Cytomegalovirus reactivation in lymphoma and myeloma patients undergoing autologous peripheral blood stem cell transplantation

Cytomegalovirus reactivation in lymphoma and myeloma patients undergoing autologous peripheral blood stem cell transplantation

Accepted Manuscript Title: Cytomegalovirus Reactivation in Lymphoma and Myeloma Patients undergoing Autologous Peripheral Blood Stem Cell transplantat...

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Accepted Manuscript Title: Cytomegalovirus Reactivation in Lymphoma and Myeloma Patients undergoing Autologous Peripheral Blood Stem Cell transplantation Authors: Radwan Massoud, Rita Assi, Elie Fares, Basel Haffar, Maya Charafeddine, Nabila Kreidieh, Rami Mahfouz, Souha S. Kanj, Aline El Zakhem, Mohamed Kharfan-Dabaja, Ali Bazarbachi, Jean El Cheikh PII: DOI: Reference:

S1386-6532(17)30223-8 http://dx.doi.org/10.1016/j.jcv.2017.08.006 JCV 3863

To appear in:

Journal of Clinical Virology

Received date: Revised date: Accepted date:

23-1-2017 5-6-2017 10-8-2017

Please cite this article as: Massoud Radwan, Assi Rita, Fares Elie, Haffar Basel, Charafeddine Maya, Kreidieh Nabila, Mahfouz Rami, Kanj Souha S, Zakhem Aline El, Kharfan-Dabaja Mohamed, Bazarbachi Ali, Cheikh Jean El.Cytomegalovirus Reactivation in Lymphoma and Myeloma Patients undergoing Autologous Peripheral Blood Stem Cell transplantation.Journal of Clinical Virology http://dx.doi.org/10.1016/j.jcv.2017.08.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cytomegalovirus Reactivation in Lymphoma and Myeloma Patients undergoing Autologous Peripheral Blood Stem Cell transplantation Radwan Massoud1, Rita Assi1, Elie Fares1, Basel Haffar1, Maya Charafeddine MPH2, Nabila Kreidieh3, Rami Mahfouz3, Souha S. Kanj4, Aline El Zakhem4, Mohamed Kharfan-Dabaja5, Ali Bazarbachi1 and Jean El Cheikh1 1

Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon 2

Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

3

Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon

4

Division of Infectious Diseases, Department of Internal Medicine American University of Beirut, Beirut, Lebanon

5

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA

Keywords: Myeloma, Lymphoma, Cytomegalovirus, Autologous stem cell transplantation. Abstract word count: 519 Text word count: 2,406 Corresponding author: Jean El-Cheikh, MD Bone Marrow Transplantation Program Department of Internal Medicine American University of Beirut, Medical Center P.O. Box 113-6044 Beirut, Lebanon Tel: +961-361-7811; Fax: +961-134-5325 Email: [email protected]

 

Highlights     

CMV reactivation is not uncommon in ASCT recipients.  CMV reactivation post ASCT may contribute to increased transplant related mortality.   MM patients may have a higher incidence, of CMV reactivation when compared to lymphoma patients post ASCT.  Increased risk of CMV reactivation post ASCT in the older population.  CMV reactivation post ASCT may decrease overall survival in Lymphoma patients.  

Abstract Background: Cytomegalovirus reactivation is often diagnosed in allogeneic hematopoietic cell transplant recipients and therefore could lead to CMV-related disease, involving many organs in these immunocompromised patients. In contrast, few studies investigated CMV reactivation and end-organ disease in patients undergoing Autologous Peripheral Blood Stem Cell Transplant (ASCT) since they are considered at low risk for both reactivation and disease. Objectives: The primary outcome of the analysis was to understand the difference in incidence of CMV reactivation between MM and Lymphoma patients. Secondary outcomes included the difference between MM and Lymphoma patients when considering the effect of CMV reactivation on transplant related mortality (TRM) overall survival (OS) progression free survival (PFS), risk factors for reactivation, and median time to reactivation. Study design: In this report, we retrospectively compared the incidence, risk factors, and outcome of CMV reactivation in adult patients with Myeloma (MM) and Lymphoma undergoing ASCT at the American university of Beirut Medical Center in Lebanon (AUBMC).

A total of 324

consecutive ASCT were performed between January 2005 and March 2016. Serial weekly monitoring for CMV quantification was done using a quantitative PCR, starting from 2   

transplantation until the hospital discharge and afterwards based on the clinical symptoms in cases of clinical suspicion of reactivation after discharge from the hospital. Results: The cumulative incidence of CMV reactivation was 16% (n=53) with a median time of 16 (range, 4–242) days after ASCT. The incidence of reactivation was significantly higher in the MM (22%) and NHL (20%) groups, when compared to the HL (4%) (P=0.001). There was a higher incidence of CMV reactivation according to age (≥50 vs ≤50 years) with higher incidence in the older population 24 % vs 10% respectively (p=0.0043). The mean time to CMV reactivation was significantly higher in the NHL group with a mean of 53.7 days when

compared to the HL and MM groups with mean 19.75 days and 12.66 (range, 4-34) days respectively (P=0.003).

