Delayed Cytomegalovirus (cmv) Infection Following Hematopoietic Cell Transplantation (HCT): City of Hope (COH) Experience.

Abstract Patients undergoing HCT are at an increased risk of developing primary and/or reactivated CMV infection, although the magnitude of risk of CMV disease has decreased with the widespread use of preemptive ganciclovir. Most episodes of reactivation occur within the first year post-HCT and are associated with risk factors such as CMV serostatus of donor and recipient, development of acute graft vs. host disease (GVHD): and the immunosuppressive therapy used for its management. Because of prolonged periods of immunosuppression post-HCT, patients may be at risk for delayed CMV infection one or more years after HCT. However, the magnitude of risk of delayed CMV infection and characteristics of those at increased risk has not been described. Given the high morbidity and mortality associated with post-HCT CMV infection, identifying patients at high risk of delayed CMV could be useful for effective management. This report includes 2700 consecutive patients who survived more than one year after undergoing HCT at COH between 1976 and 2003; these included 1404 autologous HCT recipients and 1296 allogeneic HCT recipients (1043 related donor; 253 unrelated donor recipients). Median age at HCT was 38 years (range, 0.6 to 79 years) and 59% of the cohort was males. Median follow-up time from HCT until delayed CMV infection/disease, death, or end of study period (12/31/2006), whichever occurred first, was 4.3 years (range:1–26.6 years). Medical records from COH and/or outside facilities were the main source of data for CMV occurrences. In total, 33 patients (1%) developed delayed CMV infection after surviving at least one year post-HCT (1 autologous and 32 allogeneic [20 related donor and 12 unrelated donor HCT]) developed a total of 40 episodes of delayed CMV that included pneumonia (n=16), gastrointestinal disease (n=8), retinitis (n=2), hepatitis (n=1), concurrent pneumonia and hepatitis (n=1), and asymptomatic reactivation (n=12). The overall cumulative incidence of delayed CMV infection was 1.3% (95% Confidence Interval [CI], 0.9–1.8%) at 5 years from HCT. For autologous HCT recipients, the incidence was 0.07% at 1 year based on 1 event. Among allogeneic HCT recipients, the cumulative incidence at 5 years post-HCT was 2.1% [95%CI, 1.2–3.0%] for related donor HCT recipients; and 5.0% [95%CI, 2.2–7.7%] for unrelated donor HCT recipients. Among allogeneic HCT recipients, the risk factors for the development of delayed CMV infection included unrelated donor HCT (hazard ratio [HR] = 2.5, 95% CI, 1.1–5.7) and CMV seropositive status of the recipient (HR=7.7, 95% CI 1.0–57.0) (Figure). Interestingly, donor CMV status was not associated with increased risk of delayed CMV. All 32 allogeneic HCT recipients experienced chronic GVHD, with prolonged exposures to corticosteroids (median=494 days), and cyclosporine (median=380 days). Thirty patients with delayed CMV infection (94% of the allogeneic HCT recipients with delayed CMV) were receiving immunosuppressive therapy for management of chronic GVHD at onset of delayed CMV. A total of eight patients with delayed CMV did not have a history of CMV infection in the first year, and were characterized by the following clinical and demographic features: 6 (75%) were male; median age at HCT was 35 years; one was an autologous HCT recipient, who relapsed 10 months post-HCT for non-Hodgkin lymphoma, received further chemotherapy and radiation, including Rituximab and then developed late CMV, just over one year post-HCT. The seven allogeneic HCT recipients had chronic GVHD, and were CMV serostatus positive prior to HCT, with 4 also having CMV seropositive donors. Of the 33 patients with delayed CMV in this study, 26 expired; median survival after the development of delayed CMV was 46 days. This study describes the magnitude of risk of delayed CMV infection in autologous and allogeneic HCT recipients and identifies at risk patients as those who are seropositive for CMV, undergoing unrelated HCT, and those with prolonged exposures to immunosuppressive therapy for cGVHD (Figure), suggesting the need for a close surveillance of these patients at high risk. Figure Figure

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Clinical Outcome Associated with Cytomegalovirus (CMV) Infection/Disease in CMV-Seropositive Adult Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-112151 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3382-3382

Author(s):

