredia EJ, Nesher L, Chemaly RF. Cytomegalovirus diseases after hemato- rospective and descriptive nature. No control group without poietic stem cell transplantation: a mini-review. Cancer Lett 2014; 342:1–8. CMV DNAemia was used for comparison of mortality out- 2. Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a comes. 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Letermovir prophylaxis for cytomega- were compared for continuous variables. Because our center lovirus in hematopoietic-cell transplantation. N Engl J Med 2017; 377:2433–44. performs few cord blood transplants, these conclusions are not 6. Limaye  AP, Bowden  RA, Myerson  D, Boeckh  M. Cytomegalovirus disease likely to apply to such patients. Finally, almost all of our patients occurring before engraftment in marrow transplant recipients. Clin Infect Dis 1997; 24:830–5. receive PTCy GVHD prophylaxis, so these data may not apply 7. Limaye AP, Huang ML, Leisenring W, et al. Cytomegalovirus (CMV) DNA load to other GVHD prophylaxis strategies. in plasma for the diagnosis of CMV disease before engraftment in hematopoietic stem-cell transplant recipients. J Infect Dis 2001; 183:377–82. 8. Hirsch HH, Lautenschlager I, Pinsky BA, et al. An international multicenter per- CONCLUSIONS formance analysis of cytomegalovirus load tests. Clin Infect Dis 2013; 56:367–73. 9. Ramanan  P, Razonable  RR. Evaluation of COBAS AmpliPrep/COBAS TaqMan This study describes recent practices for monitoring and pre- CMV test for use in hematopoietic stem cell transplant recipients. Expert Rev Mol emptive treatment of pre-/peri-engraftment CMV DNAemia, Diagn 2017; 17:633–9. 10. Forman M, Wilson A, Valsamakis A. Cytomegalovirus DNA quantification using in neutropenic recipients of a first allo BMT at a single institu- an automated platform for nucleic acid extraction and real-time PCR assay setup. tion. Most patients received treatment for low but quantifiable J Clin Microbiol 2011; 49:2703–5. 11. Green  ML, Leisenring  W, Stachel  D, et  al. Efficacy of a viral load-based, risk- levels of CMV DNAemia with ganciclovir or valganciclovir de- adapted, preemptive treatment strategy for prevention of cytomegalovirus disease spite the potential bone marrow suppression caused by these an- after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18:1687–99. tiviral agents. Treatment was generally initiated after a period 12. Halfon P, Berger P, Khiri H, et al. Algorithm based on CMV kinetics DNA viral of watching and waiting during which both the ANC and viral load for preemptive therapy initiation after hematopoietic cell transplantation. J load rose. This strategy did not appear to increase the risk for Med Virol 2011; 83:490–5. 6 • ofid • Martin et al Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 13. Solano C, Giménez E, Piñana JL, et al. Preemptive antiviral therapy for CMV in- Interlaboratory comparison of cytomegalovirus viral load assays. Am J Transplant fection in allogeneic stem cell transplant recipients guided by the viral doubling 2009; 9:258–68. time in the blood. Bone Marrow Transplant 2016; 51:718–21. 17. Kraft  CS, Armstrong  WS, Caliendo  AM. Interpreting quantitative cytomega- 14. Tan SK, Waggoner JJ, Pinsky BA. Cytomegalovirus load at treatment initiation is lovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis predictive of time to resolution of viremia and duration of therapy in hematopoi- 2012; 54:1793–7. etic cell transplant recipients. J Clin Virol 2015; 69:179–83. 18. Preiksaitis JK, Hayden RT, Tong Y, et al. Are we there yet? Impact of the first in- 15. Solano C, Giménez E, Albert E, et al. Pre-engraftment cytomegalovirus DNAemia ternational standard for cytomegalovirus DNA on the harmonization of results in allogeneic hematopoietic stem cell transplant recipients: incidence, risk factors, reported on plasma samples. Clin Infect Dis 2016; 63:583–9. and clinical outcomes. Bone Marrow Transplant 2019; 54:90–8. 19. Dioverti MV, Lahr B, Razonable RR. Treatment of cytomegalovirus infection and dis- 16. Pang  XL, Fox  JD, Fenton  JM, et  al.; American Society of Transplantation ease pre- and post-quantitative nucleic acid test standardization: does use of a more Infectious Diseases Community of Practice; Canadian Society of Transplantation. sensitive assay lead to longer treatment duration? Clin Transplant 2016; 30:154–60. Cytomegalovirus in Adult Allogeneic Blood • ofid • 7 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Cytomegalovirus in Adult Allogeneic Blood and Marrow Transplant Patients Before or Around the Period of Neutrophil Recovery: A Single-Center, Retrospective, Descriptive Study

