Cutaneous Squamous Cell Carcinoma in Immunocompromised Patients-A Comparison between Different Immunomodulating Conditions.

BACKGROUND: Immunosuppression is strongly associated with an increased risk of developing cutaneous squamous cell carcinoma (cSCC). Studies on solid organ transplant recipients (SOTR) and chronic lymphocytic leukemia (CLL) patients have already demonstrated higher rates of aggressive cSCC tumors in these populations compared to immunocompetent controls. Studies on other immunosuppressed patient groups are scarce. This study was aimed at assessing the effects of different immunomodulating conditions on patients diagnosed with cSCC. We sought to compare the clinical features, treatments, and survival rates among the different study groups, as well as outcomes to those of immunocompetent controls with cSCC. METHODS: A retrospective analysis of 465 cSCC patients, both immunosuppressed (IS) and immunocompetent controls. Etiologies for immunosuppression included SOTR, CLL, chronic kidney disease (CKD), psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). RESULTS: Compared to the control group, IS patients demonstrated several significant differences. These include higher rates of positive resection margins, higher recurrence rates, and multiple SCC tumors. Patients in the IS group, who were also given immunomodulating agents, demonstrated even lower survival rates. Cox regression analysis demonstrated statistically significant decreased overall survival (OS) rates for IS patients compared to the controls (OR = 1.9, p = 0.031). SOTR patients tend to have multiple cSCC tumors (35%), with the highest number of primary tumors compared to controls (2.54 tumors per patient on average, p < 0.001), but also compared to all other IS groups. The average SCC lesion size in the SOTR group was the smallest, measuring at 13.5 mm, compared to the control group and all other IS groups. Decreased survival rates were seen on Cox regression analysis compared to controls (HR = 2.4, p = 0.001), but also to all other IS groups. CLL patients also had the highest rates of positive margins compared to controls (36% vs. 9%, p < 0.01) and to all other IS groups. They were also most likely to get adjuvant or definitive oncological treatments, either radiotherapy or chemotherapy, compared to controls (36% vs. 15%, p = 0.02) and to other IS groups. Patients in the CKD group demonstrated the highest rates for multiple cSCC (OR = 4.7, p = 0.001) and the worst rates of survival on Cox regression analysis (HR = 3.2, p = 0.001). Both rheumatoid arthritis and psoriasis patients demonstrated the shortest disease-free survival rates (2.9y ± 1.1, 2.3y ± 0.7, respectively), compared to controls (4.1y ± 2.8) and to all other IS groups. CONCLUSIONS: Among cSCC patients, immunosuppression due to SOTR, CLL, CKD, RA, and psoriasis is associated with worse outcomes compared to controls and other IS groups. These patients should be regarded as high-risk for developing aggressive cSCC tumors. This study is the first to assess and compare cSCC outcomes among multiple IS patient groups.

Infection prevention practices among EBMT hematopoietic cell transplant centers: the EBMT Infectious Disease Working Party survey.

We aimed to describe the current status of infection prevention practices among EBMT centers. Questionnaires were distributed to all 553 EBMT transplant centers to capture clinical practices regarding antimicrobial prophylaxis, protective measures, isolation procedures and growth-factor support of patients undergoing hematopoietic cell transplantation. Responses from 127 centers in 32 countries were obtained. Most centers housed patients in single rooms (autologous-82%; allogeneic-98%), with high-efficiency particulate air (HEPA)-filters (autologous-73%; allogeneic-100%) and positive pressure (autologous-61%; allogeneic-88%). Pre-engraftment G-CSF was utilized by 77 and 31% of centers after autologous and allogeneic transplantation, respectively (P < 0.00001). Antibacterial prophylaxis was provided by 57 and 69% (P = 0.086) of centers and antifungal prophylaxis by 65 and 84% (P = 0.0008) of centers, to patients undergoing autologous and allogeneic transplantation, respectively. Yet, 16 and 3% of centers provided neither antibacterial nor antifungal prophylaxis to patients undergoing autologous and allogeneic transplantation, respectively. Considerable variation existed between centers and across countries in antimicrobial prophylaxis practices, medications employed and duration of preventive therapy. There were considerable discordances between guidelines and daily practices. JACIE accredited and non-accredited centers did not differ significantly in their antimicrobial prophylaxis practices. Whether these differences between transplant centers translated into differences in infectious morbidity, mortality and financial costs, warrants further research.

The role of additional chemotherapy prior to autologous HCT in patients with relapse/refractory DLBCL in partial remission-A retrospective multicenter study.

