Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation (HCT) in the Preemptive Therapy Era: Characteristics, Efficacy of PCR-Based Surveillance, and Impact on Mortality

Abstract Background: Late cytomegalovirus (CMV) disease is a well-established complication in patients undergoing HCT and extended surveillance and preemptive therapy in high-risk patients is recommended by international guidelines. The objectives of this study were to describe the incidence, clinical characteristics and outcome of, and risk factors for the development of late CMV disease in day 100 survivors of allogeneic HCT who did and did not undergo viral load-guided preemptive therapy based on a pre-defined risk algorithm. Methods: We retrospectively analyzed medical records of 1526 HCT patients (donor or recipients seropositive), who received their first allogeneic HCT at FHCRC between 2001 and 2011 and survived to day 100. PCR-based surveillance was recommended for patients who had CMV viremia or disease before day 100 or had GVHD that required systemic treatment. Preemptive therapy was recommended for CMV DNA levels of >1000 copies per mL of plasma. We evaluated all CMV disease events occurring between day 100 and 2 years. Patients were categorized by their recommended surveillance status and, among those who were in the surveillance category, adherence to the testing schedule was examined. Cox proportional hazards models were used to evaluate the risk of late CMV disease and overall mortality. Candidate variables included risk status for PCR surveillance, CMV reactivation (before day 100 and after day 100 [as time dependent variable]), steroid use (≥ 1mg/kg/day) as well as other patient/donor and transplantation related factors; for mortality late CMV disease was also analyzed as a variable. Results: Among 1526 patients there were 118 cases of late CMV disease by 2 years (cumulative incidence 8% [95% CI- 7-9%]). The first manifestation of late CMV disease was pneumonia in 57 cases (48%), gastrointestinal disease (GI) in 54 cases (46%), and retinitis in 7 cases (6%). Fifteen percent of patients with late CMV disease (1% of cohort) had a subsequent event. Among first cases of late CMV disease 97 (82%) occurred between day 100 and 1 year and 21 (18%) occurred between 1 and 2 years after HCT. The median time to first late CMV disease was 192 days for pneumonia, 196 days for GI, and 230 days for retinitis. Extended CMV surveillance after day 100 was recommended for 1246 (82%) of patients. Late CMV disease occurred in 8.7% of patients for whom continued surveillance was recommended, compared to 2.9% of patients who were considered at low risk and were not advised to continue CMV testing. The median time to first late CMV disease event was 192 days post-transplant for the high risk group and 292 days for the low risk group. Among the 8 disease cases in patients in the low risk group, 4 cases (2 pneumonia, 2 GI) occurred in the first year and 4 (1 pneumonia, 3 GI) in the second year after HCT. In a multivariable Cox model steroid treatment after day 100 (HR=6.49; 95% CI 3.4-12.3, p<0.001), CMV reactivation after day 100 (HR=3.78; 95% CI 2.5-5.7, p<0.001), and CMV reactivation before day 100 (HR=2.07; 95% CI 1.3-3.4, p=0.003) were all strongly associated with the risk of late CMV disease. The development of CMV disease and acute GVHD (grade 3-4) before day 100 were not significantly associated with late CMV disease. Late CMV disease (HR=2.2; 95% CI 1.6-3, p<0.001) and late CMV reactivation (HR=1.63; 95% CI 1.3-2, p<0.001) were associated with increased risk of death between day 100 and 2 years after HCT. An analysis of the adherence to PCR surveillance and viral load levels among breakthrough cases will be presented at the conference. Conclusions: Late CMV disease remains an important complication after HCT. Currently recommended risk stratification parameters for extended surveillance identify most patients at risk for late CMV disease, however, occasionally late CMV disease can occur in patients that were deemed at low risk at 3 months after HCT. Also, late CMV disease can occur beyond 1 year after HCT and disease recurrence is about 15%. Overall, both late CMV infection and disease continue to be independently associated with overall mortality in the preemptive therapy era. Refined strategies are needed to further reduce the late-occurring complications of CMV infection among HCT recipients. Disclosures Boeckh: Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

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Oral Valganciclovir As Preemptive Therapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Blood ◽

10.1182/blood.v124.21.5855.5855 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5855-5855 ◽

Cited By ~ 1

Author(s):

Vildan Ozkocaman ◽

Fahir Ozkalemkas ◽

Ridvan Ali ◽

Yasemin Karacan ◽

Tuba Ersal ◽

...

Keyword(s):

