Prevention Of Cytomegalovirus Infection Research Articles

Low-dose valganciclovir prohylaxis is efficacious and safe in cytomegalovirus seropositive heart transplant recipients with anti-thymocyte globulin.

Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. Hundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis. All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P=.001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients. The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis.

Reduction in mortality associated with secondary cytomegalovirus prophylaxis after solid organ transplantation.

Cytomegalovirus (CMV) is the most important viral pathogen in solid organ transplant (SOT) recipients. The role of secondary CMV prophylaxis in this population remains unclear. Retrospective cohort study in a single center. SOT recipients treated for CMV infection from 2007 to 2014 were studied to determine the efficacy and safety of secondary prophylaxis and its impact on graft loss and mortality. The outcome variable was CMV replication in the first 3months after the end of therapy. Secondary variables were crude mortality and graft lost censored at 5years after transplantation. Propensity score for the use of secondary prophylaxis was used to control selection bias. Of the 126 treated patients, 103 (83.1%) received CMV secondary prophylaxis. CMV relapse occurred in 44 (35.5%) patients. The use of secondary prophylaxis was not associated with fewer relapses (34.0% in patients with prophylaxis vs 42.9% in those without prophylaxis, P=.29). After a mean follow-up of 32.1months, graft loss was not different between both groups but patient mortality was significantly lower in patients who received secondary prophylaxis (5.8% vs 28.6%, P=.003). Secondary prophylaxis did not prevent CMV infection relapse but it was associated with improved patient survival.

Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

A cytomegalovirus (CMV) vaccine that is effective at preventing congenital infection and reducing CMV disease in transplant patients remains a high priority as no approved vaccines exist. While the precise correlates of protection are unknown, neutralizing antibodies and antigen-specific T cells have been implicated in controlling infection. We demonstrate that the immunization of mice and nonhuman primates (NHPs) with lipid nanoparticles (LNP) encapsulating modified mRNA encoding CMV glycoproteins gB and pentameric complex (PC) elicit potent and durable neutralizing antibody titers. Since the protective correlates in pregnant women and transplant recipients may differ, we developed an additional mRNA vaccine expressing the immunodominant CMV T cell antigen pp65. Administration of pp65 vaccine with PC and gB elicited robust multi-antigenic T cell responses in mice. Our data demonstrate that mRNA/LNP is a versatile platform that enables the development of vaccination strategies that could prevent CMV infection and consequent disease in different target populations.

Letermovir Effective in Preventing CMV Infection in HSCT Recipients

Two strategies are used to prevent cytomegalovirus (CMV) disease after transplantation. The preemptive strategy requires weekly monitoring of

Usefulness of valacyclovir prophylaxis for cytomegalovirus infection after anti-thymocyte globulin as rejection therapy.

Background/AimsAnti-thymocyte globulin (ATG) treatment for acute T-cell mediated rejection (TCMR) can increase the risk of cytomegalovirus (CMV) infection. We aimed to evaluate the effect of valacyclovir prophylaxis against CMV infection after ATG administration as anti-rejection therapy.MethodsWe retrospectively analyzed 55 kidney transplant recipients (KTRs) receiving ATG for steroid resistant TCMR. In all KTRs, we used intravenous ganciclovir during ATG injection. In 34 KTRs treated before July 2013, we performed preemptive therapy for CMV infection after ATG therapy. They were regarded as the historic control group (CONT). After July 2013, we used valacyclovir maintenance for 1 month after ATG therapy in 21 patients (VAL). The primary outcome was the incidence of CMV infection, and the secondary outcomes were subsequent acute rejection, and graft and patient outcome.ResultsValacyclovir prophylaxis significantly reduced the incidence of CMV infection (VAL, 9.6% vs. CONT, 67.6%; p < 0.001), and CMV-free survival rate was higher in the VAL group compared to the CONT group (p = 0.009). In the VAL group, two cases of CMV infection were limited to CMV viremia, but CMV disease or syndrome (n = 3) was detected in the CONT group. There was no difference in graft failure (CONT, 70.5% vs. VAL, 47.6%; p = 0.152), incidence of subsequent rejection after ATG treatment (CONT, 41.1% vs. VAL, 33.3%; p = 0.776), and graft or patient survival between the two groups. There were no major adverse events associated with valacyclovir prophylaxis.ConclusionsIn conclusion, valacyclovir prophylaxis is effective in the prevention of CMV infection after ATG treatment for steroid resistant TCMR.

