Impact of Pre-Engraftment Cytomegalovirus Viraemia in Allogeneic Haematopoetic Stem Cell Transplant Recipients

Background Cytomegalovirus (CMV) reactivation post- allogeneic transplant increases mortality(1). Very few studies have explored the significance of pre-engraftment CMV reactivation on subsequent CMV-related outcomes or therapy. Aim To determine the incidence and outcome of pre-engraftment CMV reactivation. Methods All consecutive patients transplanted May 2015-Jan 2019 at the Royal Melbourne Hospital were included in this observational retrospective study. Plasma CMV DNA load was monitored by real-time PCR assays twice per week. Pre-emptive CMV treatment was commenced when the CMV viral load was greater than 400 IU/ml. Risk factors for pre-engraftment CMV were assessed by univariate logistic regression analysis. The Mann-Whitney U test was used to compare post-transplant CMV reactivation and time of treatment initiation; the Fisher's exact test was used for CMV disease and acute graft versus host disease (aGVHD); neutrophil engraftment, relapse free survival (RFS) and overall survival (OS) were compared using the Log-Rank Method. Results Of the 220 patients, 182 patients had CMV reactivation and pre-engraftment CMV levels available. Of these 182, 102 (56%) had CMV detected on at least one occasion before engraftment (D-10 to D+30). No pre-transplant factors including conditioning type and CMV serostatus were found to be associated with the development of pre-engraftment CMV reactivation. Patients who had pre-engraftment viraemia patients had a shorter time to post-transplant CMV detection (p<0.0001; Y=27.2d vs N=36.3d). These patients also had a longer time to neutrophil engraftment (p=0.049, median 19d vs 18d). Despite the shorter time to detection, there was no difference in likelihood of commencement of pre-emptive anti CMV therapy (p=0.88), day of CMV therapy commencement (p=0.29) and the total length of treatment (p=0.82). Patients with pre-engraftment viraemia were not at an increased risk of CMV disease (P=0.65) or aGVHD (p=0.87). There was no difference in RFS (p=0.99) or OS (p=0.14). Conclusion These results suggest that pre-transplant CMV detection should not affect the decision to proceed to transplant or require earlier initiation of prophylactic or pre-emptive therapy. References Teira, P., Battiwalla, M., Ramanathan, M., Barrett, A. J., Ahn, K. W., Chen, M., Green, J. S., Saad, A., Antin, J. H., Savani, B. N., Lazarus, H. M., Seftel, M., Saber, W., Marks, D., Aljurf, M., Norkin, M., Wingard, J. R., Lindemans, C. A., Boeckh, M., Riches, M. L., & Auletta, J. J. (2016). Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood, 127(20), 2427-2438. Accessed June 01, 2019. https://doi.org/10.1182/blood-2015-11-679639. Disclosures Yong: Merck Ltd: Honoraria. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria.

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Mucositis during Allogeneic Transplantation Determines Post-Transplant Serum Cyclosporin Levels

Blood ◽

10.1182/blood-2019-122363 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5662-5662

Author(s):

Joanne L C Tan ◽

Eric Wong ◽

Ashish Bajel ◽

Radha Ramanan ◽

Andrew B M Lim ◽

...

Keyword(s):

Stem Cell ◽

Renal Impairment ◽

Research Funding ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Prospective Evaluation ◽

