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Keywords:

  • allogeneic stem cell transplantation;
  • cytomegalovirus;
  • Gancyclovir;
  • neutropenia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III–IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III–IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25–5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125–0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11–5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following allogeneic stem cell transplantation (Allo-SCT) [1, 2]. Therefore it must be treated as soon as positive CMV reactivation is noticed: pre-emptive therapy has been demonstrated to improve survival among patients reactivating CMV after transplantation [3, 4]. However, Ganciclovir, as well as CMV infection itself, pose a well-known marrow toxicity risk, notably neutropenia, that may consequently expose these immunosuppressed patients to other life-threatening bacterial and fungal infections [5, 6]. So far, only two studies have identified specific risk factors and outcome predictors for Ganciclovir-related neutropenia, finding low marrow cellularity between days 21 and 28, hyperbilirubinaemia >6 mg/dL during the first 20 days, serum creatinine >2 mg/L after day 21 and absolute neutrophil count to be predictive factors [7, 8]. However, transplantation has evolved in recent years; especially because of the introduction of reduced-intensity conditioning regimens and supportive care [9, 10]. The aim of the present analysis is to identifying risk factors for neutropenia among a large cohort of patients treated with pre-emptive Ganciclovir who received Allo-SCT at our Institution over the last 6 years.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

This is a retrospective study on a cohort of 547 consecutive patients receiving allotransplants from January 2005 to June 2011 at our Institution. Data collection was achieved by retrieval of electronic patient records. The study was approved by the Institut Paoli-Calmettes Institutional Board. Diagnoses were haematological malignancies, aplastic anaemia and metastatic solid tumours. Transplants were performed using three sources: bone marrow, peripheral blood stem cells and cord blood. Donors were HLA-matched siblings or matched or mismatched unrelated donors. Myeloablative, non-myeloablative and reduced-intensity conditioning regimens were administered according to local guidelines or established protocols [9, 11, 12].

GvHD prophylaxis and supportive care

Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A in 334 patients (61%), cyclosporin A + mycophenolate mofetyl in 198 patients (36%), 11 patients (2%) were free from any immunosuppressive therapy and mycophenolate mofetyl was used alone in four patients (1%). Cyclosporin A doses were adjusted to achieve blood levels between 150 and 250 ng/mL and to prevent renal dysfunction. Cyclosporin A was tapered starting on day 90 if no GvHD appeared. The main patient and transplant characteristics are shown in Table 1.

Table 1. Patients and transplant characteristics
 All patientsPatients with CMV reactivationPatients with Ganciclovir-related neutropeniap values
  1. Allo-SCT, allogeneic stem cell transplantation; AML, acute myeloid leukaemia; NHL, non-Hodgkin lymphoma; ALL, acute lymphoblastic leukaemia; PNH, paroxysmal nocturnal haemoglobinuria; CLL, chronic lymphoblastic leukaemia; CML, chronic myeloid leukaemia; CMML, chronic myelomonocytic leukaemia; MDS, myelodysplastic syndromes; IM, idiopathic myelofibrosis; PV, polycythaemia vera; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; RTC, reduced toxicity regimen; PBSC, peripheral blood stem cell; CB, cord blood; MUD, matched unrelated donor; MMUD, mismatched unrelated donor; CSA, cyclosporin; MMF, mycophenolate mofetil; GvHD, graft versus host disease.