Stem Cell ◽

Viral Load ◽

Myeloid Leukemia ◽

Preemptive Therapy ◽

Cell Transplant ◽

Cmv Infection ◽

Intravenous Ganciclovir ◽

Hematopoietic Stem ◽

Cmv Disease ◽

Cmv Reactivation

Abstract Introduction: Cytomegalovirus (CMV) infection remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (AlloHSCT). Preemptive therapy with oral VGC or intravenous ganciclovir has replaced universal prophylaxis. We investigated the effect of oral VGC as preemptive therapy on CMV reactivation or infection in AlloHSCT. Patient & Methods: We retrospectively studied 30 consecutive adult recipients of HLA-identical sibling allogeneic peripheral blood stem cell transplant from June 2011 through June 2014 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. Among 30 patients we studied the results of 13 patients with CMV DNA positivity. All 13 recipients and their donors were seropositive for CMV Ig G status. Their diagnosis of pretransplantation were as 8 acute myeloid leukemia (61 %) and 5 acute lymphocytic leukemia (39 %). Median age was 39 years (range 21-54). There were 9 men and 4 women (Table-1). The patients received no prophylaxis against CMV. Blood/serum samples from all patients were routinely monitored for CMV-DNA using PCR twice weekly. We iniciated pre-emptive therapy for CMV as the viral load was above and equal to 500 copies/ml in two consecutive samples. VGC was given twice daily 900 mg for 2 weeks, and maintened at a dose daily 900 mg until viral load is undetectable. Results: The PCR test was persistently negative in 17 patients (57 %) and positive at least once in 13 (43%)patients. All patients with CMV reactivations were on immunsupressive treatment. CMV infection was cleared in most patients within 2 weeks, but for those with stable or increasing CMV levels, the induction period was continued. Twelve patients were treated with oral VGC on an outpatient basis and they all became CMV negative after the first week of treatment. Only one patient received intravenous ganciclovir and he was also CMV negative after the first week of treatment. While no positivity was identified in any of the patients who received VGC on day 21, clinically unimportant low titer CMV positivity was noted in three of these patients. VGC was continued at same dose and no positivity was detected after 2-3 weeks. We were obligated interrupt VGC in only four patients for serious side effects namely neutropenia and thrombocytopenia. We did not observe CMV-related mortality. Conclusions: We concluded that VGC therapy could be safely used at outpatient clinics, with frequent monitorization to prevent severe myelotoxicity. In conclusion, based on our findings, oral VGC is effective and safe in the pre-emptive treatment of CMV disease following allo-HSCT. Therefore, preemptive strategy by oral VGC appears preferable to the prevention of CMV disease in alloHSCT with its advantage of effectiveness and usage in outpatient clinic condition. Table- 1: Management and outcome of the patient characteristics with CMV-reactivation Patients with CMV reactivation/Total number of patient 13/30 Median age, years (range) 39 (21-54) Gender Male Female 9 4 Diagnosis AML ALL 8 5 CMV serologic status Donor+/Recipient + 13 Preperative regimen Bu-Cy CY-TBI Flu/Amsc(FLAMSA) 8 4 1 GVHD propylaxis CSA+MTX CSA+MTX+MM 12 1 GVHD prior to CMV reactivation Acute chronic without GVHD 7 1 5 Prednisolone treatment at the time of starting VCG Yes No 8 5 IST at the time of starting VGC Yes No 13 0 Median duration of CMV reactivation (day) 44 (8-330) Viral load before antivial treament (copies/ml) 1153 (78-12800) Treatment VGC (900 mg, twice daily for induction) GC (5 mg/kg, twice daily for induction) VGC+GC 9 (70 %) 1 (7 %) 3 (23 %) Total treatment duration (day) 24 (10-51) CMV DNA at the end of the treatment Conversion to negative Persistently positive (low titer < 50 copies/ml) 10 (77 %) 3 (23 %) Serious side effects Interruption of therapy due to neutropenia Interruption of therapy due to thrombocytopenia Reactivation 3 (23 %) 1 (7 %) 2 (15 %) Abbreviations: AML: acute myeloid leukemia, ALL: acute lymphoblastic leukemia, CMV: cytomegalovirus,GVHD: graft-versus host disease, CSA: cylosporine, MTX: methotrexate, MMF: mycophenolate mofetil, PDN:prednizolone, IST: Immunosupressive treatment, VGC: valganciclovir, GC: ganciclovir, Bu: Busulfan, Cy: cylophosphamide, TBI: total body irradiation Disclosures No relevant conflicts of interest to declare.

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Evaluation of Published Single-Nucleotide Polymorphisms (SNPs) Associated with Cytomegalovirus Infection and Disease after Hematopoietic Cell Transplantation in a Large Caucasian Cohort

Blood ◽

10.1182/blood.v124.21.182.182 ◽

2014 ◽

Vol 124 (21) ◽

pp. 182-182 ◽

Cited By ~ 1

Author(s):

Sachiko Seo ◽

Wenhong Fan ◽

John A. Hansen ◽

Barry E. Storer ◽

Steven A. Pergam ◽

...

Keyword(s):

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Preemptive Therapy ◽

Candidate Snps ◽

Nucleotide Polymorphisms ◽

Cmv Infection ◽

Single Nucleotide ◽

Snp Association ◽

Genome Wide ◽

Cmv Disease

Abstract Background: Cytomegalovirus (CMV) infection is one of the most common complications after hematopoietic cell transplantation (HCT). Regardless of preemptive therapy for CMV infection, CMV disease still occurs in approximately 10% of seropositive HCT recipients, resulting in high mortality. A number of studies have reported the association between CMV infection or disease and single-nucleotide polymorphisms (SNPs), however the results have not been validated in independent cohorts. We performed a candidate gene validation study of previously reported SNPs using a large genome-wide association study (GWAS) cohort. Patients and methods: This GWAS cohort included donor-recipient (D/R) pairs who received the first allogeneic transplantation between 1990 and 2011 at the FHCRC. Of an overall cohort of 4855 D/R pairs, 2193 Caucasian CMV seropositive recipients and their donors (seropositve or seronegative) were analyzed. Two CMV phenotypes were analyzed: any infection within 100 days (only among 1585 recipients transplanted after 1995, antigenemia-based preemptive therapy administered) and CMV disease within 1 year after HCT. Published SNPs associated with CMV infection or disease were collected by a PubMed search using the keywords cytomegalovirus' and SNP' or polymorphism.' A p-value of less than 0.05 was required for validation. Genomic DNA samples from donors and recipients were analyzed using the Affymetrix GeneChip Genome-Wide Human SNP Array 5.0 (for one third of subjects) and Ilummina OmniExpress Beadchip Array (for the remainder). When the candidate SNPs were not included in the arrays, we imputed genotypes using IMPUTE software. Among genotyped and imputed SNPs, only SNPs with a minor allele frequency ≥0.05, call rate ≥90%, and Hardy-Weinberg equilibrium ≥0.0001 were analyzed. Donor serostatus, age, year of transplantation, donor type, HLA disparity, and intensity of conditioning regimen were used as adjustment factors as appropriate. Results: Among the 2193 HCT recipients in our cohort, 1009/1585 (64%) had CMV infection and 354/2193 (16%) had CMV disease. We identified 52 SNPs in 31 publications that reported significant associations between SNPs and CMV infection or disease (median number of subjects in these studies, 215; range, 37-1770). A total of 32 SNPs were available for the analysis. For CMV infection, six SNPs in four genes (TLR9, MCP1, CCR5, and CD209) in recipient or donor met our validation criteria (Table). For all SNPs but one, however, the direction of the association was opposite to that reported in the previous studies. We validated one SNP association (TLR9/rs5743836) in the recipient exactly as originally reported (adjusted HR, 1.16; 95% CI, 1.00-1.34, p=0.043). The donor genotype at this SNP was also significantly associated with CMV infection (adjusted HR, 1.47; 95% CI, 1.02-2.14, p=0.041) (Table), but an association with donor genotype was not assessed in the original publication. As for CMV disease, a different TLR9 SNP (rs352140) in donors was identified as significant (adjusted HR, 0.74; 95% CI, 1.02-2.14, p=0.029), although the ethnicity is different from the reported cohort (Table). None of the candidate SNPs in the recipient genome were associated with CMV disease. Conclusions: Of 32 SNPs that were previously reported to be associated with either CMV infection or disease, we were only able to validate two, both in TLR9. Most of the previously reported SNP associations for CMV infection or disease were not replicated in this large GWAS cohort. The inability to replicate these SNP associations does not necessarily negate the original discoveries, since many factors, including the sample size, could account for the different results. Our findings suggest that results of SNP association studies should be confirmed in multiple independent large cohorts and the biological mechanisms underlying the associations should be examined before clinical application. Unbiased discovery approaches are needed to determine the genetic associations of CMV infection and disease. Table 1 Table 1. Disclosures Boeckh: Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