Twenty-two patients (76%) and three patients (75%) patients

required specific antiviral therapy in the MM group and HL groups respectively; which was significantly higher (P<0.001) then the NHL group with 13 (65%) patients requiring specific antiviral therapy. Five patients (1.5%) developed CMV disease at a median of 60 days (range, 7–107) post ASCT: there was significant difference in the mean-time to reactivation based on disease type MM versus lymphoma 10 versus 33 days (P=0.007). In multivariate analysis, a higher age was associated with an increased risk of CMV reactivation; MM and NHL had higher risk of CMV reactivation when compared to HL, and

progressive disease at transplant was associated with increased risk of CMV reactivation. After a median follow-up of 21.5 months (range: 1 to 125), there was no significant impact on PFS, however there was significant decrease in OS of lymphoma patients who had CMV reactivation when compared to those without CMV reactivation (204 and 112 days respectively

P=0.045). TRM increased from 1.1% in patients with no CMV reactivation to 13% in patients with CMV reactivation (P=0.003). 3   

Conclusion: Our data suggests that CMV reactivation is not uncommon in ASCT recipients and may contribute to increase TRM. MM patients may have a higher incidence, of CMV reactivation with more anti-viral treatment requirements when compared to lymphoma patients, especially in older population. Keywords: Myeloma Lymphoma Cytomegalovirus Autologous stem cell transplantation Background: Autologous hematopoietic stem cell transplantation (ASCT) is accepted as a comparatively effective treatment to allogeneic HSCT (allo-SCT) for Multiple Myeloma (MM) and Lymphoma patients with the advantage of earlier engraftment.1, 2 In addition, ASCT patients do not usually develop a persistent immunodeficiency state which is common in alloSCT patients who receive immunosuppressant drugs to prevent graft-versus-host disease (GVHD). Consequently, ASCT patients are generally thought to have less viral reactivation than allo-SCT recipients.

However, the variety and frequency of viral reactivations in

patients undergoing ASCT has not been adequately studied.3, 4 Cytomegalovirus reactivation is often diagnosed in allo-SCT recipients and could cause a CMV-related disease in these immunocompromised patients, involving many organs. Several studies have indicated that viral reactivation following allo-SCT is frequent, but viral reactivation after ASCT has not been thoroughly investigated.5, 6 Autograft recipients are generally considered to have low risk of CMV reactivation or end-organ disease. Without antiviral intervention, about 50% of patients with culture-proven CMV infection will develop CMV disease.7 Preemptive anti-viral therapy has decreased the incidence of CMV disease in allo-SCT from 25-30% to less than 5%. 8-10 There are few reports of CMV infection/disease following ASCT, along with high rates of mortality primarily due to CMV pneumonia.11-14 However, most of these data are from the era preceding the novel chemotherapeutic agents. In recent years, with changing chemotherapeutic regimens, available information is limited 4   

on the clinical progression and implications of CMV reactivation after ASCT. Frequent clinical manifestations of CMV disease are interstitial pneumonitis, gastrointestinal (GI) disease, hepatitis; retinitis, and encephalitis. Bone marrow suppression as a manifestation of CMV reactivation has also been described. The current diagnostic approach to CMV infection consists of sampling the peripheral blood for either CMV pp65 antigen (antigenemia assay) or polymerase chain reaction (PCR).6, 11, 15 Pre-emptive therapy with either Ganciclovir or Foscarnet is initiated in patients detected as positive.8 Objectives: The primary outcome of the analysis was to understand the difference of CMV reactivation incidence between Lymphoma and Myeloma patients. Secondary outcomes included effect of CMV reactivation on transplant related mortality (TRM), overall survival (OS), progression free survival (PFS), risk factors for reactivation, and median time to reactivation.

Study design: In this report, we retrospectively evaluated the difference between incidence, risk factors, and outcome CMV reactivation in adult Lymphoma and Myeloma patients undergoing ASCT in a major referral hospital in Lebanon. The study was approved by the institutional review board at AUBMC, and written informed consent in accordance with the declaration of Helsinki to review charts for research purposes is regularly obtained from patients prior to transplant at our center. A total of 324 consecutive ASCT were performed for MM (41%) and lymphoma (59%) patients at the American University of Beirut Medical Center (AUBMC) between January 2005 and March 2016. None of our patients had CD34+ selection. All patients and transplantrelated characteristics are listed in Table 1. CMV DNA viral load in blood was measured by quantitative polymerase chain reaction (PCR) in cases of clinical suspicion of reactivation.