Regis Peffault De Latour ◽

Patrice Chevallier ◽

Didier Blaise ◽

Aurore Clement ◽

Thierry Allavoine ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

First Year ◽

Unrelated Donor ◽

Cmv Infection ◽

Hematopoietic Stem ◽

Increased Risk ◽

Infection Disease

Abstract Recipients of allogeneic hematopoietic stem cell transplant (HSCT) who have positive cytomegalovirus (CMV) serology are at increased risk for morbidity and mortality after HSCT. However, the exact correlation between early CMV infection and post-HSCT outcomes, notably relapse, is still a source of conflicting data, especially in the era of viral surveillance through polymerase chain reaction (PCR) and preemptive antiviral therapy. We thus decided to retrospectively investigate the clinical impact of early, post-HSCT CMV infection/disease, in a large multi-center cohort of French patients. All consecutive CMV-seropositive adults (≥ 18 years old) who received a first HSCT in 3 French centers between January 1st 2010 and December 31th 2014 were eligible. Cord blood transplantation or a second HSCT were not considered here, as these procedures are associated with a significantly higher risk of morbidity and mortality. Study data were primarily derived from existing electronic health records. The study was conducted in accordance with the Declaration of Helsinki. CMV infection/disease was defined by the initiation of a preemptive and/or a curative anti-CMV treatment in the presence of a CMV viremia detected by a quantitative PCR. The primary objective of this study was to assess the association between CMV infection/disease and overall mortality within the first-year post-transplantation. Secondary clinical endpoints addressed the association between CMV infection/disease and the following outcomes within the first-year of HSCT: graft failure, relapse of the underlying disease, non-relapse mortality (NRM), incidence of acute and chronic graft-versus-host disease (GvHD), and the occurrence of infections other than CMV. Relapse was considered as a competing risk for non-relapse mortality, and death for other events of interest (relapse, incidence of acute and chronic GvHD, and occurrence of infections). Models were adjusted for disease type, disease status at HSCT, age at HSCT, sex, donor type, stem cell source, and conditioning regimen (MAC versus RIC, use of total body irradiation or anti-thymocyte globulin). Five hundred seventy-two patients (54.5% male, 71.2% with Karnofsky >90, and median age 54 years) met the inclusion criteria. Underlying diseases were acute leukemia (33.9%), lymphoid neoplasms (25.9%), and myelodysplastic/ myeloproliferative neoplasms (22.6%). The disease was generally in complete remission at the time of HSCT (56.5%) or stable at the time of HSCT (16.4%). The majority of patients had received a reduced intensity conditioning regimen HSCT (72.5%), and peripheral blood stem cells (71.3%). Donor type was as follows: HLA-matched unrelated donor, 34.1%; HLA-matched relative donor, 46.5%; mismatched unrelated donor, 16.3% and mismatched related donor, 3.10%. CMV infection/disease was observed in 227 patients (39.7%) at a median time of 39.5 days (range, 3-295 days) post-transplant. Overall survival rate as per Kaplan-Meier analysis was 70.9% at 1-year post-HSCT. After adjusting for significant risk factors and considering CMV infection/disease as a time-dependent variable in a Cox model, overall mortality at 1-year was significantly increased in patients developing CMV infection/disease (HR 1.86, [95%CI 1.16 - 3.00], p=0.011). The Fine and Gray competing risk model showed that CMV infection/disease during the first-year post-transplant was significantly associated with higher risk of infections other than CMV (HR 2.34, 95%CI [1.63 - 3.37], p<0.0001) and, consequently, an increased risk for NRM (HR 2.62, 95%CI [1.59 - 4.30], p=0.0001). We did not find any significant association between CMV infection/disease and acute or chronic GvHD, as well as with relapse. In this large cohort of 572 consecutive CMV-seropositive adults undergoing allo-HSCT, and who were monitored with a PCR-based strategy according to routine clinical practice, we identified that CMV infection/disease were significantly associated with an increased risk of 1-year overall and non-relapse mortality, related to higher rates of infections other than CMV. Therefore, post-HSCT CMV infection/disease seemed to be a major concern in the recent healthcare setting, affecting mortality and morbidity. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Clement:MSD: Employment. Allavoine:MSD: Employment. Tadmouri:ClinSearch: Employment. Blomkvist:ClinSearch: Employment.

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Nephrotic Syndrome After Allogeneic Hematopoietic Cell Transplantation: Incidence and Outcomes.

Blood ◽

10.1182/blood.v114.22.3324.3324 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3324-3324

Author(s):

Yasser Khaled ◽

Sung Choi ◽

David A Hanauer ◽

Pavan Reddy

Keyword(s):

Nephrotic Syndrome ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Minimal Change ◽