Letermovir Approved to Prevent CMV Infection and Disease in Transplant Patients

On November 9, 2017, the FDA approved letermovir for prevention of cytomegalovirus (CMV) infection and disease in adult allogeneic hematopoietic stem

Using theory-based messages to motivate U.S. pregnant women to prevent cytomegalovirus infection: results from formative research

BackgroundAn estimated 1 in 150 infants is born each year with congenital cytomegalovirus (CMV); nearly 1 in 750 suffers permanent disabilities. Congenital CMV is the result of a pregnant woman becoming infected with CMV. Educating pregnant women about CMV is currently the best approach to prevention. Limited research is available on how to effectively communicate with women about CMV. We conducted formative research on fear appeals theory-based messages about CMV and prevention with U.S. women. Fear appeal theories suggest that message recipients will take action if they feel fear.MethodsFirst, we conducted in-depth interviews (N = 32) with women who had young children who tested positive for CMV. Second, we conducted eight focus groups (N = 70) in two phases and two cities (Phase 2: Atlanta, GA; Phase 3: San Diego, CA) with pregnant women and non-pregnant women who had young children. Few participants knew about CMV before the focus groups.Participants reviewed and gave feedback on messages created around fear appeals theory-based communication concepts. The following concepts were tested in one or more of the three phases of research: CMV is severe, CMV is common, CMV is preventable, CMV preventive strategies are similar to other behavior changes women make during pregnancy, CMV preventive strategies can be incorporated in moderation to reduce exposure, and CMV is severe but preventable.ResultsParticipants recommended communicating that CMV is common by using prevalence ratios (e.g., 1 in 150) or comparing CMV to other well-known disabilities. To convey the severity of CMV, participants preferred stories about CMV along with prevention strategies. Participants also welcomed prevention strategies when it included a message about risk reduction. In general, participants said messages were motivating, even if they felt that it could be difficult to make certain behavior changes.ConclusionsFindings from this research can contribute to future efforts to educate pregnant women about CMV, especially regarding use of fear appeals-based messages. Pregnant women may face certain challenges to practicing prevention strategies but, overall, are motivated make changes to increase their chances of having a healthy baby.

Periconceptional CMV infection prevention in Portugal: population subgroup study in a tertiary perinatal care center

Currently in Portugal, universal screening of pregnant women for Cytomegalovirus (CMV) infection is not performed. However, it is recommended to screen all women attending preconception care. We aimed to assess women’s attendance to preconception care and if their serologic status regarding CMV was known and/or investigated in that consultation. In this cross-sectional study, we interviewed 240 women admitted to the obstetrical ward of a hospital in the Metropolitan Area of Porto (Portugal) about their adherence to preconception care and collected data regarding their CMV serologic status and its investigation. We found that 71.3% of the women who attended preconception care were not screened for CMV infection. Among primigravida, the screening rate was only of 30.4% (upper limit of CI 95%: 44.8%). There were no statistically significant differences between the private and public sectors of healthcare. We observed attendance to preconception care is high (73.1%). For the population subgroup of the metropolitan area of Porto, attendance to preconception care is at least 66%, with a 95% confidence level. Portuguese guidelines stating a woman’s serologic status regarding CMV should be investigated in preconception care are not properly implemented. This suggests guidelines should assure the screening of previously non-screened women during pregnancy.

The role of immunoglobulin prophylaxis for prevention of cytomegalovirus infection in pediatric hematopoietic stem cell transplantation recipients.

Following cessation of intravenous immunoglobulin (IVIg) administration for allogeneic hematopoietic stem cell transplantation (HSCT) recipients at our unit, we observed a sharp decline in the incidence of cytomegalovirus (CMV) infection. We conducted a retrospective study of the role of IVIg in the prevention of CMV infection in children and young adults who underwent HSCT from matched related donor. We included 109 patients (IVIg+/IVIg- ratio 82/27). Median age was 8.5 years. Patients were transplanted for malignant (59.7%) and nonmalignant diseases (40.3%) with myeloablative, reduced-intensity, and nonmyeloablative conditioning in 76, 22, and 2% of the transplants, respectively. Graft sources were peripheral blood stem cells, bone marrow, and cord blood in 58.7, 39.4, and 2%, respectively. The cumulative incidence of CMV infection at 1 year after HSCT was significantly higher in the cohort that did not receive IVIg compared with the one that did (44.4% vs. 13.4%, respectively, P = 0.001). Significant risk factor for CMV infection in the cohort not receiving IVIg was conditioning with total body irradiation (TBI) (87.5% in TBI+ vs. 26.3% in TBI-, P = 0.003). We conclude that children and young adults who undergo HSCT with TBI may need a preemptive regimen of anti-CMV treatment, if they do not get IVIg prophylaxis.