OBJECTIVES: To evaluate the role of additional chemotherapy before autologous hematopoietic cell transplantation (HCT) in patients with relapse/refractory diffuse large B-cell lymphoma (DLBCL) who achieve partial remission following first salvage therapy. METHODS: We conducted a multicenter retrospective study of all adult patients with DLBCL who underwent HCT between 2008 and 2020 and achieved partial response (PR) after the first salvage and were either referred directly to HCT (n = 47) or received additional salvage therapy before HCT (n = 22). RESULTS: Post-HCT CR rate and progression-free survival were comparable between the two groups (66% vs. 68%, p = .86 and median not reached vs. 10.2 months [95% confidence interval, CI 7.1-12.3], p = .27, respectively). Median overall survival (OS) and estimated 3-year OS favored patients who were directly referred to HCT (105.8 [95% CI 63-148] months vs. 14.5 [95% CI 0-44] months, p = .035, and 65% [95% CI 51%-75%] vs. 40% [95% CI 21%-53%], p = .035, respectively). In Cox regression model, while International Prognostic Index and primary refractory versus relapse disease did not impact OS, allocation to a second salvage regimen and older age were both associated with inferior survival (hazard ratio [HR] = 2.57 95% CI 1.1-5.8, p = .023 and HR = 1.04 95% CI 0.99-1.2, p = .064, respectively). CONCLUSIONS: Referring patients with chemotherapy-sensitive disease in PR directly to HCT is associated with better OS compared to those receiving additional lines of treatment.

Using natural killer cell-derived exosomes as a cell-free therapy for leukemia.

Natural killer (NK) cells are components of the innate immune system which play a pivotal role in cancer cell surveillance. Despite promising results in clinical trials, the use of NK-based therapies is limited due to unsatisfactory efficiencies and safety issues. In recent years, exosomes have emerged as a powerful, natural therapeutic tool. Since exosomes are known to carry cargos that reflect the cellular makeup of their cell of origin, we were prompted to test whether NK-derived exosomes (NKexo) maintain the anti-leukemia capacity of NK-cells. We found NK92MI-cells to secrete large amounts of 100-200 nm cap-shaped particles expressing exosomal and NK biomarkers (CD63, CD81, CD56). We demonstrated that NKexo exert a potent, selective, anti-leukemia effect on all leukemia cell-lines tested. Furthermore, NKexo eliminated leukemia cells isolated from patients with acute and chronic leukemia and inhibited hematopoietic colony growth. While leukemia cells were targeted and severely affected by NKexo, healthy B-cells remained unaffected, indicating a selective effect. This selectivity was further confirmed by demonstrating that NKexo were specifically taken up by leukemic cells but not by healthy B-cells. Our in vivo data support our in vitro and ex vivo findings and demonstrate improved human-CD45+ leukemia blast counts and overall survival in NKexo treated humanized acute myeloid leukemia (HL-60) xenograft mice thus supporting the assumption that NKexo possess an anti-leukemia effect. Pending further analyses, our findings provide the pre-clinical evidence needed to test the NKexo approach in future pre-clinical and clinical studies to ultimately develop an acellular "off-the-shelf" product to treat leukemia.

Infectious complications and long-term outcomes in patients with diffuse large B-Cell lymphoma and diabetes mellitus.

Febrile neutropenia (FN) is a major complication in patients with diffuse large B-Cell lymphoma (DLBCL). Diabetes mellitus (DM) has deleterious effects on the immune system resulting in an increased risk of infections. We evaluated patients with DLBCL who started frontline treatment with R-CHOP, and compared outcomes according to presence of DM comorbidity. Between 2013 and 2018, 218 patients with DLBCL were included. 46 patients (21%) had DM. Rate of admissions for FN was higher for patients with DM (0.7 vs. 0.46 admissions/patient, p = .016), also after age and gender-matched subgroup analysis (p = .004). Improved glycemic control during FN hospitalizations was associated with shorter hospitalizations. Metformin was associated with improved median overall survival in diabetic patients (89 vs. 64 months, p = .018). In conclusion, Patients with DLBCL and DM had higher rates of FN hospitalizations. Improved glycemic control during FN hospitalization was associated with shorter length of stay.

STAT3 Activates the Pentraxin 3 Gene in Chronic Lymphocytic Leukemia Cells.