Infection prophylaxis Pneumocystis jiroveci prophylaxis included trimethoprim/sulfamethoxazole 20 mL suspension orally twice daily prior to transplantation, discontinued after morning dose on Day (-2) of transplant, and then resumed as soon as the absolute neutrophil count (ANC) exceeded 500/mm3. Levofloxacin 500 mg orally once daily was started when ANC was less 5   

than 1000/mm3 and discontinued when ANC was more than 1000/mm3 or fever protocol was activated regardless of ANC level. Doxycycline 100 mg orally twice daily was started from Day 0 after transplant until the removal of central IV catheter as a strategy to reduce central venous catheter infections.24 Valgancyclovir 900 mg orally twice daily was started with conditioning and discontinued after morning dose on Day (-2) of transplant. Intravenous acyclovir or oral valacyclovir was used thereafter for Herpes simplex virus prophylaxis. Voriconazole 200 mg twice a day was used as a primary prophylaxis of fungal infections for all patients and started on Day (-1) of transplantation. Definitions CMV infection: is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen.16 CMV disease: Histologically proven end-organ disease with CMV infection.16 Death was attributed to CMV if there was evidence of autopsy proven organ damage by CMV. CMV monitoring and treatment: Serial weekly monitoring for CMV quantification was done using a quantitative PCR assay with a sensitivity of 61 copies/ml and linear range 15010,000,000 copies/ml (COBAS AMPLICOR and TAQMAN 48 , assay from 2005-2009 and AMPLIPREP from 2009-present time, Roche Diagnostics, New Jersey, USA ) Monitoring was initially performed on a weekly basis , starting from transplantation until the hospital discharge and afterwards based on the clinical symptoms such as of fever, diarrhea, vomiting, and signs of bone marrow suppression, without evidence of bacterial, viral (Parvovirus B19, EBV, and HHV6) or fungal co-infections. We defined bone marrow suppression as a delay of absolute neutrophils count (ANC) and/or platelet recovery from ASCT (14 and 21 days from transplant, respectively) or a drop in ANC and/or platelet count after recovery (<1000/μl or 100,000/μl, respectively, or a 30% decrease in any of the counts. and then every week in case of reactivation. If there was evidence of reactivation (PCR >1,000 copies/mL),

17

treatment was started with Ganciclovir (5mg/kg IV twice daily, dose

adjusted per creatinine clearance in patients with renal insufficiency) for 2 weeks, provided two consecutive PCRs done three days apart became negative. If the PCR was still positive after 2 weeks of treatment, a maintenance therapy with Ganciclovir (5mg/kg IV once /day), or oral Valgancyclovir at 450 mg twice per day for another 14 days was proposed. In some 6   

cases, CMV disease was diagnosed upon the demonstration of nuclear and cytoplasmic viral inclusions with immunohistochemistry stains on organ biopsy along with clinical and radiological features consistent with CMV.8 Irrespective of PCR results, some patients suspected to have gastrointestinal involvement were biopsied. In the presence of symptomatic CMV reactivation, appropriate anti-CMV therapy was instituted. Platelets and red cells were transfused according to our institutional clinical and biological criteria.

Recurrent CMV reactivation: after resolution of the first episode with antiviral therapy. Statistical analysis: Numerical variables were summarized by their median, mean, standard deviation and range. Categorical variables were described by counts and relative frequencies. Univariate analysis of CMV reactivation with each of the independent variables including disease status, gender and disease type was compared using p values in 2x2 tables. Mean age was compared for patients who had CMV reactivation vs patients who did not have CMV reactivation using student t-test. Multivariate analysis for CMV reactivation was performed using a binary logistic regression with using backward stepwise elimination process in which only significant variables are kept at the last step. The student t-test was used to compare intervals of days to reactivation for lymphomas vs multiple myelomas, and One-way ANOVA was used to compare the mean for three groups HL, NHL and multiple myeloma, the three groups were compared using the Bonferroni for multiple- comparison correction. OS was defined as the time from initial diagnosis to death (due to any cause) or the end of follow-up (censored observations). PFS was calculated from the time of initial diagnosis to date of documented relapse or the end of follow-up. Both OS and PFS were estimated using the Kaplan-Meier method in which the log rank was calculated to test significant difference between groups. Cox regression was used to identify variables that are affecting OS time; initially all independent variables were entered individually. All variables were later added together to identify the significant variables in the model using the stepwise elimination process. All p values were 2-sided. A value of p < 0.05 was considered significant. All statistical analysis was performed using the SPSS v.23.0 statistical package. Results:

7   

The cumulative incidence of CMV reactivation was 16% (n=53) with a median time of 16 (range, 4–242) days after ASCT, we did not observe any cases of primary CMV infection. The incidence of reactivation was significantly higher in the MM (22%) and NHL (20%) groups, when compared to the HL (4%) (P=0.001). There was a higher incidence of reactivation according to age (≥50 vs ≤50 years) with higher incidence in the older population 24 % vs 10% respectively (p=0.0043) The mean time to reactivation was significantly higher in the NHL group with a mean of 53.7 (SD ±62.978) days when compared to the HL and MM groups with mean 19.75 (SD ±12.08) days and 12.66 (range, 4-34 (SD ±28.68) days respectively (P=0.003). Thirty-eight patients (72%) required anti-CMV treatment. Thirty patients (79%) and 6 patients (16%) with CMV reactivation received Ganciclovir and Valacyclovir respectively, and data was missing for 2 patients (5%). Twenty-two patients (76%) and three patients (75%) patients required specific antiviral therapy in the MM group and HL groups respectively; which was significantly higher (P<0.001) then the NHL group with 13 (65%) patients requiring specific antiviral therapy. Median age of untreated patients was 48 years (range, 25-70); all of them engrafted and had recovery of their neutropenia at time of reactivation, all of them were asymptomatic with PCR CMV<1000 copies/mL, median CMV PCR peak <150 copies/mL (range, >150-810).