Occurrence of adverse events caused by valganciclovir as pre-emptive therapy for cytomegalovirus infection after allogeneic stem cell transplantation is reduced by low-dose administration.

Pre-emptive therapy with valganciclovir (VGCV) has become the standard therapy for preventing cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The effectiveness of low-dose VGCV (900 mg per day) has been shown to be equal to that of standard-dose VGCV (900 mg twice daily); however, individualized optimal dosing and toxicity of VGCV have not been reported. We conducted a retrospective study to evaluate the optimal dose of VGCV as pre-emptive therapy for preventing CMV infection by comparing the frequency of adverse events (AEs) and clinical efficacy in a low-dose VGCV group with those in a standard-dose VGCV group. Thirty-eight patients who were administered VGCV because of CMV antigenemia after HSCT were analyzed. Neutropenia (standard-dose group: 33%, low-dose group: 15%, P = 0.26) and thrombocytopenia (standard-dose group: 39%, low-dose group: 15%, P = 0.14) were frequent AEs of VGCV, and a significantly higher frequency of overall AEs was detected in the standard-dose group than in the low-dose group (P < 0.01). In comparison of dosage based on weight, dosage of VGCV >27 mg/kg was closely related to onset of AEs (P = 0.04). Low-dose VGCV was not inferior in clinical efficacy, including clearance rate of CMV antigenemia and incidence of consequent CMV disease, to standard-dose VGCV as was previously reported. Initial low-dose VGCV for pre-emptive CMV therapy markedly reduces hematologic toxicity and has clinical efficacy equivalent to that of standard-dose VGCV. It is therefore reasonable for patients, except for noticeably overweight patients, to be given initial low-dose VGCV.

Seroprevalence of cytomegalovirus IgG antibodies among pregnant women in Japan from 2009-2014

Human cytomegalovirus (CMV) is a major cause of congenital infection. The seroprevalence of maternal CMV IgG antibodies among Japanese women is decreasing. In this study, we assessed the rate of and risk factors for CMV infection. This article includes a description of a method for the prevention of CMV infection. Medical records of 7,074 women who delivered a baby at our hospital were retrospectively reviewed. For seronegative patients, preventive educational materials were provided, and CMV IgG antibody levels were reassessed during late pregnancy. Congenital infection in neonates from seroconverted mothers was determined by urine analysis. The overall CMV IgG seropositivity rate was 69.1%. The prevalence of CMV IgG increased with age and parity. In a multivariate logistic regression analysis, parity remained an independent determinant of CMV IgG seropositivity. The seroconversion rate for CMV IgG antibody during pregnancy was 0.37%. Neonatal congenital CMV infection occurred in 37.5% of seroconverted women. The risk of primary CMV infection in mothers during their first pregnancy was 7.0%, with an average follow-up period of 2.1years. We found that parity was an independent determinant of CMV IgG seropositivity, suggesting that child-rearing may be a high risk factor for maternal CMV infection. The provision of information on hygiene may be an effective and inexpensive method for preventing CMV infection.

Meta-analysis of cytomegalovirus seroprevalence in volunteer blood donors and healthy subjects in Iran from 1992 to 2013.

