|Year : 2019 | Volume
| Issue : 4 | Page : 232-236
Impact of cytomegalovirus viremia on allogeneic peripheral blood stem cell transplantation in patients with acute leukemia: a single Egyptian center experience
Mohammed O Azazzi1, Raafat A Soliman2, Gehad A.M Hasan2, Mary G Naguib MD Degree in Internal Medicine 1
1 Department of Internal Medicine and Clinical Haematology, Faculty of Medicine, Ain Shams University, Egypt
2 Department of Hematology and Clinical Oncology, NCI Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||22-Aug-2019|
|Date of Acceptance||26-Oct-2019|
|Date of Web Publication||20-Jul-2020|
Mary G Naguib
14 Mohamed Basha Riad Street, Helioplis, Cairo, 11361
Source of Support: None, Conflict of Interest: None
Background Hematopoietic stem cell transplantation is now established as a standard therapeutic modality for a variety of malignant and nonmalignant diseases. The first successful allogeneic hematopoietic stem cell transplantation was done with bone marrow as the source of hematopoietic stem cells in 1968.
Aim This retrospective study evaluates the impact of cytomegalovirus (CMV) viremia in patients with acute myeloid leukemia and acute lymphoblastic leukemia after allogeneic stem cell transplantation.
Patients and methods Patients with acute leukemia (AML and ALL) who underwent allogeneic peripheral blood stem cell transplantation at Nasser Institute, in the time period between 2015 and 2016 (2 years) were included in the study.
Results There were 112 patients: 69 men (61.6%) and 43 women (38.4%). Age: mean=30.1±12.04, range 4–58. Overall survival of the CMV positive group is 60% which is lower than that in the CMV negative group which is 69.1% with a statistically insignificant P value of 0.3. Overall survival of CMV positive and acute graft-vs-host disease (aGVHD) patients is 53.8 which is lower than that of CMV negative patients which is 69.6% but it is statistically insignificant (P=0.1). This may be attributed to non-CMV–non-aGVHD-related mortality in acute leukemia (as disease relapse).
Conclusion The use of CMV prophylaxis routinely with new agents with lower toxicity, especially in patients at high risk of CMV replication, might reduce the incidence of CMV replications, reducing the morbidity and mortality, and according to some studies may also reduce the incidence of aGVHD and its related morbidity and mortality.
Keywords: acute graft-vs-host disease, acute leukemia, allogeneic peripheral blood stem cell transplantation, cytomegalovirus viremia
|How to cite this article:|
Azazzi MO, Soliman RA, Hasan GA, Naguib MG. Impact of cytomegalovirus viremia on allogeneic peripheral blood stem cell transplantation in patients with acute leukemia: a single Egyptian center experience. Egypt J Haematol 2019;44:232-6
|How to cite this URL:|
Azazzi MO, Soliman RA, Hasan GA, Naguib MG. Impact of cytomegalovirus viremia on allogeneic peripheral blood stem cell transplantation in patients with acute leukemia: a single Egyptian center experience. Egypt J Haematol [serial online] 2019 [cited 2020 Aug 8];44:232-6. Available from: http://www.ehj.eg.net/text.asp?2019/44/4/232/290230
| Introduction|| |
Hematopoietic stem cell transplantation (HSCT) is widely used as an important therapy in many benign and non-benign diseases. Bone marrow (BM) was used as a source of HSCs. Since the start of HSCT in 1968 but after that two other sources are available: peripheral blood stem cells (PBSc) and cord blood cells. The three sources can be used in allogenic HSCT as they are all capable to rebuild the hematological system but transplanters should choose the most suitable according to each condition as they vary in properties, advantages, and disadvantages .
Nowadays, PBSc are most widely used as a stem cell source for bone marrow transplantation, as rapid engraftment occurs and has good survival in patients with aggressive diseases .
The three stem cell sources differ in the number of mature T-cells they contain. More T-cells are found in PBSc than in cord blood cells and this variation is responsible for determining the risk of graft-vs-host disease (GVHD) and graft failure; the more T-cells in graft, the more GVHD but less graft rejection and vice versa .
Less side effects, less hospital stay, and no need for anesthesia are the main reasons why transplanters are preferring PBSc in BMT to other stem cell sources .
Many random trials in this issue found minimal differences between the use of BM stem cells and PBSc in transplanting patients with blood malignancies regarding mortality due to BMT, disease relapse, GVHD either acute or chronic and survival. On the other hand, these trials found more rapid engraftment of neutrophils in PBSc cases than BM stem cell cases. Also, there was more rapid platelet engraftment in all PBSc cases except one. Rapid engraftment is responsible for less hospital stay, earlier discharge, and less cost burden for patients receiving PBSc than BM stem cell recipients. One trial showed more rapid lymphocyte recovery in patients who received PBSc in these trials .
