Prognostic impact of immune status and hematopoietic recovery before and after fludarabine,IV busulfan,and antithymocyte globulins (FB2 regimen) reduced‐intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo‐SCT)

This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22–70)] who received a FB2 (fludarabine 120–150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced‐intensity conditioning (RIC) allo‐stem cells transplantations (SCT). With a median follow‐up of 19 months (range: 2–53), the 2‐yr overall survival, disease‐free survival (DFS), relapse incidence, and non‐relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2‐yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm³; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm³) (2‐yr OS: 81% vs. 44%, P = 0.007; 2‐yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm³) (2‐yr OS: 76% vs. 50%, P = 0.03; 2‐yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm³; 2‐yr OS: 80% vs. 45%, P = 0.004; 2‐yr DFS: 76% vs. 42%, P = 0.01) at day +30 post‐transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm³) and a higher monocytes count (>590/mm³) at day +30 post‐transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo‐SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo‐SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo‐SCT.     

Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced‐intensity conditioning regimen

A. Shigematsu, S. Yamamoto, J. Sugita, T. Kondo, M. Onozawa, K. Kahata, T. Endo, S. Shiratori, S. Ota, K. Yamaguchi, K. Wakasa, M. Takahata, H. Goto, S. Ito, R. Takemura, J. Tanaka, S. Hashino, M. Nishio, T. Koike, M. Asaka, M. Imamura. Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced‐intensity conditioning regimen.
Transpl Infect Dis 2010: 12: 412–420. All rights reserved Abstract: Although bacterial infection is a major cause of death even after reduced‐intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), little is known about the epidemiology and risk factors. The incidence of bacterial infection in 43 patients who received allogeneic bone marrow transplantation (BMT) using a RIC regimen was compared with that in 68 patients who received BMT using a myeloablative conditioning regimen, and risk factors for bacterial infection were identified. Before engraftment, incidences of febrile neutropenia (FN) and documented infections (DI) were significantly decreased in RIC patients (FN: 59.5% vs. 89.6%, P<0.01, DI: 4.8% vs. 17.9%, P<0.01). However, incidence of bacterial infection was significantly increased in RIC patients in the post‐engraftment phase (53.8% vs. 11.1%, log‐rank, P<0.01). Blood stream was the most frequent focus of infection in both groups. In multivariate analysis, RIC and acute graft‐versus‐host disease were revealed to be significant risk factors for bacterial infection in this phase. In summary, risk of bacterial infection after engraftment was significantly higher in RIC patients, although infection was decreased before engraftment, and we need to develop a RIC‐specific strategy against bacterial infection after RIC SCT.     

Early lymphocyte recovery at 28 d post‐transplant is predictive of reduced risk of relapse in patients with acute myeloid leukemia transplanted with peripheral blood stem cell grafts

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myeloid leukemia (AML). Impact of lymphocyte recovery on post‐transplant outcomes has been suggested but reports are conflicting. We evaluated the impact of lymphocyte recovery at 28 d post‐HCT in 191 AML patients using peripheral blood stem cells as graft. Patients were divided into those with absolute lymphocyte count (ALC) ≥0.5 × 10⁹/L (n = 111, 58%; high ALC group) and those with ALC <0.5 × 10⁹/L (n = 80, 42%; low ALC group), at day 28 post‐transplant. With a median follow‐up of 49 months, overall survival (OS) was significantly improved in the high ALC group (59% at 3 yr) vs. patients with low ALC (40% at 3 yr, P = 0.03). Cumulative incidence of relapse (CIR) was significantly lower in the high ALC group (16% at 3 yr) vs. low ALC group (36% at 3 yr, P = 0.001). Multivariable analysis for CIR demonstrated high ALC group as an independent factor decreasing relapse risk (P = 0.03, HR = 0.49, 95% CI = 0.26–0.92). Multivariable analysis for OS and non‐relapse mortality did not demonstrate ALC ≥0.5 × 10⁹/L at 28 d post‐transplant to be predictive. We conclude that lymphocyte recovery with ALC ≥0.5 × 10⁹/L at day 28 post‐transplant is associated with less relapse in AML patients undergoing allogeneic peripheral blood HCT, but without survival benefit.     