Human cytomegalovirus (CMV), a double-strand DNA herpesvirus, can be transmitted via blood transfusion which is especially important for immunocompromised recipients and can cause a fatal infection. CMV seroprevalence in Iran was studied on blood donors, healthy subjects, and some patients. Highly variable rates were detected. The purpose of this study was to review CMV seroprevalence in blood donors and apparently healthy individuals, in Iran. One hundred and fifty-eight electronic and paper-based resources and databases including published articles in internal and external journals, seminars, dissertations, and theses available in the database and different websites were used to be systematically reviewed as a meta-analysis. Less related articles to the issue, papers of specific high risk population, and articles with not enough information, were excluded. Eventually 22 articles that satisfied our selection criteria were systematically reviewed and analyzed. To explore heterogeneity between studies the I square (I(2)) index was used. Data were analyzed using the statistical software package (STATA) 11. The heterogeneity between selected studies was 97% with an I(2) statistic. In this study a random effects model was used for meta-analysis. The prevalence of CMV IgG and CMV IgM antibodies in the country were estimated to be 92% (95% CI: 90-94) and 2.6% (95% CI: 1.7-3.6), respectively. Given high rate of CMV seropositivity in Iran, it seems that CMVAbs screening would not be a reasonable and affordable approach to prevent CMV infection via transfusion especially for immune compromised recipients, so alternative strategies should be considered.

Acyclovir versus valganciclovir for preventing cytomegalovirus infection in intermediate-risk liver transplant recipients.

Cytomegalovirus (CMV) is an opportunistic infection that causes profound morbidity and mortality after orthotopic liver transplant (OLT). The CMV immunoglobulin G serostatuses of donors and recipients are the main factors influencing risk for development of CMV infection after transplant. To compare acyclovir and valganciclovir for preventing CMV infection after OLT. Retrospective assessment of adult OLT recipients at intermediate risk for CMV infection at New York Presbyterian Hospital. All patients received ganciclovir 5 mg/kg intravenously every 12 hours or valganciclovir 900 mg orally every 12 hours for 7 days after transplant. On postoperative day 8, patients received antiviral prophylaxis according to risk stratification: acyclovir 800 mg orally 3 times daily in donor seronegative/recipient seropositive (D-/R+) patients or valganciclovir 900 mg orally once daily in donor seropositive/recipient seropositive (D+/R+) patients. Composite incidence of CMV infection, syndrome, or tissue-invasive disease. Of 275 OLT recipients, 89 were at intermediate risk for CMV infection (29 D-/R+, 60 D+/R+). CMV infection, syndrome, or tissue-invasive disease occurred in 1 patient (3%) in the D-/R+ group and 5 patients (8%) in the D+/R+ group (P=.66). One patient (3%) in the D-/R+ group had a CMV infection develop. Five D+/R+ recipients (8%) had CMV infection; 3 of them had CMV syndrome (5%), 1 had CMV hepatitis (1.6%), and the other had CMV esophagitis (1.6%); all events occurred after prophylaxis was discontinued. The rates of CMV infection were similar in D-/R+ patients treated with acyclovir and D+/R+ patients receiving valganciclovir. This risk-stratified approach to viral prophylaxis after OLT resulted in an acceptable rate of CMV infection in D-/R+ recipients and may avoid the costs and adverse effects associated with valganciclovir therapy.

An Update on the Management and Prevention of Cytomegalovirus Infection Following Allogeneic Hematopoietic Stem Cell Transplantation

ABSTRACT A significant progress has been made in deciphering critical aspects of the biology and immunology of CMV infection in the allogeneic stem cell transplantation setting. Genetic traits predisposing to active CMV infection and CMV end-organ disease have begun to be delineated. Reliable molecular assays for CMV DNA load quantitation in body fluids have been developed. Elucidation of immune mechanisms affording control of CMV infection will help to improve the management of active CMV infection. Finally, the advent of new CMV-specific antivirals and promising vaccine prototypes as well as the development of fine procedures for large-scale ex vivo generation of functional CMV-specific T cells for adoptive T cell transfer therapies will certainly minimize the negative impact of CMV on survival in these patients.

Effects of donor/recipient human leukocyte antigen mismatch on human cytomegalovirus replication following liver transplantation.