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A Risk Score to Predict CMV Viremia within the First 100 Days after Allogeneic Stem Cell Transplantation Based on Pre-Transplant Parameters

Blood ◽

10.1182/blood.v124.21.3877.3877 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3877-3877

Author(s):

Feras Alfraih ◽

John Kuruvilla ◽

Naheed Alam ◽

Anna Lambie ◽

Vikas Gupta ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

High Risk ◽

Risk Score ◽

Risk Group ◽

Risk Groups ◽

Low Risk ◽

Cmv Infection ◽

Allogeneic Hsct ◽

Very High

Abstract Introduction: Cytomegalovirus (CMV) is a major infectious complication following allogeneic hematopoietic stem cell transplantation (HSCT). Risk of CMV infection varies between patients and individualized strategies for monitoring and therapy for CMV are needed. In this study, we attempted to establish a clinical score based on patient and transplant characteristics in order to predict the probability for early CMV viremia (CMV-V) within the first 100 days after HSCT. Methods: A total of 548 patients were evaluated after receiving HSCT between 2005 and 2012 at Princess Margaret Cancer Centre. CMV sero-negative recipients with CMV sero-negative donors (R-D-) were excluded. CMV-V was diagnosed in peripheral blood samples obtained on two occasions either by PCR (>200 IU/ml) or antigenemia testing (>2 positive cells/100000). A total of 378 patients were included into the study. Uni- and multivariable analyses were performed to identify risk factors for CMV-V. A weighted score was assigned to each factor based on the odds ratios determined by the multivariable analysis. A total score was calculated for each patient and used for assignment into one of 4 risk categories, the low risk (score 0-1), the intermediate (score 2-3), the high (score 4-5) and the very high (score 6-8). Median age for all patients was 51 years (range 17-71) and 173 (46%) were female. Matched related donors were used for two hundred fifteen patients (57%). Two hundred forty-three patients (64%) were transplanted for myeloid and 108 (29%) for lymphoid malignancies. One hundred thirteen patients (30%) were CMV sero-positive with a negative donor (R+D-) while 191 (51%) were recipient and donor CMV sero-positivity (R+D+). Graft versus host disease (GVHD) prophylaxis included CSA/MMF (n=200, 52%), and CSA/MTX (n=178, 48%). Myeloablative conditioning regimens were administered to 220 patients (58%), 158 patients (42%) were treated with a reduced intensity regimen. Three hundred-thirty seven patients (89%) received peripheral blood stem cells as a stem cell source. In vivo T cell depletion (TCD) with alemtuzumab was used in 138 (37%). Results: CMV-V occurred in 246 (64%) patients by day 100 post HSCT. The impact of patient and HSCT characteristics on the risk of CMV-V was assessed by multivariable analysis. The significant factors were CMV sero-status R+D- and R+D+, TCD, GVHD prophylaxis with MMF administration of myeloablative preparative regimens (Table 1). Table 1. Multivariate analysis for risk factors of CMV infection following allogeneic HSCT Table 1. Multivariate analysis for risk factors of CMV infection following allogeneic HSCT CMV-V rates on the 4 new risk categories amounted to 93% in the very high-risk, 78% in high-risk, 41% in intermediate-risk and 11% in low-risk group (Fig 1). The risk score was also predictive for the occurrence of multiple CMV-V reactivations with rates of 71%, 45%, 19% and 4% for the very high, high, intermediate and low-risk groups, respectively. The overall survival (OS) rate at 2 years was 33%(n=56) in the very high-risk group compared to 50% in other-risk groups (n=147) (P=0.01) (Fig 2). Non-relapse mortality (NRM) was 53% in the very high-risk versus 33% in other-risk groups (P<0.001). However, there was no difference on cumulative incidence of relapse between the groups (P=0.3). The cumulative incidence of grades 1-4 acute GVHD, grades 2-4, grades 3-4 at day 120 and overall chronic GVHD at 2 years was 68%, 47%, 25% and 39% in very high-risk group versus 65%, 52%, 21% and 52% in other-risk groups, suggesting slightly lower incidence of chronic GVHD in very high-risk vs other-risk groups. Conclusion: We present a new clinical scoring system to stratify the risk of early CMV viremia after allogeneic HSCT based on patients and HSCT characteristics. Identifying the risk for each patient would facilitate decision making with respect to strategies including CMV prophylaxis, pre-emptive treatment or inclusion into clinical trials, as well directing the CMV monitoring policy post-transplant. In addition, the risk score was associated with higher risk of overall mortality and NRM in the very high-risk versus other-risk groups. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Application of a Validated Predictive Model for Venous Thromboembolism in Cancer to Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.534.534 ◽