Community‐acquired respiratory virus lower respiratory tract disease in allogeneic stem cell transplantation recipient: Risk factors and mortality from pulmonary virus‐bacterial mixed infections

Risk factors (RFs) and mortality data of community‐acquired respiratory virus (CARVs) lower respiratory tract disease (LRTD) with concurrent pulmonary co‐infections in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is scarce. From January 2011 to December 2017, we retrospectively compared the outcome of allo‐HSCT recipients diagnosed of CARVs LRTD mono‐infection (n = 52, group 1), to those with viral, bacterial, or fungal pulmonary CARVs LRTD co‐infections (n = 15, group 2; n = 20, group 3, and n = 11, group 4, respectively), and with those having bacterial pneumonia mono‐infection (n = 19, group 5). Overall survival (OS) at day 60 after bronchoalveolar lavage (BAL) was significantly higher in group 1, 2, and 4 compared to group 3 (77%, 67%, and 73% vs 35%, respectively, P = .012). Recipients of group 5 showed a trend to better OS compared to those of group 3 (62% vs 35%, P = .1). Multivariate analyses showed bacterial co‐infection as a RF for mortality (hazard ratio[HR] 2.65, 95% C.I. 1.2‐6.9, P = .017). We identified other 3 RFs for mortality: lymphocyte count <0.5 × 10⁹/L (HR 2.6, 95% 1.1‐6.2, P = .026), the occurrence of and CMV DNAemia requiring antiviral therapy (CMV‐DNAemia‐RAT) at the time of BAL (HR 2.32, 95% C.I. 1.1‐4.9, P = .03), and the need of oxygen support (HR 8.3, 95% C.I. 2.9‐35.3, P = .004). CARV LRTD co‐infections are frequent and may have a negative effect in the outcome, in particular in the context of bacterial co‐infections.     

Persistence of recipient human leucocyte antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem cell transplantation

The effects of reduced intensity conditioning (RIC) on human leucocyte antigen (HLA)‐alloimmunization and platelet transfusion refractoriness (PTR) following allogeneic haematopoietic stem cell transplantation (Allo‐HSCT) are unknown. We studied HLA‐alloantibodies in a cohort of 16 patients (eight HLA‐alloimmunized with pre‐transplant histories of PTR and eight non‐alloimmunized controls) undergoing Allo‐HSCT using fludarabine/cyclophosphamide‐based RIC. Pre‐ and post‐transplant serum samples were analysed for HLA‐antibodies and compared to myeloid, T‐cell and bone marrow plasma cell chimaerism. Among alloimmunized patients, the duration that HLA‐antibodies persisted post‐transplant correlated strongly with pre‐transplant HLA‐antibody mean fluorescence intensity (MFI) and PRA levels (Spearman's rank correlation = 0·954 (P = 0·0048) and 0·865 (P = 0·0083) respectively). Pre‐transplant MFI >10 000 was associated with post‐transplant HLA antibody persistence >100 d (P = 0·029). HLA‐antibodies persisted ≥100 d in 3/8 patients despite recipient chimaerism being undetectable in all lympho‐haematopoietic lineages including plasma cells. Post‐transplant de‐novo HLA‐antibodies developed in three control patients with two developing PTR; the donors for two of these patients demonstrated pre‐existing HLA‐antibodies of equivalent specificity to those in the patient, confirming donor origin. These data show HLA‐antibodies may persist for prolonged periods following RIC. Further study is needed to determine the incidence of post‐transplant PTR as a consequence of donor–derived HLA alloimmunization before recommendations on donor HLA‐antibody screening can be made.     