Unrelated Donor ◽

Allogeneic Hct ◽

History Of ◽

Conditioning Regimens ◽

Related Donor ◽

Membranous Gn

Abstract Abstract 3324 Poster Board III-212 The NIH Consensus recognizes nephrotic syndrome (NS) as part of the chronic GVHD symptomatology, but this manifestation is rare and the incidence and outcomes have not been well-defined. To characterize this complication, we conducted an IRB-approved retrospective review of 626 consecutive patients (age > 16 yrs: related donor [RD], n=352; unrelated donor [URD], n=274) who underwent allogeneic hematopoietic cell transplantation (HCT) between October 2000 and December 2007 at the University of Michigan. Data abstraction was facilitated by the use of an electronic medical record search engine (EMERSE) that allowed for efficient identification of key concepts based on a specified set of key words and phrases (e.g. “GVHD,” “proteinuria,” and “nephrotic syndrome”). Conditioning regimens included full intensity (FIC) in 470 patients and reduced intensity (RIC) in 156 patients. Nephrotic range proteinuria was identified in 17 of the patients, which is the largest cohort reported to date following allogeneic HCT. Renal biopsy confirmed the diagnosis in seven of these patients. The median time to onset of NS was 7.3 months (range 1.4 – 40.6 months) following allogeneic HCT. Clinical manifestations included hypoalbuminemia (100%), hypercholesterolemia (82%), edema (76%), renal impairment (65%), and thrombosis (29%). The overall cumulative incidence of NS was 2.9%: 2.4% in FIC and 4.6% in RIC HCT recipients; and 2.3% in RD and 3.7% URD HCT recipients. Of note, in patients who received irradiation-based conditioning regimens, there was an increased cumulative incidence of NS compared to those who did not, 4.8% versus 2.1%, respectively. Diagnostic symptoms of chronic GVHD based upon the NIH Consensus was seen in 65% (n=11) of the patients, all of whom were on immunosuppressive therapy at the time of diagnosis of NS. Prior history of acute GVHD was seen in 65% (n=11) of the patients. Interestingly, history of symptomatic cystitis was seen in 53% (n=9) of the patients, eight of whom had BK virus detected in the urine. The management and treatment for NS was variable. All of the patients received systemic steroids (0.25 mg/kg – 2 mg/kg), with or without mycophenolate mofetil and a calcineurin inhibitor. Additional therapy with rituximab was administered in nine patients. Durable remission with no further recurrence of proteinuria was observed in 47% of the patients (n=8). The median time to response was 4.8 months (range 0.3 – 13.5 months). Recurrence of proteinuria was seen in 29% of the patients (n=5), and primary refractory proteinuria was observed in 23% of the patients (n=4). Overall survival for the cohort was 49.5% at 4 years (confidence interval 24% - 75%) with median follow up of 5.1 years. The median survival from diagnosis of NS was 2.5 years. As of May 2009, eight patients are alive and nine have died. The causes of death include GVHD (n=6), relapse (n=2) and unknown (n=1). NS is a rare but important complication following allogeneic HCT. Early recognition of the clinical presentations and identification of high-risk groups may limit the potential morbidity and mortality associated with NS. Patient MUD/MRD PB vs BM Age at TP Conditioning Regimen DX Proteinuria estimate (g/24h) Gender GVHD Regimen Kidney Biopsy 1 MUD PB 53 FluBuTLI MPD 5.5 F Tacro/MTX Minimal change GN 2 MUD PB 56 FluBuTLI MM 14 M Tacro/MTX Membranous GN 3 MRD PB 57 BuCy MDS 14 M Tacro/MTX Membranous GN 4 MUD PB 55 BAC AML 3.4 M Tacro/MTX N/A 5 MRD PB 30 CVB NHL 3.74 M Tacro/MTX Membranous GN 6 MRD PB 47 BAC AML 10 M Tacro/MTX Membranous GN 7 MUD PB 49 FluBuTLI NHL 6.9 M Tacro/MMF N/A 8 MUD PB 38 BuCy AML 8.7 F Tacro/MMF N/A 9 MUD BM 18 CyATG Aplastic Anemia 4.22 F Tacro/MTX N/A 10 MRD PB 34 BAC AML 5.96 F Tacro/MTX N/A 11 MUD PB 61 FluBuTLI MDS 13.27 M Tacro/MTX N/A 12 MRD PB 26 BuCy CMML 3.58 F Tacro/MMF N/A 13 MRD PB 63 FluBuTLI NHL 4.54 F Tacro/MMF/MTX N/A 14 MUD PB 55 BuCy AML 22.57 M Tacro/MTX/Etanercept Minimal change GN 15 MRD PB 59 CVB-R NHL 3.37 M Tacro/MMF N/A 16 MRD PB 62 FluBuTLI AML 5.47 F Tacro/MMF/MTX Membranous GN 17 MUD PB 46 CyTBI AML 7.96 F Tacro/MTX/Etanercept N/A MUD = matched unrelated donor; MRD = matched related donor; PB = peripheral blood; BM = bone marrow; GN = glomerulonephritis; N/A = non applicable; MTX = methotrexate; MMF = mycophenolate mofetil; FluBuTLI = Fludarabine, Busulfan, Total Lymphoid Irradiation; BuCy = Busulfan, Cytoxan; BAC = Busulfan, Ara-C, Cytoxan; CVB = Cytoxan, Etoposide, BCNU; CyATG = Cytoxan, ATG Disclosures Hanauer: UMERSE, LLC: Consultancy, Patents & Royalties.

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Delayed Chronic Kidney Disease (CKD) after Hematopoietic Cell Transplantation (HCT).

Blood ◽

10.1182/blood.v108.11.552.552 ◽

2006 ◽

Vol 108 (11) ◽

pp. 552-552

Author(s):

Andrea R. Carter ◽

Michael Choi ◽

Can-Lan Sun ◽

Liton Francisco ◽

Stephen J. Forman ◽

...