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© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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Abstract

Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 applyparastyle “fig//caption/p[1]” parastyle “FigCapt” Open Forum Infectious Diseases MAJOR ARTICLE Cytomegalovirus in Adult Allogeneic Blood and Marrow Transplant Patients Before or Around the Period of Neutrophil Recovery: A Single-Center, Retrospective, Descriptive Study 1,2 2 3 3 3 4, Isabella Martin, Alexandra Valsamakis, Douglas Gladstone, Richard Jones, Richard Ambinder, and Robin K. Avery 1 2 3 Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA, Division of Infectious Diseases, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA  Background. Few reports exist on pre-engraftment cytomegalovirus (CMV) DNAemia in allogeneic blood or marrow trans- plant (allo BMT) recipients. We describe this clinical entity, its management, and the potential effect of 3 different quantitative CMV deoxyribonucleic acid (DNA) tests used during the 6-year study period.  Methods. We performed a retrospective, single-center study of allo BMT recipients from 2010 to 2015 who developed CMV DNAemia before neutrophil recovery (absolute neutrophil count [ANC] <1000 cells/mm , “pre-engraftment CMV”) or who became neutropenic concomitant with detectable CMV DNA (“peri-engraftment CMV”). Clinical data were collected from the electronic medical record. Results. Among 1151 adult allo BMT patients, 73 developed CMV DNAemia before engraftment or while neutropenic aer ft in- itial engraftment. Most patients were eventually treated (valganciclovir or ganciclovir, N = 68; foscarnet, N = 1); 4 were not treated. First CMV detection occurred at median day +12 (range, 0–48), but treatment was not started until median day +33 (range, 4–105) at median ANC of 760 cells/mm . Six patients had peak viral loads >5000 IU/mL; none had tissue-invasive disease. One developed ganciclovir resistance. No significant differences were observed upon stratification by quantitative CMV DNA test.  Conclusions. Cytomegalovirus DNA was detected in 6.3% of pre- and peri-engraftment allo-HSCT patients. Ganciclovir deriva- tives were commonly used for treatment despite risk of neutropenia. Treatment was typically deferred until CMV DNA and ANC rose. With rare exceptions, this treatment strategy did not appear to have adverse clinical consequences with respect to acute CMV. Different CMV DNA quantification tests used performed similarly from a clinical perspective despite different analytical perfor - mance characteristics. Keywords. bone marrow transplant; CMV; pre-engraftment. Cytomegalovirus (CMV) disease remains a significant infec- have continued the strategy of serial monitoring of CMV de- tious cause of morbidity and mortality in patients undergoing oxyribonucleic acid (DNA) in blood and preemptive therapy, in allogeneic blood or marrow transplant (allo BMT) despite ad- which infection is treated before disease onset. With preemptive vances in monitoring and treatment [1, 2]. Cytomegalovirus therapy, postengraftment CMV DNA detection in blood (CMV replication and disease are well recognized complications DNAemia) of asymptomatic patients is far more common than postengraftment, when the newly acquired immune system CMV disease [3]. However, progressive, tissue-invasive infec- becomes functional [3]. Prophylaxis with valganciclovir or tion of the gastrointestinal tract, lungs, liver, central nervous letermovir has been demonstrated to be effective in preventing system, retina, or other sites can occur occasionally. postengraftment CMV disease [4, 5]; however, many centers In contrast to postengraftment CMV infection, less is un- derstood about CMV detection early aer t ft ransplantation, from the period before engraftment to around the time neu- Received 22 January 2020; editorial decision 24 February 2020; accepted 4 March 2020. trophil recovery. One study noted that CMV disease before Correspondence: Robin Avery, MD, 1830 E. Monument Street, #449, Baltimore, MD 21205 engraftment was uncommon, occurring in approximately 