Abstract
Background aims
Cytomegalovirus (CMV) reactivation is a significant complication following allogeneic
hematopoietic stem cell transplant (HSCT) and affects upwards of 40% of pediatric
HSCT patients. Pre-emptive therapy remains the only effective treatment strategy available
for pediatric patients following CMV reactivation. Little is known about how the timing
of induction treatment following CMV reactivation impacts outcomes in pediatric patients,
especially following ex vivo T-cell-depleted (TCD) HSCT.
Methods
The authors evaluated how the timing of induction treatment after CMV reactivation
impacts overall survival (OS) and CMV disease in pediatric patients undergoing TCD
HSCT at a single institution. The authors retrospectively analyzed patients treated
on the pediatric service who received an initial ex vivo TCD HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) from January 2010 to June
2018. CMV reactivation was defined as ≥1 CMV polymerase chain reaction >500 copies/mL
in whole blood or >137 IU/mL in plasma within the first 180 days after allogeneic
HSCT. To analyze the impact of the timing of induction treatment, the authors’ primary
study outcome was OS and secondary outcome was CMV disease.
Results
A total of 169 patients who underwent an initial allogeneic TCD HSCT on the pediatric
service at MSKCC from January 2010 to June 2018 were included in the analysis. Thirty-seven
(22%) patients reactivated CMV during the first 180 days following HSCT. Of those
patients who reactivated CMV, CMV donor/recipient (D/R) serostatus was as follows:
D+/R+ n = 28 (76%) and D–/R+ n = 9 (24%). There was no CMV reactivation observed among
recipients who were CMV-seronegative irrespective of donor serostatus. In those patients
who reactivated CMV, the median time from HSCT to CMV reactivation was 24 days (interquartile
range, 20–31). Eleven patients ultimately developed CMV disease in addition to CMV
viremia, whereas the remaining patients had only CMV viremia. The cumulative incidence
of CMV reactivation at 60 days was 45.2% (95% confidence interval [CI], 32.8–57.5)
in the D+/R+ subgroup and 31% (95% CI, 14.2–47.9) in the D–/R+ subgroup. For those
patients who reactivated CMV, 30 (81%) received induction treatment with ganciclovir
or foscarnet. To analyze the impact of the timing of induction treatment on clinical
outcomes, the authors restricted the analysis to those patients who reactivated CMV
and received induction treatment (n = 30). The timing of induction treatment was significantly
associated with OS, with optimal timing of initiation within a week of CMV reactivation
(P = 0.02). There was no significant impact on the timing of induction treatment and
risk of CMV disease (P = 0.30).
Conclusions
In ex vivo TCD HSCT in pediatric patients, early initiation of induction treatment after CMV
reactivation is associated with improved OS.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to CytotherapyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Current Use of and Trends in Hematopoietic Cell Transplantation in the United States.Biol Blood Marrow Transplant. 2020; 26: e177-e182
- Hematopoietic Stem Cell Transplantation Activity in Pediatric Cancer between 2008 and 2014 in the United States: A Center for International Blood and Marrow Transplant Research Report.Biol Blood Marrow Transplant. 2017; 23: 1342-1349
- Age-dependent determinants of infectious complications profile in children and adults after hematopoietic cell transplantation: lesson from the nationwide study.Ann Hematol. 2019; 98: 2197-2211
- Risk factors and outcomes of cytomegalovirus viremia in pediatric hematopoietic stem cell transplantation patients.J Microbiol Immunol Infect. 2017; 50: 307-313
- The impact of alternative donor types on viral infections in pediatric hematopoietic stem cell transplantation.Pediatr Transplant. 2018; 22: e13109
- Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Risk Factors for Primary Infection and Cases of Recurrent and Late Infection at a Single Center.Biol Blood Marrow Transplant. 2016; 22: 1275-1283
- Seroprevalence of cytomegalovirus among children 1 to 5 years of age in the United States from the National Health and Nutrition Examination Survey of 2011 to 2012.Clin Vaccine Immunol. 2015; 22: 245-247
- Changes in Cytomegalovirus Seroprevalence Among U.S. Children Aged 1 to 5 Years: The National Health and Nutrition Examination Surveys.Clin Infect Dis. 2021; 72: e408-e411
- Cytomegalovirus Treatment in Pediatric Hematopoietic Stem Cell Transplant Patients.J Pediatr Hematol Oncol. 2017; 39: 241-248
- Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004.Clin Infect Dis. 2010; 50: 1439-1447
- Risk Factors for Cytomegalovirus Infection After Allogeneic Hematopoietic Cell Transplantation in Malignancies: Proposal for Classification.Anticancer Res. 2017; 37: 6551-6556