BackgroundNatural immunity against cytomegalovirus (CMV) can control virus replication after solid organ transplantation; however, it is not known which components of the adaptive immune system mediate this protection. We investigated whether this protection requires human leukocyte antigen (HLA) matching between donor and recipient by exploiting the fact that, unlike transplantation of other solid organs, liver transplantation does not require HLA matching, but some donor and recipient pairs may nevertheless be matched by chance.MethodsTo further investigate this immune control, we determined whether chance HLA matching between donor (D) and recipient (R) in liver transplants affected a range of viral replication parameters.ResultsIn total, 274 liver transplant recipients were stratified according to matches at the HLA A, HLA B, and HLA DR loci. The incidence of CMV viremia, kinetics of replication, and peak viral load were similar between the HLA matched and mismatched patients in the D+/R+ and D−/R+ transplant groups. D+/R− transplants with 1 or 2 mismatches at the HLA DR locus had a higher incidence of CMV viremia >3000 genomes/mL blood compared to patients matched at this locus (78% vs. 17%; P = 0.01). Evidence was seen that matching at the HLA A locus had a small effect on peak viral loads in D+/R− patients, with median peak loads of 3540 and 14,706 genomes/mL in the 0 and combined (1 and 2) mismatch groups, respectively (P = 0.03).ConclusionOverall, our data indicate that, in the setting of liver transplantation, prevention of CMV infection and control of CMV replication by adaptive immunity is minimally influenced by HLA matching of the donor and recipient. Our data raise questions about immune control of CMV in the liver and also about the cells in which the virus is amplified to give rise to CMV viremia.

Effect of Early Conversion to Everolimus Together With Prophylaxis With Valganciclovir in the Prevention of Cytomegalovirus Infection in Heart Transplant Recipients

IntroductionViral infections, especially cytomegalovirus (CMV), are a leading cause of early death and morbidity after heart transplantation. Several strategies have been used to minimize the risk, including universal prophylaxis with ganciclovir or valganciclovir and preemptive therapy. Lately, everolimus (EVE) efficacy studies have shown a protective effect against CMV infection. MethodsWe studied retrospectively a series of 223 heart transplant patients, dividing them into 5 groups according to CMV prevention strategy: 16 patients were at low risk for infection (negative recipient [R−]/negative donor [D−]) and received no treatment; 26 patients received prophylactic therapy with ganciclovir, 8 patients prophylaxis with valganciclovir, 145 patients received preemptive therapy and 28 patients prophylaxis with valganciclovir and early conversion to EVE. ResultsThere were no cases of CMV infection in the low-risk group. There was 1 case of CMV infection in the group that received valganciclovir and conversion to EVE. Among the patients who received prophylaxis with ganciclovir or valganciclovir or preemptive therapy, CMV infection was detected in 68 patients (37%). ConclusionsEarly conversion to EVE in addition to valganciclovir prophylaxis was superior to other strategies in our series for the prevention of CMV infection.

Seroprevalence of Cytomegalovirus Antibodies in Pregnant Women, Benue State, Nigeria

Cytomegalovirus (CMV), a member of the herpes family, belongs to a group of vertically transmitted infections referred to as the TORCH complex including: Toxoplasmosis, Rubella, Cytomegalovirus and Herpes Simplex. Known to be frequently transmitted to developing foetus, it remains one of the leading causes of congenital viral infections. Although the infection has been detected in Nigerian neonates, its awareness is limited particularly in a growing metropolitan city like Makurdi, Nigeria. In this study, the prevalence of CMV antibodies and their association with some socio-demographic factors in pregnant women was evaluated. Pregnant women (N=375; age range=15 to 50 years) attending ante-natal clinic in different hospitals in Makurdi were screened for the infection. Five-ml venous blood was collected from each participant for serological studies, and structured questionnaire was used to obtain socio-demographic data. Serum samples were assayed using enzyme-linked immunosorbent assay (ELISA) technique. The overall prevalence of anti-CMV IgG-antibodies was 93.3% (n=350) and was 3.5% (n=13) for anti- CMV IgM-antibodies. Prevalence of anti-CMV IgG and IgM antibodies was significantly associated with gravidity (PIgG=0.012; PIgM=0.001), while prevalence of anti-CMV IgM only was associated with marital status (P=0.035). The prevalence of anti-CMV IgG antibodies was highest (100%) in older pregnant women aged 41-50 years, but was lowest (85.0%) in younger ones aged 15-20 years. Risk factors for the disease such as history of blood transfusion, scarification, and multiple sexual partners were important, even though not statistically significant (P>0.05). Women of child-bearing age in the growing metropolitan city of Makurdi, Nigeria need to be educated on precautionary measures that will prevent cytomegalovirus infection.