1% (ravery4@jhmi.edu). of allo BMT recipients, but was associated with a high mor- Open Forum Infectious Diseases © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases tality rate [6]. A  subsequent study demonstrated that CMV Society of America. This is an Open Access article distributed under the terms of the Creative DNAemia was identified in a greater proportion of patients Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any with CMV disease and at higher levels compared with controls medium, provided the original work is not altered or transformed in any way, and that the [7]. Cytomegalovirus DNAemia was also detectable approxi- work is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofaa081 mately 2 weeks before disease, suggesting that monitoring CMV Cytomegalovirus in Adult Allogeneic Blood • ofid • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 DNA in plasma might help identify patients at risk of this pre- neutrophil recovery (defined as ANC <1000 cells/mm , n = 60) engraftment complication [7]. and a second, smaller group with peri-engraftment neutropenia Extension of monitoring for CMV DNA into the pre- (n = 13) who developed recurrent neutropenia after neutrophil engraftment period has been facilitated by the ready availability recovery, with their first episode of CMV DNAemia detectable of quantitative nucleic acid amplification tests for CMV DNA after recurrent neutrophil decline. These latter patients were in- measurement (CMV qNAATs), which are now routine compo- cluded because the treatment dilemma in this group was similar nents of test menus at centers performing allo BMT. However to that in patients with pre-engraftment CMV. Patients who had many questions remain regarding pre-engraftment CMV undergone a prior allo BMT were excluded. DNAemia including its prevalence when monitoring is initi- Data collected from retrospective medical record review in- ated immediately aer a ft llo BMT, its clinical characteristics, the cluded age, gender, underlying disease, allograft type, donor/re- risk of progression to tissue-invasive disease, and whether pre- cipient CMV serostatus, conditioning regimen, CMV qNAAT engraftment CMV DNAemia should be treated and when. In results, ANCs at specific time points (at time CMV DNA was addition, it is unclear which antivirals should be used in these detectable, at time CMV DNA was greater than assay’s lower medically tenuous patients, given the myelosuppressive poten- limit of quantification [LLOQ], and at time of treatment initi- tial of first-line therapy (ganciclovir, valganciclovir) and neph- ation), CMV treatment (what antiviral agent was used, if any, rotoxicity of second-line drugs (foscarnet and cidofovir). and treatment duration), CMV disease within 100 days of allo At our center, post-allo BMT monitoring includes weekly BMT, and death within 6 months of allo BMT. This study was CMV qNAAT from plasma starting at day 0 (day of receipt of the approved by the Johns Hopkins Medicine Institutional Review allo BMT). This practice allowed us to perform a retrospective, Board. descriptive study of CMV DNAemia in neutropenic patients Cytomegalovirus Management in Allogeneic Blood or Marrow Transplant before engraftment and among those who became neutro- Post-allo BMT CMV DNA monitoring at this center in- penic again aer en ft graftment (peri-engraftment neutropenia). cludes weekly CMV qNAAT from plasma, starting from day e m Th ain aims of this study were to determine the prevalence 0 (date of allo BMT). In the electronic medical record, CMV of CMV DNAemia during pre- and peri-engraftment neutro- DNA ≥LLOQ was flagged as an abnormal result. Once this penia, define its clinical characteristics, and describe thera- occurred, management was per clinician choice and included peutic practices such as whether CMV DNAemia was treated, decisions such as CMV DNA monitoring frequency (could clinical parameters at treatment initiation (CMV DNA level and increase to twice weekly), initiation of preemptive treatment, absolute neutrophil count [ANC]), and treatment regimens. CMV antiviral drug selection, duration of preemptive treat- Furthermore, we sought to assess whether clinicians’ decisions ment (until CMV qNAATs results were either <LLOQ or to treat (or to wait), depending on the viral load and ANC, had undetectable), and duration of CMV DNA monitoring after