- How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation.Blood. 2020; 135: 1619-1629
- Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission.Oncotarget. 2016; 7: 17230-17241
- Effect of Cytomegalovirus Reactivation on Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Leukemia.Biol Blood Marrow Transplant. 2016; 22: 300-306
- Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children.Br J Haematol. 2014; 166: 229-239
- Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis.Blood. 2016; 127: 2427-2438
- Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation.Blood Adv. 2020; 4: 1051-1061
- Prockop S. T-cell depleted allogeneic hematopoietic cell transplants as a platform for adoptive therapy with leukemia selective or virus-specific T-cells.Bone Marrow Transplant. 2015; 50: S43-S50
- Cytomegalovirus Infection after CD34(+)-Selected Hematopoietic Cell Transplantation.Biol Blood Marrow Transplant. 2016; 22: 1480-1486
- Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions.Blood. 1999; 93: 467-480
- Cytomegalovirus reactivation in pediatric hemopoietic progenitors transplant: a retrospective study on the risk factors and the efficacy of treatment.J Pediatr Hematol Oncol. 2005; 27: 411-415
- Predictors for persistent cytomegalovirus reactivation after T-cell-depleted allogeneic hematopoietic stem cell transplantation.Transpl Infect Dis. 2007; 9: 286-294
- Factors associated with cytomegalovirus infection in children undergoing allogeneic hematopoietic stem-cell transplantation.Medicine (Baltimore). 2019; 98: e14172
- Risk Factors and Utility of a Risk-Based Algorithm for Monitoring Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections in Pediatric Recipients after Allogeneic Hematopoietic Cell Transplantation.Biol Blood Marrow Transplant. 2016; 22: 1646-1653
- Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution.Biol Blood Marrow Transplant. 2019; 25: 577-586
- Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation.Infect Dis Ther. 2018; 7: 1-16
- Cytomegalovirus in hematopoietic stem cell transplant recipients.Hematol Oncol Clin North Am. 2011; 25: 151-169
- CMV viral load kinetics as surrogate endpoints after allogeneic transplantation.J Clin Invest. 2021; : 131
- How we treat cytomegalovirus in hematopoietic cell transplant recipients.Blood. 2009; 113: 5711-5719
- Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation.N Engl J Med. 2017; 377: 2433-2444
- A survey of infectious disease clinical practices among pediatric blood and marrow transplant programs in the United States.Pediatr Blood Cancer. 2015; 62: 731-735
- Cytomegalovirus resistance in CD34(+) -selected hematopoietic cell transplant recipients.Transpl Infect Dis. 2018; 20: e12881
- Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials.Clin Infect Dis. 2017; 64: 87-91
- R: A language and environment for statistical computing.R Foundation for Statistical Computing, Vienna, Austria2019
Gerds T. Prodlim: Product-limit estimation for censored event history analysis. R package version 2019;11:132019.
Gordon M, Seifert R. Greg: Regression Helper Functions. R package version 1.3.1 2019. https://CRAN.R-project.org/package=Greg.
- Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy.Int J Mol Sci. 2019; 20: 2666
- Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation.Biol Blood Marrow Transplant. 2016; 22: 1654-1663
- Ganciclovir inhibits lymphocyte proliferation by impairing DNA synthesis.Biol Blood Marrow Transplant. 2007; 13: 765-770
- Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2012; 18: 1687-1699
- Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study.Lancet Haematol. 2016; 3: e119-e127
- Cytomegalovirus viral load kinetics predict cytomegalovirus end-organ disease and mortality after hematopoietic cell transplant.J Infect Dis. 2021; 224: 620-631
- The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy.Blood. 2004; 103: 2003-2008
- Impact of CMV and EBV on Immune Recovery After Allogeneic Hematopoietic Cell Transplantation in Children.Anticancer Res. 2018; 38: 6009-6013
- The immune response to cytomegalovirus in allogeneic hematopoietic stem cell transplant recipients.Cell Mol Life Sci. 2015; 72: 4049-4062
- Cytomegalovirus Prophylaxis versus Pre-emptive Strategy: Different CD4(+) and CD8(+) T Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.Transplant Cell Ther. 2021; 27: 518.e1-518.e4
- Primary prophylaxis with letermovir for prevention of CMV infection in two children.Acta Haematologica Polonica. 2020; 51: 263-264
- Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study.Bone Marrow Transplant. 2020; 56: 1171-1179
Article info
Publication history
Published online: January 15, 2022
Accepted:
October 11,
2021
Received:
August 25,
2021
Identification
Copyright
© 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