Post Transplant ◽

Oral Cyclosporin ◽

Significant Difference ◽

Cmv Reactivation

Introduction Intestinal mucosal injury is a common complication following allogeneic stem cell transplant (alloHSCT), especially with myeloablative and TBI-based (total body irradiation) conditioning regimens1. Prospective evaluation studies have shown that intestinal malabsorption persists for several weeks following conditioning, beyond visible resolution of mucositis and bowel integrity2. Serum cyclosporin levels in the post-transplant period (when patients are taking oral cyclosporin) may be affected by reduced gut absorption and could influence early transplant related outcomes. Aim To determine the relationship between mucositis severity, cyclosporin levels, and post-transplant outcomes. Methods 169 patients who received myeloablative (BuCy, CyTBI, EtoTBI) or reduced-intensity (FluMel) allo-HSCT at the Royal Melbourne Hospital were studied. Serum cyclosporin levels were measured at 2 hours post oral dosing. Days of post-transplant total parental nutrition (TPN) were used as a surrogate for severity of gastrointestinal mucositis. To determine degree of renal impairment, creatinine values were recorded at baseline, D+30, D+60 and D+100. The incidence and severity of acute graft-versus-host disease (aGVHD) was recorded before D+100. The incidence of CMV viraemia before D+100 was recorded and analysed according to serum viral load. Patients with disease relapse (<6m versus >6m) were compared with patients without. Results Linear regression analysis showed an inverse correlation between days requiring TPN with the post SCT 100-day median cyclosporin level (p<0.0001, R2=0.23). Higher median cyclosporin level was associated with a greater percentage increase of creatinine above baseline (p=0.004, R2= 0.051). There was no significant correlation between incidence (p=0.05) and severity (p=0.47) of aGVHD with lower cyclosporin levels. CMV reactivation was associated with higher cyclosporin levels (p<0.0001). There was no significant difference in cyclosporin levels according to viral copy number (p=0.067). There was no significant difference in cyclosporin levels between disease-relapsed groups and non-relapsed groups (p=0.33). Conclusion Our data suggest that patients who have significant mucositis have lower serum cyclosporin levels with oral cyclosporin dosing, which in turn impact upon post-transplant outcomes, in particular renal impairment and CMV reactivation. References 1. Chaudhry, Hafsa M. et al. "The Incidence And Severity Of Oral Mucositis Among Allogeneic Hematopoietic Stem Cell Transplantation Patients: A Systematic Review." Biology of Blood and Marrow Transplantation 22.4 (2016): 605-616. Web. 2. Blijlevens, N M A, J P Donnelly, and B E de Pauw. "Prospective Evaluation Of Gut Mucosal Barrier Injury Following Various Myeloablative Regimens For Haematopoietic Stem Cell Transplant." Bone Marrow Transplantation 35.7 (2005): 707-711. Disclosures Bajel: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: travel funding. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria.

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Outcomes of Cytomegalovirus Monitoring in Autologous Transplantation: A Single Institution Experience

Blood ◽

10.1182/blood-2021-147499 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3949-3949

Author(s):

Mark Fesler ◽

Mackenzie J Poole ◽

Linda Goldenberg ◽

Alexis Guennette ◽

Kara J Christopher

Keyword(s):