any adverse effects in terms of development of tissue-invasive treatment cessation. CMV disease or high peak viral loads. Finally, CMV DNA quantitative testing evolved during the 6-year study period to Cytomegalovirus Quantitative Nucleic Acid Amplification Tests exploit the diagnostic gains ao ff rded by improved automation Three different qNAATs were used sequentially during the and by the adoption of a US Food and Drug Administration- 6-year study period (Table  1) [10]. Testing eras 1 and 2 were approved assay that incorporated a new international standard reported in copies/mL, whereas era 3 was calibrated according for CMV qNAAT calibration [8, 9]. The utilization of different to the CMV WHO International Standard and reported in IU/ assays at our center allowed us to compare clinical features mL [9]. Validation studies performed before test implementa- and treatment characteristics of pre-/peri-engraftment CMV tion demonstrated a mean difference in CMV DNA measure- DNAemia in 3 sequential eras during the study period when 3 ment of −0.12 log for era 2 qNAAT versus era 1 (era 2 qNAAT CMV qNAATs with varying performance characteristics were values were on average 0.12 log , or 1.3-fold, greater than era 1 in use, in order to discern the clinical impact of deploying as- qNAAT) and 0.31 log for era 3 qNAAT versus era 2 qNAAT says with slightly different functionality. (era 3 qNAAT values were on average 0.31 log , or 2-fold, less than era 2 qNAAT). METHODS Clinical Record Review Statistical Analysis Subjects who underwent allo BMT between January 2010 and Descriptive statistics (means, medians) were analyzed with December 2015 were identified through 2 databases of adult Stata version 14. Associations between discrete variables allo BMT recipients at the Sidney Kimmel Comprehensive (such as assay era) and continuous variables (such as the day Cancer Center at the Johns Hopkins Hospital. Two groups posttransplant when CMV DNA was first detectable) were of first-time allo BMT patients were selected for inclusion, tested using one-way analysis of variance. P < .05 was con- one group with detectable CMV DNAemia occurring before sidered significant. 2 • ofid • Martin et al Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Table 1. Clinical CMV qNAATs During Study Period Era 1 Era 2 Era 3 Dates January 1, 2010 (study start)–May 1, 2012 May 2, 2012–April 2, 2013 April 3, 2013–December 31, 2015 (study end) Test Laboratory developed test Laboratory developed test (7) COBAS AmpliPrep (extraction)/ COBAS TaqMan (real-time PCR) • Extraction BioRobot M48 (QIAGEN) QIASymphony (QIAGEN) CMV (Roche Molecular Diagnos- • Amplification SDS 7500 (Applied Biosystems) RGQ (Rotorgene, QIAGEN) tics) Test system approved by • Real-time PCR reagents Artus (QIAGEN) Artus (QIAGEN) the US Food and Drug Admin- istration LLOQ 300 copies/mL 100 copies/mL 137 IU/mL LOD 100 copies/mL 50 copies/mL 91 IU/mL Abbreviations: CMV, cytomegalovirus; LLOQ, lower limit of quantification; LOD, limit of detection; PCR, polymerase chain reaction; qNAAT, quantitative nucleic acid amplification tests  Conversion from copies to IU between tests used in era 2 and era 3, 1.09 copy/IU as per era 3 validation studies using clinical plasma samples. A sensitivity analysis was performed, either including or in the total 1151 patient cohort; most patients with pre- or excluding patients (n  =  13) who initially engrae ft d then again peri-engraftment CMV DNA had received nonmyeloablative became neutropenic by the time their CMV DNAemia was de- conditioning regimens (78%) and haploidentical allografts tected. The analysis that excluded these patients included only using posttransplant cyclophosphamide (PTCy) (82%). those who had detectable CMV DNAemia before initial neutro- Cytomegalovirus serologic status was documented for all re- phil recovery (n = 60). cipients and for 70 of 73 (96%) of donors (Table  2). Most re- cipients were CMV immunoglobulin (Ig)G seropositive (R+, 68 RESULTS of 73, 93%). Donor CMV IgG serology was positive in 43 of 73 (D+, 59%) and negative in 27 of 73 (37%). The greatest propor- Patients tion of patients were D+/R+ (55%) (Table 2). During the study period, 73 of 1151 (6.3%) adult patients who underwent allo BMT met the case definitions of CMV DNA de- Clinical Features of Pre-/Peri-Engraftment Cytomegalovirus Among All tection in plasma with ANC <1000 (pre- or peri-engraftment). Case Patients and Stratified by Testing Era Demographic information and basic clinical characteristics To better understand the clinical entity of pre-/peri-engraftment were retrieved (Table  2). The conditioning regimen type and CMV, clinical features related to plasma CMV DNA detection donor and graft types in these 73 patients mirrored that seen were characterized. Overall, CMV DNAemia was first detect- able at a median of 12  days posttransplant (range, 0–48  days) and rose to levels above the LLOQ at a median of 28  days Table 2. Patient Demographic and Clinical Characteristics (n = 73) posttransplant (range, 0–49  days). The median ANC at which Median age (years) 52 (23–76) CMV DNA became detectable and measurable (>LLOQ) was Gender less than 500 cells/mm . The median peak CMV DNA of the Male 39 (53%) pre-/peri-engraftment episode was <1000 copies/mL, but it Female 34 (47%) ranged considerably (790–84  300 copies or IU/mL). Only 6 Donor/Recipient CMV Serology Recipient seropositive (total) 68 (93%) patients (8%) had peak CMV DNA  >5000 (data not shown). Recipient seronegative (total) 5 (7%) Stratified analysis according to test era to determine the effect Donor seropositive (total) 43 (59%) of qNAAT demonstrated no significant difference between the Donor seronegative (total) 27 (37%) 3 testing eras for the following parameters: day posttransplant Donor serology missing 3 (4%) and ANC at which CMV DNA was first detectable, day D+/R+ 40 (55%) posttransplant and ANC at which CMV DNA was first above D-/R+ 25 (34%) D+/R− 3 (4%) the LLOQ, or peak CMV DNA of the episode (Table 3). In ad- D−/R− 2 (3%) dition, a sensitivity analysis demonstrated no significant differ- Induction Regimen ence in these results when excluding the group of 13 patients Myeloablative 16 (22%) who had initially engrafted and then had become neutropenic Nonmyeloablative 57 (78%) again by the time that CMV DNA was detected. Allograft Type Matched related 7 (9%) Haploidentical 60 (82%) Treatment of Pre-/Peri-Engraftment Cytomegalovirus Among All Case Patients and Stratified by Testing Era Unrelated donor 5 (7%) Cord blood 1 (1%) Most patients with CMV DNAemia in the pre- and peri- Abbreviations: CMV, cytomegalovirus; D, donor, R, recipient. engraftment period were eventually treated with antiviral drugs Cytomegalovirus in Adult Allogeneic Blood • ofid • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Table 3. Clinical Features of CMV Among All Patients and Stratified by Testing Era All Patients Era 1 Patients (n = 20) Era 2 Patients (n = 14) Era 3 Patients (n = 39) (n = 73) (<300 copies/mL) (<100 copies/mL) (<137 IU/mL) Median (Range) Median (Range) Median (Range) Median (Range) P Value Day posttransplant when 12 (0–48) 10 (2–48) 13 (3–38) 12 (0–34) .72 CMV first detectable Day posttransplant when 28 (0–49) 28 (9–48) 28 (3–45) 30 (0–49) .79 CMV > LLOQ ANC when CMV first de- 110 (20–4030) 76 (50–1647) 90 (20–1340) 125 (20–4030) .99 tectable (cells/mm ) ANC when CMV 423 (20–2560) 416 (50–1632) 610 (20–2560) 350 (20–1660) .76 first > LLOQ Peak CMV DNA of ep- 790 (137–84 300) 1127 (300–22 122) 449 (211–2489) 829 (137–84 300) .46 isode (copies/mL or IU/mL) Abbreviations: ANC, absolute neutrophil count; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; LLOQ, lower limit of quantification.  Upper end of range is >1000 because the cohort includes peri-engraftment patients with recovered ANCs who again became neutropenic after plasma CMV was detected. duration, there was a trend toward significance between era 2, (69 of 73, 95%) (Table  4). Most patients (69 of 73, 95%) were when a qNAAT with the lowest LLOQ and limit of detection started on CMV treatment on the basis of preemptive CMV PCR (LOD) was in use, and eras 1 and 3 (<300 copies/mL and <137, monitoring (Table 4), but treatment initiation was deferred until respectively). The median duration of treatment in era 2 was after engraftment (median 33  days posttransplant) (Table  5) 36 days, compared with 31 and 34 days for era 1 and era 3, re- relative to initial detection (median 12  days posttransplant) spectively (P = .04) (Table 5). (Table  3). Valganciclovir (41 of 69, 59% of treated patients; 41 of 73, 56% of all case patients) and intravenous (IV) ganciclovir Acute Cytomegalovirus-Related Outcomes (27 of 69, 39% of treated patients; 27 of 73, 37% of all case pa- No patients