Five patients (1.5%) developed CMV disease at a median of 60 days (range, 7–107) post ASCT: 4 had disseminated GI involvement with nuclear and cytoplasmic viral inclusions with immunohistochemistry stains on colon biopsy, two patients of whom had negative CMV PCR in the blood. One patient had CMV pneumonitis with viral inclusions detected on lung wedge biopsy. One of them died of CMV disease while two patients died of disease progression. Recurrent reactivation was seen in 6 patients, with no significant difference between the 5 patients with NHL and the single patient with MM. Adding to that there was significant difference in the mean-time to reactivation based on disease type MM versus lymphoma 10 versus 33 days (P=0.007). In multivariate analysis, a higher age was associated with an increased risk of CMV reactivation; NHL and MM had higher risk of CMV reactivation when compared to HL, and progressive disease at transplant was associated with increased risk of CMV reactivation (table multivariate). However, we did not observe any effect of gender, on incidence of CMV reactivation post ASCT.

8   

After a median follow-up of 21.5 months (range: 1 to 125), there was no significant impact on PFS, however there was significant decrease in OS of lymphoma patients who had CMV reactivation when compared to those without CMV reactivation (204 and 112 days respectively P=0.045). Adding to that CMV reactivation had no effect on PFS and OS in MM patients. Even though we observed no significant difference in OS and PFS of all patients when grouped together (CMV reactivation vs no CMV reactivation), TRM increased from 1.1% in patients with no CMV reactivation to 13% in patients with CMV reactivation (P=0.003). seven deaths in the CMV reactivation group were labeled as TRM.; with 4 patients dying from CMV reactivation, one patient from bacterial sepsis, one from cardiotoxicity, and one from Veno-occlusive disease. Discussion: Infections in MM and lymphoma patients undergoing ASCT represent a clinical challenge. The list of potential pathogens is long and changes over the disease course.18 The aim of our study was to understand the difference of CMV reactivation between MM and lymphoma patients. The incidence of CMV reactivation/CMV disease after ASCT is much lower than that after allo-SCT. A recent study using regular weekly CMV reactivation monitoring until day 42 post ASCT with CMV pp65 antigen (antigenemia assay) on 210 Lymphoma and MM patients, reports an CMV reactivation incidence of 17.6%, with no effect on Overall survival.19 We report similar findings, with an CMV reactivation incidence of 16% using weekly PCR CMV monitoring until hospital discharge, and no effect on OS. Another study that compared clinically driven approach (286 patients) was investigated by CMV PCR upon clinical suspicion of infection to a prospective surveillance strategy (86 patients), in which PCR was performed weekly in all patients regardless of clinical suspicion for at least 5 weeks after transplant. they report an incidence of 11% and 31.4% in the clinically driven strategy group and prospective surveillance group respectively. It should also be noted that 92.9% of patients in the former group had symptomatic infection, while 37% of patients in the later developed symptomatic CMV reactivation. There were no differences in mortality rate among patients with CMV reactivation between the two groups.20 Our results fall in between the two cohorts, since our approach was regular monitoring during hospital stay and a clinically driven approach after discharge.

9   

A previous study

with a similar sample size, population, and monitoring technique

(quantitative PCR), reported a lower incidence of CMV reactivation (11% vs 16% in ours).21 However it should be noted that, this study did not adopt a routine monitoring technique before hospital discharge, as blood CMV DNA viral Load was measured only in patients who showed signs and symptoms of CMV reactivation. While in our study we had a routine monitoring strategy until hospital discharge, which explains the higher incidence of CMV reactivation in our study. Furthermore, the percentage of patients requiring antiviral treatment for a symptomatic CMV infection is the same (11% in this study vs 12% in our study). With the recent use of the monoclonal antibodies such as Rituximab during chemotherapy or conditioning regimens prior to transplantation, there has been an increasing concern of opportunistic infections including CMV.22-25 Moreover, another study that included nearly one thousand patients investigating the effect of Rituximab on CMV reactivation after ASCT reports less than one percent incidence of CMV reactivation.26 However only 239 patients were tested for CMV reactivation, of which 2.9% were positive CMV reactivation vs 16% in our study. It should be noted that they may have missed asymptomatic CMV reactivation due to the lack of a routine monitoring strategy. This may explain the discrepancy in our results. Even though all of the aforementioned studies investigated the incidence of CMV reactivation in MM and lymphoma patients undergoing ASCT, none of them addressed the diseases independently. We found a significantly higher incidence of CMV reactivation (22%) in the MM group when compared to the NHL (20%) and HL (4%) group. It also should be noted that the proportion of patients requiring specific antiviral therapy for a symptomatic CMV reactivation was significantly higher in the MM group when compared to the HL group (P<0.001), while we observed no significant difference between the MM and NHL groups. The higher incidence, and the higher proportion of patients requiring therapy for CMV reactivation in the MM group could be attributed to the immunodeficiency related to MM, and the novel anti-myeloma drugs used pre-transplant which predispose the patient to various opportunistic infections