Patients undergoing allogeneic stem cell transplantation (allo-SCT) face many complications. One of them is infection with cytomegalovirus (CMV) in spite of using antiviral therapy. One other important complication is acute GVHD (aGVHD) despite the use of immunosuppressive therapy .
Some studies have found a relation between infection with CMV and the occurrence of aGVHD in allo-SCT patients. Immunosuppressive therapy for GVHD facilitates CMV infection. Unfortunately, CMV infection aggravates the occurrence of GVHD via infected endothelial cells which secrete inflammatory cytokines. These cytokines may stimulate the occurrence of aGVHD. Interleukin 6 is one of the involved cytokines which contribute to the previous pathology .
CMV infected patients suffer from many complications, but the most common presentations are gastroenteritis, hepatitis, and pneumonitis. However, the risk of CMV-induced pneumonia declined a lot after the use of prophylactic antiviral drugs early in allo-SCT recipients .
Some risk factors are responsible for the risk of CMV infection in allo-SCT patients including the donor serology test for CMV and recipient CMV serology before BMT. When the donor and the recipient CMV serology are negative, the risk of recipient infection by CMV is minimal, considering the use of CMV-negative blood products. GVHD whether acute or chronic, antithymocyte globulin use, including fludarabine in conditioning protocols and if donors are unrelated or mismatched, all these risk factors increase the risk of CMV infection in allo-SCT recipients .
Post-allo-SCT, follow up of CMV patient’s serology via CMV immunoglobulin (Ig)G and IgM is done to determine the risk of CMV infection of recipients; however, transplanters cannot depend on serology to diagnose CMV infection in allo-SCT recipients. A more sensitive and specific technique is done by using PCR to measure the viral load (CMV DNA). The patient is considered CMV infected by a high viral load measured by PCR for CMV .
| Aim|| |
This retrospective study evaluates the impact of CMV viremia in patients with acute myeloid leukemia and acute lymphoblastic leukemia after allogeneic SCT in the time period from January 2015 to December 2016 regarding (112 patients) the correlation between acute GVHD and the incidence of CMV infection, CMV-related mortality, disease-free survival, and overall survival (OS).
| Patients and methods|| |
Patients with acute leukemia (AML and ALL) who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) at Nasser Institute, in the time period between 2015 and 2016 (2 years) were included in the study. We started our study after the approval of the ethical commitee of Ain-shams university. Also a signed consent from each patient has been provided. Their age vary between 19 and 58 years. Our patients were AML or ALL patients who are in remissions from their diseases and are eligible for transplantation with matched related donors. Pretransplant evaluation of the patients included detailed history and thorough physical examination, BM aspiration with cytogenetic evaluation, ABO, Rh blood grouping, and HLA tissue typing. Liver function, kidney function, ECG, Echo, renal scan, creatinine clearance, serological screening tests especially hepatitis C virus antibody, hepatitis B virus surface antigen, HIV Ab, Epstein–Barr virus IgG, and IgM. Patients and their donors were evaluated pretransplant for CMV infection via CMV IgG and IgM with PCR for CMV. We used PBSc as a source for BMT. Patients are kept on GVHD prophylaxis regimen: cyclosporine A, corticosteroids and methotrexate and prophylactic Acyclovir 1500/m2 from D– (according to the type of conditioning regimen) till D+100 and are evaluated regularly up to day 100 post-transplant via regular CBC and differential counts, liver function tests: bilirubin (total and direct), albumin, aspartate transaminase, alanine transaminase. Kidney function tests blood urea nitrogen, urea, creatinine, uric acid. Electrolytes: Na, K, Mg levels. random blood sugar (RBS), cyclosporin level, chimerism test, BM aspirate, cytogenetics, and minimal residual disease. Our patients are also evaluated for the occurrence of aGVHD proved by tissue biopsy and grading was determined based on established criteria and for CMV infection by CMV IgG and IgM with PCR for CMV. Assessment of the relationship between reactivation of CMV and aGVHD is done on the study group.
Data were analyzed using the Statistical Program for the Social Sciences (SPSS) version 20.0 (IBM© Corp., Armonk, NY, USA). Quantitative data were expressed as mean±SD. Qualitative data were expressed as frequency and percentage. P value less than or equal to 0.05 was considered significant. P value less than or equal to 0.001 was considered as highly significant. P value greater than 0.05 was considered insignificant.
| Results|| |
Our patients included 112 patients, of which 69 were men (61.6%) and 43 were women (38.4%). Age: mean=30.1 SD=±12.04, range 4–58 ([Table 1]), 20 patients had aGVHD ([Table 2]), OS of the study group is 68% ([Figure 1]), disease-free survival of the study group is 64.8% ([Figure 2]), 15 patients were CMV positive, 13 patients had both CMV and acute GVHD. This indicates a very strong relation between acute GVHD and CMV with strong statistical significance (P<0.00001) ([Table 3]). OS of the CMV positive group is 60% which is lower than that in the CMV negative group which is 69.1% which is statistically insignificant at a P value of 0.3 ([Figure 3]); OS of CMV positive and aGVHD patients is 53.8 which is lower than that of CMV negative patients which is 69.6% but it is statistically insignificant (P=0.1). This may be attributed to non-CMV–non-aGVHD-related mortality in acute leukemia (e.g. relapse) ([Figure 4]).
