XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells.

Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors. SIGNIFICANCE: XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3.

Pre-Hematopoietic Stem Cell Transplantation Rituximab for Epstein-Barr Virus and Post-Lymphoproliferative Disorder Prophylaxis in Alemtuzumab Recipients.

Epstein-Barr virus (EBV) reactivation and EBV-related post-transplantation lymphoproliferative disorder (PTLD) are often fatal complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The risk of EBV reactivation may be mitigated by depletion of B cells with rituximab. Starting in January 2020, allo-HSCT recipients undergoing T-cell depletion with alemtuzumab received 1 dose of rituximab before transplantation. The objective of this study was to evaluate the cumulative incidence of EBV reactivation and EBV-PTLD in recipients of allo-HSCT and in vivo T-cell depletion with alemtuzumab who received pre-HSCT rituximab compared to patients who did not. This was a single-center retrospective analysis of adult patients who consecutively received an HLA-identical allo-HSCT between January 2019 and May 2021 and in vivo T-cell depletion with alemtuzumab. Patients were included in the rituximab cohort if they received rituximab within 6 months before their transplantation. The primary endpoint was incidence of EBV reactivation at day 180 among those receiving pre-HSCT rituximab versus those not receiving rituximab. Secondary endpoints included cumulative incidence of EBV-PTLD at 1 year, time to engraftment, immune reconstitution, and incidence of infections and acute graft-versus-host disease (aGVHD) at day 180. Eighty-six consecutive patients who received an allo-HSCT with alemtuzumab T-cell depletion were reviewed; 43 patients who received pre-HSCT rituximab after our protocol modification were compared to 43 patients who did not receive pre-HSCT rituximab before this change. Median age was 57 (interquartile range [IQR] 40-69) years, and the majority of patients had acute myeloid leukemia or myelodysplastic syndrome. Baseline characteristics were similar between the cohorts. EBV reactivation at day 180 occurred in 23 (53%) patients without prior rituximab exposure versus 0 patients with pre-HSCT rituximab exposure (P < .0001). Similarly, 6 patients without prior rituximab exposure developed PTLD at 1 year compared to no cases of PTLD among patients receiving pre-HSCT rituximab. There was no difference in neutrophil engraftment, incidence of infections, or aGVHD at day 180 between the 2 cohorts. There was a delay in time to platelet engraftment in the rituximab cohort (median 16 [IQR 15-20] days versus 15 [IQR 14-17] days; P = .04). Administration of pre-HSCT rituximab before allo-HSCT in patients receiving T-cell depletion with alemtuzumab was associated with a significant decrease in the risk for EBV reactivation and EBV-PTLD, without increasing aGVHD or infection rates.

Colonization with Gastrointestinal Pathogens Prior to Hematopoietic Cell Transplantation and Associated Clinical Implications.

Infectious diarrhea following hematopoietic cell transplantation (HCT) significantly contributes to morbidity and mortality. Most HCT recipients experience diarrhea in the post-transplantation period, and infectious pathogens are frequently detected during diarrheal episodes. However, little is known about how frequently these patients are colonized with gastrointestinal (GI) pathogens before their transplantation and whether colonization predicts future diarrheal illness. We sought to determine how frequently HCT recipients are colonized with GI pathogens before HCT and the degree to which pre-HCT colonization predicts post-transplantation infectious diarrheal illness. We conducted a prospective cohort study of allogeneic and autologous HCT recipients at a single center between December 2016 and January 2019. Stool samples were collected during the week before HCT, and formed samples were evaluated for the presence of 22 diarrheal pathogens using the BioFire FilmArray GI panel. We determined the frequency with which participants were colonized with each pathogen and identified factors associated with colonization. We then determined how frequently pretransplantation colonization led to post-transplantation diarrheal infections due to the colonizing pathogen and whether colonization was associated with increased number of days of post-transplantation diarrhea during the transplant hospitalization. We enrolled 112 asymptomatic patients (allogeneic, 61%; autologous, 39%) who had a formed stool specimen before HCT, of whom 41 (37%) had a GI pathogen detected. The most commonly detected organisms were Clostridioides difficile (n = 21; 19%), Yersinia enterocolitica (n = 9; 8%), enteropathogenic Escherichia coli (EPEC) (n = 6; 6%), and norovirus (n = 5; 4%). Female sex and previous C. difficile infection were associated with C. difficile colonization, and having non-Hodgkin lymphoma was associated with being colonized with a diarrheal pathogen other than C. difficile. Thirteen of 21 patients (62%) with pretransplantation C. difficile colonization developed a clinical C. difficile infection post-transplantation, and 8 of 10 patients (80%) colonized with EPEC or enteroaggregative E. coli developed post-transplantation infections due to their colonizing pathogen. Pretransplantation C. difficile colonization was also associated with an increased duration of post-transplantation diarrhea (P = .048). Conversely, none of the 9 patients with pretransplantation Yersinia enterocolitica colonization developed a post-transplantation Y. enterocolitica infection. Patients admitted for HCT are frequently colonized with a diverse range of GI pathogens. Colonization with C. difficile colonization and diarrheagenic E. coli is frequently associated with post-transplantation diarrheal infections caused by these organisms, but the clinical significance of colonization with other GI pathogens is not clear.