27, 28

. A cumulative

suppression of cell mediated immunity is particular to MM, this results from the combined effect of repetitive use of high-dose corticosteroids, the chronic nature of the disease with multiple relapses requiring salvage therapies (almost always containing dexamethasone), and the

addition

of

bortezomib,

a

powerful

immunosuppressive

agent,

or

other

immunomodulatory agents like thalidomide and lenalidomide in different treatment phases could also support our findings. 27, 29 A recent report from the Rome Transplant Network has 10   

indicated a higher risk of CMV reactivation in patients with MM treated with bortezomibbased regimens, as mentioned in the study, this might be the result of increased CMV screening in patients receiving bortezomib.30 The drug is known to increase susceptibility to viral infections due to decreased number and function of natural killer cells and CD8+/CD4+ T cells.31, 32 Moreover, interestingly in our study we found an impact of the age of patients on CMV reactivation with an increase of risk from 10% in the young patients group to 24% in the older group (≥50 years) (p=0.0043) and also we found a proportional increase of 1.038 in relative risk of CMV reactivation per year increase in age (p=0.011). (Table 3) This could be explained by a higher proportion of older patients had MM who showed a higher incidence of CMV reactivation. This correlation could be attributed both to age and disease type (HL and young age). Adding to that, this difference was proven to be statistically significant both in univariate and multivariate analysis. (Table 3). Finally, we found that two out of 5 patients with CMV disease had a negative CMV PCR in blood, but positive tissue biopsies. This suggests that in the setting of persistent clinical symptoms and irrespective of PCR CMV results in blood, the organ should be biopsied and appropriate anti-CMV therapy rapidly initiated in cases with confirmed disease. Our data suggests that CMV reactivation is not uncommon in ASCT recipients and may contribute to increase TRM without impacting OS. It should be noted also that routine monitoring has no impact on CMV reactivation outcomes, and only constitute financial and logistical burdens that hinder the transplant process and therefore should not be recommended for implementation. MM patients may have a higher incidence of CMV reactivation with more anti-viral treatment requirements when compared to lymphoma patients, especially in older population.

11   

Transparency declaration The authors have no conflicts of interest to declare.

Acknowledgments: We thank the nursing staff for providing excellent care for our patients and the physicians in the Hematology and Oncology division at the American University of Beirut Medical Center and referring physicians from Lebanon and the Middle East region for their significant contributions and dedicated patients’ care.

References 1. 

  2. 

  3. 

  4. 

  5. 

Fernandez HF, Escalon MP, Pereira D, Lazarus HM. Autotransplant conditioning regimens for  aggressive lymphoma: are we on the right road? Bone Marrow Transplant 2007; 40(6): 505‐ 513. doi: 10.1038/sj.bmt.1705744  Sebban  C,  Brice  P,  Delarue  R,  Haioun  C,  Souleau  B,  Mounier  N  et  al.  Impact  of  rituximab  and/or  high‐dose  therapy  with  autotransplant  at  time  of  relapse  in  patients  with  follicular  lymphoma:  a  GELA  study.  J  Clin  Oncol  2008;  26(21):  3614‐3620.  doi:  10.1200/JCO.2007.15.5358  Miyoshi H, Tanaka‐Taya K, Hara J, Fujisaki H, Matsuda  Y, Ohta H et al. Inverse relationship  between  human  herpesvirus‐6  and  ‐7  detection  after  allogeneic  and  autologous  stem  cell  transplantation.  Bone  Marrow  Transplant  2001;  27(10):  1065‐1070.  doi:  10.1038/sj.bmt.1703033  Piukovics  K,  Borbenyi  Z,  Rajda  C,  Csomor  A,  Deak  J,  Terhes  G.  Monitoring  human  herpesvirus‐6  in  patients  with  autologous  stem  cell  transplantation.  In  vivo  2014;  28(6):  1113‐1117.   Declerck  L,  Queyrel  V,  Morell‐Dubois  S,  Dewilde  A,  Charlanne  H,  Launay  D  et  al.  [Cytomegalovirus and systemic lupus: severe infection and difficult diagnosis]. La Revue de  medecine  interne  /  fondee  ...  par  la  Societe  nationale  francaise  de  medecine  interne  2009;  30(9): 789‐793. doi: 10.1016/j.revmed.2009.03.019 

  12   

6. 

  7. 

  8. 

  9. 

  10. 

  11. 

  12. 

  13. 

  14. 

  15. 