Pentraxin-related protein 3 (PTX3), commonly produced by myeloid and endothelial cells, is a humoral pattern recognition protein of the innate immune system. Because PTX3 plasma levels of patients with chronic lymphocytic leukemia (CLL) are high and most circulating cells in patients with CLL are CLL cells, we reasoned that CLL cells produce PTX3. Western immunoblotting revealed that low-density cells from seven of seven patients with CLL produce high levels of PTX3, flow cytometry analysis revealed that the PTX3-producing cells are B lymphocytes coexpressing CD19 and CD5, and confocal microscopy showed that PTX3 is present in the cytoplasm of CLL cells. Because STAT3 is constitutively activated in CLL cells, and because we identified putative STAT3 binding sites within the PTX3 gene promoter, we postulated that phosphorylated STAT3 triggers transcriptional activation of PTX3. Immunoprecipitation analysis of CLL cells' chromatin fragments showed that STAT3 Abs precipitated PTX3 DNA. STAT3 knockdown induced a marked reduction in PTX3 expression, indicating a STAT3-induced transcriptional activation of the PTX3 gene in CLL cells. Using an EMSA, we established and used a dual-reporter luciferase assay to confirm that STAT3 binds the PTX3 gene promoter. Downregulation of PTX3 enhanced apoptosis of CLL cells, suggesting that inhibition of PTX3 might benefit patients with CLL.

Humoral serological response to the BNT162b2 vaccine after allogeneic haematopoietic cell transplantation.

OBJECTIVES: To assess the humoral immune response to the BNT162b2 vaccine after allogeneic haematopoietic cell transplantation (HCT). METHODS: This is a prospective cohort study. The SARS-CoV-2 IgGII Quant (Abbott©) assay was performed 4-6 weeks after the second BNT162b2 vaccine for quantitative measurement of anti-spike antibodies. RESULTS: The cohort included 106 adult patients. Median time from HCT to vaccination was 42 (range 4-439) months. Overall, 15/106 (14%, 95% confidence interval (CI) 7-21%) were seronegative despite vaccination, 14/52 patients on immunosuppression (27%, 95%CI 19-35%) compared to only 1/54 patients off immunosuppression (1.8%, 95%CI 1-4%) (p 0.0002). The proportion of seronegative patients declined with time; it was 46% (6/13) during the first year, 12.5% (3/24) during the second year and 9% (6/69) beyond 2 years from transplant. Patients with acute graft-versus-host disease (GVHD) (odds ratio (OR) 3.3, 95%CI 0.97-11.1, p 0.06) and moderate to severe chronic GVHD (OR 5.9, 95%CI 1.2-29, p 0.03) were more likely to remain seronegative. Vaccination was well tolerated by most patients. However, 7% (7/106) reported that GVHD-related symptoms worsened within days following vaccination. CONCLUSION: A significant proportion of allogeneic HCT recipients receiving immunosuppression demonstrated an inadequate humoral response to the BNT162b2 vaccine. These patients should be recognized and instructed to take appropriate precautions. Recipients who were off immunosuppression had a humoral response that was comparable to that of the general population.

Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

Humoral serological response to the BNT162b2 vaccine is abrogated in lymphoma patients within the first 12 months following treatment with anti-CD2O antibodies.

Patients with lymphoma, especially those treated with anti-CD20 monoclonal antibodies, suffer high COVID-19-associated morbidity and mortality. The goal of this study was to assess the ability of lymphoma patients to generate a sufficient humoral response after two injections of BNT162b2 Pfizer vaccine and to identify factors influencing the response. Antibody titers were measured with the SARS-CoV-2 IgG II Quant (Abbott ) assay in blood samples drawn from lymphoma patients 4 2 weeks after the second dose of vaccine. The cutoff for a positive response was set at 50 AU/mL. Positive serological responses were observed in 51% of the 162 patients enrolled in this cross-sectional study. In a multivariate analysis, an interval of <12 months between the last anti-CD20 monoclonal antibody dose and the second vaccine dose (odds ratio=31.3 [95% confidence interval: 8.4-116.9], P<0.001) and presence of active lymphoma (odds ratio=4.2 (95% confidence interval: 2.1- 8.2), P=0.006) were identified as negative response predictors. The rate of seropositivity increased from 3% in patients vaccinated within 45 days after the last monoclonal antibody administration to 80% in patients vaccinated >1 year after this therapy. The latter percentage was equal to that of patients never exposed to monoclonal antibodies. In conclusion, lymphoma patients, especially those recently treated with anti- CD20 monoclonal antibodies, fail to develop sufficient humoral response to BNT162b2 vaccine. While a serological response is not the only predictor of immunity, its low level could make this population more vulnerable to COVID-19, which implies the need for a different vaccination schedule for such patients.

Eltrombopag for enhancement of platelet engraftment in patients undergoing allogeneic cord blood transplantation.

Platelet recovery after allogeneic umbilical cord blood (UCB) transplantation is delayed compared to other graft sources. We conducted a multicenter phase 2a study to explore whether eltrombopag, a thrombopoietin-receptor agonist, would enhance platelet recovery after UCB transplantation. Between 02/2013 and 07/2016, 12 (10 adults, 2 children) individuals (median age 50; range 6-74 years) with hematological malignancies in complete remission were enrolled. Eltrombopag was given for a median of 76 (range 15-175) days and was safe even at doses of 300 mg/day. Median time to neutrophil engraftment was 23 (range 16-40) days. Median time to platelets >20,000/µl and >50,000/µl was 55 (range 25-199) and 66 (range 31-230) days, respectively. A historical cohort comparison did not reveal an advantage for eltrombopag. In conclusion, in the present study eltrombopag seems safe. Based on our limited data, it seems unlikely that eltrombopag could enhance platelet engraftment after UCB transplantation.