Stem Cell ◽

Autologous Transplantation ◽

Screening Tests ◽

Cell Transplant ◽

Post Transplant ◽

Autologous Transplant ◽

Preparative Regimen ◽

Cmv Disease ◽

Dna Pcr ◽

Cmv Reactivation

Abstract Introduction: Identification of patients seropositive for cytomegalovirus (CMV) prior to stem cell transplant (SCT) is a well-accepted practice across institutions designed to reduce a known cause of morbidity and mortality in this population, but the role of monitoring and preemptive approaches to CMV identification and treatment are controversial and not standardized in autologous transplantation. The preemptive approach necessitates the use of significant resources and requires persistent patient involvement. Patients undergoing autologous SCT are at a relatively low risk for CMV reactivation, especially those seronegative for CMV at the time of transplant. Here, we show that the necessity of routine monitoring of autologous transplant patients is of minimal clinical value. Methods: To determine the efficacy of the CMV monitoring protocol currently in place at our institution in detecting patients who would later develop CMV reactivation and disease following autologous SCT, we retrospectively analyzed the charts of 218 adult patients between 11/1/14 and 8/1/19 who underwent transplant at St. Louis University Hospital. No patients underwent CD34 selected stem cell infusions. The protocol stipulated the following: CMV IgG/IgM and CMV DNA PCR prior to preparative regimen followed by weekly CMV DNA PCR to day +30 . We correlated the predictive ability of positive results on any of these screening tests to identify whether patients would later develop quantifiable CMV DNA PCR positivity, clinical manifestations of CMV disease, and/or require pharmacologic treatment for CMV. Results: Quantifiable pre-BMT DNA PCR was positive in only 0.46% of patients, and 97.79% of patients were DNA PCR negative prior to transplant. CMV IgG was positive in 56.4% patients, and only 22.1% of patients in this group went on to develop a quantifiable post-transplant PCR. Of the remaining 43.6% of patients initially testing negative for CMV IgG, no patients went on to develop a quantifiably positive post-transplant PCR. Regardless of seropositivity, only 0.08% of the 1,191 PCRs performed during the study period were found to be quantifiable. Further, no patients in our cohort developed CMV disease or required CMV treatment during the monitoring period. This trend persisted despite stratification by age, diagnosis, transplant number, and preparative regimen. Conclusion: When clinically-significant CMV is defined by cases requiring treatment or the development of end-organ disease, no screening tests performed elicited clinical action. Laboratory-based CMV surveillance, based on our data, has minimal diagnostic implications and represents an overly-stringent practice in a set of patients already utilizing a substantial share of healthcare resources. We believe that pre-transplant screening for CMV IgM serology and CMV DNA PCR can be safely eliminated in the autologous SCT population at our institution while CMV IgG still plays a role in determining candidacy for CMV-negative blood products. We also propose the elimination of serial post-transplant monitoring with DNA PCR in patients without clinical signs, symptoms, or pathologic findings suggestive of CMV disease. We have changed the protocol to test for CMV PCR only if there are clinical scenarios that indicate a utility, such as prolonged fever post-transplant, unexplained cytopenias, or unexplained pneumonitis, colitis, or hepatitis. By extension, other centers should consider determining the necessity of CMV screening in their autologous transplant population given the potential resource conservation and reduction in healthcare expenditures. Disclosures Fesler: abbvie: Consultancy, Speakers Bureau; incyte: Consultancy, Speakers Bureau; sanofi: Speakers Bureau; morphosys: Speakers Bureau; epizyme: Consultancy; jazz: Consultancy; Skipta: Consultancy; Best Doctors: Consultancy; Aptitude Health: Consultancy; Care Dx: Consultancy; Opinionsite: Consultancy. Goldenberg: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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Pre-Stem Cell Transplant Induction Therapy Does Not Affect Post-Transplant Survival In Light Chain (AL) Amyloidosis

Blood ◽

10.1182/blood.v116.21.370.370 ◽

2010 ◽

Vol 116 (21) ◽

pp. 370-370 ◽

Cited By ~ 4

Author(s):

Sumit Madan ◽

Shaji Kumar ◽

Martha Lacy ◽

Angela Dispenzieri ◽

Francis Buadi ◽

...

Keyword(s):

Stem Cell ◽

Induction Therapy ◽

Light Chain ◽

Research Funding ◽

Rank Test ◽

Al Amyloidosis ◽

Cell Transplant ◽

Exact Test ◽

Post Transplant ◽

Hematologic Response

Abstract Abstract 370 Background: Light chain (AL) amyloidosis is characterized by the deposition of amyloid derived from immunoglobulin light chains in various organs. Autologous peripheral blood stem cell transplantation (SCT) is a commonly used and effective treatment for AL. For patients (pts) undergoing this procedure, a proportion of pts receive treatment similar to induction therapy employed in pts with myeloma undergoing SCT. However, the significance of induction therapy and its impact on the overall survival (OS) in AL is unknown. We conducted this study to ascertain the role of pre-SCT therapy on the post-transplant outcomes in AL. Patients and methods: 435 pts with AL who underwent SCT at our institution between March 1996 and May 2010 form the study group. Groups were compared using Fisher's exact test or t-test, and survival was calculated using Kaplan Meier method. Survival curves were compared using log rank test. Result: The median (range) age of pts at the time of SCT was 57.4 years (26-75); 260 (60%) were males. The median (range) duration from AL diagnosis to SCT was 4 mos (1-87), and 284 (65%) pts were alive at the time of analysis. Melphalan 200/m2 (271 pts) or Mel/TBI (17 pts) was used for conditioning in 66% pts, whereas the remaining one-third had reduced doses of melphalan (100-160 mg/m2). The median OS for pts that received pre-SCT therapy (N=286) compared with those who did not (N=149) was 94.7 and 96.5 months, respectively (P=0.6) (Fig 1). Among the group of pts who underwent pre-SCT therapy and were evaluable for response, the median OS for those with a hematologic response (N=42) and no hematologic response (N=42) was 82.1 and 51 months (P=0.2), respectively (Fig 2). Conclusion: Our study demonstrates no difference in the OS of AL patients who received a pre-SCT therapy compared with those who received a SCT after their diagnosis of AL. In patients receiving pre-SCT therapy, there was a trend towards reduced OS among those with no hematologic response to pre-transplant therapy, but this difference was not significant. Disclosure: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