Inazawa  N,  Hori  T,  Nojima  M,  Saito  M,  Igarashi  K,  Yamamoto  M  et  al.  Virus  reactivations  after autologous hematopoietic stem cell transplantation detected by multiplex PCR assay.  Journal of medical virology 2016. doi: 10.1002/jmv.24621  Marchesi F, Pimpinelli F, Dessanti ML, Gumenyuk S, Palombi F, Pisani F et al. Evaluation of  risk of symptomatic cytomegalovirus reactivation in myeloma patients treated with tandem  autologous stem cell transplantation and novel agents: a single‐institution study. Transplant  infectious disease : an official journal of the Transplantation Society 2014; 16(6): 1032‐1038.  doi: 10.1111/tid.12309  Ljungman P, Reusser P, de la Camara R, Einsele H, Engelhard D, Ribaud P et al. Management  of  CMV  infections:  recommendations  from  the  infectious  diseases  working  party  of  the  EBMT. Bone Marrow Transplant 2004; 33(11): 1075‐1081. doi: 10.1038/sj.bmt.1704505  Zaia  JA,  Schmidt  GM,  Chao  NJ,  Rizk  NW,  Nademanee  AP,  Niland  JC  et  al.  Preemptive  ganciclovir  administration  based  solely  on  asymptomatic  pulmonary  cytomegalovirus  infection  in  allogeneic  bone  marrow  transplant  recipients:  long‐term  follow‐up.  Biology  of  blood and marrow transplantation : journal of the American Society for Blood and Marrow  Transplantation 1995; 1(2): 88‐93.   Navarro D, Amat P, de la Camara R, Lopez J, Vazquez L, Serrano D et al. Efficacy and Safety of  a Preemptive Antiviral Therapy Strategy Based on Combined Virological and Immunological  Monitoring  for  Active  Cytomegalovirus  Infection  in  Allogeneic  Stem  Cell  Transplant  Recipients. Open forum infectious diseases 2016; 3(2): ofw107. doi: 10.1093/ofid/ofw107  Boeckh  M,  Stevens‐Ayers  T,  Bowden  RA.  Cytomegalovirus  pp65  antigenemia  after  autologous marrow and peripheral blood stem cell transplantation. The Journal of infectious  diseases 1996; 174(5): 907‐912.   Holmberg  LA,  Boeckh  M,  Hooper  H,  Leisenring  W,  Rowley  S,  Heimfeld  S  et  al.  Increased  incidence of cytomegalovirus disease after autologous CD34‐selected peripheral blood stem  cell transplantation. Blood 1999; 94(12): 4029‐4035.   Bilgrami  S,  Aslanzadeh  J,  Feingold  JM,  Bona  RD,  Clive  J,  Dorsky  D  et  al.  Cytomegalovirus  viremia, viruria and disease after autologous peripheral blood stem cell transplantation: no  need  for  surveillance.  Bone  Marrow  Transplant  1999;  24(1):  69‐73.  doi:  10.1038/sj.bmt.1701827  Konoplev  S,  Champlin  RE,  Giralt  S,  Ueno  NT,  Khouri  I,  Raad  I  et  al.  Cytomegalovirus  pneumonia  in  adult  autologous  blood  and  marrow  transplant  recipients.  Bone  Marrow  Transplant 2001; 27(8): 877‐881. doi: 10.1038/sj.bmt.1702877  Preiser  W,  Rabenau  HF,  Vogel  JU,  Brixner  V,  Doerr  HW.  Performance  characteristics  of  an  automated  PCR  assay  for  the  quantification  of  cytomegalovirus  DNA  in  plasma.  Journal  of  virological methods 2002; 101(1‐2): 149‐157.   13 

 

  16. 

  17.    18. 

  19. 

  20. 

  21. 

  22. 

  23. 

  24. 

  25. 

Ljungman P,  Boeckh M, Hirsch  HH,  Josephson F, Lundgren J, Nichols G et al. Definitions of  Cytomegalovirus  Infection  and  Disease  in  Transplant  Patients  for  Use  in  Clinical  Trials.  Clinical  infectious  diseases  :  an  official  publication  of  the  Infectious  Diseases  Society  of  America 2017; 64(1): 87‐91. doi: 10.1093/cid/ciw668  Ljungman  P.  CMV  infections  after  hematopoietic  stem  cell  transplantation.  Bone  marrow  transplantation 2008; 42 Suppl 1: S70‐S72. doi: 10.1038/bmt.2008.120  Offidani M, Corvatta L, Olivieri A, Rupoli S, Frayfer J, Mele A et al. Infectious complications  after  autologous  peripheral  blood  progenitor  cell  transplantation  followed  by  G‐CSF.  Bone  Marrow Transplant 1999; 24(10): 1079‐1087. doi: 10.1038/sj.bmt.1702033  Al‐Rawi  O,  Abdel‐Rahman  F,  Al‐Najjar  R,  Abu‐Jazar  H,  Salam  M,  Saad  M.  Cytomegalovirus  Reactivation  in  Adult  Recipients  of  Autologous  Stem  Cell  Transplantation:  a  Single  Center  Experience.  Mediterranean  journal  of  hematology  and  infectious  diseases  2015;  7(1):  e2015049. doi: 10.4084/MJHID.2015.049  Mengarelli  A,  Annibali  O,  Pimpinelli  F,  Riva  E,  Gumenyuk  S,  Renzi  D  et  al.  Prospective  surveillance  vs  clinically  driven  approach  for  CMV  reactivation  after  autologous  stem  cell  transplant. The Journal of infection 2016; 72(2): 265‐268. doi: 10.1016/j.jinf.2015.11.005  Marchesi  F,  Pimpinelli  F,  Gumenyuk  S,  Renzi  D,  Palombi  F,  Pisani  F  et  al.  Cytomegalovirus  reactivation after autologous stem cell transplantation in myeloma and lymphoma patients:  A single‐center study. World J Transplant 2015; 5(3): 129‐136. doi: 10.5500/wjt.v5.i3.129  Nissen JC, Hummel M, Brade J, Kruth J, Hofmann WK, Buchheidt D et al. The risk of infections  in  hematologic  patients  treated  with  rituximab  is  not  influenced  by  cumulative  rituximab  dosage  ‐  a  single  center  experience.  BMC  infectious  diseases  2014;  14:  364.  doi:  10.1186/1471‐2334‐14‐364  Goldberg  SL,  Pecora  AL,  Alter  RS,  Kroll  MS,  Rowley  SD,  Waintraub  SE  et  al.  Unusual  viral  infections  (progressive  multifocal  leukoencephalopathy  and  cytomegalovirus  disease)  after  high‐dose  chemotherapy  with  autologous  blood  stem  cell  rescue  and  peritransplantation  rituximab. Blood 2002; 99(4): 1486‐1488.   Suzan  F,  Ammor  M,  Ribrag  V.  Fatal  reactivation  of  cytomegalovirus  infection  after  use  of  rituximab for a post‐transplantation lymphoproliferative disorder. The New England journal  of medicine 2001; 345(13): 1000. doi: 10.1056/NEJM200109273451315  Lee MY, Chiou TJ, Hsiao LT, Yang MH, Lin PC, Poh SB et al. Rituximab therapy increased post‐ transplant  cytomegalovirus  complications  in  Non‐Hodgkin's  lymphoma  patients  receiving  autologous hematopoietic stem cell transplantation. Ann Hematol 2008; 87(4): 285‐289. doi:  10.1007/s00277‐007‐0397‐0 