in this cohort developed biopsy-proven tissue- tients) were used most commonly. Only one patient received invasive CMV disease within the first 100 days posttransplant. foscarnet initially. Cytomegalovirus Ig was used at some point in Fifty-nine (80%) patients were alive at 6  months. Stratified the course of treatment in 6 (8%) patients. Four patients (4 of 73, analysis according to test era demonstrated that there was no 5%) were managed with continued monitoring and no antiviral significant association between survival at 6  months and the therapy. At initiation of therapy, the median CMV DNA level day posttransplant on which treatment was started (P  =  .17). was 656 copies or IU/mL and the median ANC was 760 cells/ In addition, there was no significant association between sur- 3 3 mm (compared with median 110 cells/mm at initial detection vival at 6 months and the ANC at which treatment was started of CMV). The median treatment duration was 34 days (Table 5). (P = .62). Stratified analysis according to test era to determine the effect er Th e was no significant association between the ANC at of qNAAT on treatment of pre-/peri-engraftment CMV dem- start of treatment and the time from transplant until neutro- onstrated no significant differences in the 3 testing eras for the phil engraftment (ANC >500; P = 1.0), nor was there a signif- following parameters: day posttransplant when treatment was icant association between treatment/no treatment and time to started, CMV DNA level when treatment was started, and ANC engraftment (P = .9). However, all but 4 patients in this cohort on the day treatment was started (Table  5). There was also no were treated for CMV. significant association between the peak CMV DNA level and One patient developed ganciclovir-resistant CMV during a the day posttransplant on which treatment was started (P = .99) recrudescence of CMV DNAemia, approximately 3  months or the peak CMV DNA level and the ANC at which treatment into the course of CMV treatment. This patient’s CMV DNA was started (P = .56, data not shown). However, for treatment level peaked at 53  900 IU/mL during initial treatment with valganciclovir, fell to a level that was detectable but not quanti- Table 4. Patient Treatment Information (n = 73) fiable (<137 IU/mL) while on IV ganciclovir, and rose again in the setting of graft-versus-host disease (GVHD) and oncologic Initial Agent Used to Treat CMV DNAemia Number (%) relapse. Cytomegalovirus DNAemia persisted in the 3000–4000 Valganciclovir 41 (56%) IU/mL range, and foscarnet treatment was required due to the Ganciclovir 27 (36%) development of ganciclovir resistance, with UL97 mutations Foscarnet 1 (1%) M460V and A594V detected by direct sequencing. Four addi- No treatment 4 (6%) tional patients were tested for antiviral resistance and were not Abbreviations: CMV, cytomegalovirus. CMV immunoglobulin was used at some point of treatment in 6 (8%) patients. found to have UL97 resistance mutations. 4 • ofid • Martin et al Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Table 5. CMV Treatment Among All Patients and Stratified by Testing Era Era 1 (<300 copies/mL) Era 2 (<100 copies/mL) Era 3 (<137 IU/mL) Total (n = 20) (n = 14) (n = 39) (n = 73) Median (Range) Median (Range) Median (Range) P Value Median (Range) Day posttransplant when treatment initiated 29 (10–50) 29 (4–48) 36 (4–105) .23 33 (4–105) CMV DNA level at treatment initiation 1127 (428–4262) 439 (175–1660) 736 (159–22 900) .46 656 (159–22 900) (copies/mL or IU/mL) ANC at treatment initiation (cells/mm ) 492 (28–1590) 890 (60–5840) 1070 (50–9680) .11 760 (28–9680) Treatment duration (days) 31 (9–66) 36 (25–392) 34 (11–243) .04 34 (9–392) Days of treatment until 2 consecutive unde- 33 (20–80) 34 (17–228) 37 (12–341) .38 34 (12–341) tectable CMV qNAAT results Abbreviations: ANC, absolute neutrophil count; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; qNAAT, quantitative nucleic acid amplification test. DISCUSSION Pre-engraftment CMV was first described in the premolecular era [6], and it was noted to be associated with significant dis- In this descriptive study, pre- or peri-engraftment CMV ease and mortality. There is a paucity of published data on pre- DNAemia occurred in 6.3% of adult allo BMT recipients. engraftment CMV in the current era, in which CMV DNA is Treatment of this entity is not protocolized at our