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Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors

Blood ◽

10.1182/blood-2002-05-1496 ◽

2002 ◽

Vol 100 (13) ◽

pp. 4358-4366 ◽

Cited By ~ 668

Author(s):

Kieren A. Marr ◽

Rachel A. Carter ◽

Michael Boeckh ◽

Paul Martin ◽

Lawrence Corey

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Invasive Aspergillosis ◽

Respiratory Virus ◽

Stem Cell Transplant ◽

Myelogenous Leukemia ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Increased Risk ◽

Cmv Disease

The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation (≤ 40 days) and after engraftment (41-180 days). Older patient age was associated with an increased risk during both periods. Chronic myelogenous leukemia (CML) in chronic phase was associated with low risk for early IA compared with other hematologic malignancies, aplastic anemia, and myelodysplastic syndrome. Multiple myeloma was associated with an increased risk for postengraftment IA. Use of human leukocyte antigen (HLA)–matched related (MR) peripheral blood stem cells conferred protection against early IA compared with use of MR bone marrow, but use of cord blood increased the risk of IA early after transplantation. Factors that increased risks for IA after engraftment included receipt of T cell–depleted or CD34-selected stem cell products, receipt of corticosteroids, neutropenia, lymphopenia, GVHD, CMV disease, and respiratory virus infections. Very late IA (> 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s.

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Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2019-129872 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4496-4496 ◽

Cited By ~ 1

Author(s):

Luke Eastburg ◽

David A. Russler-Germain ◽

Ramzi Abboud ◽

Peter Westervelt ◽

John F. DiPersio ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Early Mortality ◽

Cell Transplant ◽

Advisory Committees ◽

Post Transplant ◽

Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Pre-transplant cytomegalovirus-specific cellular immunity and risk of viral reactivation following lung transplantation: a prospective cohort study

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa750 ◽

2020 ◽

Author(s):

Mohammed Altaf ◽

Katie Lineburg ◽

Pauline Crooks ◽

Sweera Rehan ◽

Katherine K Matthews ◽

...

Keyword(s):

Lung Transplant ◽

Viral Reactivation ◽

Transplant Recipients ◽

Post Transplant ◽

Transplant Patients ◽

Cell Immunity ◽

Increased Risk ◽

Significant Burden ◽

Lung Transplant Recipients ◽

Cmv Reactivation

Abstract Cytomegalovirus (CMV) remains a significant burden in lung transplant recipients. Deficiencies in T-cell immunity post-transplant increase the risk of CMV-associated complications. However, it is not clear if underlying poor pre-transplant immunity increases risk. To assess this, we recruited 39 prospective lung transplant patients and performed QuantiFERON-CMV on their peripheral blood. More than a third of prospective CMV-seropositive transplant recipients were CMV non-immune-reactive (CMV-NIR) pre-transplant. CMV-NIR status was associated with a significantly higher incidence of CMV reactivation post-transplant, demonstrating that dysfunctional CMV immunity in prospective lung transplant recipients is associated with an increased risk of viral reactivation post-transplant.

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Early CMV Reactivation Still Remains a Cause of Increased Transplant Related Mortality in the Current Era: A CIBMTR Analysis

Blood ◽

10.1182/blood.v124.21.47.47 ◽

2014 ◽

Vol 124 (21) ◽

pp. 47-47 ◽

Cited By ~ 1

Author(s):

Muthalagu Ramanathan ◽

Pierre Teira ◽

Minoo Battiwalla ◽

A. John Barrett ◽

Caroline A Lindemans ◽

...