14   

  26. 

  27.    28. 

  29. 

  30. 

  31. 

  32. 

Jain T, John J, Kotecha A, Deol A, Saliminia T, Revankar S et al. Cytomegalovirus infection in  autologous stem cell transplant recipients in the era of rituximab. Ann Hematol 2016; 95(8):  1323‐1327. doi: 10.1007/s00277‐016‐2700‐4  Hasegawa T, Aisa Y, Shimazaki K, Ito C, Nakazato T. Cytomegalovirus reactivation in patients  with multiple myeloma. Eur J Haematol 2016; 96(1): 78‐82. doi: 10.1111/ejh.12551  Fassas  AB,  Bolanos‐Meade  J,  Buddharaju  LN,  Rapoport  A,  Cottler‐Fox  M,  Chen  T  et  al.  Cytomegalovirus  infection  and  non‐neutropenic  fever  after  autologous  stem  cell  transplantation: high rates of reactivation in patients with multiple myeloma and lymphoma.  Br J Haematol 2001; 112(1): 237‐241.   Naithani R, Tarai B. Cytomegalovirus reactivation after autologous stem cell transplantation  in  multiple  myeloma patients  treated with novel agents.  Transplant  infectious  disease  :  an  official journal of the Transplantation Society 2015; 17(6): 931‐932. doi: 10.1111/tid.12449  Marchesi F, Mengarelli A, Giannotti F, Tendas A, Anaclerico B, Porrini R et al. High incidence  of  post‐transplant  cytomegalovirus  reactivations  in  myeloma  patients  undergoing  autologous  stem  cell  transplantation  after  treatment  with  bortezomib‐based  regimens:  a  survey from the Rome transplant network. Transplant infectious disease : an official journal  of the Transplantation Society 2014; 16(1): 158‐164. doi: 10.1111/tid.12162  Heider U, Rademacher J, Kaiser M, Kleeberg L, von Metzler I, Sezer O. Decrease in CD4+ T‐ cell counts in patients with multiple myeloma treated with bortezomib. Clinical lymphoma,  myeloma & leukemia 2010; 10(2): 134‐137. doi: 10.3816/CLML.2010.n.019  Berges C, Haberstock H, Fuchs D, Miltz M, Sadeghi M, Opelz G et al. Proteasome inhibition  suppresses  essential  immune  functions  of  human  CD4+  T  cells.  Immunology  2008;  124(2):  234‐246. doi: 10.1111/j.1365‐2567.2007.02761.x 

 

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time of reactivation by disease 40 35

RCMV

30 25 20

MM

15

Lymphoma

10

total

5 0 0‐1 month

1‐3 months

3‐6 months 6‐12 months

interval time to reactivation

 

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DISEASE PATIENTS CONDITIONING REGIMEN AGE at ASCT: Mean (Standard deviation) GENDER: Female/Male CMV IgG pre-transplant Positive

TOTAL N(%)

MM N(%)

HL N(%)

NHL N(%)

P value

324

132 (41)

91 (28)

101 (31)

0.015

Melphalan

Beam

Beam

44.7 (±14.4)

54.0 (±8.2)

32.9 (±12.7)

43.1 (±13.8)

<0.001

144 (44)/180 (56)

53 (40)/79 (60)

42 (46)/49 (54)

49 (49)/52 (51)

0.419

225 (69)

93 (70)

58 (63)

72 (72)

18 (6) 81 (25)

6 (4) 32 (24)

9 (10) 24 (26)

3 (3) 25 (25)