Poor graft function after T cell-depleted allogeneic hematopoietic stem cell transplant.

PGF implies persistent cytopenia in the presence of predominant donor chimerism. We examined contributors to PGF in 104 HCT recipients who survived ≥100 days without relapse or major complications. Surrogate parameters for PGF were: Hg <10 g/dl, RBC transfusion dependence, platelet count <20 × 109/L or ANC < 0.5 × 109/L. All patients received T cell depletion with alemtuzumab or ATG. The 2-year OS and PFS probabilities were 66%, 95%CI (56 - 75%) and 51%, 95%CI (41-60%) respectively. Fifty-four patients (52%) met one or more PGF criteria. There was significant association between major ABO incompatibility and platelet <20 × 109/L (OR = 4.7, 95%CI 1.05-21.26, p = .043), acute GVHD and Hg <10 g/dl (OR 3.7, 95%CI 1.4-9.6, p = .005) and CMV viremia and ANC < 0.5 × 109/L (OR 3.0, 95% CI 1.0, 8.7, p = .043). NRM was significantly higher in the PGF group compared to patients with adequate graft function (45.5% vs 16.7%, p = .014).

Cord blood transplants supported by unrelated donor CD34+ progenitor cells.

Alternative donor transplantation with the haplo-cord platform allows the use of a lower-dose single umbilical cord blood unit (CBU) by co-infusion of third-party CD34+-selected cells from a haploidentical relative, which provides early transient engraftment while awaiting durable CBU engraftment. In our experience, ~15% of patients lack a suitable haploidentical donor. Here we report 26 patients who underwent haplo-cord transplant using CD34+-selected partially matched unrelated donor grafts. Twenty-four were conditioned with fludarabine/melphalan +/- low-dose TBI (n = 16). Twenty-five received ATG and all received posttransplant tacrolimus and mycophenolate mofetil. Median time to neutrophil and platelet recovery was 11 and 18 days. CBU engraftment, with CD33 and CD3 >5% cord chimerism in the myeloid/lymphoid compartment by day +60, occurred in 20 of 24 patients (83%). Incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 27% at day +100, and chronic GVHD was 4% at 1 year. Overall survival at 1 year was 54%. For patients in need of an alternative transplant who lack a haploidentical donor, haplo-cord transplantation using CD34+-selected partially matched unrelated donor grafts results in rapid engraftment with no increased rate of cord graft failure or GVHD.

High-dose bendamustine and melphalan conditioning for autologous stem cell transplantation for patients with multiple myeloma.

High-dose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma (MM). Bendamustine induces responses in MM resistant to other alkylators. Our prior Phase I trial adding bendamustine to MEL200 transplant conditioning resulted in no additional toxicity. We now report a single-arm, phase II study that evaluated the efficacy of bendamustine 225 mg/m2 with MEL200 conditioning for ASCT in 18 patients with newly diagnosed MM (NDMM) and 17 with relapsed or refractory MM (RRMM). The primary end point was the complete response (CR/sCR) rate at day+ 100. Sample size was determined according to Simon's two-stage design. At stage 1, sixteen patients entered the study. As there were eight patients with CR/sCR, enrollment increased to 28 patients. Sixteen out of the first 28 evaluable patients achieved CR/sCR, meeting the design criteria. Enrollment was then expanded to a total of 35 patients. 51% achieved a CR/sCR. After a median follow-up of 65 months, 21 patients progressed, including 7 deaths. The median PFS for NDMM and RRMM was 48 and 45 months, respectively. Bendamustine/MEL200 conditioning resulted in excellent overall and depth of response as well as PFS, particularly in the RRMM patients, and is worthy of further investigation (NCT00916058).