Efficacy of Extended Valganciclovir Prophylaxis in Preventing Cytomegalovirus Infection in Pediatric Kidney Transplantation

Cytomegalovirus (CMV) is one of the most frequent opportunistic infection in renal transplant (RTx) recipients. Valganciclovir (VGC) has been showed to be safe and highly effective in prophylaxis of CMV infection in RTx recipients. Recently, an increase in delayed onset CMV disease has been noted with some arguing that longer prophylaxis may decrease the late-onset disease. We retrospectively tested the hypothesis that extended term prophylaxis (ETP) of VGC for 12 months is more effective than short term prophylaxis (STP) of 6 months in preventing CMV infection and disease in pediatric RTx performed at the University of Florida from July 2003 to December 2010. In this period, all recipients underwent prospective CMV PCR (Polymerase Chain Reaction) monitoring and were maintained on similar immunosuppression. Eighty six patients received RTx during that period. All eligible subjects had to have at least 12 months of graft survival and 18 months of follow up, leaving 73 eligible subjects in final study group. CMV infection or disease occurred in 6/29 (20%) in the STP group vs 6/44 (14%) in the ETP group with no statistical significant difference (P= 0.42). Donor positive/recipients negative CMV serology status (D+/R-) were associated with a higher risk of CMV infection in both univariate and multivariate analysis (P=0.01). Anemia and Leucopenia directly associated with VGC were similar in both groups (P=0.58 and P=0.2 respectively). Biopsy-proven acute rejection was also non-significant in both groups (P=0.39). Although ETP for CMV from 6 months to 12 months is safe and has minimal adverse effect, it did not reduce CMV infection or disease. Further controlled studies in pediatrics age group are considered to compare longer versus shorter periods of prophylaxis and their impact on prevention of CMV infection, resistance, cost, and toxicity.

Efficacy of Extended Valganciclovir Prophylaxis in Preventing Cytomegalovirus Infection in Pediatric Kidney Transplantation.

Cytomegalovirus (CMV) is one of the most frequent opportunistic infection in renal transplant (RTx) recipients. Valganciclovir (VGC) has been showed to be safe and highly effective in prophylaxis of CMV infection in RTx recipients. Recently, an increase in delayed onset CMV disease has been noted with some arguing that longer prophylaxis may decrease the late-onset disease.We retrospectively tested the hypothesis that extended term prophylaxis (ETP) of VGC for 12 months is more effective than short term prophylaxis (STP) of 6 months in preventing CMV infection and disease in pediatric RTx performed at the University of Florida from July 2003 to December 2010. In this period, all recipients underwent prospective CMV PCR (Polymerase Chain Reaction) monitoring and were maintained on similar immunosuppression.Eighty six patients received RTx during that period. All eligible subjects had to have at least 12 months of graft survival and 18 months of follow up, leaving 73 eligible subjects in final study group. CMV infection or disease occurred in 6/29 (20%) in the STP group vs 6/44 (14%) in the ETP group with no statistical significant difference (P= 0.42). Donor positive/recipients negative CMV serology status (D+/R-) were associated with a higher risk of CMV infection in both univariate and multivariate analysis (P=0.01). Anemia and Leucopenia directly associated with VGC were similar in both groups (P=0.58 and P=0.2 respectively). Biopsy-proven acute rejection was also non-significant in both groups (P=0.39).Although ETP for CMV from 6 months to 12 months is safe and has minimal adverse effect, it did not reduce CMV infection or disease. Further controlled studies in pediatrics age group are considered to compare longer versus shorter periods of prophylaxis and their impact on prevention of CMV infection, resistance, cost, and toxicity.

Induction Treatment with Alemtuzumab Combined with Polychemotherapy Containing Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) Followed By Alemtuzumab Maintenance in Patients with T-Cell Prolymphocytic Leukaemia (T-PLL): First Analysis of a Prospective Multicenter Phase-II-Trial (T-PLL2) Conducted By the German CLL Study Group (GCLLSG)

