Pediatr Blood Cancer
BRIEF REPORT Incidence and Risk Factors for Cytomegalovirus (CMV) Reactivation Following Autologous Hematopoietic Stem Cell Transplantation in Children Ayad Ahmed Hussein, MD, MS,1* Eman T. Al-Antary, MD,1 Rula Najjar, PharmD,2 Dua’a S. Al-Hamdan, RN,1 Abdulhadi Al-Zaben, MD,1 and Haydar Frangoul, MD3 There are limited data on the incidence of CMV reactivation following autologous HSCT (AHSCT) in children. We retrospectively reviewed the incidence and risk factors for CMV reactivation in 72 children who received AHSCT. Twenty-two patients (31%) had positive CMV antigenemia at a median of 23 days (12–31) following transplant. Four patients (6%) required preemptive therapy and all
episodes resolved. None of the patients developed CMV disease. Only being CMV seropositivity prior to transplant was significantly associated with CMV reactivation (P < 0.001). The incidence of CMV reactivation following pediatric AHSCT is low, and surveillance beyond 30 days is not needed. Pediatr Blood Cancer # 2014 Wiley Periodicals, Inc.
Key words: autologous hematopoietic stem cell transplantation; CMV reactivation; children
INTRODUCTION Hematopoietic stem cells transplantation (HSCT) can offer a curative therapy for children and adolescents with malignant disorders. Autologous HSCT (AHSCT) can improve the outcome of children with metastatic and high-risk solid tumors and lymphomas. Despite improved supportive care measures, infection remains to be a major complication associated with HSCT. Cytomegalovirus (CMV) infection remains a serious cause of major morbidity and mortality [1,2]. Multiple risk factors have been associated with CMV reactivation, including recipient’s prior therapy, hematopoietic stem cells source, CD34 dose, pre-transplantation conditioning, viral prophylaxis regimens, and engraftment kinetics [3–5]. Generally, the incidence of CMV reactivation and infection is significantly lower following AHSCT compared to allogeneic HSCT. Although the rate of CMV reactivation and infection is low following autologous HSCT, it has been associated with significant morbidity [1,2]. The incidence of CMV reactivation and disease for adult patients following AHSCT ranges from 12% to 40% [5–8]. On the contrary, data on CMV monitoring, reactivation and disease in children receiving AHSCT are scant. We sought to study the incidence and risk factors of CMV reactivation following AHSCT in children.
PATIENTS AND METHODS Patients’ Characteristics We report on all patients who underwent AHSCT at the Bone Marrow and Stem Cell Transplantation Program at King Hussein Cancer Center (KHCC) in Amman, Jordan from January 2005 to September 2013. The stem cell transplant database at KHCC contains prospectively collected data on all patients transplanted at our center. The local Institutional Review Board approved the study. For these patients, all available medical records, notes, and correspondence were reviewed.
Supportive Care All patients were hospitalized for their transplant and received prophylaxis against Pneumocystis jiroveci infection with trimethoprim–sulfamethoxazole (TMP–SMX), viral prophylaxis with acyclovir and fluconazole for fungal prophylaxis. Intravenous immunoglobulin C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25292 Published online in Wiley Online Library (wileyonlinelibrary.com).
(IVIG) was administered if IgG level less than 600 mg/dl. All blood products given where leukofiltered and irradiated. CMV reactivation was monitored by CMV pp65 antigenemia test weekly from the time of neutrophil engraftment until 60 days post transplantation. Preemptive treatment with ganciclovir was initiated when two constitutive positive antigenemia of more than 5 cells per 250 white blood cells, until a minimum of two negative tests were obtained. CMV disease was defined as any proven organ involvement with CMV infection.
Definition The time to neutrophil recovery was defined as the first day of three consecutive days with absolute neutrophil count greater than 0.5 109/L. The time to platelet recovery was defined as the first of seven consecutive days with platelet count greater than 20 109/L without transfusion support for at least 7 days. Transplant related mortality (TRM) was defined as mortality from any cause not directly related to relapse of primary disease. Overall survival was calculated from time of transplant until death from any cause.