Post‐Transplant Lymphoproliferative Disorder in Kidney Transplant Recipients: A Single‐Center Experience in Japan

Post‐transplant lymphoproliferative disorder is a serious complication of solid organ transplantation; however, few large studies have been performed in Asian institutions. We review our single‐center experience with post‐transplant lymphoproliferative disorder patients in Japan. We retrospectively evaluated patients with post‐transplant lymphoproliferative disorder following kidney transplantation between January 1985 and December 2013. The patients were divided into early‐onset post‐transplant lymphoproliferative disorder (<1 year) and late‐onset post‐transplant lymphoproliferative disorder (≥1 year) groups. Thirteen patients had the disorder, an incidence rate of 0.75% (13/1730). Early‐onset post‐transplant lymphoproliferative disorder (N = 3) had not occurred for the last two decades. In the late‐onset group (N = 10), the median time of onset was 108.7 months. The Kaplan–Meier 10‐year overall survival rates were 76.9% and 95.4% in patients with and without the disorder, respectively (P = 0.0001). Post‐transplant lymphoproliferative disorder significantly affected transplant recipients' mortality. Late‐onset occurred even > 10 years after transplantation; therefore, long‐term monitoring of patients is needed.     

Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation

K.A. Walsh, G.A. Davis, D. Jr Hayes, R.J. Kuhn, K.A. Weant, J.D. Flynn. Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation.
Transpl Infect Dis 2011: 13: 616–621. All rights reserved Study objectives. To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant. Design. Retrospective, single‐center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half‐life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation. Setting. Medical school‐affiliated teaching hospital. Patients. Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years). Interventions. None. Main results. Sixty‐nine sets of pre‐ (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1 h^‐1 (P<0.001), with a related increase of 200% in half‐life from 2.8±0.8 to 8.4±8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3±32.3 to 50.2±15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7±2.5 and 7.6±1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0–3 weeks and ≥6 weeks post transplant, based on available data. Clearance and Vd ≥6 weeks post transplant did not significantly differ from pre‐transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary. Conclusions. The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter‐patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant.     

Prognostic impact of minimal residual disease analysis by flow cytometry in patients with acute myeloid leukemia before and after allogeneic hemopoietic stem cell transplantation

Allogeneic stem cell transplantation (allo‐SCT) has become the treatment of choice in patients with intermediate‐risk and high‐risk acute myeloid leukemia (AML). The quality of response to treatment, assessed in terms of detection of minimal residual disease (MRD), has been consistently associated with prognosis and clinical outcome in patients with AML. The aim of the present study was to evaluate the prognostic impact of analyzing MRD in bone marrow using 4‐color multiparametric flow cytometry (MFC) in 29 patients with AML before and after allo‐SCT. Eighteen patients who were shown to be MRD‐negative [≤0.1% leukemia‐associated immunophenotypes (LAIPs)] by MFC at transplantation and underwent allo‐SCT had lower rates of relapse (15% vs. 66%, P = 0.045), better overall 1‐yr survival (83% vs. 52%, P = 0.021) and a lower cumulative incidence of relapse (P = 0.032) than patients who were MRD‐positive (>0.1%). All post‐transplant MRD‐positive patients underwent a therapeutic intervention after transplant (tapering of immunosuppression, donor lymphocyte infusion, or re‐transplant) with the intention of preventing relapse. Disease was controlled and MRD disappeared in five of these patients. Disease recurred in the other seven patients. We can conclude that follow‐up with MFC for the detection of MRD in AML before and after SCT is useful for predicting relapse. In the post‐transplant setting, monitoring of MRD by MFC could be a key preemptive intervention.     

Predictive value of risk assessment scores in patients with hematologic malignancies undergoing reduced‐intensity conditioning allogeneic stem cell transplantation

Reduced‐intensity conditioning allogeneic stem cell transplantation (RIC allo‐SCT) is associated with less toxicity and is used for older patients. We retrospectively studied the predictive value of two risk assessment scores, which were the hematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) and the pre‐transplantation assessment of mortality (PAM) score, for assessing the outcome of RIC allo‐SCT. Seventy‐eight patients underwent transplantation between 2005 and 2013 at a single institution. RIC was performed with fludarabine and melphalan with/without total body irradiation. The 3‐year overall survival of patients with an HCT‐CI >3 was significantly worse than that of patients with an HCT‐CI 0–3 (31.6% vs. 59.6%, P = 0.020). Also, the 3‐year overall survival of patients with a PAM score >24 was significantly worse than that of those with a PAM score ≤24 (29.2% vs. 61.4%, P = 0.005). The present findings suggest that changing the cut‐off values of these risk assessment scores can improve prediction of outcomes in patients receiving RIC allo‐SCT with this conditioning regimen and we need validation by large‐scale study with other regimens. Am. J. Hematol. 89:E138–E141, 2014. © 2014 Wiley Periodicals, Inc.     