Keyword(s):

Research Funding ◽

Negative Impact ◽

Multivariable Analysis ◽

Time Dependent ◽

Positive Serology ◽

Increased Risk ◽

The Impact ◽

Cmv Reactivation ◽

Risk Of Relapse ◽

Related Mortality

Abstract Introduction: Since the early days of allogeneic hematopoietic cell transplantation (HCT), positive serology for cytomegalovirus (CMV) in either the recipient or the donor, and CMV reactivation have been associated with poorer outcomes. In the 90’s, development of effective monitoring and potent antiviral drugs minimized and occasionally abrogated this negative impact. Recently, some studies have reported an unexpected association between early CMV reactivation and decreased incidence of relapse in AML. The Center for International Blood and Marrow Research (CIBMTR) sought to conduct a retrospective large scale study to reassess the impact of CMV serology and CMV reactivation in the current era. Methods: The analysis includes comprehensive data of 11,153 patients undergoing first allogeneic HCT between 2003 and 2010 reported to the CIBMTR. Separate analyses were conducted for each of the 6 patient categories: AML transplanted with bone marrow (BM) or peripheral blood stem cell (PBSC) (n=5310), AML transplanted with cord blood (CB) (n= 925), ALL with BM/PBSC (n=1883), ALL with CB (n= 759), CML with BM/PBSC (n=1079) and MDS with BM/PBSC (n=1197). CMV serology from the donor (D) or recipient (R), and reactivation of CMV (as a time-dependent co-variate) within the first year after HCT were analyzed as risk factors for outcomes. The median duration of follow up was 56 months (1 – 127 months). Results: The median time to CMV reactivation was 40 days (1 – 362 days) after HCT and 98% of reactivations occurred before day 100 (D+/R+ 32%, D+/R- 11%, D-/R+ 34%, D-/R- 4%). In multivariable analysis, throughout the 6 groups, a positive serology (D+/R+, D+/R-, D-/R+) vs a negative serology (D-/R-),had no effect on the risk of GVHD (acute or chronic) or the risk of relapse, except for an increased risk of chronic GVHD for BM/PBSC recipients with ALL. CMV positive serology was associated with a higher transplant related mortality (TRM) and a poorer overall survival (OS). For a R+ patient, a D- compared to a D+, had no negative impact except for ALL with BM/PBSC where a D- was associated with a poorer OS. After PBSC/BM transplantation, CMV reactivation was associated with a higher TRM for MDS (RR=1.61, p=0.0002), CML (RR=1.86, p=0.0004), AML (RR=1.68; p<0.0001) and ALL (RR=1.95; p<0.0001), translating into lower OS (range of RR from 1.27 to 1.49; p value from 0.003 to <0.0001). Only among AML patients following CB transplantation, CMV reactivation did not worsen OS. Moreover, CMV reactivation had no effect on the incidence of relapse irrespective of the diagnosis or the source of stem cells. Finally, we conducted a subset analysis focusing on the group of AML, transplanted with PBSC after a myeloablative conditioning regimen and with a GVH prophylaxis relying on Ciclosporine and Methotrexate only. In multivariable analysis, there was no difference in the risk of relapse based on CMV reactivation as a time-dependent co-variate [RR 0.96 (0.65 – 1.4), p=0.8385]. Conclusion: Positive D/R CMV serology still results in increased TRM and decreased OS after HSCT in the current era. Early CMV reactivation did not prevent relapse in patients with AML, MDS, CML or ALL after HCT. Disclosures Boeckh: Chimerix: Consultancy, Research Funding; Viropharma: 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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Use of CMV Unselected Blood Products Does Not Increase the Risk of CMV Reactivation in Patients Undergoing Hematopoetic Stem Cell Transplant (HSCT)

Blood ◽

10.1182/blood.v126.23.2346.2346 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2346-2346

Author(s):

Jayne Peters ◽

Jonathon Elliott ◽

Adrian Bloor ◽

Michael Dennis ◽

John Murray ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Cell Transplant ◽