No. of patients547 (100%)190 (35%)80 (42%)n.s
Median age at Allo-SCT (range)51 (17–71)51 (17–51)51 (17–69)n.s
Disease   n.s
AML193 (35%)55 (29%)22 (28%) 
NHL98 (17.9%)42 (22%)21 (26%) 
MM63 (11.5%)24 (13%)8 (10%) 
ALL54 (9.8%)22 (12%)9 (11%) 
MDS33 (6%)11 (6%)3 (3.8%) 
CLL23 (4.2%)10 (5%)5 (6%) 
Aplastic anaemia12 (2.2%)7 (4%)3 (3.8%) 
Hodgkin's disease23 (4.2%)5 (3%)2 (2.5%) 
CML13 (2.4%)4 (2%)2 (2.5%) 
Breast cancer7 (1.3%)3 (2%)2 (2.5%) 
IM12 (2.2%)3 (1%)1 (1.3%) 
PNH3 (0.5%)2 (1%)1 (1.3%) 
CMML4 (0.7%)1 (0.5%)1 (1.3%) 
Waldenstrom1 (0.2%)1 (0.5%)0 (0%) 
PV2 (0.4%)0 (0%)0 (0%) 
Ovarian cancer5 (0.9%)0 (0%)0 (0%) 
Uterine cancer1 (0.2%)0 (0%)0 (0%) 
Conditioning   n.s
MAC30 (5.5%)8 (4%)3 (3.8%) 
BOOST10 (1.8%)2 (1%)64 (80%) 
RIC431 (78.8%)154 (81%)12 (15%) 
RTC76 (13.9%)26 (14%)1 (1.2%) 
Prophylaxis of GvHD   n.s
CSA332 (60.7%)111 (58%)40 (50%) 
CSA + MMF202 (37%)76 (40%)38 (47.4%) 
MMF3 (0.5%)2 (1%)1 (1.3%) 
None10 (1.8%)1 (0.5%)1 (1.3%) 
CMV serology Donors/Recipients   n.s
Donor +/Recipient +191 (35%)69 (36%)25 (31%) 
Donor +/Recipient −156 (28.5%)91 (48%)41 (51%) 
Donor −/Recipient +57 (10.4%)3 (1.5%)1 (1.3%) 
Donor −/Recipient −108 (20%)9 (5%)4 (5%) 
Unknown35 (6.4%)18 (9.5%)9 (11.2%) 
Stem cell source   n.s
PBSC423 (77.3%)142 (75%)57 (72%) 
CB84 (15.3%)33 (17%)14 (17.5%) 
BM40 (7.4%)15 (8%)9 (11.5%) 
T-cell depletion   n.s
Yes370 (67.6%)110 (58%)54 (67.5%) 
No177 (32.4%)80 (42%)26 (32.5%) 
Donor type   n.s
Related donor301 (55%)90 (47%)40 (50%) 
MUD128 (23.4%)49 (26%)21 (26.3%) 
MMUD118 (21.6%)51 (27%)19 (23.7%) 
GvHD   n.s
GvHD grade 0/I74 (13.5%)22 (11.5%)4 (5%) 
GvHD grade II–IV154 (28%)75 (39.5%)37 (46%) 
None319 (58.5%)93 (49%)39 (49%) 

Our protocol for providing supportive care was the same throughout this time period. Prophylactic treatment against Pneumocystis jirovecii and toxoplasmosis consisted of trimethoprim-sulfamethoxazole (10 mg/kg/day trimethoprim) administered twice weekly. Patients also received daily oral amoxicillin (500 mg × 3/day) as prophylaxis against encapsulated bacteria and oral valacyclovir (500 mg × 2/day) as prophylaxis against herpes simplex virus.

CMV monitoring and treatment

Serial weekly monitoring for CMV quantification was done using either pp65 antigen (between 2000 and 2009) or a quantitative PCR assay on the whole blood (COBAS R, Roche Diagnostics, Branchburg, NJ, USA; with a lower detection limit of 30 copies/mL) (from 2009 to the present). Monitoring was performed weekly initially, starting from transplantation until day 90, and then every 4–8 weeks during the next 6 months. If there was evidence of reactivation (pp65 >2 cells/200 000 or PCR >1000 copies/mL), treatment was started with Ganciclovir (5 mg/kg intravenous twice daily) for 2 weeks, provided two consecutive PCRs performed 3 days apart became negative. If the PCR was still positive after 2 weeks of treatment, a maintenance therapy with Ganciclovir (5 mg/kg intravenously once per day) for another 14 days was proposed. CMV disease was diagnosed on demonstration of tissue invasion in biopsy specimens or demonstration of a positive CMV early antigen test on bronchoalveolar lavage, along with clinical and radiological features consistent with CMV. Only the first episode of CMV reactivation or CMV disease was taken into account.

