Human CMV‐specific T‐cell responses in kidney transplantation; toward changing current risk‐stratification paradigm

Despite the great efficacy of current antiviral preventive strategies, hCMV infection is still a major complication after renal transplantation, significantly challenging patient and graft survival. This issue seems to be explained because of the rather poor immunologic monitoring of the antiviral immune response. An important body of evidence has shown that monitoring the hCMV‐specific T‐cell response, at different time points of the transplant setting, seems to add crucial information for predicting the risk of viral infection, thus potentially helping individualization of therapeutic decision‐making in clinical transplantation. While several immune‐cellular assays have shown its capability for accurately monitoring hCMV‐specific T‐cell responses, only few such as the IFN‐γ ELISPOT and the ELISA based technology assays might be reliable for its application in the clinic. Nonetheless, an important effort has to be made among the transplant community to standardize and validate such immune assays. Noteworthy, large‐scale prospective randomized trials are highly warranted to ultimately introduce them in current clinical practice as a part of the highly desired personalized medicine.     

Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients

This study aimed to evaluate the outcome following myeloablative allogeneic hematopoietic stem cell transplantation (SCT) among patients older than 50 yr of age. A total of 215 patients with a median age of 57 yr underwent allogeneic hematopoietic SCT for early (41%) or advanced (59%) hematologic malignancies. After a median follow-up of 36 months a 10-yr survival estimate of 56 +/- 6% could be assessed for patients in early disease stages while patients with advanced diseases showed a significantly decreased survival probability of 31 +/- 5% (p < 0.0002). Transplant related mortality (TRM) at day 100 and 365 post-transplant was 13% and 30% for early but increased to 21% and 49% for advanced disease stages. As major determinants of TRM advanced disease stage (p < 0.0001) and occurrence of grades II-IV graft-vs.-host disease (GVHD) (p < 0.0001) were identified. These results show that hematopoietic SCT following myeloablative conditioning is also applicable to elderly patients whereas disease stage and high-grade GVHD represent the essential prognostic factors for outcome.     

The significance of cytomegalovirus viremia at day 100 or more following allogeneic hematopoietic stem cell transplantation

We conducted a single‐center retrospective review of patients who had received allogeneic hematopoietic stem cell transplantation (HSCT) between January 2003 and December 2007, to assess the incidence and risk factors for late CMV infection and evaluate its effects on outcomes. Twenty of 49 HSCT recipients (41%) developed CMV infection at day ≥100 after transplant. Univariable analysis showed that having a matched unrelated donor, having early CMV infection, having a diagnosis of lymphoma, and receipt of antithymocyte globulin were risks for developing late CMV. On multivariable analysis, the occurrence of CMV prior to day 100 and lymphoma conferred a significant risk for late CMV infection. Of the 20 patients with late CMV infection, two patients manifested CMV disease (10%). Despite the relatively low incidence of CMV disease, patients with late CMV infection had a 4.8‐fold increased risk of death compared to patients without late CMV. Identifying patients at increased risk for developing late CMV infection may be important for prompting more intensive monitoring of infection late after HSCT, particularly because this manifestation of CMV is associated with poorer outcomes.     

Viral load,CMV‐specific T‐cell immune response and cytomegalovirus disease in solid organ transplant recipients at higher risk for cytomegalovirus infection during preemptive therapy

Despite advances in prevention, cytomegalovirus (CMV) recurrence is an important challenge in high‐risk organ recipients. The present study prospectively evaluates the impact of CMV‐specific T‐cell immune response and secondary prophylaxis on the risk of recurrence in a cohort of CMV high‐risk organ recipients and whether it is possible to determine a safe standardized viral load value below which CMV disease is unlikely. Thirty‐nine recipients were included. Thirty‐six had primary infections, and 88.9% recurred. Rate and duration of recurrent CMV infection was similar in patients with and without secondary prophylaxis: 57.9% vs. 53.6%, P = 0.770 and 16 vs. 15 days, P = 0.786, respectively. The only factor independently associated with no episodes of CMV recurrence was the acquisition of CMV‐specific T‐cell immune response (OR: 0.151, 95% CI: 0.028–0.815; P = 0.028). Cytomegalovirus diseases (N = 5) occurred in patients with CMV viral load above 1500 IU/ml who did not follow the planned monitorization schedule. Our observations suggest that episodes of recurrent CMV infection are common after preemptive therapy despite secondary prophylaxis and that CMV‐specific T‐cell immune response is associated with a decreased risk of recurrent infections. Preemptive therapy may be safe in patients at high risk for CMV infection with strict close monitoring of the CMV viral load.     