Blood Products ◽

Advisory Committees ◽

Hematopoetic Stem Cell ◽

Before And After ◽

Key Factor ◽

Full Intensity ◽

Cmv Reactivation

Abstract Introduction: Conventionally patients receiving allogeneic HSCT (AlloHSCT) have received CMV negative blood products to obviate the risk of transfusion related CMV transmission. In the era of leucodepletion with more than log 4 reduction in blood product WBC content, the utility of this practice has been questioned and, in line with SABTO (Safety of Blood, Tissues and Organs) guidance, most UK transplant centers have adopted the policy of using unselected blood products for this patient cohort. At this center, our policy was changed to conform to recommended national practice in April 2013. This analysis was carried out to evaluate if this change has resulted in an increased incidence of CMV reactivation. Methods: 868 (M: 561; median age: F: 307; median age:) patients who received HSCT from January 1998 to November 2014 were included in analysis. Transplant types included AutoHSCT (n=384), AlloHSCT-Sibling (n=217) and AlloHSCT-MUD (n=267). Diagnosis was Ac Leukaemia (n=313), Chr Leukaemia (n=36), Myeloma (n=216), Lymphoma (n=261) or other malignancies (n=42). Commonest indication for AutoHSCT was myeloma or lymphoma. TBI based condition was used in 225 AlloHSCT and 50 AutoHSCT cases. RIC was used in 268 cases and full intensity in 215 cases (unknown in 1). Alemtuzumab or ATG was used in conditioning for 274 cases. Source of stem cell was PBSC (AutoHSCT: 363, AlloHSCT: 382), BM (AutoHSCT: 7, AlloHSCT: 97), both (AutoHSCT: 2, AlloHSCT: 9) and 8 AlloHSCT were UCB grafts. Results: 26, 345 blood PCR results were evaluated. 3100 tests were requested in AutoHSCT patients and 109 (3.6%) were positive. There were no differences in the incidence of positive CMV PCR results before and after use of CMV unselected blood products. Further analysis was limited to AlloHSCT patients. AlloHSCT patients were divided in two groups, GrpA: 1998 to 2013 and GrpB: 2013 to 2014 to evaluate the effect of using CMV unselected blood products. In AlloHSCT group, 9.1% of 23278 samples tested for CMV PCR were positive (Median log: 2.7, range: 0.3-7.3). Incidence of CMV reactivation was not different in GrpB as compared to GrpA (47.7% vs. 48.1%, p=0.93). There was no difference with gender (M: 45.8% vs. F: 53.1%, p=0.13), type of donor (Sibling: 48.6% vs. MUD: 47.9%, p=0.98), use of Alemtuzumab/ATG (50.6% vs. 45.4%, p=0.51), source of stem cells (BM: 36.4% vs. PBSC: 51.3%, p=0.07), use of TBI (43.8% vs. 52.3%, p=0.06). Higher incidence was observed with use of RIC transplant (53.2% vs. 42.3%, p=0.02) and donor-recipient CMV mismatch (NP: 24.5%, PN: 80%, PP: 90.8%, p<0.0001). Conclusion: This analysis suggests that the risk of CMV reactivation is related to the donor-recipient CMV mis-match and the transplant intensity. Use of CMV unselected blood products does not increase the risk of CMV reactivation and careful selection of donors using CMV sero-status is the key factor to reduce the risk of CMV reactivation post AlloHSCT. Disclosures Cavet: Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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The Frequency of Cytomegalovirus (CMV)-Specific CD8+ T Cells Distinguishes CMV Clinical Outcomes Following Hematopoietic Allogeneic Stem Cell Transplant: A Prospective Multicentre Cohort Study

Blood ◽

10.1182/blood.v126.23.4312.4312 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4312-4312

Author(s):

Michelle K Yong ◽

Monica Slavin ◽

David S. Ritchie ◽

Andrew Spencer ◽

Paul U Cameron ◽

...

Keyword(s):