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Unrelated Donor ◽

Transplant Recipients ◽

Increased Risk ◽

Autologous Hct ◽

One Year

Abstract Exposure to pre-transplant nephrotoxic agents, total body irradiation (TBI), and presence of chronic graft-versus-host disease (cGVHD) have been identified as risk factors for developing CKD after HCT. However, small sample size, short follow-up post-HCT, and varying definitions of CKD have precluded a precise estimation of the magnitude of risk and associated risk factors. The aim of the current study was to describe the incidence and risk factors associated with the development of delayed CKD in HCT survivors. Eligible subjects underwent HCT for hematological malignancies or severe aplastic anemia at City of Hope, survived at least one year post-transplant, and were free of CKD at one year post-HCT. Information on pre-transplant therapeutic exposures and post-transplant CKD was obtained via medical record abstraction. All CKD cases were defined according to the National Kidney Foundation’s definition based on glomerular filtration rate (GFR) values. The endogenous filtration marker creatinine was used to estimate GFR values. CKD was defined as a sustained elevation of serum creatinine which infer a GFR of less than 60 mL/min/1.73 m2 for 3 months or longer. The equation used to calculate GFR was as follows: GFR = 186 x (Pcr) −1.154 x (age) − 0.203 (x 0.742 if female) (x 1.210 if African American). Totally, 1,546 eligible subjects were identified (median age at HCT of 34.4, median length of follow-up 6.2 years; autologous HCT in 718 patients [46%], related donor HCT in 726 patients [47%], and unrelated donor HCT in 102 patients [7%]; 59% of subjects (n=913) were male). A total of 65 patients were identified with CKD, resulting in a cumulative incidence of 3.6% [95% confidence interval (CI), 2.6% to 4.6%] at five years post–HCT and 4.8% at 10 years (autologous HCT: 2.9% at five years; matched sibling HCT: 4.1%; matched unrelated donor HCT: 10.5%, p<0.05). In allogeneic transplant recipients, older age at HCT (RR per increase of five years, 1.34; 95% CI, 1.30 to 1.38), prophylaxis/treatment of GvHD with cyclosporine and/or tacrolimus (RR, 4.32; 95% CI, 1.25 to 14.89), and a primary diagnosis of Multiple Myeloma (RR=5.38, 95% CI=1.79 to 16.15) were associated with increased risk. For autologous transplant recipients, older age at HCT was associated with increased risk (RR per increase of five years, 1.33; 95% CI, 1.29 to 1.38). Of note, use of TBI, and chemotherapeutic agents for conditioning, and a history of fungal infection were not associated with risk of delayed CKD development. This study describes the magnitude of risk of delayed chronic kidney disease in a large cohort of long-term survivors of autologous and allogeneic HCT, as well as identifies high risk groups in this population, thus setting the stage for appropriate long-term follow-up of the vulnerable sub–groups. Incidence of Chronic Kidney Disease in 1+ Year Survivors of HCT Incidence of Chronic Kidney Disease in 1+ Year Survivors of HCT Incidence of Chronic Kidney Disease in 1+ Year Survivors of HCT (by Type of Transplant) Incidence of Chronic Kidney Disease in 1+ Year Survivors of HCT (by Type of Transplant)

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Early Mortality After Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies Performed In the Recent Era

Blood ◽

10.1182/blood.v116.21.902.902 ◽

2010 ◽

Vol 116 (21) ◽

pp. 902-902

Author(s):

Lester A. Laddaran ◽

Can-Lan Sun ◽

Ari M. VanderWalde ◽

Liton Francisco ◽

Saro Armenian ◽

...

Keyword(s):

Cumulative Incidence ◽

Hematologic Malignancies ◽

First Year ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Entire Cohort ◽

Related Donor ◽

Referent Group ◽

Autologous Hct ◽

Related Mortality

Abstract Abstract 902 Background: HCT is a curative option for patients with hematologic malignancies. However, the procedure carries a high risk of death in the immediate post-HCT period in part due to disease recurrence (relapse-related mortality [RM]), but also due to treatment-related mortality (TRM) resulting from the following: i) toxicity due to high intensity treatment; ii) graft vs. host disease (GvHD) and its management; and iii) infections. Previous studies utilizing data from HCTs performed in 1980s and 1990s indicate that the 1-yr cumulative incidence of TRM exceeds 20% for related donor and 30% for unrelated donor HCTs. However, gaps in knowledge remain related to the cause-specific cumulative incidence of TRM and RM after autologous and allogeneic HCT performed in the more recent eras. Methods: Between 2005 and 2008, a total of 1,673 consecutive patients received HCT at City of Hope at a median age of 50 years for AML (n=433), NHL (n=428), MM (n=369), ALL (n=176), and HL (n=154); 913 patients received autologous HCT; 382 allogeneic related donor; and 378 unrelated donor HCT. Reduced intensity conditioning was used for 268 patients. Early mortality was defined as death in the first year after HCT due to disease (RM) or treatment (TRM). Information regarding vital status and cause of death were obtained from medical records, supplemented with Social Security Death Index. Overall survival (OS) and cumulative incidence of TRM and RM were calculated for 30 d, 6 mo and 1 yr after HCT for i) the entire cohort, and by ii) diagnosis and iii) type of HCT. Multivariable models identified predictors of TRM and RM. Results: A total of 323 deaths (19.3% of the entire cohort) were observed within the first year after HCT; 55.5% attributed to TRM and 44.5% to RM. Among deaths due to TRM, 59% were attributed to infections, 12.9% to acute or chronic GvHD, and 9.5% to organ toxicity. Among autologous, related and unrelated donor HCT recipients, overall survival (OS) was 87.2%, 76.6% and 63.5% at 1 yr (p<0.001) (Figure 1A). Among autologous, related donor, and unrelated donor HCT recipients, 1-yr cumulative incidence of TRM was 1.6%, 12.1%, and 25.6% respectively (p<0.001) (Figure 1B), and cumulative incidence of RM was 8.2%, 6.9%, and 8.7% respectively (p=0.73) (Figure 1C). OS and cumulative incidence of TRM and RM by disease and type of HCT are summarized in Table. Predictors of increased RM included age at HCT 40–60 yr (HR: 1.6, p=0.04; referent group: <40 yr), and diagnosis of NHL (HR=2.0, p=0.008; referent group: AML); receipt of HCT in the later years was associated with decreased RM (2007: HR=0.5, p=0.02; 2008: HR=0.5, p=0.04; referent group: HCT in 2005). Of note, RM for NHL and AML did not differ by type of HCT (p=0.94). Predictors of TRM included allogeneic HCT (related: HR=4.3, p=0.0003; unrelated: HR=10.2, p<0.0001; referent group: autologous HCT). Among related and unrelated HCT recipients, use of reduced intensity conditioning did not have a significant impact on TRM (HR=1.2, p=0.6) or RM (HR=1.2, p=0.7). Conclusion: For patients with NHL and AML, cumulative incidence of RM does not differ by HCT type. Unrelated donor HCT continues to be associated with the highest risk of TRM. Infection is the most frequent cause of TRM, accounting for 62% of deaths due to TRM in unrelated donor, 52% in related donor, and 46% in autologous HCT recipients – reinforcing the need for aggressive measures for prevention and treatment of infections in this immune compromised population. Disclosures: No relevant conflicts of interest to declare.