Grade III neutropenia is defined by an absolute neutrophil count (ANC) between 500 and 1000/μL and a grade IV neutropenia by an ANC <500/μL. (Table 1).

Objectives and statistical analysis

The principal objective of the study was to identify factors associated with the occurrence of grade III–IV neutropenia among patients receiving antiviral therapy due to CMV reactivation. The following variables were analysed among patients with CMV reactivation: initial replicating virus copies (determined both by antigenaemia and PCR), time from transplant to CMV reactivation, patient's age, diagnosis, stem cell source, conditioning regimen, serum creatinine, hyperbilirubinaemia, absolute neutrophil count at CMV reactivation, presence of GvHD at CMV reactivation, relapse or progressive disease at CMV reactivation. These factors were then correlated with grade III–IV neutropenia during antiviral therapy. We considered values of PCR >5000 copies/mL and antigenaemia >10 infected cells as a high viral load, to be compared with lower values. Logistic regression was used both for univariate and multivariate analyses. Patients with grade III–IV neutropenia at the moment of CMV reactivation were excluded from this analysis. Variables with p <0.20 were then included in the multivariate analysis; only factors with p <0.05 were retained in the final model.

Secondarily, overall survival, transplant-related mortality (TRM) and relapse/progression were analysed and compared between patients who reactivated CMV versus those who did not. As CMV reactivation is a post-transplant event, landmark analysis was performed. Estimates of overall survival were calculated by the Kaplan–Meier method with respective 95% confidence intervals, starting from day of transplant. TRM, relapse/progression, CMV reactivation and grade III–IV neutropenia were evaluated by cumulative incidence; relapse/progression and TRM were considered competing events. Death from any cause was considered as a competing event in CMV reactivation and grade III–IV neutropenia analyses. The SPSS v16.0 and R v2.12.2 programs were used.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

A total of 547 patients were included in the analysis. One hundred and ninety patients presented with CMV reactivation (35%). Thirty patients were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 patients were analysed. Solid tumours and non-malignant haematological diseases represented a very small proportion of transplant patients. A minority of patients received T-depletion by anti-thymocyte globulin.

Peripheral blood stem cells were the main type of grafts used. Eighty of 160 (50%) patients presented Ganciclovir-related neutropenia, 39 patients had grade III neutropenia and 41 patients had grade IV. The average time between the introduction of Ganciclovir and the occurrence of neutropenia was 35 days (range 2–216 days). All patients with grade III–IV neutropenia (80 patients in all) received granulocyte colony-stimulating factor until ANC recovered to >1000/μL for at least three consecutive days. At CMV reactivation, median antigenaemia was nine infected cells (range 9–969) and the median number of copies according to PCR was 6149/mL (range 995–2 228 620). The median number of days before CMV reactivation was 42 (range 12–969). Eighty-eight percent of all CMV reactivation had occurred by day 100 post-transplant. The cumulative incidence of CMV reactivation, as shown in Fig. 1, was 34% (95% CI 30–38%). CMV reactivation was 36% (69/191), 58% (91/156), and 5% (3/56) among donor/patient pairs with positive/positive, positive/negative and negative/positive CMV serostatus. Nine primary CMV infections were observed among donor/patient pairs with negative/negative CMV serostatus. Twenty-seven patients (14%) developed a CMV disease (18 disseminated gastrointestinal colitis, two pneumonitis and seven disseminated gastrointestinal and lung disease).

image

Figure 1. Cumulative incidence of cytomegalovirus.

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In those 80 patients with Ganciclovir-related neutropenia, 20 patients (25%) developed concomitant bacterial infections, and 16 patients (20%) developed concomitant invasive fungal infections.