|Figure 1 Kaplan–Meier showing overall survival of the study group (68%).|
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|Figure 2 Kaplan–Meier showing disease-free survival of the study group (64.8%).|
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|Table 3 Relation between cytomegalovirus and acute graft-vs-host disease:|
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|Figure 3 Kaplan–Meier showing overall survival according to cytomegalovirus. Overall survival of the cytomegalovirus positive group is 60% which is lower than that in the cytomegalovirus negative group 69.1% put it is statistically insignificant P value of 0.3.|
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|Figure 4 Kaplan–Meier showing overall survival of cytomegalovirus negative vs cytomegalovirus positive and acute graft-vs-host disease. OS of cytomegalovirus positive and acute graft-vs-host disease patients is 53.8 which is lower than that of cytomegalovirus negative patients which is 69.6% but it is statistically insignificant (P=0.1). This may be attributed to noncytomegalovirus–nonacute graft-vs-host disease-related mortality in acute leukemia (e.g. relapse).|
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| Discussion|| |
CMV infection and GVHD are important complications after allo-HSCT with a clear link. Multiple studies have shown that GVHD and its treatment put patients at risk for CMV replication. We analyzed the impact of CMV replication in 112 acute leukemia patients treated with allogeneic HSCT between 2015 and 2016.
This retrospective single-center study examines and describes the relationship between CMV replication and aGVHD in patients undergoing allogeneic HSCT. The role of aGVHD as a risk factor for CMV disease is well known. Miller et al.  described aGVHD as an important risk factor for CMV replication. These early data also suggested a direct immunosuppressive effect of aGVHD independent of that of GVHD treatment (i.e. systemic steroids), which increases the risk of CMV replication. Multiple other studies have since confirmed that patients with aGVHD are at an increased risk of CMV disease ,.
The data in our current study are in line with these studies, and confirm the association between aGVHD and CMV replication. In our study, 112 AL patients who underwent allogeneic peripheral HSCT entered the analysis; the cumulative incidence of aGVHD by day 100 is calculated as 24%, whereas the cumulative incidence of CMV viremia was 13.4% in the same time period. In our study 27 (24%) patients developed aGVHD grades II–IV (treated with systemic corticosteroids), and 15 (13.4%) patients developed CMV viremia; 13 patients with aGVHD developed CMV viremia (P<0.00001).
Six patients out of 15 (40%) who developed CMV replication died, which indicates a high incidence of CMV-related mortality despite antiviral prophylaxis and therapy. Eleven patients out of 27 (40%) who developed aGVHD died. Six (46%) patients out of 13 who developed both aGVHD and CMV replication died, which indicates a very high mortality in patients with both aGVHD and CMV replication.
OS of the study group was 68%. OS according to CMV PCR post-BMT was 60%. OS according to aGVHD and CMV viremia was 53.8%.
In another large-scale retrospective study Cantoni et al.  which analyzed the association of CMV replication with acute GVHD (aGVHD) in 515 patients treated with allogeneic HSCT between 1993 and 2008 showed evidence for a bidirectional relationship between CMV replication and aGVHD.
Cumulative incidences at day 100 were 17% for CMV replication, 68% for aGVHD grade I–IV, and 48% for GVHD grade II–IV. As in our study, this study confirmed the strong relationship between aGVHD and CMV replication (61% in patients treated with steroids and 35% in patients not treated with steroids). In this previous study by Cantoni et al. , Cox modeling showed that the presence of aGVHD grades I–IV significantly increased the risk of CMV replication [hazard ratio (HR): 1.55, P=0.2], as GVHD itself and GVHD treatment are both immunosuppressive and may therefore contribute to the increased risk of CMV reactivation.On the other hand, CMV may also play a role in the development of GVHD. They found that patients were at an increased risk of developing aGVHD during episodes of CMV replication (HR for the development of any grade aGVHD: 2.18, 95% confidence interval: 1.30–3.65, P<0.1).
Broers et al.  and Larsson et al.  indicated an increased incidence of GVHD in CMV-positive patients. This may be attributed to interleukin 6 and other cytokines secreted by endothelial cells infected by CMV which initiates the occurrence of GVHD via an inflammatory process. The use of preemptive treatment have minimized CMV infection and CMV-related mortality in patients post-HSCT .
However, CMV is still considered a cause of death post-allo-HSCT .
| Conclusion|| |
The use of CMV prophylaxis routinely with new agents with lower toxicity, especially in patients at high risk of CMV replication, might reduce the incidence of CMV replications, thereby reducing morbidity and mortality, and according to some studies may also reduce the incidence of aGVHD and its related morbidity and mortality.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]