Jeffery J. Auletta

Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.

Human Mesenchymal Stromal Cells Attenuate Graft‐Versus‐Host Disease and Maintain Graft‐Versus‐Leukemia Activity Following Experimental Allogeneic Bone Marrow Transplantation

We sought to define the effects and underlying mechanisms of human, marrow‐derived mesenchymal stromal cells (hMSCs) on graft‐versus‐host disease (GvHD) and graft‐versus‐leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T cells and treated with hMSCs had reduced systemic GvHD, donor T‐cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72 hours, and target tissues harvested from hMSC‐treated allogeneic BMT (alloBMT) mice had less GvHD than untreated controls. Cryoimaging more precisely revealed that hMSCs preferentially distributed to splenic marginal zones and regulated T‐cell expansion in the white pulp. Importantly, hMSCs had no effect on in vitro cytotoxic T‐cell activity and preserved potent GvL effects in vivo. Mixed leukocyte cultures containing hMSCs exhibited decreased T‐cell proliferation, reduced TNFα, IFNγ, and IL‐10 but increased PGE2 levels. Indomethacin and E‐prostanoid 2 (EP2) receptor antagonisms both reversed while EP2 agonism restored hMSC‐mediated in vitro T‐cell suppression, confirming the role for PGE2. Furthermore, cyclo‐oxygenase inhibition following alloBMT abrogated the protective effects of hMSCs. Together, our data show that hMSCs preserve GvL activity and attenuate GvHD and reveal that hMSC biodistribute to secondary lymphoid organs wherein they attenuate alloreactive T‐cell proliferation likely through PGE2 induction. Stem Cells 2015;33:601–614

Emerging Influence of the Intestinal Microbiota during Allogeneic Hematopoietic Cell Transplantation: Control the Gut and the Body Will Follow

The intestinal microbiota has many critical roles in maintaining gastrointestinal epithelial and gastrointestinal systemic immune homeostasis. This review provides insight into how allogeneic hematopoietic cell transplantation (HCT) and its associated complications and supportive care therapies affect the microbiota. Additionally, the review discusses how preservation and restoration of the microbiota might be advantageous in decreasing HCT-related morbidity and mortality.

The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis.

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Interleukin 12 and interferon-γ synthetic deficiency is associated with dendritic cell cytopenia after cardiac surgery

Traumatic or inflammatory injury associates with deactivation of monocytes and impaired synthesis of proinflammatory cytokines. We conducted a prospective, observational study to test whether cardiac surgery additionally impaired dendritic and natural killer (NK) cell functions responsible for innate immune production of interleukin (IL)-12-dependent interferon (IFN)-γ in response to bacteria or toll-like receptor agonists. Blood samples were taken just before induction of anesthesia and 24 h postoperatively. LPS- and fixed Staphylococcus aureus-inducible IFNγ synthesis in whole blood culture after surgery was reduced to 5% of preoperative values (P < 0.001). Production of IL-12 p70, a critical inducer of IFNγ in the innate immune response, was reduced to 30% of that produced by preoperative samples (P = 0.013). Circulating CD11c+, DR+ myeloid dendritic cells (DC) that are known sources of IL-12 p70 in normal blood, declined to approximately 25% of presurgical numbers (P = 0.004). Experimental depletion of CD11c+, but not CD14+, cells from normal peripheral blood mononuclear cell (PBMC) similarly disabled Staphylococcus aureus Cowan 1 (SAC)-induced production of IL-12 p70 and IFNγ. Consistent with SAC-induced IFNγ expression in CD56+ NK and NK-T cells, CD56 depletion ablated IFNγ production in normal whole blood. However, repletion of IL-12 p70, IL-18, IL-15, and IL-23 in postoperative blood failed to restore presurgical levels of IFNγ synthesis (P < 0.05). We conclude that DC cytopenia after major surgery is sufficient to explain postoperative IL-12 p70 and IFNγ synthetic deficiency. In addition, postoperative blood became hyporesponsive to IFNγ-inducing cytokines as a further contribution to IFNγ insufficiency. The novel finding of DC cytopenia after major surgery may portend a lack of other immunologic functions provided by this potent accessory cell population.

Impact of early CMV reactivation in cord blood stem cell recipients in the current era

Several studies have reported an association between CMV reactivation and a decreased incidence of relapse for AML after adult donor allogeneic hematopoietic cell transplantation (HCT). Limited data, however, are available on the impact of CMV reactivation on relapse after cord blood (CB) stem cell transplantation. The unique combination of higher incidence of CMV reactivation in the seropositive recipient and lower incidence of graft versus host disease (GvHD) in CB HCT permits a valuable design to analyze the impact of CMV reactivation. Data from 1684 patients transplanted with CB between 2003 and 2010 for AML and ALL were analyzed. The median time to CMV reactivation was 34 days (range: 2–287). CMV reactivation and positive CMV serology were associated with increased non-relapse mortality (NRM) among both AML and ALL CB recipients (reactivation, AML: relative risk (RR) 1.41 (1.07–1.85); ALL: 1.60 (1.14–2.23); Serology, AML: RR 1.39 (1.05–1.85), ALL: RR 1.61 (1.18–2.19)). For patients with ALL, but not those with AML, this yielded inferior overall survival (P<0.005). Risk of relapse was not influenced by CMV reactivation or positive CMV serostatus for either disease.

Human leukocyte antigen mismatching and survival after lung transplantation in adult and pediatric patients with cystic fibrosis.

INTRODUCTION The influence of human leukocyte antigen (HLA) mismatching on survival in adult and pediatric patients with cystic fibrosis (CF) after lung transplantation (LTx) is unknown. METHODS The United Network for Organ Sharing database was queried from 1987 to 2013 to determine the influence of HLA mismatching on survival in adult and pediatric CF LTx recipients by assessing the association of HLA mismatching with survival in first-time adult (aged ≥ 18 years) and pediatric (aged <18 years) recipients. RESULTS Of 3149 adult and 489 pediatric patients with CF, 3145 and 489 were used for univariate Cox analysis, 2687 and 363 for Kaplan-Meier survival analysis, and 2073 and 257 for multivariate Cox analysis, respectively. Univariate analyses in adult and pediatric patients with CF demonstrated conflicting associations between HLA mismatching and survival (adult hazard ratio [HR], 1.0; 95% confidence interval [CI], 0.97-1.1; P = .45 vs pediatric HR, 0.87; 95% CI, 0.77-0.99; P = .032). Multivariate Cox models including both pediatric and adult patients confirmed that HLA mismatching had an initially protective effect at young ages (HR, 0.85; 95% CI, 0.73-0.99; P = .044) and that this protective effect diminished at older ages and was no longer associated with survival at P < .05 beyond age 10 years. CONCLUSIONS HLA mismatching has significantly different implications for survival after LTx in adult compared with pediatric patients with CF.

Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

X‐linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B‐cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patients leukemia. Pediatr Blood Cancer 2015;62:1674–1676.

Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: A CIBMTR study

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.