Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents.

Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well-tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single-arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non-major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six-month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non-major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low-dose apixaban was safe and well-tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low-dose apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs.

The use of venetoclax-based salvage therapy for post-hematopoietic cell transplantation relapse of acute myeloid leukemia.

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.

Early viral reactivation despite excellent immune reconstitution following haploidentical Bone marrow transplant with post-transplant cytoxan for sickle cell disease.

BACKGROUND: Haploidentical bone marrow transplant (haplo-BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo-BMT for SCD. METHODS: A multi-institution learning collaborative was developed in the context of a phase II clinical trial of a non-myeloablative, related haplo-BMT with post-transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. RESULTS: Median age was 14.8 years. Out of 23, 18 participants received pre-conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo-BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event-free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV-6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post-transplant lymphoproliferative disease. CONCLUSION: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo-BMT with post-transplant cyclophosphamide for SCD.

New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Cell Transplant Is Initiated by Insulin Resistance, Not Immunosuppressive Medications.

New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P = .005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P = .648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P = .047) and decreased peripheral/skeletal muscle uptake (P = .031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P = .039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT.

Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects.

Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope-specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV- HCMV+ HLA-DR7+ cohort or with HLA-DR7-restricted CD4+ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory-RA+ subsets with restricted TCRß usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+ The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.

Defining Incidence and Risk Factors for Catheter-Associated Bloodstream Infections in an Outpatient Adult Hematopoietic Cell Transplantation Program.

Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line-associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P = .0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P = .0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P < .001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations.

Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count.

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P = .03). For low recipient ALC (10th percentile, or .56 × 102/µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 102/µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing.

A Prospective Trial of Extracorporeal Photopheresis for Chronic Graft-versus-Host Disease Reveals Significant Disease Response and No Association with Frequency of Regulatory T Cells.

Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft-versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic, .09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the provider's response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to .14 mg/kg, P < .001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD.

Metabolic Complications Precede Alloreactivity and Are Characterized by Changes in Suppression of Tumorigenicity 2 Signaling.

New-onset post-transplantation diabetes mellitus (PTDM) occurs commonly after allogeneic hematopoietic cell transplantation (HCT) and is associated with inferior survival. We hypothesize that PTDM and nonrelapse mortality (NRM) are related to IL-33/suppression of tumorigenicity 2 (ST2) signaling and that soluble ST2 (sST2) levels will predict PTDM diagnosis. sST2 was measured at engraftment and day +30 in 36 euglycemic HCT recipients followed prospectively for PTDM (cohort 1). Results were confirmed in a validation cohort of 26 patients without pre-existing diabetes analyzed retrospectively for PTDM (cohort 2). Twelve patients with established diabetes before HCT were analyzed in cohort 3. When compared with recipients without PTDM, patients developing PTDM (n = 24) from cohort 1 had elevated sST2 levels at engraftment (P = .02) and at day +30 (P < .01). Cohort 2 confirmed this finding at engraftment (P = .01). Cohort 3 patients with pretransplantation diabetes had higher sST2 at engraftment than patients maintaining euglycemia after HCT from cohort 2 (P = .03). Multivariate analysis of cohorts 1 and 2 showed high engraftment sST2 predicted increased PTDM and NRM risk, independent of conditioning and grades 3 to 4 acute graft-versus-host-disease. sST2 was elevated in PTDM, indicating a relationship between glucose homeostasis and the IL-33/ST2 axis after transplantation. Correction of metabolic complications may decrease sST2 and improve NRM.

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies.

Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

Geographic distance is not associated with inferior outcome when using long-term transplant clinic strategy.

The optimal healthcare model for follow-up of allogeneic hematopoietic stem cell transplantation (HSCT) recipients after day 100 is not clear. We previously demonstrated that longitudinal follow-up at the transplant center using a multidisciplinary approach is associated with superior survival. Recent data suggest that increased distance from the transplant center is associated with inferior survival. A dedicated long-term transplant clinic (LTTC) was established in 2006 at our center. We hypothesized that geographic distance would not be associated with inferior outcome if patients are followed in the LTTC. We studied 299 consecutive patients who underwent HSCT and established care in an LTTC. The median distance from the transplant center was 118 miles (range, 1 to 1591). The 75th percentile (170 miles) was used as the cut-off to analyze the impact of distance from the center on outcome (219 patients ≤ 75th percentile; 80 patients >75th percentile). The 2 groups were balanced for pretransplant characteristics. In multivariate analyses adjusted for donor type, Center for International Blood and Marrow Transplant Research risk, and transplant regimen intensity, distance from transplant center did not impact outcome. Our study suggests that geographic distance from the transplant center is not associated with inferior outcome when follow-up care is delivered via a dedicated LTTC incorporating well-coordinated multidisciplinary care.