Prophylactic rituximab prevents EBV PTLD in haplo-cord transplant recipients at high risk.

Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD) are common and potentially fatal complications after allogeneic transplantation with mismatched donors and T-cell depletion. Haplo-cord transplantation combines a mismatched UCB graft with third-party cells. Conditioning involves thymoglobulin. EBV reactivation and PTLD were common in initial patients. As of March 2017, we administered a prophylactic dose of rituximab 375 mg/m2 pre-transplant. Among 147 patients who did not receive rituximab, the cumulative incidence of post-transplant EBV reactivation and of EBV PTLD was 13% and 8%, respectively. Among 51 who received pre-transplant rituximab, the incidences were 2% (p = .0017) and 0% (p = .04), respectively. There was no difference in time to hematopoietic recovery, in the incidence of CMV reactivation, of invasive blood stream infections or of proven or probable invasive fungal infections. Pre-transplant administration of rituximab is an effective and nontoxic intervention that drastically reduces EBV reactivation and PTLD in high-risk patients.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.

Colonization With Levofloxacin-resistant Extended-spectrum ß-Lactamase-producing Enterobacteriaceae and Risk of Bacteremia in Hematopoietic Stem Cell Transplant Recipients.

Background: Bacteremia caused by extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is associated with inadequate empirical therapy and substantial mortality in neutropenic patients. Strategies are needed to identify neutropenic patients at high risk of these infections. Methods: From April 2014 to September 2016, we collected perianal swabs, both at admission and weekly thereafter, from patients undergoing hematopoietic stem cell transplantation (HSCT). Patients received prophylactic levofloxacin while neutropenic. Swabs were plated onto selective agar, colonies were identified and underwent antimicrobial susceptibility testing, and phenotypic ESBL testing and polymerase chain reaction for ß-lactamase genes were performed on ceftriaxone-resistant Enterobacteriaceae. We then determined the prevalence of pre-transplant ESBL-E colonization and risk of ESBL-E bacteremia. Colonizing and bloodstream isolates from patients with ESBL-E bacteremia underwent multilocus sequence typing and pulsed-field gel electrophoresis. Results: We analyzed 312 patients, including 212 allogeneic and 100 autologous HSCT recipients. Ten percent (31/312) of patients had pre-transplant ESBL-E colonization. Susceptibility rates of colonizing ESBL-E were: levofloxacin, 25%; cefepime, 9%; piperacillin-tazobactam, 84%; and meropenem, 97%. Of 31 patients colonized with ESBL-E pre-transplant, 10 (32%) developed ESBL-E bacteremia during their transplant admission, compared to 1 (0.4%) of 281 patients not colonized with ESBL-E (P < .001). All bloodstream ESBL-E were levofloxacin-resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. Conclusions: HSCT recipients who are colonized with levofloxacin-resistant ESBL-E pre-transplant and receive levofloxacin prophylaxis have high rates of bacteremia from their colonizing strain during neutropenia. Assessing for ESBL-E colonization in neutropenic patients could lead to optimization of empirical antibacterial therapy.

Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia.

Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.

The Addition of Low-Dose Total Body Irradiation to Fludarabine and Melphalan Conditioning in Haplocord Transplantation for High-Risk Hematological Malignancies.

BACKGROUND: Preliminary evidence indicates that the addition of low-dose total body irradiation (TBI) (2-4 Gy) to reduced intensity conditioning may reduce the rate of relapse in allogeneic stem cell transplants. In very high-risk patients receiving combination haploidentical single-unit cord blood transplants, we have added 4 Gy TBI to the widely used fludarabine, melphalan conditioning regimen, in hopes of reducing relapse and decreasing graft rejection. METHODS: We retrospectively reviewed the posttransplant outcomes of patients who underwent haplocord stem cell transplant between May 2013 and March 2015 and who received fludarabine 30 mg/m day (D)-7 to -3, melphalan 140 mg/m D-2, and 2 Gy TBI D-4 and -3. RESULTS: All 25 patients achieved primary neutrophil engraftment after a median of 12 days. The median time to platelet engraftment was 27 days. The cumulative incidence of nonrelapse mortality was 16% by D+100 and 33% by 1 year. The cumulative incidence of grade III to IV acute graft-versus-host disease was 36% by D+100. The CIR was 13% by D+100 and 29% by 1 year. The estimated 1-year overall survival and progression-free survival were 40% and 37%, respectively. In a subgroup analysis, we compared the outcome of 13 acute myeloid leukemia patients receiving this conditioning regimen with age and disease risk index-matched acute myeloid leukemia patients receiving fludarabine-melphalan without TBI. The TBI group had lower incidence of relapse at 1 year (15% vs 54%, P = 0.05). CONCLUSIONS: Overall, combination fludarabine-melphalan with low-dose TBI after haplocord stem cell transplant assures good engraftment and leads to acceptable toxicity and disease control in the setting of high risk, heavily pretreated patients. These findings warrant further investigation at a larger-scale, prospective level.