2016 ◽

Vol 128 (22) ◽

pp. 534-534

Author(s):

Natasha Catherine Edwin ◽

Jesse Keller ◽

Suhong Luo ◽

Kenneth R Carson ◽

Brian F. Gage ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

Discriminative Ability ◽

Blood Institute ◽

C Statistic

Abstract Background Patients with multiple myeloma (MM) have a 9-fold increased risk of developing venous thromboembolism (VTE). Current guidelines recommend pharmacologic thromboprophylaxis in patients with MM receiving an immunomodulatory agent in the presence of additional VTE risk factors (NCCN 2015, ASCO 2014, ACCP 2012). However, putative risk factors vary across guidelines and no validated VTE risk tool exists for MM. Khorana et al. developed a VTE risk score in patients with solid organ malignancies and lymphoma (Blood, 2008). We sought to apply the Khorana et al. score in a population with MM. Methods We identified patients diagnosed with MM within the Veterans Health Administration (VHA) between September 1, 1999 and December 31, 2009 using the International Classification of Diseases (ICD)-03 code 9732/3. We followed the cohort through October 2014. To eliminate patients with monoclonal gammopathy of undetermined significance and smoldering myeloma, we excluded patients who did not receive MM-directed therapy within 6 months of diagnosis. We also excluded patients who did not have data for hemoglobin (HGB), platelet (PLT) count, white blood count (WBC), height and weight, as these are all variables included in the Khorana et al. risk model. Height and weight were assessed within one month of diagnosis and used to calculate body mass index (BMI). We measured HGB, PLT count, and WBC count prior to treatment initiation: within two months of MM diagnosis. A previously validated algorithm, using a combination of ICD-9 code for VTE plus pharmacologic treatment for VTE or IVC filter placement, identified patients with incident VTE after MM diagnosis (Thromb Res, 2015). The study was approved by the Saint Louis VHA Medical Center and Washington University School of Medicine institutional review boards. We calculated VTE risk using the Khorana et al. score: We assigned 1 point each for: PLT ≥ 350,000/μl, HGB < 10 g/dl, WBC > 11,000/μl, and BMI ≥ 35 kg/m2. Patients with 0 points were at low-risk, 1-2 points were considered intermediate-risk and ≥3 points were termed high-risk for VTE. We assessed the relationship between risk-group and development of VTE using logistic regression at 3- and 6-months. We tested model discrimination using the area under the receiver operating characteristic curve (concordance statistic, c) with a c-statistic range of 0.5 (no discriminative ability) to 1.0 (perfect discriminative ability). Results We identified 1,520 patients with MM: 16 were high-risk, 802 intermediate-risk, and 702 low-risk for VTE using the scoring system in the Khorana et al. score. At 3-months of follow-up, a total of 76 patients developed VTE: 27 in the low-risk group, 48 in the intermediate-risk group, and 1 in the high-risk group. At 6-months of follow-up there were 103 incident VTEs: 41 in the low-risk group, 61 in the intermediate-risk group, and 1 in the high-risk group. There was no significant difference between risk of VTE in the high- or intermediate-risk groups versus the low-risk group (Table 1). The c-statistic was 0.56 at 3-months and 0.53 at 6-months (Figure 1). Conclusion Previously, the Khorana score was developed and validated to predict VTE in patients with solid tumors. It was not a strong predictor of VTE risk in MM. There is a need for development of a risk prediction model in patients with MM. Figure 1. Figure 1. Disclosures Carson: American Cancer Society: Research Funding. Gage:National Heart, Lung and Blood Institute: Research Funding. Kuderer:Janssen Scientific Affairs, LLC: Consultancy, Honoraria. Sanfilippo:National Heart, Lung and Blood Institute: Research Funding.

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Letermovir Is Effective for Prevention of Cytomegalovirus Reactivation in HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2021-152116 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2858-2858

Author(s):

Takahide Ara ◽

Yuta Hasegawa ◽

Hiroyuki Ohigashi ◽

Souichi Shiratori ◽

Atsushi Yasumoto ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Research Funding ◽