T Cell ◽

Clinical Outcomes ◽

T Cell Immunity ◽

Cell Transplant ◽

Viral Control ◽

Specific Immunity ◽

Cell Immunity ◽

Ifn Γ ◽

Cmv Disease ◽

Cmv Reactivation

Abstract Introduction: A simple test to identify recovery of CMV-specific T cell immunity in the post hematopoietic stem cell transplant (HSCT) period could assist clinicians in managing CMV related complications. The current assays of cell mediated immunity require specialised personnel and equipment, take a long time to perform and are often not available in a routine diagnostic laboratory. We therefore assessed CMV-specific CD8+ T cell immunity using a rapid high throughput Quantiferon-CMV assay to characterise the kinetics of CMV-specific immunity following HSCT. Methods: An observational multi-centre prospective study of allogeneic HSCT recipients who were at risk of CMV disease was conducted. Study bloods were taken pre-transplant and at 3, 6, 9 and 12 months post-HSCT. CMV-specific immunity was assessed using the Quantiferon-CMV assay which quantifies interferon gamma (IFN-γ) production by ELISA following stimulation with 22 CMV peptides derived from pp65, IE1, IE2, pp50, pp28 and gB, as well as a traditional ELISPOT assay using CMV overlapping peptide pools covering pp65 and IE1. The Quantiferon-CMV assay provides qualitative (reactive, non-reactive, indeterminate) and quantitative results expressed as IFN-γ levels (IU/ml). All participants had CMV surveillance with weekly CMV-PCR until day 100 or beyond in presence of graft versus host disease (GVHD). Participants were either managed with universal routine ganciclovir prophylaxis or CMV monitoring with pre-emptive treatment depending on the treating institution. CMV clinical outcomes were classified as (1) CMV disease with clear tissue involvement, (2) treated CMV reactivation (CMV DNA ³600cp/ml plus antivirals) and (3) spontaneous viral control defined as the resolution of any level of CMV DNA without CMV directed antivirals. Results: The median age of participants (n=94) was 51 years (IQR 40-56) and the most common indication for transplantation was AML (35%). Sixty-three percent of transplants received myeloablative conditioning, 54% had unrelated donors and 9% were umbilical cord transplants. Seventy-three percent of patients underwent pre-emptive CMV monitoring whilst 27% were on universal prophylaxis. CMV clinical outcomes included CMV disease (n=8), treated CMV reactivation (n=26), spontaneous viral control (n=25) and no detectable CMV DNA (n=31). A further 4 patients had low level viremia (CMV DNA<600copies/ml) treated with antiviral agents. CMV reactivation and CMV disease occurred at a median of 48 and 65 days respectively post HCT. Significant risk factors for CMV disease were donor/recipient CMV serostatus R+/D- (p=0.004), umbilical cord transplant (p=0.003) and acute GVHD (p=0.03). At baseline, there was no difference in the level of IFN-γ producing CMV specific T cells (Quantiferon) between patients who subsequently had CMV disease, CMV reactivation or spontaneous viral control (p=0.24). At 3 months post HSCT patients with CMV disease had significantly lower CMV IFN-γ responses compared to those with CMV reactivation or spontaneous viral control (median IFN-γ 0.04 vs 0.23 vs 1.86 IU/ml respectively, K-Wallis test p=0.001). An indeterminate Quantiferon-CMV result at 3 months was associated with CMV disease (p=0.001) whereas a reactive test was associated with spontaneous viral control (p=0.002). There were no significant differences in CMV IFN-γ levels measured by the Quantiferon-CMV assay results between the clinical groups at 6, 9 or 12 months post HSCT. A significant delay was observed in the time to development of CMV-specific immunity (defined as IFN-γ ³0.1IU/ml) in patients with CMV disease compared to CMV reactivation and spontaneous control (median time 240 vs 110 vs 97 days Mantel-Cox logrank test p=0.02). Twelve month survival was strongly associated with the Quantiferon-CMV result measured 3 months post HSCT being non-reactive, reactive or indeterminate (100% vs 90% vs 61.9% respectively Mantel-Cox Logrank test p=0.002, Graph 1). Conclusion: At 3 months post HSCT, the results of the Quantiferon-CMV assay which measures CMV-specific CD8+ T cell immunity can identify clinically relevant CMV related outcomes including 12 month survival. The Quantiferon-CMV assay may compliment current CMV prophylactic strategies and assist clinicians to identify patients at high risk of CMV related complications and poor survival. Figure 1. Twelve month survival curve by 3 month Quantiferon-CMV assay result Figure 1. Twelve month survival curve by 3 month Quantiferon-CMV assay result Disclosures No relevant conflicts of interest to declare.