Statistical Analysis Descriptive statistics were performed on demographic data and information of patients, showing counts and percentages for categorical data and median and range for continuous data. A comparison between variables was done using t-test or Chisquared test as appropriate, depending on the assumptions required for each test. A significance criterion of P < 0.05 was used in the analysis. All analysis was performed using SPSS version 19.
1
Bone Marrow and Stem Cell Transplantation Program, King Hussein Cancer Center, Amman, Jordan; 2Department of Pharmacy, King Hussein Cancer Center, Amman, Jordan; 3Pediatric Stem Cell Transplant Program, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee Conflict of interest: Nothing to declare.
Correspondence to: Ayad Ahmed Hussein, King Hussein Cancer Center, Queen Rania Al Abdullah Street, P.O. Box 1269, Amman 11941, Jordan. E-mail: [email protected] Received 11 August 2014; Accepted 9 September 2014
2
Hussein et al.
TABLE I. Patients and Transplant Characteristics Variable
Number (%)
Number of patients Median age, year (range) Male/female Underlying disease Solid tumor Neurobalstoma Brain tumors Germ cell tumors Ewing sarcoma Retinoblastoma Wilms’ tumor Lymphoma Hodgkin lymphoma Non-Hodgkin lymphoma Source of stem cells Peripheral blood Bone marrow Conditioning regimen CEM BEAM TCE TEAM Others Median days to neutrophil engraftment (range)
72 5 (1–22) 43 (59.7)/29 (40.3) 49 (68.1) 41 (83.7) 3 (6.1) 2 (4.1) 1 (2) 1 (2) 1 (2) 23 (31.9) 17 (73.9) 6 (26.1) 70 (97.2) 2 (2.8)
two patients received bone marrow as stem cell source. All patients had neutrophil and platelet recovery following transplantation, at a median time of 10 (8–30) and 17 (5–41) days, respectively. Twenty-two patients (31%) had positive CMV antigenemia, at a median of 23 days (range, 12–31). The median number of cells was one cell per 250 WBC (range, 1–163). Only four patients (6%) required pre-emptive therapy, three of them were below 3 years of age and the fourth one received rituximab prior to AHSCT for diffuse large B cell lymphoma (DLBCL) (Table II). All episodes resolved completely with ganciclovir therapy. None of the patients developed CMV disease. In a univariate analysis, neither age (P ¼ 0.217), sex (P ¼ 0.077), primary diagnosis (P ¼ 0.187), or pretransplant hypogammaglobulinemia (P ¼ 0.531) was associated with development of CMV reactivation. Only being CMV seropositive prior to transplant was significantly associated with CMV reactivation P < 0.001). At a median follow up of 52 months (8–104), the overall survival was 57%, with zero transplant-related mortality.
DISCUSSION
38 (52.8) 22 (30.6) 4 (5.6) 1 (1.4) 7 (9.7) 10 (8–30)
RESULTS A total of 72 patients were identified, median age was 5 years (1–22). Forty-three (60%) were males. Forty-nine patients (68%) had solid tumors and 23 patients (32%) had lymphoma. Sixty-six patients (91%) were positive CMV serostatus prior to transplantation. Detailed patient and transplant characteristics are presented in Table I. Forty patients with solid tumors received CEM regimen (Carboplatin, Etoposide, and Melphalan), five received TCE regimen (Thiotepa, Carboplatin, and Etoposide), and four patients received other different regimens. Twenty-two patients with lymphoma received BEAM regimen (BCNU, Etoposide, Cytarabine, and Melphalan), and one patient received TEAM regimen (Thiotepa, Etoposide, Cytarabine, and Melphalan). Seventy patients (97%) received peripheral blood stem cells, and
The current study retrospectively reviewed the incidence of CMV reactivation following AHSCT over a 9-year period in a total of 72 pediatric patients at a single center. CMV reactivation was observed in 31% of our patients at a median of 23 days, no reactivation was observed beyond the first month post transplant, and only four patients (6%) required preemptive therapy. The true incidence of CMV reactivation and CMV disease following AHSCT in children is not known. Most published reports include adult patients and report an incidence of 1.4–15% of CMV viremia following AHSCT across all ages, between 22 and 41.5 days following transplant [5,9–11]. In a large study by Bilgrami et al. [12] including 200 patients with a median age of 44 years (range 2–65) who underwent AHSCT the incidence of viremia was 13% and all the cases were in adult patients. Being CMV seropositive prior to transplant was the only significant risk factor for CMV viremia. This is similar to our current study were being CMV seropositive prior to transplant is the only significant risk factor for CMV reactivation. Other reported factors that increase the risk of CMV reactivation and CMV disease post AHSCT include the use of CD34-selected PBSC, high dose steroids, and the use of total body irradiation or fludarabine in the preparative regimen [7,13]. More recently, there are case reports of patients developing CMV disease after treatment with rituximab [14–16].