A rare complication after allogeneic stem cell transplantation: post‐transplant erythrocytosis

Post‐transplant erythrocytosis is an infrequent complication and has been reported after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in aplastic anemia, acute myeloid leukemia, and chronic myeloid leukemia. The pre‐disposing factors and treatment are not clearly defined. We present 11 post‐transplant erythrocytosis cases. More studies should be conducted to distinguish the pathogenesis and follow‐up for this rare complication.     

Use of G‐CSF‐stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review

Chang Y‐J, Huang X‐J. Use of G‐CSF‐stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review.
Clin Transplant 2011: 25: 13–23. © 2010 John Wiley & Sons A/S. Abstract: In recent years, several researchers have unraveled the previously unrecognized effects of granulocyte colony‐stimulating factor (G‐CSF) on hematopoiesis and the immune cell functions of bone marrow in healthy donors. In human leukocyte antigen‐matched or haploidentical transplant settings, available data have established the safety of using G‐CSF‐stimulated bone marrow grafts, as well as the ability of this source to produce rapid and sustained engraftment. Interestingly, G‐CSF‐primed bone marrow transplants could capture the advantages of blood stem cell transplants, without the increased risk of chronic graft‐versus‐host disease that is associated with blood stem cell transplants. This review summarizes the growing body of evidence that supports the use of G‐CSF‐stimulated bone marrow grafts as an alternative stem cell source in allogeneic hematopoietic stem cell transplantation.     

Impact of cyclosporine‐A concentration in T‐cell replete haploidentical allogeneic stem cell transplantation

This paper aims to study whether cyclosporine‐A (CSA) levels have an impact on the clinical outcome of patients with T‐cell replete haploidentical allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We analyzed 140 consecutive patients who had been given T‐cell replete haploidentical allo‐HSCT in our institute to assess the effect of CSA concentration in the early stages of allo‐HSCT on clinical outcomes, such as hematopoietic recovery, acute graft vs host disease (aGVHD), infection, disease‐free survival (DFS), and overall survival (OS). The median concentrations of CSA in the blood in the 1st, 2nd, 3rd, and 4th week after allo‐HSCT were 218, 235, 263, and 270 ng/mL, respectively. Additionally, 46%, 40%, 27%, and 18% of the patients had CSA blood levels below 200 ng/mL during those weeks. In total, 39 patients developed aGVHD (grade II‐IV), for a cumulative incidence of 27.8%, at a median of 32 days. Patients having a low CSA concentration (below 200 ng/mL) in the 3rd week had a higher cumulative incidence of grade II‐IV aGVHD (P = .02). In addition, multivariate logistic regression analysis showed that low CSA concentration (below 200 ng/mL) in the 3rd week was an independent risk factor of grade II‐IV aGVHD (P = .02; odds ratio = 2.66; 95% CI, 1.15‐6.17). However, CSA levels during the first 4 weeks did not have a significant impact on the patients’ hematopoietic recovery, infection, DFS, and OS. Our data indicated that adequate management of CSA levels during the peri‐engraftment period might improve clinical outcomes for those with T‐cell replete haploidentical allo‐HSCT.     

No effect of HLA‐C mismatch after allogeneic hematopoietic stem cell transplantation with unrelated donors and T‐cell depletion in patients with hematological malignancies

HLA‐C mismatch in unrelated donor's hematopoietic stem cell transplantation (HSCT) has been associated with poor patient outcome. However, the impact of HLA‐C mismatch in the context of HSCT combined with in vivo T‐cell depletion remains unclear. We therefore performed a single‐center, retrospective analysis of the clinical outcome on patients with hematological malignancies treated with allo‐HSCT, who underwent T‐cell depletion. The majority of the patients (n=276) received a HLA‐A, HLA‐B, HLA‐DRB1‐matched graft that were either also HLA‐C matched (n=260), or patients with the permissive HLA‐C*03:03/03:04 mismatch (n=16), while the remaining patients (n=95) received a HLA‐C‐mismatched graft (excluding HLA‐C*03:03/03:04 mismatches). We did not observe any significant differences between the HLA‐C‐matched patients (including the permissive HLA‐C*03:03/03:04 mismatch) and the HLA‐C‐mismatched patients regarding cumulative proportion surviving, graft failure, relapse‐free survival, relapse, or acute graft‐versus‐host disease. Our data suggest that in the context of high dose T lymphocyte‐depleting agents, HLA‐C matching is not essential for patients with hematological malignancies.     