Cmv Infection ◽

Advisory Committees ◽

Cmv Disease ◽

Cmv Reactivation

Abstract [Introduction] Cytomegalovirus (CMV) infection is a common viral infection in recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT). Early CMV reactivation after allo-SCT is associated with worse non-relapse mortality (NRM) and overall survival (OS). Recently, T-cell replete HLA-haploidentical SCT using post-transplant cyclophosphamide (PTCy-haplo SCT) has been developed and spread rapidly worldwide. Rationale of this strategy is assumed to be selective and cytotoxic depletion of alloreactive T cells which are responsible for graft-versus-host disease (GVHD), while preserving non-alloreactive T cells which can contribute to fight infections. However, recent studies showed that PTCy-haplo SCT was associated with the increased incidence of CMV infection. Letermovir (LET), a novel anti-CMV agent, which inhibits the CMV DNA terminase complex, was approved for the prevention of CMV reactivation in allo-SCT recipients in 2018 in some countries including Japan based on the result of a phase 3 trial. Our facility performs LET prophylaxis in allo-SCT recipient if either donor or recipient is seropositive CMV. Although LET is effective for the prevention of CMV reactivation in allo-SCT recipients, the clinical effectiveness of LET prophylaxis in PTCy-haplo SCT is not well elucidated. Based on these things, we retrospectively evaluated the efficacy of LET prophylaxis in PTCy-haplo SCT. [Methods] We retrospectively analyzed consecutive 99 recipients who received PTCy-haplo SCT at Hokkaido University Hospital from March 2013 to March 2021. We compared the cumulative incidence of CMV reactivation between the LET prophylaxis group (LET group, 33 patients) and LET non-prophylaxis group (non-LET group, 66 patients). LET was initiated on the day 0 at a dosage of 480mg daily. All patients were monitored for CMV reactivation by using the anti-CMV pp65 monoclonal antibody HRP-C7 assay at least once a week from the time of engraftment. CMV reactivation was defined as the detection of CMV antigen positive cells per 50000 white blood cells, whereas CMV disease was defined by organ dysfunction attributable to CMV. [Results] As baseline patient's characteristics were summarized in Table1, there were no difference between LET and non-LET group in terms of age, sex, underlying disease, disease risk at transplantation, prior transplantation, conditioning intensity, and CMV serostatus. All patients received peripheral blood stem cell transplantation. GVHD prophylaxis consisted of Cy (40-50 mg/kg on day 3 and 4), tacrolimus (from day 5), and mycophenolate mofetil (from day 5). The cumulative incidence of CMV reactivation at 150 days after transplantation in LET group was significantly lower than that in non-LET group (30.3% versus 69.7%; P <.001, Figure1A). Importantly, CMV disease were occurred in three patients without LET prophylaxis (gastritis, enteritis, and retinitis), but not in the patients with LET prophylaxis. The cumulative incidence of NRM at 1 year was similar between the patients with and without LET prophylaxis (17.6% versus 9.2%; P=0.366, Figure1B), as was OS at 1 year (71.5% versus 69.4%; P=0.801, Figure1C). Neutrophil engraftment was achieved in 32 patients (97%) at a median of 15 days in LET group and 64 patients (97%) at a median of 14.5 days in non-LET group (P=0.243). Furthermore, platelet engraftment was achieved in 26 patients (79%) at a median of 34 days in LET group and 57 patients (86%) at a median of 31 days in non-LET group (P=0.282). These findings suggest that LET does not affect engraftment. Interestingly, the length of hospitalization in the LET group was significantly shorter than that in non-LET group (the median, 59.5 days versus 71 days; P=0.0488), suggesting that LET suppresses CMV reactivation leading to early discharge. [Conclusion] To our best knowledge, this is the largest retrospective study about the efficacy of LET in PTCy-Haplo SCT. LET is effective for prevention of CMV reactivation in PTCy-haplo SCT. Further studies focused on the long term effect of LET prophylaxis in PTCy-haplo SCT, such as the incidence of relapse and chronic GVHD, is warranted. Figure 1 Figure 1. Disclosures Nakagawa: AbbVie GK: Research Funding; Takeda Pharmaceutical Company: Research Funding. Teshima: Gentium/Jazz Pharmaceuticals: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Fuji pharma CO.,Ltd: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; TEIJIN PHARMA Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Sanofi S.A.: Research Funding.

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Cytomegalovirus Viraemia after Allogeneic Transplant: A Prospective Study of a Risk-Adapted Strategy in a Single Transplant Unit.

Blood ◽

10.1182/blood.v106.11.5374.5374 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5374-5374

Author(s):

Amanda J. Johnston ◽

Anthony J. Dodds ◽

David D. Ma ◽

Samuel T. Milliken ◽

Keith C. Fay ◽

...

Keyword(s):

Viral Load ◽

High Risk ◽

Prospective Study ◽

Morbidity And Mortality ◽

Unrelated Donor ◽

Preventive Strategy ◽

Allogeneic Transplant ◽

Post Transplant ◽

Cmv Disease ◽

Cmv Reactivation

Abstract CMV infection causes significant morbidity and mortality following allogeneic transplantation. In 2003, the NSW Bone Marrow Transplant network adopted a uniform CMV prevention policy. This prospective study aimed to evaluate the impact of the policy on the rate, management and outcome of CMV reactivation in allogeneic transplant recipients at St Vincent’s Hospital, Sydney. All patients at high risk for CMV reactivation (recipient and/or donor CMV seropositive pre-transplant) had weekly blood samples screened using nucleic acid tests for CMV RNA and DNA. Patients with a related donor were screened from day +21 to +84 post-transplant and received antiviral treatment for CMV only if reactivation was detected. Patients with an unrelated donor received ganciclovir 5mg/kg 3x/week from day +21 to +84, in addition to screening tests. Between October 2003 and June 2005, 40 patients (median age 44 years, range 20-67) received allogeneic transplants, with 21 (53%) originating from an unrelated donor. Thirty-six (90%) patients were high risk for CMV disease and 13 (33%) developed CMV viraemia at a median of 39 days (range 16–101) post-transplant. Six of the 13 (46%) PCR positive patients had unrelated donors, and three had severe, steroid resistant GVHD requiring monoclonal antibody therapy. The median CMV viral load was 3200 copies/mL (range 870 to >100,000) and three of the 13 patients had CMV disease (all biopsy-proven CMV enteritis). All viraemic patients were treated with ganciclovir 5mg/kg BD for a median of 2 weeks, with clinical improvement and reduction in viral load in 10 patients. Overall survival of the CMV viraemia group was 85% at a median of 303 days follow up, compared with 78% for the whole group (p = NS). The described risk-adapted CMV preventive strategy is associated with acceptable rates of viral reactivation and low morbidity and mortality post-allogeneic transplant.