center; monitored routinely with sensitive quantification assays. Our therefore, this study offered the opportunity to document ap- findings along with a recent report by Solano et al [15] clarify proaches to its management. Studies of postengraftment CMV some aspects of pre-engraftment CMV in the current clinical infection have suggested treatment initiation at levels ranging era. Unlike the original report [6], CMV disease seems to be from 135 IU/mL to 1000 copies/mL or based on the doubling uncommon among individuals with detectable CMV DNA in time of DNA levels [11–14]. However, there is still a lack of this setting. We observed no CMV end-organ disease before en- consensus on treatment thresholds in the pre-engraftment pop- graftment among 73 patients with pre-engraftment DNAemia. ulation. Although the biology of those with pre- versus peri- Likewise, Solano et  al [15] found only 1 patient among 29 engraftment CMV DNAemia may be distinct, we chose to with pre-engraftment CMV with nonfatal CMV esophagitis include both groups in this study because the clinical manage- before engraftment (day 18 aer t ft ransplant). In addition, pre- ment dilemma is similar in these 2 populations. The sensitivity engraftment CMV DNAemia occurs more commonly among analysis performed, excluding the smaller peri-engraftment CMV-seropositive than CMV-seronegative recipients. In our group, did not change the overall analysis of results. study, 68 patients (93%) were CMV-seropositive recipients Our study demonstrated that most providers at our center among 73 patients with pre/peri-engraftment CMV. Likewise, elected preemptive treatment. However, therapy was typically in a univariate analysis, Solano et  al [15] found that recipient deferred approximately 3 weeks, suggesting that clinicians seropositivity had the greatest odds ratio (4.6; 95% confidence waited for the CMV DNA level and/or ANC to rise before interval, 0.59–35.58) among pretransplant variables associ- initiating treatment. It appeared that treatment was deferred ated with pre-engraftment CMV and trended as a risk factor until there was evidence that CMV might become clinically (P  =  .14). These findings suggest that pre-engraftment CMV problematic and/or that the bone marrow had recovered suffi- reactivation is more likely to be recipient-derived rather than ciently to potentially withstand the adverse effects of ganciclovir donor-transmitted. and valganciclovir, which were used in almost all patients despite Other aspects of pre-engram ft ent CMV remain unclear, as the potential for bone marrow toxicity. This deferred treatment highlighted by differences in findings between our study and the strategy did not appear to adversely ae ff ct short-term outcomes report by Solano et al [15]. Prevalence appears to be variable; in relating to acute CMV infection, because only 8% of patients de- our study, it was lower than in the previous report (~6.5% versus veloped viral loads over 5000 copies or IU/mL, and no patient ~15%). Whether this relates to differences in patients or trans- developed biopsy-proven tissue-invasive CMV. e Th relative lack plant approaches (for example, virtually all of our patients receive of high-viral-load CMV and end-organ involvement suggests PTCy as GVHD prophylaxis) is unknown. Moreover, Solano that CMV DNAemia remained manageable even when treat- et al [15] showed that in a subset of patients, CMV DNAemia de- ment was deferred until aer t ft he ANC rose, to avoid hemato- velops much earlier than previously recognized; approximately logic toxicity. In addition, the timing of treatment did not appear one quarter of all pre-engraftment episodes initiated before in- to ae ff ct the time to engraftment. Despite these findings, careful fusion. We were unable to study this further because CMV DNA management of these patients is still warranted, because occa- monitoring is initiated at the time of bone marrow or peripheral sional patients can develop complex CMV syndromes including blood-derived stem cell infusion at our center. ganciclovir resistance, as seen in 1 patient in our cohort. Cytomegalovirus in Adult Allogeneic Blood • ofid • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/7/3/ofaa081/5800045 by DeepDyve user on 30 March 2020 Cytomegalovirus qNAATs have been demonstrated to tissue-invasive disease, because no biopsy-proven invasive dis- perform