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Unrelated Donor (URD) or Partially Matched Related Donor (PMRD) Peripheral Stem Cell Transplant (PSCT) with CD34+ Selection and CD3+ Addback for Pediatric Patients with Leukemias.

Blood ◽

10.1182/blood.v104.11.2159.2159 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2159-2159

Author(s):

Nancy Bunin ◽

Stephan Grupp ◽

Giuliana Pierson ◽

Robert Iannone ◽

Dmitri Monos ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Graft Failure ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Cell Transplant ◽

Increased Risk ◽

Related Donor ◽

Cd34 Selection

Abstract PSCT is becoming increasingly more common, as large doses of PSCs may result in faster engraftment than bone marrow, and high PSC doses may be advantageous in decreasing graft rejection. PSCs contain several logs more T cells than bone marrow, and most studies have shown an increased risk of extensive chronic GVHD with unmodified PSCs. However, purified CD34+ cells may be associated with increased graft failure (Bornhauser, et al. Br J Haematol118:1095, 2002) or relapse. To decrease the risks of both chronic GVHD and graft failure, and maintain potential graft vs. leukemia effect, we used CD34+ selection with a defined dose of CD3+ cells in the product at the time of infusion for URD or PMRD PSCT. We report on the first 23 patients (pts) on this IRB approved study. Conditioning was thiotepa 10mg/kg, cyclophosphamide 120 mg/kg and TBI 12 Gy/6 fractions. Lung shielding after 8 Gy and methylprednisolone 1 mg/kg at day+8 were initiated when it became apparent that engraftment syndrome was being observed in the first 10 patients. GVHD prophylaxis was cyclosporine, followed by oral tacrolimus, which was weaned by 120 days in the absence of GVHD. CD34+ selection was accomplished with the Isolex 300i device and resulted in an average T cell depletion of 4.2 logs. The positive fraction had an average purity of 94%, and T cells obtained from the negative fraction were added to the positively selected product at the time of infusion to achieve the defined T-cell dose of 5 x 105/kg CD3+. The remaining portion of the negative fraction was cryopreserved in multiple aliquots for DLI, if needed. There were 12 males; median age was10 yrs (range, 3–22). Diagnoses included: ALL: 6, AML/MDS:12, CML: 3, JMML: 2. URDs were used for 22 patients, and related donor for 1. This was the second transplant for one pt with MDS. Donors were matched by high resolution typing for13 pts; mismatches included A for 5 pts, B and C loci for 3 pts, DQB1 for 2 pts. The median CD34+ dose infused was 6.6 x 106/kg (1.3–12.4). Engraftment occurred in all pts, with ANC>500 at a median of 14 days (10–19), and platelets >20K in 15 pts at a median of 22 days (13–33). Eleven patients (48%) are alive in remission 7–25 months post SCT (med, 18). Grades I-II GVHD occurred in 15 pts, grade III in 1, and grade IV in association with HHV6 in 1 pt. Limited chronic GVHD occurred in 8 of 12 evaluable pts (67%), and has resolved in all but one. Two pts with AML relapsed at 3 and 18 months. Ten pts died at d 32–85 from CMV (2), ARDS (5), HHV6/infection (2), bacterial sepsis(1). Both pts who developed CMV pneumonitis were seropositive, with seronegative donors; one developed pneumonitis at day +20, with negative antigenemia. Pts with CML were negative for bcr-abl by PCR <6 months post SCT and have remained negative without GVHD. There was a trend toward higher mortality with mismatched donors (RR 2.6, p=0.06). This study demonstrates that PSC engineering with CD34+ positive selection with a defined dose of CD3+ cells results in prompt engraftment. With this approach, the risk of extensive chronic GVHD with URD or PMRD PSCs may be reduced.

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Incidence and Risk of Post-Herpetic Neuralgia after Varicella Zoster Virus (VZV) Infection in Hematopoietic Cell Trasnplantation (HCT) Recipients.