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Combining Information Regarding Chromosomal Aberrations t(4;14), Del(17p13) and the Copy Number of 1q21 with the International Staging System Classification Allows Stratification of Myeloma Patients Undergoing Autologous Stem Cell Transplantation: Results From the HOVON-65/GMMG HD4 Trial

Blood ◽

10.1182/blood.v118.21.332.332 ◽

2011 ◽

Vol 118 (21) ◽

pp. 332-332

Author(s):

Kai Neben ◽

Henk M. Lokhorst ◽

Anna Jauch ◽

Uta Bertsch ◽

Thomas Hielscher ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Risk Group ◽

Staging System ◽

Risk Groups ◽

Low Risk ◽

Advisory Committees ◽

International Staging System

Abstract Abstract 332 PURPOSE : In Multiple Myeloma (MM), the combination of serum beta-2-microglobulin level with serum albumin concentration has been proposed as an outcome predictor in the International Staging System (ISS). More recently, subgroups of MM defined by genetic and cytogenetic abnormalities have been associated with unique biologic, clinical, and prognostic features. PATIENTS AND METHODS: We analyzed the prognostic value of 12 chromosomal abnormalities by fluorescent in situ hybridization (FISH) in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Patients with newly diagnosed MM were randomized to receive either three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). All patients underwent autologous stem cell transplantation (ASCT) followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. In addition, a second cohort of patients was analyzed as a control group (n=462), undergoing ASCT at the University of Heidelberg between September 1994 and December 2010. RESULTS: For the entire group of patients treated within the HOVON-65/GMMG-HD4 trial, we identified 233 patients with 2 copies (67.7%), 95 patients with 3 copies (27.6%) and 16 patients (4.7%) with more than three copies of the chromosomal region 1q21. In addition to del(17p13) and t(4;14), we added +1q21 (>3 copies) to the group of high-risk aberrations, since the outcome of these patients was almost as poor as it was observed for patients with del(17p13). Subsequently, we analyzed whether combining the ISS score with information on the presence of high-risk aberrations could improve the prognostic value with regard to patients' outcome. A combination of the presence or absence of del(17p13), t(4;14), or +1q21 (>3 copies) with the ISS score allowed patients to be stratified into three distinct groups: low-risk [absence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS I], high-risk [presence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS II/III], and intermediate-risk (all remaining patients). Most of the patients belonged to the low- (33%) and intermediate-risk (49%) groups, whereas 18% were allocated to the high-risk group. The median PFS times for the low-, intermediate-, and high-risk groups were 41.9 months, 31.1 months (HR=1.7; p=0.0018) and 18.7 months (HR=3.6; p<0.0001), respectively. The 3yr-overall survival (OS) decreased from 94% in the low-risk group to 80% (HR=4.6; p=0.0001) and 43% (HR=12.8; p<0.0001) in the intermediate- and high-risk groups, respectively. These results were confirmed in the independent cohort of patients: From date of first ASCT, the median PFS times for the low-, intermediate-, and high-risk groups were 43.3 months, 23.0 months (HR=1.5; p=0.015) and 13.8 months (HR=2.4; p=0.0003), respectively. The 4yr-OS decreased from 84% in the low-risk group to 71% (HR=2.1; p=0.0043) and 49% (HR=3.84; p<0.0001) in the intermediate- and high-risk groups, respectively. CONCLUSION: In our series, the ISS/FISH-based score/algorithm predicted PFS and OS much better than the ISS alone. Our results with molecular cytogenetic techniques may already have implications for the risk-adapted clinical management of patients with MM particularly in younger patients. Disclosures: van de Velde: Ortho Biotech Oncology Research & Development: Employment. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

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The Combination of SKY92 and ISS Provides a Powerful Tool to Identify Both High Risk and Low Risk Multiple Myeloma Cases, Validation in Two Independent Cohorts

Blood ◽

10.1182/blood.v126.23.2970.2970 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2970-2970 ◽

Cited By ~ 3

Author(s):

Martin van Vliet ◽

Joske Ubels ◽

Leonie de Best ◽

Erik van Beers ◽

Pieter Sonneveld

Keyword(s):