Epstein–Barr virus (EBV) genotypes among human immunodeficiency virus (HIV)‐related B‐cell Lymphomas and B‐cell post‐transplant lymphoproliferative disorders (B‐PTLD) – late‐onset lymphomas,especially in the HIV setting,are associated with type‐B‐EBV

We investigated 26 B‐cell post‐transplant lymphoproliferative disorders (B‐PTLD) and 15 human immunodeficiency virus‐related aggressive B‐cell lymphomas (HIV‐BCL) from England that were associated with Epstein–Barr virus (EBV) for the polymorphic sequences of the EBV‐encoded nuclear antigen 3C (EBNA3C) gene to distinguish the two different EBV strains. Type‐A‐EBV was identified in 92% of B‐PTLDS and in 53% of HIV‐BCL (P = 0.003). Among HIV‐BCL, patients associated with type‐B‐EBV had been HIV positive for significantly longer when compared to those associated with type‐A (P = 0.037) although there were no correlations with ethnicity, CD4 cell counts or plasma HIV viral load.     

Minimal residual disease monitoring after allogeneic transplantation may help to individualize post‐transplant therapeutic strategies in acute myeloid malignancies

This study evaluates the prognostic value of minimal residual disease (MRD) monitoring by multiparametric flow cytometry in 41 patients with acute myeloid leukemia or myelodysplastic syndrome undergoing allogeneic transplantation. MRD assessment after transplant (day +100) allowed to discriminate different risk populations, being the most significant cut‐off value for outcome level of MRD ?3. Outcome was significantly better among patients with low (<10^?3) versus high (≥10^?3) MRD at day +100 after transplant. Thus, overall survival was 73% versus 25% at 4 years among patients with low versus high MRD at day +100 after transplant (P = 0.002); 74% of patients with low MRD were event free at 4 years as compared to 17% among patients with high MRD (P = 0.01). In multivariate analysis, MRD value as well as chronic GVHD significantly influenced outcome. In conclusion, MRD monitoring early post‐transplant is an important tool for outcome prediction and should be considered in decision making after allogeneic transplantation. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.     

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients

D. Neofytos, J.A. Fishman, D. Horn, E. Anaissie, C.‐H. Chang, A. Olyaei, M. Pfaller, W.J. Steinbach, K.M. Webster, K.A. Marr. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.
Transpl Infect Dis 2010: 12: 220–229. All rights reserved Abstract: Contemporary epidemiology and outcomes of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients are not well described. From March 2004 through September 2007, proven and probable IFIs were prospectively identified in 17 transplant centers in the United States. A total 429 adult SOT recipients with 515 IFIs were identified; 362 patients received a single and 67 patients received ≥2 organs. Most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%), and other molds (5.8%). Invasive candidiasis (IC) was the most frequently observed IFI in all groups, except for lung recipients where invasive aspergillosis (IA) was the most common IFI (P<0.0001). Almost half of IC cases in liver, heart, and lung transplant recipients occurred during the first 100 days post transplant. Over half of IA cases in lung recipients occurred >1 year post transplant. Overall 12‐week mortality was 29.6%; liver recipients had the highest mortality (P=0.05). Organ damage, neutropenia, and administration of corticosteroids were predictors of death. These results extend our knowledge on the epidemiology of IFI in SOT recipients, emphasizing the occurrence of IC early after non‐lung transplant, and late complications with molds after lung transplant. Overall survival appears to have improved compared with historical reports.     

Epstein‐Barr virus associated post‐transplant lymphoproliferative disorder mimicking acute graft versus host disease

We present a case series of 3 patients to highlight the fact that PTLD post‐transplant can mimic GVHD, and should be part of the differential diagnosis for diarrhea post allo‐HCT. Awareness of this presentation has important therapeutic implications, as increased immune suppression for the management of GVHD, can worsen clinical features of PTLD. Diagnostic imaging and tissue biopsies should be undertaken early in post‐transplant patients presenting with diarrhea or hepatic abnormalities, especially with atypical presentations like fever, and EBV PCR monitoring can expedite clinical decision‐making in such complicated scenarios while awaiting results of gut biopsies.     