variably, demonstrating quantitative bias, varying ease occurred in this cohort. However, the occasional experience quantification ranges, and differences in sensitivity [16]. The of individual patients with complex courses means that pre- introduction of an international biological standard prepa- engraftment CMV is not always clinically mild, and it should not ration of CMV intended for use as a global calibrator has im- be viewed as inconsequential. Furthermore, because most pa- proved quantitative agreement. However, interassay differences tients in this cohort did eventually get treated, these data should in quantification persist [17, 18], suggesting that the interna- not be interpreted to mean that treatment is not necessary. tional standard’s goal of harmonization has not been achieved Additional prospective studies are necessary to further define yet. Interassay differences could ae ff ct the clinical description appropriate thresholds for treatment of pre-engraftment CMV. and management of any CMV-mediated syndrome. A  pre- vious study demonstrated that a shift from an unstandardized Acknowledgments Author contributions. I.  M.  contributed to design of the project, data laboratory-developed qNAAT to a more sensitive commercial collection and analysis, and writing and revision of the manuscript. R.  K. test that reports results in international units per milliliter had A.  contributed to design of the project, data collection and analysis, and minimal clinical impact [19]. Our study oer ff ed the unique op- revision of the manuscript. D. G. contributed to data collection and anal- portunity to describe clinical aspects and management prac- ysis and critical review and revision of the manuscript. R. J. contributed to critical review and revision of the manuscript. R. A. contributed to critical tices of pre-engraftment CMV over 3 eras during which assays review and revision of the manuscript. A.  V.  contributed to design of the with small differences in LOD and LLOQ were used. We ob- project and critical review and revision of the manuscript. served no significant differences in the clinical features of pre- Financial support. This work was funded by National Institutes of Health, National Cancer Institute Grants PO1 CA015396 (to R.  J.) and engraftment CMV stratified by testing era. The lone difference P30CA06973 (W. N.). Dr William Nelson is the head of the Johns Hopkins in CMV treatment parameters was a predictable one—slightly Sidney Kimmel Cancer Center. longer median duration of treatment in era 2, when a qNAAT Potential coni fl cts of interest. R. K. A. received study/grant support on studies related to cytomegalovirus and other viruses from AiCuris, Astellas, with the lowest LOD and LLOQ was in use. The small number Chimerix, Merck, Oxford Immunotec, QIAGEN, and Shire/Takeda. A. V. is of pre-engraftment CMV cases during each era precludes defin- now employed by Roche Molecular Systems. All authors have submitted the itive conclusions regarding the clinical impact of different tests. ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that However, the data are somewhat reassuring in that they suggest the editors consider relevant to the content of the manuscript have been disclosed. that the clinical performance of the 3 assays was fairly similar, which is consistent with previous findings [19]. References This study has several limitations, the first of which is its ret- 1. Ariza-Heredia EJ, Nesher L, Chemaly RF. Cytomegalovirus diseases after hemato- rospective and descriptive nature. No control group without poietic stem cell transplantation: a mini-review. Cancer Lett 2014; 342:1–8. CMV DNAemia was used for comparison of mortality out- 2. Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a comes. 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Pang  XL, Fox  JD, Fenton  JM, et  al.; American Society of Transplantation ease pre- and post-quantitative nucleic acid test standardization: does use of a more Infectious Diseases Community of Practice; Canadian Society of Transplantation. sensitive assay lead to longer treatment duration? Clin Transplant 2016; 30:154–60. Cytomegalovirus in Adult Allogeneic Blood • ofid • 7

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Open Forum Infectious DiseasesOxford University Press

Published: Mar 1, 2020

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