Blood ◽

10.1182/blood.v112.11.1152.1152 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1152-1152

Author(s):

Masahiro Onozawa ◽

Satoshi Hashino ◽

Takashi Fukuhara

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Male Gender ◽

First Year ◽

Healthy Individuals ◽

Post Herpetic Neuralgia ◽

Varicella Zoster ◽

Allogeneic Hct ◽

Increased Risk ◽

Autologous Hct

Abstract Reactivation of varicella-zoster virus (VZV) is a common event in patients undergoing hematopoietic cell trasnplantation (HCT). In post HCT recipients, VZV reactivation can occur frequently as localized zoster and sometimes as disseminated cutaneous lesions resembling varicella with or without visceral involvement, which results in a high mortality rate. The most common complication associated with zoster in healthy individuals is chronic and often debilitating pain called post-herpetic neuralgia (PHN), which can last for several yeas and may reduce quality of life. Although, many previous studies have shown a high incidence of VZV reactivation after HCT, incidence and risk of PHN in HCT recipients have not yet been clarified. To assess the incidence and risk factors associated with PHN after post-HCT VZV infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT in Hokkaido Cooperative Hematology Group (HCHG) between April 2005 and March 2007. HCHG is multicentric clinical study group that includes “all” hematology departments in Hokkaido prefecture, consisting of 26 clinical groups of 19 institutes. VZV infection was defined by the appearance of typical cutaneous vesicular lesions or the detection of VZV antigen. Localized zoster was defined as the presence of vesicular lesions in a dermatomal distribution. Disseminated zoster was defined as a generalized vesicular eruption that is identical to that of varicella. Visceral dissemination was defined as clinical evidence of internal organ involvement in the absence of other identified pathogens that might have accounted for the clinical syndrome. Post-herpetic neuralgia was defined as dermatomal pain that persisted beyond rash healing. Information on pre-transplant therapeutic exposures, HCT procedures and post-transplant health complications was obtained via evaluation form. A total of 418 patients were included in this study. Male/Female ratio was 221/197, median age at HCT was 47 years (range, 0–69 years), autologous HCT/allogeneic HCT/syngeneic HCT ratio was 154/263/1, and median length of follow-up was 344 days (range, 3–1165 days). Seventy-eight patients developed VZV infection after HCT (M/F=36/42; median age, 48 (range, 3–68) years; auto/allo/syngeneic=29/48/1). Sixty-two patients had localized zoster (single dermatome in 53, double dermatome in 9), 12 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster (involvement of GI the tract). All cases were treated by ACV or VACV, and there was no VZV infection-related death. After resolution of VZV infection, VZV infection reoccurred in 5 cases (localized zoster in 4 cases and visceral zoster in 1 case). Cummulative incidences of VZV infecion in allo-HCT and auto-HCT recipients were estimated to be 34% and 22%, respectively, at 2 years after HCT. In autologous HCT, 96.6% of the cases of VZV infection occurred during the first year after HCT, but in allogeneic HCT, only 75.5% of the cases of VZV infection occurred during the first year after HCT. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection (M/F=15/12; median age, 56 (range, 21–64) years; auto/allo=13/14). Although incidences of VZV infection were not different between age groups, the incidence of PHN increased with advance of age (Figure). In HCT recipients, the incidence of PHN increased at a younger age than that in healthy individuals. Multivariate analysis showed that advanced age (P=0.0031; OR=1.09; 95% CI, 1.03 to 1.15) and male gender (P=0.046; OR=3.09; 95% CI, 1.02 to 9.35) were associated with increased risk of PHN. Auto vs allo, CST vs RIST, and onset of VZV infection after HCT were not significant. In allogeneic HCT recipients, existence of GVHD at onset of VZV infection and prophylaxis of GVHD with tacrolimus were associated with increased risk of PHN in univariate analysis, but these factors were not significant in multivariate analysis. This study showed the magnitude of risk of PHN in HCT recipients and revealed advanced age and male gender to be risk factors, suggesting the usefulness of acyclovir as prophylaxis for prolonged periods in these patients. Figure Figure

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Human Papillomavirus (HPV)-Attributable Subsequent Neoplasms (SNs) After Hematopoietic Cell Transplantation (HCT) – a Potentially Preventable Outcome

Blood ◽

10.1182/blood.v120.21.605.605 ◽

2012 ◽

Vol 120 (21) ◽

pp. 605-605

Author(s):

J Berano Teh ◽

Can-Lan Sun ◽

Sharon Wilczynski ◽

Joel Epstein ◽

R. Spielberger ◽

...

Keyword(s):