Risk factors for neutropenia

Upon univariate analysis, risk factors significantly associated with a grade III–IV Ganciclovir-related neutropenia at the time of treatment initiation included a high viral load (hazard ratio (HR) = 2.61, 95% CI 1.42–4.85, p 0.002); ANC >3000/μL was a protective factor (HR = 0.32, 95% CI 0.17–0.63; p 0.001) while serum creatinine over 2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.12, 95% CI 1.04–4.34; p 0.04). All other parameters studied were not statistically significant (Table 2a). Bilirubin could not be analysed because only six patients presented with hyperbilirubinaemia.

Table 2. (a) Univariate analysis; (b) multivariate analysis
VariablesHazard ratio95% CIp
  1. ANC, absolute neutrophil count.

(a)
Patient's age >55 years vs <55 years1.390.78–2.480.27
Diagnosis  0.57
Conditioning0.70.14–3.560.67
Donor type  0.55
 ANC >3000 vs <30000.320.17–0.630.001
 Creatinine >2 mg/dL after Day + 21 vs Creatinine <2 mg/dL2.121.04–4.340.04
 Hight viral load vs low viral load2.611.42–4.850.002
GvHD Yes vs No0.880.49–1.590.67
Progressive disease1.610.84–3.100.15
(b)
ANC >3000 vs <30000.260.12–0.54<0.0001
Creatinine >2 mg/dL after Day + 21 vs creatinine <2 mg/dL2.41.11–5.170.002
High virus load vs low virus load2.681.25–5.740.01

All parameters statistically significant in the univariate analysis were still relevant upon multivariate analysis. Hence, ANC >3000 is a protective factor, (HR = 0.26, 95% CI 0.125–0.545, p <0001). Creatinine <2 mL/dL after 21 days was a risk factor for Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11–5.17, p 0.002) as well as a high viral load (HR = 2.68, 95% CI 1.25–5.737, p 0.01; Table 2b).

CMV and transplant outcomes

Since 88% of CMV reactivation occurred within 100 days after Allo-SCT, we chose a landmark day of +100. The analysis of overall survival at 5 years revealed significantly lower overall survival in patients with CMV reactivation, 43% (32–54) versus 57% (46–68), respectively (p <0.0001; Fig. 2a).

image

Figure 2. (a) Overall survival. (b) treatment-related mortality and relapse.

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We found a higher TRM at 5 years among patients who developed CMV reactivation: 29% (21–36) versus 12% (8–17; p 0.003). There was no significant difference in the risk of relapse in patients who reactivated CMV compared with those who did not reactivate, 32% versus 34% (p value not significant; Fig. 2b).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

Neutropenia following reactivation itself and/or antiviral therapy may represent a potentially life-threatening complication because of the risk of bacterial or fungal infections, especially in patients with concomitant GvHD who are undergoing steroid treatment [13-16]. For this reason, we decided to conduct a retrospective analysis of 547 consecutive patients transplanted at our Institution, to identify risk factors of neutropenia and potentially prevent this complication in those patients at risk in the future.

In this large series of adult patients presenting with CMV reactivation after Allo-SCT, we found patient age, serum CMV load and ANC value at viral reactivation to be significant predictive factors of neutropenia [17-19]. CMV reactivation is a well-known risk factor for mortality after transplantation [20]. Pre-emptive therapy has been shown to improve survival and monitoring of CMV levels is recommended in high-risk patients [21].

In addition, whenever possible, a CMV-negative donor is chosen for CMV-negative patients to avoid viral reactivation [18, 20, 22-24]. In this study, one clinical and two biological variables were associated with higher risk of Ganciclovir-related neutropenia; such variables can be easily identified at the start of antiviral therapy and so may lead clinicians to adopt adequate preventive measures (such as more attentive and frequent monitoring, granulocyte colony-stimulating factor, prophylactic antibacterial therapy, etc.).