Overall Survival ◽

High Risk ◽

Research Funding ◽

Prognostic Markers ◽

Risk Group ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Kaplan Meier ◽

Standard Risk

Abstract Introduction Multiple Myeloma (MM) is a heterogeneous disease with a strong need for robust markers for prognosis. Frequently occurring chromosomal abnormalities, such as t(4;14), gain(1q), and del(17p) etc. have some prognostic power, but lack robustness across different cohorts. Alternatively, gene expression profiling (GEP) studies have developed specific high risk signatures such as the SKY92 (EMC92, Kuiper et al. Leukemia 2012), which has shown to be a robust prognostic factor across five different clinical datasets. Moreover, studies comparing prognostic markers have indicated that the SKY92 signature outperforms all other markers for identifying high risk patients, both in single and multivariate analyses. Similarly, when assessing the prognostic value of combinations of various prognostic markers, the SKY92 combined with ISS was the top performer, and also enables detection of a low risk group (Kuiper et al. ASH 2014). Here, we present a further validation of the low and high risk groups identified by the SKY92 signature in combination with ISS on two additional cohorts of patients with diverse treatment backgrounds, containing newly diagnosed, previously treated, and relapsed/refractory MM patients. Materials and Methods The SKY92 signature was applied to two independent datasets. Firstly, the dataset from the Total Therapy 6 (TT6) trial, which is a phase 2 trial for symptomatic MM patients who have received 1 or more prior lines of treatment. The TT6 treatment regime consists of VTD-PACE induction, double transplant with Melphalan + VRD-PACE, followed by alternating VRD/VMD maintenance. Affymetrix HG-U133 Plus 2.0 chips were performed at baseline for n=55 patients, and OS was made available previously (Gene Expression Omnibus identifier: GSE57317). However, ISS was not available for this dataset. Secondly, a dataset of patients enrolled at two hospitals in the Czech Republic, and one in Slovakia (Kryukov et al. Leuk&Lymph 2013). Patients of all ages, and from first line up to seventh line of treatment were included (treatments incl Bort, Len, Dex). For n=73 patients Affymetrix Human Gene ST 1.0 array, OS (n=66), and ISS (n=58) was made available previously (ArrayExpress accession number: E-MTAB-1038). Both datasets were processed from .CEL files by MAS5 (TT6), and RMA (Czech), followed by mean variance normalization per probeset across the patients. The SKY92 was applied as previously described (Kuiper et al. Leukemia 2012), and identifies a High Risk and Standard Risk group. In conjunction with ISS, the SKY92 Standard Risk group is then further stratified into low and intermediate risk groups (Kuiper et al. ASH 2014). Kaplan-Meier plots were created, and the Cox proportional hazards model was used to calculate Hazard Ratios (HR), and associated 1-sided p-values that assess whether the SKY92 High Risk group has worse survival than SKY92 Standard Risk group (i.e. HR>1). Results Figure 1 shows the Kaplan Meier plots of the SKY92 High Risk and Standard Risk groups on the TT6 and Czech cohorts. On the TT6 dataset, the SKY92 signature identifies 11 out of 55 patients (20%) as High Risk. In both datasets, the SKY92 High Risk group has significantly worse overall survival, HR=10.3, p=7.4 * 10-6 (TT6), and HR=2.6, p=2.2 * 10-2 (Czech). In addition, the combination of SKY92 with ISS on the Czech dataset identifies a low risk group of 14 out of 61 patients (23%), with a five year overall survival estimate of 100% versus 28.7% in the SKY92 High Risk group (HR=inf). Robustness of the SKY92 signature is further demonstrated by the fact that it validates on both datasets, despite different microarray platforms being used. Conclusions The SKY92 high risk signature has been successfully validated on two independent datasets generated using different microarray platforms. In addition, on the Czech data, the low risk group (SKY92 Standard Risk combined with ISS 1) has been successfully validated. Together, this signifies the robust nature of the SKY92 signature for high and low risk prediction, across treatments, and with applicability in newly diagnosed, treated, and relapsed/refractory MM patients. Figure 1. Kaplan-Meier plots showing a significantly poorer overall survival in patients identified as SKY92 High Risk (red curves), relative to SKY92 Standard Risk, on both the TT6 (left), and Czech (middle) datasets, as well as a low risk group by SKY92 & ISS1 on the Czech dataset (green curve, right). Figure 1. Kaplan-Meier plots showing a significantly poorer overall survival in patients identified as SKY92 High Risk (red curves), relative to SKY92 Standard Risk, on both the TT6 (left), and Czech (middle) datasets, as well as a low risk group by SKY92 & ISS1 on the Czech dataset (green curve, right). Disclosures van Vliet: SkylineDx: Employment. Ubels:SkylineDx: Employment. de Best:SkylineDx: Employment. van Beers:SkylineDx: Employment. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding.

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Prognostic and Biologic Significance of Long Non-Coding RNA (lncRNA) Profiling in Cytogenetically Abnormal Acute Myeloid Leukemia (CA-AML)

Blood ◽

10.1182/blood-2018-99-114035 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2767-2767

Author(s):

Dimitrios Papaioannou ◽

Deedra Nicolet ◽

Xiaoqing Rong-Mullins ◽

Krzysztof Mrózek ◽

Jessica Kohlschmidt ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Group Status ◽

Advisory Committees ◽

Expression Levels ◽

Pathway Analyses

Abstract Introduction: Aberrant expression levels of lncRNAs have been shown to independently associate with outcome of younger and older patients (pts) with cytogenetically normal AML. However, the prognostic and biologic significance of lncRNA expression in CA-AML pts have not been extensively studied. Methods: We performed whole transcriptome profiling (RNA-seq) in 469 pts with de novo CA-AML. Cytogenetic analyses were performed in institutional laboratories and the results were reviewed centrally. All pts were treated on frontline Cancer and Leukemia Group B (CALGB)/Alliance protocols. Results: To evaluate the prognostic significance of lncRNA expression in CA-AML, we analyzed RNA-seq data of 469 pts by applying a machine learning algorithm-based approach. As CA-AML pts constitute a heterogeneous group, we first determined which other clinical and molecular parameters were prognostic [i.e., associated with event-free survival (EFS)] in our dataset. Among the parameters tested, the European LeukemiaNet (ELN) Risk Group status and age group [i.e., younger than 60 years (y) or aged 60 y and older] significantly associated with clinical outcome of CA-AML pts. Next, we individually identified each lncRNA that associated with EFS while adjusting for ELN Risk Group and age group. We conducted random forest analyses to select the prognostic lncRNAs, whose combined expression levels could generate an effective outcome predictor for CA-AML pts. For each step of the random forest analyses, a bootstrap technique was applied; a simple random sample of pts was drawn which served as the training set and the out-of-sample pts were used as the independent validation set. We identified 55 prognostic lncRNAs and used their expression levels to separate our CA-AML cohort into a lncRNA low-risk (n=161) and a lncRNA high-risk (n=308) group. With regard to clinical characteristics, pts in the lncRNA low-risk group were younger (P<.001) and had lower platelet counts (P<.001) and higher white blood cell counts (P=.01) than pts in the lncRNA high-risk group. Concerning cytogenetic abnormalities, pts in the low-risk group more often had core-binding factor translocations or inversions (P<.001) and less often complex karyotypes (P<.001) than pts in the high-risk group. Pts in the lncRNA low-risk group had higher complete remission (CR) rates than pts in the high-risk group (91% vs 48%, P<.001). LncRNA low-risk group status also associated with longer disease-free survival (DFS; 5-y rates 49% vs 12%, P<.001), overall survival (OS; 5-y rates: 58% vs 14%, P<.001) and EFS (5-y rates: 45% vs 6%, P<.001). With regard to the accuracy of outcome prediction, the lncRNA risk classification had a C-index of 0.73, which compares favorably with other prognostic classifiers of AML pts. In multivariable analyses, lncRNA low-risk status was an independent marker for higher CR rates, as well as for longer DFS, OS and EFS (P<.001 in all comparisons), after adjusting for other covariates. Finally, we examined the prognostic value of the lncRNA risk classification within the Favorable and Intermediate ELN Groups of our dataset, for which lncRNA risk groups had adequate pt numbers. Among pts in ELN Favorable Group, lncRNA low-risk pts (n=128) had higher CR rates (P=.003) and longer DFS (P<.001), OS (P<.001) and EFS (P<.001) than lncRNA high-risk pts (n=32). Similarly, in the ELN Intermediate Group (n=85), lncRNA low-risk group status (n=28) associated with higher CR rates (P=.01), longer OS (P=.01) and EFS (P=.005) and a trend for longer DFS (P=.08). To gain biological insights, we examined the molecular pathways regulated by the 55 prognostic lncRNAs. To minimize the confounding effects of differences in the concurrent cytogenetic abnormalities, we restricted these analyses to the ELN Favorable Group. We identified approximately 900 transcripts that were differentially expressed between lncRNA low- and high-risk pts. DAVID pathway analyses showed enrichment of genes involved in the processes of phosphorylation, acetylation and RNA-binding. Ingenuity pathway analyses of up-stream regulators identified aberrant activity of homeobox genes such as MEIS1, HOXA9 and HOXA10 in the lncRNA low-risk group and other transcription factors such as MYC, FOSB and JUN in the high-risk group. Conclusion: We conclude that lncRNA profiling provides meaningful prognostic and biologic information in CA-AML pts. Disclosures Kolitz: Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Stone:Cornerstone: Consultancy; Astellas: Consultancy; Orsenix: Consultancy; Merck: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Novartis: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Fujifilm: Consultancy; Ono: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Wang:Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy.