TABLE II. Characteristics of Patients Required Pre-Emptive Therapy Following AHSCT Age (years)/ gender
Primary disease
CMV serostatus prior to AHSCT
Conditioning regimen
Neutrophil engraftment (days)
No. of CMV positive cells
Day of detection post AHSCT
Treatment
Outcome
1
11/M
DLBCL
Positive
BEAM
11
19
17
Ganciclovir
2
3/M
NBL
Positive
CEM
10
163
12
Ganciclovir
3
1.5/F
Brain tumor
Positive
TCE
9
5
12
Ganciclovir
4
1/M
NBL
Positive
CEM
11
112
31
Ganciclovir
Resolved, no recurrence Resolved, no recurrence Resolved, no recurrence Resolved, no recurrence
No.
M, male; F, female; DLBCL, diffuse large B-cell lymphoma; NBL, neuroblastoma; BEAM, BCNU, Etoposide, Cytarabine and Melphalan; CEM, Carboplatin, Etoposide, and Melphalan; TCE, Thiotepa, Carboplatin, and Etoposide. Pediatr Blood Cancer DOI 10.1002/pbc
CMV Reactivation Following Pediatric AHSCT Interestingly one of our patients (patient #1) who developed CMV reactivation received rituximab as part of the salvage chemotherapy prior to AHSCT. All three other patients who developed CMV reactivation were
BRIEF REPORT Incidence and Risk Factors for Cytomegalovirus (CMV) Reactivation Following Autologous Hematopoietic Stem Cell Transplantation in Children Ayad Ahmed Hussein, MD, MS,1* Eman T. Al-Antary, MD,1 Rula Najjar, PharmD,2 Dua’a S. Al-Hamdan, RN,1 Abdulhadi Al-Zaben, MD,1 and Haydar Frangoul, MD3 There are limited data on the incidence of CMV reactivation following autologous HSCT (AHSCT) in children. We retrospectively reviewed the incidence and risk factors for CMV reactivation in 72 children who received AHSCT. Twenty-two patients (31%) had positive CMV antigenemia at a median of 23 days (12–31) following transplant. Four patients (6%) required preemptive therapy and all
episodes resolved. None of the patients developed CMV disease. Only being CMV seropositivity prior to transplant was significantly associated with CMV reactivation (P < 0.001). The incidence of CMV reactivation following pediatric AHSCT is low, and surveillance beyond 30 days is not needed. Pediatr Blood Cancer # 2014 Wiley Periodicals, Inc.
Key words: autologous hematopoietic stem cell transplantation; CMV reactivation; children
INTRODUCTION Hematopoietic stem cells transplantation (HSCT) can offer a curative therapy for children and adolescents with malignant disorders. Autologous HSCT (AHSCT) can improve the outcome of children with metastatic and high-risk solid tumors and lymphomas. Despite improved supportive care measures, infection remains to be a major complication associated with HSCT. Cytomegalovirus (CMV) infection remains a serious cause of major morbidity and mortality [1,2]. Multiple risk factors have been associated with CMV reactivation, including recipient’s prior therapy, hematopoietic stem cells source, CD34 dose, pre-transplantation conditioning, viral prophylaxis regimens, and engraftment kinetics [3–5]. Generally, the incidence of CMV reactivation and infection is significantly lower following AHSCT compared to allogeneic HSCT. Although the rate of CMV reactivation and infection is low following autologous HSCT, it has been associated with significant morbidity [1,2]. The incidence of CMV reactivation and disease for adult patients following AHSCT ranges from 12% to 40% [5–8]. On the contrary, data on CMV monitoring, reactivation and disease in children receiving AHSCT are scant. We sought to study the incidence and risk factors of CMV reactivation following AHSCT in children.