Lack of evidence for a reciprocal interaction between bacterial and cytomegalovirus infection in the allogeneic stem cell transplantation setting

Pathogenic interactions between bacteria and cytomegalovirus (CMV) may potentially occur early after allogeneic stem cell transplantation (allo‐SCT). This possibility nevertheless has not been investigated in depth. This was a retrospective study that included 170 consecutive patients who underwent 173 allo‐SCTs. Both bacterial infection (most of which were bacteremic) and CMV DNAemia were detected in 78 allo‐SCTs (62.9%). In total, 51 and 32 episodes of bacterial infection preceded or occurred after CMV DNAemia detection, respectively. Both events were diagnosed concurrently in four allo‐SCTs. The cumulative incidence of bacterial infection (of any type) over the study period was comparable in patients with or without a preceding episode of CMV DNAemia (P = 0.321). Cox proportional hazards regression analysis failed to identify CMV DNAemia as a significant risk factor for bacterial infection. Likewise, the cumulative incidence of CMV DNAemia within the study period was not significantly different in patients with or without a preceding episode of bacterial infection (P = 0.189). Furthermore, the occurrence of bacterial infection within episodes of active CMV infection had no apparent impact on the kinetics of CMV DNAemia. Our data, thus, do not support the existence of a bidirectional synergistic effect between bacterial infection and active CMV infection in the allo‐SCT setting.     

Prospective study of infectious complications in allogeneic hematopoietic stem cell transplant recipients

Martín‐Peña A, Aguilar‐Guisado M, Espigado I, Parody R, Cisneros JM. Prospective study of infectious complications in allogeneic hematopoietic stem cell transplant recipients.
Clin Transplant 2011: 25: 468–474. © 2010 John Wiley & Sons A/S. Abstract: This is a prospective, observational study of a consecutive cohort of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) adult recipients conducted between July 2003 and May 2006, with the aim of identifying the current incidence, etiology, risk factors for infections and associated mortality up to two yr after allo‐HSCT. Seventy‐four episodes of infection were recorded in 38 patients, 50 consecutive adult patients underwent 54 allo‐HSCT. The incidence of infection was 1.36 (68/50) episodes/patient after the first year of transplantation and 1.48 (74/50) episodes/patient after first two yr of transplantation. The most common syndrome was cytomegalovirus (CMV) infection, followed by catheter‐related bloodstream infection and pneumonia. An etiological diagnosis was established in 85.1% of the episodes. Bacteria were the most common etiology (55.5%), followed by viruses (41.3%) and fungi (4.8%). CMV was the most common viral agent (73%), and all fungal infections were caused by molds. Myeloablative conditioning regimen, chronic graft‐versus‐host disease, and medical complications post‐transplant were independent risk factors for infection. The global mortality two yr after transplantation was 32%, and death was infection related in 12%. In spite of advances, infections continue to be a common cause of morbidity and mortality following allo‐HSCT.     

Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single‐center experience

To examine risk factors for Stenotrophomonas maltophilia (S. maltophilia) infection during allogeneic hematopoietic stem cell transplantation (allo‐HSCT), we retrospectively analyzed 259 patients who underwent allo‐HSCT. Not only S. maltophilia infection but also S. maltophilia colonization was associated with mortality during allo‐HSCT. Among 52 episodes in 39 patients in whom S. maltophilia was detected, documented infection developed in 33 episodes (25 patients). The onset of S. maltophilia infection in the period from the conditioning regimen to engraftment was associated with a high mortality rate. Breakthrough S. maltophilia infection developed in 24% of the patients during prophylactic administration of fluoroquinolones, to which S. maltophilia is sensitive. Reinsertion of a central venous catheter (CVC) immediately after removal was suggested to be a risk for persistent S. maltophilia infection in the period of neutropenia. Our results indicated that (i) onset of S. maltophilia infection in the period from the conditioning therapy to engraftment and (ii) removal and immediate reinsertion of a CVC as treatment after the onset of S. maltophilia infection are possible risk factors for S. maltophilia‐related mortality during allo‐HSCT.     

Radiation and host retinoic acid signaling promote the induction of gut‐homing donor T cells after allogeneic hematopoietic stem cell transplantation

Intestinal graft‐versus‐host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut‐tropic donor T cells expressing integrin α4β7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing α4β7 expression on T cells. In this study, we showed that gene expression of retinaldehyde dehydrogenase, the key enzyme involved in RA biosynthesis, is significantly increased in the spleen and mesenteric lymph nodes (MLNs) of irradiated mice. In a C57BL/6‐into‐B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of α4β7⁺‐donor T cells in mesenteric lymph nodes and spleen. Furthermore, we found that the RA pathway modulates the ability of dendritic cells to imprint gut‐homing specificity on alloreactive T cells. We also showed that host dendritic cell RA signaling influences GVHD risk. Our studies identified radiation and recipient RA signaling as 2 primary factors that dictate the magnitude of gut‐homing donor T cell induction after allogeneic HSCT. Attenuating radiation‐associated inflammation and modulating host RA signaling represent feasible strategies to mitigate intestinal GVHD by reducing gut‐seeking pathogenic donor T cells.     

Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA. METHODS: A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC). RESULTS: Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed. CONCLUSIONS: The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.     

A case–control study of bronchiolitis obliterans syndrome following allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans syndrome (BOS) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, the pathogenesis and risks for the development of BOS have remained unclear. Therefore, a case–control study was conducted to investigate the risk factors for the development of BOS, which included the largest number of BOS cases; 196 patients with BOS were identified and compared with 1960 control recipients. The following were identified as significantly higher risk factors for the development of BOS: female recipients (OR 1.47, P = 0.019), ABO‐mismatch HSCT (minor mismatch, OR 1.67, P = 0.015; major mismatch, OR 1.73, P = 0.012; bidirectional mismatch, OR 1.96, P = 0.018), busulfan+cyclophosphamide‐based myeloablative conditioning (OR 1.74, P = 0.016), and acute graft‐versus‐host disease (GVHD) involving the skin (OR 1.55, P = 0.011). On the other hand, the risk for the development of BOS was significantly lower in patients receiving cord blood transplantation (OR 0.26, P = 0.0011). With respect to other target organs of chronic GVHD, ocular involvement was significantly associated with BOS (OR 2.53, P < 0.001). Prospective studies are required to elucidate the risk factors for the development of BOS, and future investigations should focus on finding a prophylactic approach against BOS based on these findings.     

Clinical efficacy of prophylactic strategy of long-term low-dose acyclovir for Varicella-Zoster virus infection after allogeneic peripheral blood stem cell transplantation

Varicella-Zoster virus infection (VZV) has a high incidence post-allogeneic peripheral blood stem cell transplant (PBSCT). However, data regarding long-term acyclovir prophylaxis for VZV prevention are limited. We evaluated the clinical efficacy of long-term low-dose acyclovir prophylaxis for VZV infection after allogeneic PBSCT at the Princess Margaret Hospital (PMH), Canada and the Kyungpook National University Hospital (KNUH), Korea. The acyclovir prophylaxis regimen at PMH was acyclovir 400 mg/d orally until engraftment, and at KNUH was acyclovir 800 mg/d orally until immunosuppression discontinuation. Long-term acyclovir prophylaxis was given to 26/193 (14%) patients in the PMH group and 73/79 (92%) patients in the KNUH group. In the PMH group, 42 cases (22%) developed VZV infection, while six cases (8%) had VZV infection in the KNUH group (p = 0.005). With a median of 26.5 months of follow-up, the incidences of VZV infection at one and two yr were 15.8% and 20.7% in the PMH group, and 2.5% and 5.8% in the KNUH group, respectively (p = 0.001). By controlling the other potential risk factors for VZV infection in multivariate analysis, the use of long-term acyclovir was the only protective factor for VZV infection after allogeneic PBSCT (p = 0.04, hazard ratio = 0.296). Long-term use of acyclovir appears to be protective for VZV infection after allogeneic PBSCT, especially during the period of immunosuppressive therapy.     

Role of plasmacytoid dendritic cells in immunity and tolerance after allogeneic hematopoietic stem cell transplantation

Dendritic cells (DC) may play an important role in the pathogenesis of alloimmune reactions, such as graft-vs.-host disease after allogeneic hematopoietic stem cell transplantation (HSCT). In humans, two types of DC-myeloid DC (mDC) and plasmacytoid DC (pDC) have been characterized and have distinct origins and functions. The data obtained from studies in vitro suggest that pDC are involved in the regulation of immunity, including the induction and maintenance of tolerance, as well as in the defence against viruses. The authors will review all the evidence currently available from reports exploring the role of pDC in clinical allogeneic HSCT.     

Metabolic bone diseases in patients after allogeneic hematopoietic stem cell transplantation: Report from the Consensus Conference on Clinical Practice in chronic graft‐versus‐host disease

With improved outcome of allogeneic stem cell transplantation (allo‐SCT) for hematologic malignancies, long‐term complications gain greater importance. Skeletal complications such as osteoporosis or avascular necrosis (AVN) occur frequently in allogeneic recipients with a cumulative incidence of diminished bone mineral density of 24–50% between 2 and 12 months after allo‐SCT and a cumulative incidence of AVN in as many as 19% of patients 3 years after allo‐SCT. Here, we present a review as part of the German, Austrian, and Swiss Consensus Conference on clinical practice in chronic graft‐versus‐host disease, held 2009 in Regensburg. The Consensus Conference aimed to achieve a consensus on the current evidence of diagnosis, prevention, and therapeutic options of late complications after allo‐SCT summarizing and discussing the literature on these topics. In this report, we provide recommendations for metabolic bone diseases agreed upon by the working party. This includes guidelines for diagnosis, prevention, and therapeutic options in patients with low bone mass or AVN.