Oral Cancer ◽

General Population ◽

Genital Tract ◽

Chronic Gvhd ◽

Female Genital Tract ◽

Unrelated Donor ◽

Cox Regression Analysis ◽

Increased Risk ◽

Autologous Hct ◽

Female Genital

Abstract Abstract 605 Background: Centers for Disease Control estimate that 26,000 cancers diagnosed each year in the general population are attributable to HPV; oropharyngeal and female genital cancers account for 75% of these. We hypothesized that HCT recipients are at an especially increased risk of HPV-attributable SNs, because of exposure to high-intensity therapy, coupled with immune dysregulation. However, the magnitude of this risk and sub-populations at highest risk are not known. Clinically this information is important because of the ability to institute primary prevention (HPV vaccine) for the young (<26y-olds); and the need to develop targeted surveillance and intervention strategies across all age groups. Methods: We determined the risk of post-HCT oral/pharyngeal and female genital neoplasms in 5701 (2424 female, 3277 male) consecutive patients transplanted for hematologic malignancies (leukemia [49%], lymphoma [35%], myeloma [12%]) between 1976 and 2007 at a single institution. Near-complete ascertainment of SNs was accomplished by combining institutional follow-up with linkage of the cohort with California Cancer Registry, and National Death Index Plus programs. Results: Median age at HCT was 41y (0–78); 48% had received autologous HCT; 37% related and 15% unrelated donor HCT. Chronic graft vs. host disease (GvHD) developed in 44% of related and 66% of unrelated donor HCT recipients. Oral/pharyngeal cancer: After 34,621 p-y of observation, 25 patients developed oral cancer; 76% after allogeneic HCT. Squamous cell carcinoma (SCC) of tongue, lip, and mouth/alveolar ridge accounted for 84% of the oral SNs; 16% were salivary gland tumors. Pathology reports did not capture HPV status. Oral/cutaneous (adjacent to lip) chronic GvHD was present in 62% of SCC, and 6% of non-SCC oral cancers. Median latency from HCT to oral cancer was 7.7y (0.9–32); median age at diagnosis was 45y (24–69). While autologous HCT recipients were not at statistically significant increased risk (standardized incidence ratio [SIR] = 1.9 (p=0.12), related donor recipients were at a 9-fold (4.5–14.8, p<0.001) and unrelated donor HCT recipients at a 23-fold (10.7–43.4, p<0.001) increased risk of developing oral cancer compared with the age- and sex-matched general population. Multivariate Cox-regression analysis (adjusted for age at HCT, gender, race/ethnicity, conditioning, and year of HCT) revealed that unrelated donor HCT recipients with chronic GvHD were at a 10.8-fold increased risk of developing oral cancer (p=<0.001), compared with autologous HCT recipients. Female genital tract neoplasms: Evaluation of the 2424 female HCT recipients with 14,587 p-y of follow-up revealed 51 patients with genital tract neoplasms (premalignant and malignant lesions of the cervix, vagina, vulva and clitoris); 71% of the cases among allogeneic HCT recipients had chronic GvHD. Forty-nine of the 51 neoplasms were of squamous cell origin. Importantly, 39 of 41 (95%) evaluable cases had findings consistent with HPV infection. Median latency from HCT to genital tract SNs was 3.3y (0.2–16.5); median age at diagnosis was 42y (20–66). In an analysis restricted to SEER-reportable neoplasms, the cohort was at 5.8-fold (3.2–9.5, p<0.001) increased risk of developing genital tract neoplasms when compared with an age-matched general population. Autologous, allogeneic related and unrelated HCT female recipients were at 4.1- (1.5–8.7, p=0.002), 7.2- (2.9–14.6, p<0.001) and 10.8-fold (1.8–33.8, p<0.001) increased risk respectively, of developing genital tract neoplasms compared with the general population. Multivariate Cox-regression analysis (adjusted for age at HCT, race/ethnicity, conditioning, and year of HCT) revealed that unrelated donor HCT recipients with chronic GvHD were at a 2.5-fold increased risk of developing female genital tract neoplasms (p=0.04) when compared with autologous HCT recipients. Conclusion: Chronic GvHD significantly increases risk of oral and female genital tract neoplasms; populations at risk should be followed closely, with appropriate and aggressive management of suspicious lesions. Over 90% of post-HCT female genital tract neoplasms are attributable to HPV. The contribution of specific HPV strains to the development of post-HCT oral and female genital tract neoplasms is currently underway, as are studies examining immunogenicity/safety of HPV vaccine for the <26y-old HCT survivors. Disclosures: No relevant conflicts of interest to declare.

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Excellent Long Term Survival Among Patients Who Are Disease-Free at One Year after Allogeneic Hematopoietic Cell Transplantation: A Single Center Analysis of 667 Consecutive Patients

Blood ◽

10.1182/blood.v128.22.4622.4622 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4622-4622

Author(s):

Melhem Solh ◽

Asad Bashey ◽

Scott R. Solomon ◽

Lawrence E. Morris ◽

Xu Zhang ◽

...

Keyword(s):