PATIENTS AND METHODS Patients’ Characteristics We report on all patients who underwent AHSCT at the Bone Marrow and Stem Cell Transplantation Program at King Hussein Cancer Center (KHCC) in Amman, Jordan from January 2005 to September 2013. The stem cell transplant database at KHCC contains prospectively collected data on all patients transplanted at our center. The local Institutional Review Board approved the study. For these patients, all available medical records, notes, and correspondence were reviewed.
Supportive Care All patients were hospitalized for their transplant and received prophylaxis against Pneumocystis jiroveci infection with trimethoprim–sulfamethoxazole (TMP–SMX), viral prophylaxis with acyclovir and fluconazole for fungal prophylaxis. Intravenous immunoglobulin C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25292 Published online in Wiley Online Library (wileyonlinelibrary.com).
(IVIG) was administered if IgG level less than 600 mg/dl. All blood products given where leukofiltered and irradiated. CMV reactivation was monitored by CMV pp65 antigenemia test weekly from the time of neutrophil engraftment until 60 days post transplantation. Preemptive treatment with ganciclovir was initiated when two constitutive positive antigenemia of more than 5 cells per 250 white blood cells, until a minimum of two negative tests were obtained. CMV disease was defined as any proven organ involvement with CMV infection.
Definition The time to neutrophil recovery was defined as the first day of three consecutive days with absolute neutrophil count greater than 0.5 109/L. The time to platelet recovery was defined as the first of seven consecutive days with platelet count greater than 20 109/L without transfusion support for at least 7 days. Transplant related mortality (TRM) was defined as mortality from any cause not directly related to relapse of primary disease. Overall survival was calculated from time of transplant until death from any cause.
Statistical Analysis Descriptive statistics were performed on demographic data and information of patients, showing counts and percentages for categorical data and median and range for continuous data. A comparison between variables was done using t-test or Chisquared test as appropriate, depending on the assumptions required for each test. A significance criterion of P < 0.05 was used in the analysis. All analysis was performed using SPSS version 19.
1
Bone Marrow and Stem Cell Transplantation Program, King Hussein Cancer Center, Amman, Jordan; 2Department of Pharmacy, King Hussein Cancer Center, Amman, Jordan; 3Pediatric Stem Cell Transplant Program, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee Conflict of interest: Nothing to declare.
Correspondence to: Ayad Ahmed Hussein, King Hussein Cancer Center, Queen Rania Al Abdullah Street, P.O. Box 1269, Amman 11941, Jordan. E-mail: [email protected] Received 11 August 2014; Accepted 9 September 2014
2
Hussein et al.
TABLE I. Patients and Transplant Characteristics Variable
Number (%)
Number of patients Median age, year (range) Male/female Underlying disease Solid tumor Neurobalstoma Brain tumors Germ cell tumors Ewing sarcoma Retinoblastoma Wilms’ tumor Lymphoma Hodgkin lymphoma Non-Hodgkin lymphoma Source of stem cells Peripheral blood Bone marrow Conditioning regimen CEM BEAM TCE TEAM Others Median days to neutrophil engraftment (range)
72 5 (1–22) 43 (59.7)/29 (40.3) 49 (68.1) 41 (83.7) 3 (6.1) 2 (4.1) 1 (2) 1 (2) 1 (2) 23 (31.9) 17 (73.9) 6 (26.1) 70 (97.2) 2 (2.8)
two patients received bone marrow as stem cell source. All patients had neutrophil and platelet recovery following transplantation, at a median time of 10 (8–30) and 17 (5–41) days, respectively. Twenty-two patients (31%) had positive CMV antigenemia, at a median of 23 days (range, 12–31). The median number of cells was one cell per 250 WBC (range, 1–163). Only four patients (6%) required pre-emptive therapy, three of them were below 3 years of age and the fourth one received rituximab prior to AHSCT for diffuse large B cell lymphoma (DLBCL) (Table II). All episodes resolved completely with ganciclovir therapy. None of the patients developed CMV disease. In a univariate analysis, neither age (P ¼ 0.217), sex (P ¼ 0.077), primary diagnosis (P ¼ 0.187), or pretransplant hypogammaglobulinemia (P ¼ 0.531) was associated with development of CMV reactivation. Only being CMV seropositive prior to transplant was significantly associated with CMV reactivation P < 0.001). At a median follow up of 52 months (8–104), the overall survival was 57%, with zero transplant-related mortality.