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Recovery of CMV-Specific T Cells Following Alternative Donor Allogeneic Transplant with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v126.23.5462.5462 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5462-5462

Author(s):

Ayman Saad ◽

Samantha B Langford ◽

Shin Mineishi ◽

Lawrence S. Lamb

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Recovery ◽

Post Transplant ◽

Increased Risk ◽

Cmv Reactivation

Abstract Background: Post-transplant cyclophosphamide (PTCy) is increasingly used for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation (HCT) using alternative donors. However, immune reconstitution can be delayed posing an increased risk for CMV reactivation. We evaluated the outcomes of patients who received HCT-apheresis products comparing the impact of PTCy on lymphocyte recovery, CMV reactivation and CMV-specific CD8+ T cell recovery following haplo-identical (HAPLO), matched unrelated donor (MUD), and mismatched unrelated donor (mMUD) grafts vs. with conventional matched related donor (MRD) graft recipients. Methods: We examined 26 patients (median age, 49 years; range, 20-72 years) with advanced hematologic malignancies; n=5 (HAPLO); 6 (MRD); 15 (MUD). All patients received myeloablative conditioning regimens that was either busulfan- or total body irradiation (TBI)-based. PTCy (50 mg/kg/day) was administered on days +3 and +4 following HAPLO and on day +3 following MUD/mMUD transplant. Peripheral blood lymphocyte reconstitution and frequency of circulating CMV-directed CD8+ T cells was assessed (day ± 10 days) on post-transplant days +30, +60, and +90. Circulating anti-CMV T cell frequency was assessed using a phycoerythrin-tagged MHC dextramer against HLA-specific CMV pp65, IE-1, or pp50 peptides (Immudex; Copenhagen, DK) in combination with Tru-Count¨ tubes and fluorescent-labeled monoclonal antibodies against CD3, CD8, CD4, CD16/56, and CD19 (BD Biosciences; San Jose, CA). Anti-CMV CD8+ T cell immunity was defined as a CMV-dextramer (CMV/DEX) positive count of ≥7cells/ml. CMV reactivation was defined as a serologic titer of >500IU/mL. All patients with CMV reactivation received ganciclovir therapy until CMV titer became negative. Results: Day +30 total T cell recovery was significantly faster in MRD than CY-treated recipients (p=0.015) due principally to more robust CD8+ T cell recovery. CD4 T cell recovery remained below normal range in all groups through day +100. NK cells recovered to normal numbers at day +28 in all groups. Neither PTCy nor donor source significantly impacted the percentage of patients that recovered anti-CMV CD8+ T cells at each time interval (p = 0.8232). Excluding donors (D) and recipients (R) that were both negative, CMV/DEX+ T cells recovery was >7/mL in 4/5 MRD, 7/14 MUD, and 3/5 HAPLO by day +100. Among MRD recipients either D+ or R+ (n=5), 2 patients showed CMV reactivation within 40 days of transplant that was associated with <7 CMV/DEX+ T cells on day +30. Subsequent high (>90/mL) CMV/DEX T cell response in one patient shortened the duration of viremia to 10 days (vs. 16 days with poor responder) and 3 patients showed no CMV reactivation and a high CMV/DEX+ T cell response by day +60. For MUD CMV D+ and/or R+ recipients (n=14), 3 showed CMV reactivation within 50 days of transplant. All 3 patients had suboptimal CMV/DEX T cell response on day +30. Robust CMV/DEX+ T cell response on day +60 predicted shorter duration of viremia (20 days vs. average of 32 days). For HAPLO CMV D+ and/or R+ (n=5) recipients, 4 experienced CMV reactivation within 50 days of transplant. All patients had a <7 CMV/DEX+ T cells/mL +30. Robust CMV/DEX+ T cell response by day +60 was associated with shorter duration of viremia (range 7-21 days), while one patient with <7/mL CMV/DEX+ T cells had continued CMV viremia for 36 days. Conclusion: In this preliminary analysis, neither PTCy nor donor source significantly impacted the percentage of patients that recovered anti-CMV CD8+ T cells at each time interval. A weak CMV/DEX+ response (<7 cells/mL) on day +30 was consistent with increased risk of CMV reactivation (viremia) in all groups. A CMV/DEX+ T cell count ≥7 cells/mL was not immediately protective against CMV reactivation, but higher counts were associated with a shortened duration of viremia while on antiviral therapy. Conversely, subnormal counts were associated with a longer duration of viremia. This interim analysis suggests that CMV/DEX+ T cell enumeration is a useful biologic correlate for determining clinical response to antiviral therapy, and that donor-derived CMV specific T cell immunity is not further compromised with following PTCy in alternative donor HCT. Disclosures No relevant conflicts of interest to declare.

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