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Prognostic Factors for CMV Reactivation/Infection after Stem Cell Transplantation and Value of Oral Valganciclovir for Preemptive Therapy.

Blood ◽

10.1182/blood.v106.11.5369.5369 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5369-5369

Author(s):

Thorsten Graef ◽

Tatjana Bobrikova ◽

Ortwin Adams ◽

Roland Fenk ◽

Leilani Ruf ◽

...

Keyword(s):

Stem Cell ◽

Prognostic Factors ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Therapeutic Response ◽

Preemptive Therapy ◽

Cmv Infection ◽

Oral Valganciclovir ◽

Cmv Disease ◽

Cmv Reactivation

Abstract INTRODUCTION: Cytomegalovirus (CMV) infection and disease are major complications of allogeneic stem cell transplantation (SCT). Different strategies have been developed to reduce the risk for CMV-associated disease and death. Before routine use of prophylactic regimens, CMV seropositive allogeneic HCT recipients had a 70 to 80 percent risk of reactivation of this virus, and one-third of these patients developed CMV disease. Preemptive antiviral therapy has markedly reduced the incidence and severity of CMV disease, but in spite of these advances significant morbidity and mortality are associated with CMV. PATIENTS AND METHODS: In this unicenter retrospective study, we studied 197 adults who received allogeneic HSCT mostly because of myeloid leukaemia between 2000 and 2004. The median age was 46 years (range, 17-68), included were 80 female and 117 male patients. The grafts consisted mainly of PBSC (94%) and in 54% unrelated donors were used. Conditioning regimens included TBI in 42% cases. The CMV-serostatus proportions were D-/P- 34%, D-/P+ 20%, D+/P- 14% and D+/P+ 32%. All patients with ablative regimens received prophylactic i.v. acyclovir starting one day after SCT. After discharge oral CMV-prophylaxis consisted of famciclovir (52%), acyclovir (30%), valacyclovir (8%) or ganciclovir (10%). The prognostic factors for CMV reactivation in recipients were assessed by univariate analyses and Pearson correlations. RESULTS: CMV seropositive recipients (p=.00001) and donors (p=.03) were significantly associated with a higher rate of CMV reactivations, and also the use of an unrelated donor was a prognostic factor for more frequent CMV reactivations (p=.007). TBI, age and GvHD were not associated with more frequent of CMV reactivations. Famciclovir and acyclovir were associated (p=.0001) with a higher rate of CMV-reactivations in CMV+ recipients, than valacyclovir or ganciclovir. In all, we observed 60 cases (31%) of CMV reactivation/infection (D-/P- 14%, D-/P+ 30%, D+/P- 7% and D+/P+ 49%) after a median of 50 days (range, 9-403). 48 of them (80%) were CMV+ before SCT and 50 of 60 (83%) were successfully treated. In all, 30 patients (7 CMV-, 23 CMV+) were treated with valganciclovir and 30 (5 CMV-, 25 CMV+) received other agents (valacyclovir n=11, foscarnet n=4 or ganciclovir n=15) after a single dose of i.v. IG. 29 of 30 patients who received valganciclovir had a negative PCR result, confirmed by 2 consecutive CMV-PCRs, after a median of 24 days (range, 9 – 365). In the group of the CMV+ recipients, valganciclovir resulted in a statistically superior therapeutic response (p=0.024) when compared to other agents. Oral valganciclovir therapy was well tolerated and toxicity was limitted to manageable cytopenia. 11 of 12 CMV- recipients (91%) were also successfully treated after CMV-infection, with no significant difference between the different therapeutic agents. CONCLUSION: CMV seropositive recipient is the primary prognostic factors for CMV reactivation after allogeneic SCT. The prophylactic use of valacyclovir and ganciclovir were significantly better in CMV+ recipients, than famciclovir or acyclovir. Valganciclovir resulted in a better therapeutic response in comparison to other agents after CMV reactivation and should be tested as primary preemptive therapy in randomized trials.

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