Negative Unknown

Table1: transplant and patients’ characteristics

Legend: MM Multiple Myeloma, HL Hodgkin Lymphoma, NHL Non Hodgkin Lymphoma, ASCT Autologous Peripheral Stem Cell Transplant, CMV Cytomegalovirus, PCR Polymerase Chain Reaction, Beam Carmustine Etoposide Cytarabine Melphalan, (+) positive, (-) negative

Table 2 CMV reactivation characteristics. Total N (%)

MM N (%)

HL N(%)

NHL N(%)

p value

Total CMV reactivation

53 (16)

29 (22)

4 (4)

20 (20)

<0.001

CMV PCR Blood + / Biopsy -

51 (96)

28 (97)

4 (100)

19 (95)

<0.001

0-150 copies1

14 (27)

8 (29)

1 (25)

5 (26)

151-1000 copies1

12 (26)

9 (32)

0 (0)

3 (10)

>1000 copies

25 (49)

11 (40)

3 (75)

11 (60)

CMV DISEASE (Pathology)

5 (9.4)

3 (10)

0 (0)

2 (10)

Colitis/Ileitis2

4 (80)

3 (100)

0 (0)

1 (50)

2

Pneumonitis PCR Blood - / Biopsy +2 PCR Blood + / Biopsy +2

1 (20) 2 (40)

0 (0) 1 (33)

0 (0) 0 (0)

1 (50) 1 (50)

PCR < 150 copies1,2

1

2 (40)

2 (67)

0 (0)

0 (0)

1,2

1(20)

0 (0)

0 (0)

1 (50)

REQUIRING ANTI-CMV TREATMENT treatment type Ganciclovir

38 (72)

22 (76)

3 (75)

13 (65)

0.001

30 (79)

18 (81)

1 (33)

11 (85)

0.001

PCR>10000copies

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Valagancyclovir Unknown treatment

6 (16) 2 (5)

3 (14) 1 (5)

2 (67) 0 (0)

1 (8) 1 (8)

0.877

CMV Disease mean (±SD) days to reactivation

28.7 (±43.4)

12.7 (±7.7)

19.8 (±12.0)

53.7 (±63.0)

0.003 3

CMV Disease mean (±SD) days to reactivation reactivations according to year of transplant

28.7 (±43.4)

12.7 (±7.7)

19.8 (±12.0)

53.7 (±63.0)

NS

2005-2009

14 (17)

8 (24)

0 (0)

6 (24)

2010-2016

39 (16)

21 (21)

4 (6)

14 (18)

<50 years

18 (10)

6 (17)

3 (4)

9 (14)

>50

35 (24)

23 (24)

1 (7)

11 (30)

reactivation according to age

reactivation according to status at transplant

0.004 NS

Relapse/Progression

6 (30)

1 (100)

1 (8)

4 (50)

Partial response

36 (17)

127 (21)

2 (5)

7 (17)

Complete remission

11 (12)

4 (25)

1 (3)

9 (17)

resolved

31 (60)

17 (59)

3 (75)

11(55)

0.008

dead before resolution

7 (13)

3 (10)

1 (25)

3 (15)

0.712

not applicable (no viremia) unknown

2 (4) 13 (25)

1 (3) 8 (28)

0 (0) 0 (0)

1 (5) 5 (25)

14.8 (±13.3)

16.8 (±14.7)

23.0 (±19.0)

9.5 (±7.6)

0.202

6 (11)

1 (2)

0 (0)

5 (9)

0.219

3 (1) 7 (13)

0 (0) 2 (7)

1 (1) 1 (25)

2 (1) 4 (20)

viremia resolution

Time to resolution mean (standard deviation)4 Recurrent Reactivation Transplant related mortality No R-CMV R-CMV

Legend: MM Multiple Myeloma, HL Hodgkin Lymphoma, NHL Non Hodgkin Lymphoma, ASCT Autologous Peripheral Stem Cell Transplant, CMV Cytomegalovirus, PCR Polymerase Chain Reaction, Beam Carmustine Etoposide Cytarabine Melphalan, (+) positive, (-) negative, 1 max load by PCR, 2 percentage from total patients that developed CMV disease, 3 significant difference between NHL and MM only, 4 time to resolution of CMV infection in all patients (both treatment induced and spontaneous clearance of viremia )

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Table 3 univariate and multivariate analysis

Variables

Univariate and multivariate analyses of CMV reactivation Univariate Multivariate P value Risk Ratio (95% CI) P Value

Disease HL NHL MM Status at transplant CR PR Relapse/Progression Gender Male Female Mean age at transplant

4.3 % 19.8 % 21.9 %

0.001

1 4.9 (1.5-16.3) 4.6 (1.2-17.7)

0.03 0.01 0.03

11.7 % 17.2 % 28 %

NS

1 0.9 (0.4-2.5) 4.9 (1.4-17.6)

0.03 0.9 0.01

17.2 % 15.2 %

NS

51.7 yr

0.0001

NS

1.04 (1.07-1.1)

0.01

Legend: MM Multiple Myeloma, HL Hodgkin Lymphoma, NHL Non-Hodgkin Lymphoma, CR complete response, PR partial response, yr Year, NS not significant, CI confidence interval

 

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