Significant post‐transplant hypogammaglobulinemia in six heart transplant recipients: an emerging clinical phenomenon?

Background: The recent development of powerful agents such as mycophenolate mofetil and tacrolimus has altered current regimens for the prevention and treatment of allograft rejection. Questions have been raised about these newer regimens in terms of susceptibility to opportunistic infections and effects on host defenses. Severe hypogammaglobulinemia has been infrequently described in solid organ transplant recipients, but has been recently noted in six heart transplant recipients at one center, of whom five were receiving a combination of tacrolimus, mycophenolate mofetil, and prednisone. Methods: Case summaries of six recent heart transplant recipients with total immunoglobulin G (IgG) levels of less than 310 mg/dl, five of whom had cytomegalovirus (CMV) infection and three of whom had multiple infections including Nocardia, invasive Trichophyton, and Acinetobacter bacteremia. Previous literature was reviewed with the aid of a Medline search using the search terms hypogammaglobulinemia; kidney, liver, heart, lung, and organ transplantation; mycophenolate mofetil; tacrolimus; cyclosporine; azathioprine; and nocardiosis. Results: We here report six cardiac transplant recipients seen over a period of one year who were found to have immunoglobulin G levels of 310 mg/dl or below (normal: 717–1400 mg/dl). The first five patients were diagnosed because of evaluation for infections; the sixth, who was asymptomatic with an IgG level of 175, was found during screening for hypogammaglobulinemia instituted as a result of these first five patients. All six patients had received steroid pulses for rejection; all received mycophenolate mofetil; and 5/6 had been switched from cyclosporine to tacrolimus because of steroid‐resistant rejection. Transient neutropenia (absolute neutrophil count less than 1000) was observed in 2/6; 3/6 had received OKT3 therapy for refractory rejection. These six patients were treated with a combination of antimicrobials, immunoglobulin replacement, and decrease in immunosuppressive therapy. Conclusions: The finding of unexpected hypogammaglobulinemia and concomitant infectious complications in six heart transplant recipients highlights a possible complication in a subset of patients receiving newer immunosuppressive agents. A larger prospective study is underway to determine risk factors for development of post‐transplant hypogammaglobulinemia and to assess pre‐transplant immune status of these recipients. Monitoring of immunoglobulin levels in high‐risk patients receiving intensified immunosuppressive therapy for rejection may help to prevent infectious complications.     

Allogeneic hematopoietic stem cell transplantation for adult patients with mixed phenotype acute leukemia: results of a matched‐pair analysis

Adult patients with mixed phenotype acute leukemia (MPAL) have a poor prognosis, and the therapeutic role of allogeneic stem cell transplantation (allo‐SCT) for MPAL remains to be elucidated. Thus, we retrospectively assessed the efficacy of allo‐SCT for MPAL. Eighteen patients with MPAL were identified from the transplant outcome database of Kanto Study Group for Cell Therapy (KSGCT). We also selected 215 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) as control cohorts using an optimal matching method. The 5‐yr overall survival (OS) rate of patients with MPAL was 48.1%, and patients in remission at the time of transplant showed significantly better survival than those not in remission (5‐yr OS: 71.8% vs. 0%, P = 0.001). No significant differences were seen in OS when stratifying patients according to immunophenotype, cytogenetic abnormalities, or the type of induction therapy. The 5‐yr OS rate of patients with MPAL was not significantly different compared with AML control patients (48.1% vs. 48.1%; P = 0.855) or ALL control patients (48.1% vs. 37.8%; P = 0.426). These results suggested that allo‐SCT is an effective treatment for MPAL, especially early in the disease course, and innovative transplant approaches are warranted to improve the transplant outcome of patients with MPAL who are not in remission.     