Introduction: T-cell prolymphocytic leukemia (T-PLL) is a very rare & aggressive disease. Therapeutic advances during recent years have been very limited. Even after initial response, the vast majority of T-PLL patients (pts) relapse quickly and the median overall survival remains below 2 years (ys). This also holds true for induction therapies with the anti-CD52 antibody Alemtuzumab (A). Furthermore, life-threatening viral infections are a severe problem in pts treated with this antibody. In a precursor trial (Hopfinger et al, Cancer 2013), we evaluated a consolidation therapy with A after polychemotherapy induction.In the T-PLL2 trial, we evaluated feasibility, safety and efficacy of the addition of A s.c. to an induction treatment with Fludarabine, Mitoxantrone & Cyclophosphamide (A-FMC), followed by an A s.c. maintenance therapy.Patients and Methods: 16 pts (12 untreated and 4 with pretreatments) with T-PLL were enrolled between 06/2010-09/2013. Pts received an induction treatment with A 10mg s.c. on day (d) 1-3 combined with 20mg/m2 Fludarabine i.v. d 1-3, 6mg/m2 Mitoxantrone i.v. d1 & 200mg/m2 Cyclophosphamide d1-3. After 2 cycles the A dose was increased to 30 mg s.c., if a stable disease (SD) or a partial remission (PR) was achieved. A-FMC treatment was administered every 28 days for up to 4 cycles, followed by a maintenance treatment with 30mg A s.c. starting 1 month (mo) after final staging. During the first 6 mo, A s.c. was administered monthly and in addition once in mo 10 and 13. For younger and fit pts, the option of allogeneic transplantation (tx) was explicitly recommended after induction therapy. Peripheral blood (PB) samples were taken at diagnosis & at the time of relapse/progression. Valganciclovir was recommended for prophylaxis.Results: 16 pts with a median age of 68 ys (range 32-78) and a median score on the cumulative illness rating scale of 3 (range 0-6) were enrolled. The diagnosis of T-PLL was established based on clinico-pathologic characteristics, with the lead finding of a monoclonal mature T-cell population in PB. All leukaemias (100%) were CD52 positive, 15/16 cases (93.75%) expressed TCL1 & the most frequent abnormalities by FISH/classical karyotyping were aberrations involving 14q32.1 in 14/14 cases (100%), gains of chromosome 8q in 10/14 cases (71%), & deletion 11q23 in 8/14 cases (57%).A median number of 4 courses (range 2-4) were administered for induction treatment. Six pts (37.5%) proceeded with maintenance treatment with a median of 4 (range 1-6) A applications.In total, 94 non-infectious CTC grade 3-4 adverse events (AE) & 28 episodes of CTC grade 1-4 infections were documented. Non-infectious grade 3/4 AEs were most frequently due to myelosuppression: neutropenia/leukopenia occurred in 14/16 pts (87.5%), anaemia in 7/16 pts (43.75%) & thrombocytopenia in 10/16 pts (62.5%). Two cases of cytomegalovirus (CMV) & 1 case of varicella zoster infection were documented. Most AEs could be successfully managed, however 2 (12.6%), possibly treatment related deaths occurred, both from fatal bleeding in thrombocytopenia. In all pts response data after induction treatment was available. The overall response rate was 68.75% (11/16pts) with complete remissions (CR) in 4 pts (25%), CR with insufficient bone marrow recovery in 1 pt (6.25%) & a PR in 6 pts (37.5%). Progressive disease (PD) was documented in 4 pts (25%), a SD in 1 pt (6.25%). The trial was terminated in May 2014. Until today, 11 deaths (68.75%) were reported & 1 pt (6.25%) was lost to follow-up. Prophylaxis with Valgancyclovir was administered in 12/16 pts (75%), 2 pts (12.5%) received prophylactic Valaciclovir & 2 pts (12.5%) received no viral prophylaxis at all.Seven pts (43.75%) received an allogeneic tx after the study treatment: 3 pts after the induction phase, 1 pt after 5 maintenance applications & 3 pts after bridging/salvage therapy. Tx outcomes were documented with 5 CRs & 2 PDs.Conclusion: A s.c. combined with FMC & A maintenance therapy is a relatively safe and feasible regimen in pts with T-PLL. However, safety seems to come at the cost of response quality. Therefore, the authors currently recommend using A i.v. as part of the initial therapy for T-PLL pts. Prophylaxis with Valganciclovir was effective in preventing CMV infection, one of the major threats to pts treated with A. Most importantly, the study emphasizes the need for new therapies and intensified clinical research for pts with T-PLL. DisclosuresOff Label Use: Therapeutic off-label use of Alemtuzumab, Fludarabine, Cyclophophamide and Mitoxantron in T-PLL. Hopfinger:Genzyme: Research Funding. Weit:Beckman Coulter GmbH, Krefeld, Germany: Employment. Stilgenbauer:Genzyme : Consultancy, Honoraria, Research Funding. Eichhorst:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Gilead: Consultancy. Hallek:Genzyme, Bayer: Research Funding.