Our cumulative incidence of CMV reactivation was 35% (190/547 patients), which is comparable with the article of George et al. (39%) [24].

On the other hand, the difference from other study by Green et al. could be related to the higher proportion of myeloablative conditioning and also by a different definition of a CMV reactivation (>500 copies/mL and >100 copies/mL in patients receiving anti-thymocyte globulin and CAMPATH) [25].

Moreover, we also confirmed in this study that CMV reactivation is associated with inferior survival because of higher TRM, and we cannot exclude the possibility that Ganciclovir-related neutropenia could at least in part contribute to TRM. Many years ago, Salzberger et al. [7, 26] and Boeckh et al. [7, 26] determined that low marrow cellularity between days 21 and 28 is a risk factor for Ganciclovir-related neutropenia. Moreover, in 2004, Tomonari et al. [8] showed that incidence of Ganciclovir-related neutropenia in patients with an ANC <1000 (250 and 500/μL) was significantly lower after Allo-SCT using cord blood cells in comparison with grafts from bone marrow cells. When analysing these results in light of the scientific literature, our study differs from previous ones in many important respects. First, compared with the paper of Salzberger et al. [8], who found that early liver dysfunction, an increase in serum creatinine and low marrow cellularity were risk factors for Ganciclovir-related neutropenia, in our study conditioning was different because reduced-intensity conditioning regimen transplants were used (81%), compared with the above-mentioned study where only myeloablative conditioning was used; this probably explains the low liver toxicity in our patients, with bilirubin in the first 20 days of transplantation exceeding 6 mg/dL in only six patients (3.75%).

Second, our results regarding ANC <3000 as a risk factor for Ganciclovir-related neutropenia are consistent with the results of Tomonari et al. [8] and Salzberger et al. [8], who consider marrow toxicity and low absolute neutrophil count (<1000) as risk factors related to Ganciclovir neutropenia [7, 8]. Third, the study of Tomonari et al. [8] was a comparative study between cord blood and marrow transplantation whereas in our study we compared all stem cell sources and did not find any significant differences between the graft sources with respect to Ganciclovir-related neutropenia (Table 1).

Fourth, in our study, 544 patients were included, which is higher than in the previous studies (278 and 37 patients, respectively). Finally, regarding the impact of renal failure on Ganciclovir-related neutropenia, we can suppose that a poor elimination of Ganciclovir leads to higher bone marrow toxicity because of accumulation of Ganciclovir [27].

In conclusion, in this large analysis we could identify three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after Allo-SCT; prompt identification of patients at risk when antiviral therapy is started may allow physicians to adopt adequate preventive measures; this could probably reduce the morbidity and mortality associated with CMV reactivation, warranting further prospective studies.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

We thank the nursing staff for providing excellent care for our patients and the physicians of the Haematology Department at the Institut Paoli-Calmettes for their important study contributions and dedicated patient care.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

G. Venton and J. El-Cheikh conceived and designed the study, collected and analysed data, performed statistical analyses, provided clinical care, and wrote and revised the manuscript; G. Venton and R. Crocchiolo collected and analysed data, performed statistical analyses, provided clinical care and revised the manuscript. S. Furst, C. Faucher, C. Oudin, A. Granata, D. Coso, R. Bouabdallah and N. Vey provided clinical care and commented on the manuscript. P. Berger and M. Merlin performed microbiological and virological monitoring and controls and commented on the manuscript. C. Chabannon, P. Ladaique are in charge of the cell therapy facility that collected and delivered the allogeneic blood cell grafts infused into patients included in this analysis, and commented on the manuscript. D. Blaise recruited patients, provided clinical care and commented on the manuscript.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References

We would like to thank the Association pour la Recherche sur le Cancer (ARC) (Pole ARECA) for their generous support of our research. Our group was supported by several grants from the French Ministry of Health as part of the Programme Hospitalier de Recherche Clinique (PHRC).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Author contributions
  9. Funding
  10. Transparency Declaration
  11. References
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