Long‐term outcomes of direct acting antivirals in post‐transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis

Long‐term functional outcomes of sofosbuvir‐based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post‐transplant hepatitis C virus (HCV) recurrence. Seventy‐three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24‐week sofosbuvir with ribavirin±pegylated interferon or interferon‐free sofosbuvir‐based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82‐112) weeks. Twelve of 73 (16.4%) died (10 non‐FCH, 2 FCH) and two underwent re‐LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non‐FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow‐up, MELD and Child‐Turcotte‐Pugh scores improved both in non‐FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short‐treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long‐term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child‐Turcotte‐Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals‐based treatments for severe post‐transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long‐term survival. The setting of severe HCV recurrence may require the identification of “too‐sick‐to‐treat patients” to avoid futile treatments.     

Infectious complications in living‐donor liver transplant recipients: a 9‐year single‐center experience

Background. Infectious complications following living‐donor liver transplantation (LDLT) remain a major cause of morbidity and mortality. We analyzed the frequency and type of infectious complications according to the post‐transplantation period, and their risk factors with regard to morbidity and mortality. Methods. We retrospectively analyzed 208 subjects who had undergone LDLT during a 9‐year period. Results. The rate of infection was 1.69 per patient during the study period. The predominant infections were intra‐abdominal infections (37.6%), primary bacteremia (17.4%), and pneumonia (14.5%). Within the first post‐transplant month, 140 (39.9%) infections were detected, and catheter‐related coagulase‐negative staphylococci (44) were the most common infectious agents. During the 2–6‐month post‐transplant period, 109 infectious episodes occurred (31.1%), and Enterococcus sp. (n=16) related to biliary infection was the most frequent isolate. After the sixth month, 96 infectious episodes (29%) occurred, and biliary tract‐related Escherichia coli (n=19) was the major causative organism. The overall mortality was 24.5% (51/208); 1‐year survival rate was 88% (196/208). Post‐transplant infection‐related mortality was 52.9% (27/51). Biliary tract complications, such as biliary stenosis or leakage, significantly increased the mortality (P=0.01); however, reoperation (retransplantation or resurgery for biliary tract obstruction/leakage or to control bleeding) significantly reduced the mortality (P=0.01). Conclusions. Our data showed that early catheter removal would mainly aid in reducing infectious complications in the 1‐month post‐transplantation period. Aggressive management, including reoperation, would lower the mortality in the LDLT recipients.     

Post‐transplant recurrent hepatitis C: immunohistochemical detection of hepatitis C virus core antigen and possible pathogenic implications

Introduction: The mechanisms by which severe cholestatic hepatitis develops after liver transplantation are not fully understood. Reports on immunohistochemical distribution of hepatitis C virus (HCV) antigens are still scarce, but recently, HCV immunostaining was suggested for early diagnosis of cholestatic forms of recurrent hepatitis C in liver grafts. After purification, Rb246 pab anticore (aa1‐68) yielded specific, granular cytoplasmic staining in hepatocytes. Signal amplification through the Envision‐Alkaline Phosphatase System avoided endogenous biotin and peroxidase. Aims/Methods: Rb246 was applied to liver samples of explants of 12 transplant recipients, six with the most severe form of post‐transplantation recurrence, severe cholestatic hepatitis (group 1) and six with mild recurrence (group 2). We also assessed immuno‐reactivity at two time‐points post‐transplantation (median 4 and 22 months) in both groups. HCV‐core Ag was semiquantified from 0 to 3+ in each time point. Serum HCV‐RNA was also measured on the different time points by branched DNA. Results: In the early post‐transplant time point, one patient had a mild staining (1+), two patients had a moderate staining (2+) and the other three had no staining in group 1, compared with five patients with no staining (0) and one patient with mild staining (1+) in group 2. Late post‐transplant liver samples were available in nine patients, and two out of four samples in group 1 showed a mild staining, compared with no staining patients in five patients in group 2. Strikingly, on the explant samples, HCV immunostaining was strongly positive in group 1, and mildly positive in group 2. Two out of five samples showed 3+ staining, and three samples showed 2+ staining in group 1; two out of five samples showed no staining, two samples showed 1+ staining and one sample showed 2+ staining in group 2. Serum HCV‐RNA was significantly higher in group 1, on both time‐points post‐transplantation. HCV‐core Ag was not directly associated with serum HCV‐RNA on the different time points. Conclusion: These preliminary results suggest that strong HCV immunostaining in the explant is predictive of more severe disease recurrence.     