DISCUSSION
38 (52.8) 22 (30.6) 4 (5.6) 1 (1.4) 7 (9.7) 10 (8–30)
RESULTS A total of 72 patients were identified, median age was 5 years (1–22). Forty-three (60%) were males. Forty-nine patients (68%) had solid tumors and 23 patients (32%) had lymphoma. Sixty-six patients (91%) were positive CMV serostatus prior to transplantation. Detailed patient and transplant characteristics are presented in Table I. Forty patients with solid tumors received CEM regimen (Carboplatin, Etoposide, and Melphalan), five received TCE regimen (Thiotepa, Carboplatin, and Etoposide), and four patients received other different regimens. Twenty-two patients with lymphoma received BEAM regimen (BCNU, Etoposide, Cytarabine, and Melphalan), and one patient received TEAM regimen (Thiotepa, Etoposide, Cytarabine, and Melphalan). Seventy patients (97%) received peripheral blood stem cells, and
The current study retrospectively reviewed the incidence of CMV reactivation following AHSCT over a 9-year period in a total of 72 pediatric patients at a single center. CMV reactivation was observed in 31% of our patients at a median of 23 days, no reactivation was observed beyond the first month post transplant, and only four patients (6%) required preemptive therapy. The true incidence of CMV reactivation and CMV disease following AHSCT in children is not known. Most published reports include adult patients and report an incidence of 1.4–15% of CMV viremia following AHSCT across all ages, between 22 and 41.5 days following transplant [5,9–11]. In a large study by Bilgrami et al. [12] including 200 patients with a median age of 44 years (range 2–65) who underwent AHSCT the incidence of viremia was 13% and all the cases were in adult patients. Being CMV seropositive prior to transplant was the only significant risk factor for CMV viremia. This is similar to our current study were being CMV seropositive prior to transplant is the only significant risk factor for CMV reactivation. Other reported factors that increase the risk of CMV reactivation and CMV disease post AHSCT include the use of CD34-selected PBSC, high dose steroids, and the use of total body irradiation or fludarabine in the preparative regimen [7,13]. More recently, there are case reports of patients developing CMV disease after treatment with rituximab [14–16].
TABLE II. Characteristics of Patients Required Pre-Emptive Therapy Following AHSCT Age (years)/ gender
Primary disease
CMV serostatus prior to AHSCT
Conditioning regimen
Neutrophil engraftment (days)
No. of CMV positive cells
Day of detection post AHSCT
Treatment
Outcome
1
11/M
DLBCL
Positive
BEAM
11
19
17
Ganciclovir
2
3/M
NBL
Positive
CEM
10
163
12
Ganciclovir
3
1.5/F
Brain tumor
Positive
TCE
9
5
12
Ganciclovir
4
1/M
NBL
Positive
CEM
11
112
31
Ganciclovir
Resolved, no recurrence Resolved, no recurrence Resolved, no recurrence Resolved, no recurrence
No.
M, male; F, female; DLBCL, diffuse large B-cell lymphoma; NBL, neuroblastoma; BEAM, BCNU, Etoposide, Cytarabine and Melphalan; CEM, Carboplatin, Etoposide, and Melphalan; TCE, Thiotepa, Carboplatin, and Etoposide. Pediatr Blood Cancer DOI 10.1002/pbc
CMV Reactivation Following Pediatric AHSCT Interestingly one of our patients (patient #1) who developed CMV reactivation received rituximab as part of the salvage chemotherapy prior to AHSCT. All three other patients who developed CMV reactivation were