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

Clinical and molecular epidemiology of human rhinovirus infections in patients with hematologic malignancy.

BACKGROUND: Human rhinoviruses (HRVs) are common causes of upper respiratory tract infection (URTI) in hematologic malignancy (HM) patients. Predictors of lower respiratory tract infection (LRTI) including the impact of HRV species and types are poorly understood. OBJECTIVES: This study aims to describe the clinical and molecular epidemiology of HRV infections among HM patients. STUDY DESIGN: From April 2012-March 2013, HRV-positive respiratory specimens from symptomatic HM patients were molecularly characterized by analysis of partial viral protein 1 (VP1) or VP4 gene sequence. HRV LRTI risk-factors and outcomes were analyzed using multivariable logistic regression. RESULTS: One hundred and ten HM patients presented with HRV URTI (n=78) and HRV LRTI (n=32). Hypoalbuminemia (OR 3.0; 95% CI, 1.0-9.2; p=0.05) was independently associated with LRTI, but other clinical and laboratory markers of host immunity did not differ between patients with URTI versus LRTI. Detection of bacterial co-pathogens was common in LRTI cases (25%). Among 92 typeable respiratory specimens, there were 58 (64%) HRV-As, 12 (13%) HRV-Bs, and 21 (23%) HRV-Cs, and one Enterovirus 68. LRTI rates among HRV-A (29%), HRV-B (17%), and HRV-C (29%) were similar. HRV-A infections occurred year-round while HRV-B and HRV-C infections clustered in the late fall and winter. CONCLUSIONS: HRVs are associated with LRTI in HM patients. Illness severity is not attributable to specific HRV species or types. The frequent detection of bacterial co-pathogens in HRV LRTIs further substantiates the hypothesis that HRVs predispose to bacterial superinfection of the lower airways, similar to that of other community-acquired respiratory viruses.

Impact of Prophylactic Levofloxacin on Rates of Bloodstream Infection and Fever in Neutropenic Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Few studies have evaluated the role of antibacterial prophylaxis during neutropenia in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation (HSCT). At our center, levofloxacin prophylaxis was initiated in June 2006 in patients with myeloma who were undergoing autologous HSCT. We compared the incidence of bloodstream infection (BSI) and fever and neutropenia (FN) within 30 days of transplantation before (January 2003 to May 2006) and after (June 2006 to April 2010) the initiation of levofloxacin prophylaxis in patients undergoing autologous HSCT for myeloma. We also compared rates of BSI and FN during the same time periods in autologous HSCT recipients with lymphoma who did not receive antibacterial prophylaxis during either time period. After the initiation of levofloxacin prophylaxis, the BSI rate decreased from 41.2% (49 of 119) to 14.7% (23 of 156) and the rate of FN decreased from 91.6% to 60.9% in patients with myeloma (P < .001, for each). In contrast, rates of BSI (43.1% versus 47.3%; P = .50) and FN (98.8% versus 97.1%; P = .63) did not change in patients with lymphoma. Levofloxacin prophylaxis was independently associated with decreased odds of BSI (odds ratio, .27; 95% confidence interval, .14 to .51; P < .001) and FN (odds ratio, .18; 95% confidence interval, .09 to .36; P < .001) in multivariate analysis. Patients with myeloma had a nonsignificant increase in the risk of BSI due to levofloxacin-resistant Enterobacteriaceae (5% versus 1%, P = .08) and Clostridium difficile infection (7% versus 3%, P = .12) after the initiation of levofloxacin prophylaxis but did not have higher rates of BSI due to other resistant bacteria. Levofloxacin prophylaxis is associated with decreased risk of BSI and FN in patients with myeloma undergoing autologous HSCT.

Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single-centre study with focus on emerging pathogens.

With increased use of expanded-spectrum triazoles for antifungal prophylaxis, the epidemiology of invasive fungal infections (IFIs) after allogeneic haematopoietic stem cell transplantation (HSCT) continues to evolve. To define the contemporary epidemiology of IFIs in this population, we reviewed all European Organization for Research and Treatment of Cancer-Mycoses Study Group proven and probable IFIs in adults transplanted from 2002 to 2011 and determined the incidence and risk factors for IFI and post-IFI mortality. All patients received antifungal prophylaxis. Fifty-three (14%) of 378 allogeneic HSCT recipients developed an IFI. There were 62 IFI episodes, of which aspergillosis (n = 31; 50%) and candidaemia (n = 15; 24%) were most common. Sixteen episodes (26%) were caused by other fungi, including Mucorales (n = 6; 10%) and the following uncommon pathogens: Trichosporon asahii, Arthrographis sp., Cladosporium sp., Geosmithia argillacea and Hormographiella aspergillata. Independent IFI risk factors were hospitalisation in an intensive care unit [ICU; odds ratio (OR) = 6.0], graft-versus-host disease (OR = 5.3), central venous catheter use (OR = 5.2) and hypoalbuminaemia (OR = 0.3 g(-1)  dl(-1) increase in albumin). The 90-day mortality rate after IFI was 57%. Non-cytomegalovirus systemic viral co-infection (OR = 3.5) and stay in an ICU (OR = 2.9) were independent risk factors for death. Despite antifungal prophylaxis, IFIs remain common after allogeneic HSCT and previously uncommon pathogens are emerging.

MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis.

From 2007 to 2011, 66 patients with primary myelofibrosis or myelofibrosis (MF) preceded by essential thrombocythemia or polycythemia vera were enrolled into a prospective phase 2 clinical trial of reduced-intensity allogeneic hematopoietic stem cell transplantation (AHSCT), Myeloproliferative Disorder Research Consortium 101 trial. The study included patients with sibling donors (n = 32) receiving fludarabine/melphalan (FluMel) as a preparative regimen and patients with unrelated donors (n = 34) receiving conditioning with FluMel plus anti-thymocyte globulin (ATG). Patient characteristics in the 2 cohorts were similar. Engraftment occurred in 97% of siblings and 76% of unrelated transplants, whereas secondary graft failure occurred in 3% and 12%, respectively. With a median follow-up of 25 months for patients alive, the overall survival (OS) was 75% in the sibling group (median not reached) and 32% in the unrelated group (median OS: 6 months, 95% confidence interval [CI]: 3, 25) (hazard ratio 3.9, 95% CI: 1.8,8.9) (P < .001). Nonrelapse mortality was 22% in sibling and 59% in unrelated AHSCT. Survival correlated with type of donor, but not with the degree of histocompatibility match, age, or JAK2(V617F) status. In patients with MF with sibling donors, AHSCT is an effective therapy, whereas AHSCT from unrelated donors with FluMel/ATG conditioning led to a high rate of graft failure and limited survival. This trial was registered at www.clinicaltrials.gov as #NCT00572897.

The emergence of vancomycin-resistant enterococcal bacteremia in hematopoietic stem cell transplant recipients.

Abstract As antimicrobial resistance increases, understanding the current epidemiology of bloodstream infections (BSIs) in hematopoietic stem cell transplant (HSCT) recipients is essential to guide empirical antimicrobial therapy. We therefore reviewed microbial etiologies, timing and outcomes of BSIs in patients who were transplanted from September 2007 to December 2011. Vancomycin-resistant enterococci (VRE) were the most common pathogens in allogeneic HSCT recipients and the fourth most common after autologous transplant. VRE did not cause any of 101 BSIs in neutropenic patients who were not receiving antibacterials, but caused 32 (55%) of 58 BSIs in neutropenic patients receiving a broad-spectrum ß-lactam agent (p < 0.001). Rates of septic shock and 7-day mortality were 5% and 0% for streptococcal bacteremia, 12% and 18% for VRE bacteremia, and 20% and 14% for Gram-negative bacteremia. In conclusion, VRE bacteremia was the most common BSI in allogeneic HSCT recipients, occurred primarily in neutropenic patients receiving broad-spectrum ß-lactams and was associated with poor outcomes.