Overall Survival ◽

Chronic Gvhd ◽

First Year ◽

Term Survival ◽

Allogeneic Hct ◽

Kaplan Meier ◽

One Year ◽

Disease Free ◽

Very High

Abstract Introduction: Overall survival after allogeneic hematopoietic cell transplantation (HCT) is dependent on multiple patient, transplant and donor related factors. The national marrow donor program publishes survival outcomes from transplant centers focusing on the first year after allogeneic HCT. The first 12 months post allogeneic HCT carry a high risk of morbidity and mortality as well as a high risk of disease relapse. Many centers use the publically available one year data to advise patients on transplant risks and overall survival. The survival outcomes and the factors that affect these outcomes among allogeneic recipients who are alive and disease free at one year after HCT are not reported. The availability of such information will be of importance to council patients during their first anniversary visit and to identify the subgroup of survivals carrying a higher risk for later morbidity and mortality. Methods: We analyzed the outcomes of 667 consecutive adult patients at our center who received a first allogeneic transplant between 2005 and 2015. Patients were excluded from this analysis if they had less than one year of follow up (n=54), if died or had relapse of their disease (n=224) prior to the first year post-transplant. Patient characteristics and outcome parameters were extracted from our institutional database where they had been prospectively entered. Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) were calculated and the cumulative incidence method with competing risks was used to calculate rates of non-relapse mortality (NRM) and relapse. Cumulative incidences of acute and chronic GVHD were estimated with death being treated as the competing risk. Cox proportional hazards models, were developed using OS and relapse as endpoints and other parameters as covariates. All survival estimates were reported beyond the 1 year timeframe. GVHD was prospectively documented using established criteria including NIH consensus criteria for chronic GVHD and rates calculated using the cumulative incidence method. All patients were transplanted in the outpatient setting with hospital admissions for complications that could not be handled outpatient. Results: A total of 389 patients were included in the final analysis with a median age of 51 (19-75) years. Patients' characteristics were as follows: male (55%), race (white 77%, black 19%), disease ( AML 34%, ALL 15%, MDS/MPD 23%, NHL 24%), donor type ( MRD 37%, MUD 39%, haplo 24%), conditioning intensity (RIC 74%, myeloablative 53%), cell source ( bone marrow 19%), HCT comorbidity index >=3 (35%) and disease risk index DRI (high/very high 26%, intermediate 24%). The survival estimates at one and three years beyond the first year after transplant were Overall survival 91% and 82%, disease free survival 86% and 78%, transplant related mortality 7% and 12% and relapse of 7% and 10%. After adjusting for age, sex, race, diagnosis, cell source, CMV serostatus, disease risk index, transplant conditioning regimen, donor type, acute and chronic GVHD before 1 year and other significant factors, the cox model on mortality showed that male gender (HR 1.87, p=0.02), need of immunosuppression at 1 year (HR 2.17, p=0.006), and year of transplant (HR 0.62, p=0.026 for patients transplanted in 2013-2015 versus 2005-2009) were associated with higher mortality rate (fig 1). Cox model on relapse showed that male gender (HR 2.09, p=0.036), high/very high DRI (HR 26.40, p=0.002) to be associated with higher relapse whereas developing acute 2-4 GVHD (HR 0.32, p=0.011) or chronic GVHD (HR 0.33, p=0.001) in the first year after HCT was associated with lower relapse rates. Conclusion: patients who are alive and without relapse at one year post allogeneic HCT have an excellent long term survival and very low chance of disease relapse. A subset of patients with high/very high DRI remain at significant risk of later relapse and should be followed more closely with long term strategies to prevent delayed relapses. Figure 1 Kaplan-Meier Overall Survival Graphs by Gender, DRI and Year of Transplant Figure 1. Kaplan-Meier Overall Survival Graphs by Gender, DRI and Year of Transplant Disclosures No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis

Blood ◽

10.1182/blood.2020009362 ◽

2021 ◽

Author(s):

Scott R Goldsmith ◽

Muhammad Bilal Abid ◽

Jeffery J. Auletta ◽

Asad Bashey ◽

Amer Beitinjaneh ◽

...

Keyword(s):

Cytomegalovirus Infection ◽

Calcineurin Inhibitor ◽

Chronic Gvhd ◽

Infection Risk ◽

Prevention Strategies ◽

Cmv Infection ◽

Post Transplant ◽

Transplant Outcomes ◽

Increased Risk

Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.

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One-year outcomes in atrial fibrillation presenting during infections: a nationwide registry-based study

European Heart Journal ◽

10.1093/eurheartj/ehz873 ◽

2019 ◽

Vol 41 (10) ◽

pp. 1112-1119 ◽

Cited By ~ 4

Author(s):

Anna Gundlund ◽

Jonas Bjerring Olesen ◽

Jawad H Butt ◽

Mathias Aagaard Christensen ◽

Gunnar H Gislason ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cox Regression ◽

Absolute Risk ◽

First Year ◽

Thromboembolic Events ◽

Nationwide Registry ◽

Increased Risk ◽

Study Population ◽

Multivariable Analyses ◽

One Year

Abstract Aims Thromboprophylaxis guidelines for patients with concurrent atrial fibrillation (AF) during infections are unclear and not supported by data. We compared 1-year outcomes in patients with infection-related AF and infection without AF. Methods and results By crosslinking Danish nationwide registry data, AF naïve patients admitted with infection (1996–2016) were identified. Those with AF during the infection (infection-related AF) were matched 1:3 according to age, sex, type of infection, and year with patients with infection without AF. Outcomes (AF, thromboembolic events) were assessed by multivariable Cox regression. The study population comprised 30 307 patients with infection-related AF and 90 912 patients with infection without AF [median age 79 years (interquartile range 71–86), 47.6% males in both groups]. The 1-year absolute risk of AF and thromboembolic events were 36.4% and 7.6%, respectively (infection-related AF) and 1.9% and 4.4%, respectively (infection without AF). In the multivariable analyses, infection-related AF was associated with an increased long-term risk of AF and thromboembolic events compared with infection without AF: hazard ratio (HR) 25.98, 95% confidence interval (CI) 24.64–27.39 for AF and HR 2.10, 95% CI 1.98–2.22 for thromboembolic events. Further, differences in risks existed across different subtypes of infections. Conclusion During the first year after discharge, 36% of patients with infection-related AF had a new hospital contact with AF. Infection-related AF was associated with increased risk of thromboembolic events compared with infection without AF and our results suggest that AF related to infection may merit treatment and follow-up similar to that of AF not related to infection.

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