Post‐transplant consolidation plus lenalidomide maintenance vs lenalidomide maintenance alone in multiple myeloma: A systematic review

Background

In newly diagnosed multiple myeloma (NDMM), autologous stem cell transplantation (ASCT) remains the standard approach for transplant‐eligible patients. To control the inevitable relapse, post‐transplant consolidation/maintenance strategies are commonly used. However, the benefit of post‐transplant consolidation is still uncertain

Method

We conducted a systematic review of phase II/III studies to compare the efficacy of post‐ASCT consolidation plus lenalidomide maintenance (CON+LEN) vs lenalidomide maintenance alone (LEN alone) in NDMM. A meta‐analysis using fixed and random effects models was performed.

Results

Fourteen studies were included with 2275 participants with NDMM treated with ASCT and lenalidomide maintenance. Two groups were identified: CON+LEN group (n = 1102) and LEN alone group (n = 1173). There was no statistically significant difference in the complete response rate between the two groups [RR = 1.1; 95% CI: 0.83‐1.44; P = .490]. Interestingly, we found that very good partial response or better rate is around 1.5‐fold significantly higher in the CON+LEN group compared to LEN alone group [RR: 1.46; 95% CI: 1.25‐1.70; P < .0001]. However, there was no significant difference between the two groups regarding PFS [RR: 1.0; 95% CI: 0.92‐1.08, P = .929] and OS [RR: 0.9; 95% CI: 0.92‐1.01; P = .148] at 3‐4 years follow‐up. The risk of secondary primary malignancy (SPM) was also similar between the two groups (RR: 1.2; 95% CI: 0.84‐1.92; P = .2). Data on adverse events were limited.

Conclusion

Our data suggest that, in NDMM patients treated with upfront ASCT, post‐transplant consolidation may improve depth of response, but does not add to OS or PFS, compared to lenalidomide maintenance alone. However, data in this context are still immature.     

Risk factors and clinical outcomes of pediatric liver transplant recipients with post‐transplant lymphoproliferative disease in a multi‐ethnic Asian cohort

Background

We aimed to evaluate clinical characteristics, risk factors, and disease outcomes for liver transplant recipients (LTR) with post‐transplant lymphoproliferative disease (PTLD) at our center.

Methods

Retrospective review of data of all pediatric LTR (1991‐2015) was conducted.

Results

The overall incidence of PTLD was 16.4% (18/110), the majority (13/18) were early lesions, while 3/18 were polymorphic/monomorphic PTLD. The risk factors significant on univariate analysis were as follows: mean age (years) at transplant (1.66 vs 4.76, P = .006); age <2 years at transplant (odds ratio [OR] 3.53 [95% confidence interval [CI]: 1.16‐10.73], P = .026); cytomegalovirus (CMV) primary infection (OR 11.39 [95% CI: 3.44‐37.7], P < .001); recipient CMV seronegativity (OR 7.50 [95% CI: 2.02‐27.78], P = .003); presence of CMV end‐organ disease (OR 4.00 [95% CI: 1.22‐13.16], P = .022); Chinese ethnicity; and higher mean duration of intravenous ganciclovir prophylaxis. In multivariate analysis, CMV primary infection (OR 5.22 [95% CI: 1.25‐21.87], P = .024), CMV seronegativity (OR 5.91 [95% CI: 1.13‐30.90, P = .035]), and having acute cellular rejections (ACR) prior to PTLD (OR 5.53 [95% CI: 1.43‐21.48, P = .013]) were significant risk factors for PTLD, with the latter two factors having a synergistic effect in increasing PTLD risk in a stratified analysis. The final multivariate model in predicting the risk of PTLD, utilizing CMV primary infection, recipient CMV seronegativity, and ACR before PTLD as predictive variables, was statistically significant (likelihood ratio chi square statistic = 25.18, P < .0001 with df = 3).

Conclusions

We report a unique clinicopathologic and risk factor profile in our cohort—early lesion PTLD accounts for the majority and the incidence of monomorphic PTLD remains low. In addition, we show a synergism between CMV naivety and ACR on PTLD risk, a higher prevalence of gastrointestinal manifestations, and a lack of significant association with Epstein‐Barr virus seronegativity.