Predicting posttransplantation diabetes mellitus by regulatory T-cell phenotype: implications for metabolic intervention to modulate alloreactivity.

Chronic inflammation and decreased frequency of regulatory T cells (Tregs) in visceral adipose tissue contribute to the propagation of insulin resistance to diabetes mellitus. We tested the hypothesis that new-onset posttransplantation diabetes mellitus (PTDM) is associated with measurable changes in Treg subsets after allogeneic hematopoietic stem cell transplantation (HSCT). PTDM before day 100 and Treg phenotype at engraftment were determined in 36 HSCT recipients without preceding history of diabetes mellitus. Among patients with new-onset PTDM (N = 24), the frequency of circulating CLA(+) (skin-homing) Tregs was decreased (1.53% vs 3.99%; P = .002) and the percentage of α(4)ß(7)(+) (gut-homing) Tregs was increased (17.9% vs 10.7%; P = .048). In multivariate analysis, patients with PTDM continued to demonstrate elevated ratios of α(4)ß(7)(+) Tregs to CLA(+) Tregs (odds ratio, 18.1; P = .020). PTDM is associated with altered immune regulation after HSCT and could represent a target to modulate alloreactivity.

Extracorporeal photopheresis as second-line treatment for acute graft-versus-host disease: impact on six-month freedom from treatment failure.

Second-line therapy for corticosteroid-refractory or -dependent acute graft-versus-host disease remains ill-defined, due to limited efficacy of drugs and evolving clinical trial endpoints. Six-month freedom from treatment failure has been proposed as a novel clinical trial endpoint and is defined by the absence of death, malignancy relapse/progression, or addition of a next line of systemic immunosuppressive therapy within 6 months of intervention and prior to diagnosis of chronic graft-versus-host disease. We analyzed the 6-month freedom from treatment failure endpoint in 128 patients enrolled from three centers who were treated with extracorporeal photopheresis as second-line therapy for acute graft-versus-host disease. The incidence of 6-month freedom from treatment failure was 77.3% with a 2-year survival rate of 56%. Corticosteroid dose or response status at onset of second-line therapy did not influence outcome. Higher grade of acute graft-versus-host disease (grade 2 versus grades 3-4) at onset of photopheresis predicted for poor outcome as measured by survival (hazard ratio 2.78, P<0.001), non-relapse mortality (hazard ratio 2.78, P=0.001) and 6-month freedom from treatment failure (hazard ratio 3.05, P<0.001). For the 91 patients who achieved 6-month freedom from treatment failure, 1-year, 2-year and 3-year survival rates were 78.9%, 70.8% and 69.5%, respectively. Six-month freedom from treatment failure is a reasonable early surrogate for outcome and should be considered as a clinical trial endpoint. This study demonstrates the durable effect of photopheresis as second-line therapy for corticosteroid-refractory or -dependent acute graft-versus-host disease using 6-month freedom from treatment failure as the primary endpoint.

Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios.

BACKGROUND: Necrotising enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Immaturity of gastrointestinal immune regulation may predispose preterm infants to NEC as FOXP3 T regulatory cells (Treg) are critical for intestinal immune homoeostasis. OBJECTIVE: To investigate the hypothesis that abnormal developmental regulation of lamina propria Treg would define premature infants with NEC. DESIGN: Lamina propria mononuclear cell populations from surgically resected ileum from 18 patients with NEC and 30 gestational age-matched non-NEC surgical controls were prospectively isolated. Polychromatic flow cytometry was performed to phenotype and analyse lamina propria T cell populations. The cytokine gene expression profile in NEC tissue was compared with that of non-NEC controls. RESULTS: The total number of Treg, CD4, or CD8 T cells in each ileum section was independent of gestational age, age or postmenstrual age and similar between patients with NEC and controls. In contrast, the ratio of Treg to CD4 T cells or Treg to CD8 T cells was significantly lower in NEC ileum than in infants without NEC (medians 2.9% vs 6.6%, p=0.001 and medians 6.6% vs 25.9%, p<0.001, respectively). For any given number of CD4 or CD8 T cells, Treg were, on average, 60% lower in NEC ileum than in controls. NEC tissue cytokine gene expression profiles were characteristic of inhibited Treg development or function. Treg/CD4 and Treg/CD8 ratios recovered between initial resection for NEC and reanastomosis. CONCLUSION: The proportion of lamina propria Treg is significantly reduced in the ileum of premature infants with NEC and may contribute to the excessive inflammatory state of this disease.

Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis.

The optimal therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is undefined. We studied patients with SR aGVHD, comparing extracorporeal photopheresis (ECP; n = 57) and anticytokine therapy (n = 41). In multivariate analyses, ECP, adjusted for steroid dose (odds ratio, 3.42; P = .007), and grade >II aGVHD (odds ratio, 68; P < .001) were independent predictors of response. ECP therapy, adjusted for conditioning regimen intensity and steroid dose, was associated with superior survival (hazard ratio [HR], 4.6; P = .016) in patients with SR grade II aGVHD. Grade >II aGVHD at onset of salvage therapy (HR, 9.4; P < .001) and lack of response to therapy (HR, 3.09; P = .011) were associated with inferior survival. These findings require validation in a prospective randomized study.

Genetic variation in recipient B-cell activating factor modulates phenotype of GVHD.

B-cell activating factor (BAFF) single nucleotide polymorphisms (SNPs) are associated with autoimmune diseases. Because patients with classic and overlap chronic GVHD (cGVHD) have features of autoimmune diseases, we studied the association of recipient and/or donor BAFF SNPs with the phenotype of GVHD after allogeneic stem cell transplantation. Twenty tagSNPs of the BAFF gene were genotyped in 164 recipient/donor pairs. GVHD after day 100 occurred in 124 (76%) patients: acute GVHD (aGVHD) subtypes (n = 23), overlap GVHD (n = 29), and classic cGVHD (n = 72). In SNP analyses, 9 of the 20 tag SNPs were significant comparing classic/overlap cGVHD versus aGVHD subtypes/no GVHD. In multivariate analyses, 4 recipient BAFF SNPs (rs16972217 [odds ratio = 2.72, P = .004], rs7993590 [odds ratio = 2.35, P = .011], rs12428930 [odds ratio2.53, P = .008], and rs2893321 [odds ratio = 2.48, P = .009]) were independent predictors of GVHD subtypes, adjusted for conventional predictors of cGVHD. This study shows that genetic variation of BAFF modulates GVHD phenotype after allogeneic stem cell transplantation.

New allergies after cord blood transplantation.

BACKGROUND AIMS: Umbilical cord blood transplantation (CBT) is an effective treatment for benign and malignant diseases. Late effects of CBT are not well described in the literature. In the present study, we present our experience of new-onset allergies in long-term survivors after CBT. METHODS: After an initial patient had a severe peanut allergic reaction after CBT, all CBT patients were prospectively followed for new allergy development. Fifty patients received CBT between March 2006 and June 2011. RESULTS: The median follow-up after CBT was 447 days (range, 12-2022). At the time of analysis, 30 patients were alive, with 3-year survival of 55.5%; median follow-up of surviving patients was 910 days (range, 68-2022). The allergic syndrome developed in five patients, with the cumulative incidence of new allergies at 2 years of 18.4% (95% confidence interval, 10.8-26). The median time to onset of new allergy after transplantation was 298 days (range, 250-809). CONCLUSIONS: Allergy development has been linked to a delayed maturation of the immune system in several studies. We present the first case series of patients who had new allergies after CBT. Further study of this novel complication as well as counseling of patients after CBT would be important.

Noninfectious Pulmonary Complications after Hematopoietic Stem Cell Transplantation.

Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are important sources of morbidity and mortality. Improvements in infection-related complications have made noninfectious pulmonary complications an increasingly significant driver of transplantation-related mortality. Broadly, these complications can be characterized as either early or late complications, with idiopathic pneumonia syndrome and bronchiolitis obliterans syndrome the most prevalent early and late complications, respectively. Outcomes with historical treatment consisting mainly of corticosteroids are often poor, highlighting the need for a deeper understanding of these complications' underlying disease biology to guide the adoption of novel therapies that are being increasingly used in the modern era.

TP53 Mutations Are Associated with Increased Infections and Reduced Hematopoietic Cell Transplantation Rates in Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n = 352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P = .028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P = .005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.