Post-transplantation maintenance with sorafenib or midostaurin for FLT3 positive AML patients - a multicenter retrospective observational study.

The role of post allogeneic stem-cell transplantation (AlloSCT) FLT3 inhibition for acute myeloid leukemia in the real-world setting is unclear, especially in the era of widespread pre-transplant use of tyrosine kinase inhibitors (TKIs). In a multicenter nationwide study, we assessed 41 patients who were treated with post-transplant TKIs (sorafenib, n = 23, midostaurin, n = 18). The majority also received TKIs pre-transplant (n = 32, 79%). After a median follow up of 10 months post-transplant (range 3-53.6), 29 patients (71%) were alive and in complete remission. Similar results were seen in a subgroup analysis of pre-transplant TKI recipients (78%). In Univariate analysis, HCT-CI score < 4 and Type of TKI (sorafenib versus midostaurin) predicted longer overall survival. Seventeen patients (41%) suffered from side effects and seven patients (17%) stopped TKI therapy due to adverse events. Overall, our data suggest that post-transplant use of TKIs is safe and effective in an era of their widespread use prior to AlloSCT.

Diarrheal Morbidity During Hematopoietic Cell Transplantation: The Diagnostic Yield of Stool Cultures.

INTRODUCTION: Diarrhea affects a significant proportion of patients undergoing hematopoietic cell transplantation (HCT). We explored the diagnostic yield of stool cultures for enteric pathogens among patients undergoing HCT. METHODS: This is a single-center, retrospective study. Between 5/2007 and 4/2020, consecutive patients who underwent HCT were included if inpatient bacterial stool cultures were collected. Patient characteristics, results, and timing of stool cultures obtained during hospitalization were collected. RESULTS: A total of 1072 individuals underwent autologous (n = 603) and allogeneic (n = 469) HCT. Overall, 947 stool culture samples were obtained from 561 (52%) patients with diarrheal illness during hospitalization for HCT. Most (99%) samples were obtained beyond 3 days of admission, mainly (77%) during neutropenia. Overall, only four (0.42%) (autologous, n = 3; allogeneic, n = 1) patients had a positive stool culture and in all cases Campylobacter spp. were the pathogens identified. The number of stool cultures needed-to-test to diagnose one case of bacterial infection was 237. The cost of diagnosing one case of bacterial diarrhea was US $8770. Patients with a positive stool culture did not have discerning characteristics. CONCLUSIONS: In our experience, the yield of stool cultures for enteropathogens in patients undergoing HCT is extremely low and thus should be avoided in most cases.

STAT3 induces the expression of GLI1 in chronic lymphocytic leukemia cells.

The glioma associated oncogene-1 (GLI1), a downstream effector of the embryonic Hedgehog pathway, was detected in chronic lymphocytic leukemia (CLL), but not normal adult cells. GLI1 activating mutations were identified in 10% of patients with CLL. However, what induces GLI1 expression in GLI1-unmutated CLL cells is unknown. Because signal transducer and activator of transcription 3 (STAT3) is constitutively activated in CLL cells and sequence analysis detected putative STAT3-binding sites in the GLI1 gene promoter, we hypothesized that STAT3 induces the expression of GLI1. Western immunoblotting detected GLI1 in CLL cells from 7 of 7 patients, flow cytometry analysis confirmed that CD19+/CD5+ CLL cells co-express GLI1 and confocal microscopy showed co-localization of GLI1 and phosphorylated STAT3. Chromatin immunoprecipitation showed that STAT3 protein co-immunoprecipitated GLI1 as well as other STAT3-regulated genes. Transfection of CLL cells with STAT3-shRNA induced a mark decrease in GLI1 levels, suggesting that STAT3 binds to and induces the expression of GLI1 in CLL cells. An electromobility shift assay confirmed that STAT3 binds, and a luciferase assay showed that STAT3 activates the GLI1 gene. Transfection with GLI1-siRNA significantly increased the spontaneous apoptosis rate of CLL cells, suggesting that GLI1 inhibitors might provide therapeutic benefit to patients with CLL.

Anticoagulation in patients with atrial fibrillation, thrombocytopenia and hematological malignancy.

Managing anticoagulation in hematological malignancy patients with atrial fibrillation and thrombocytopenia is a clinical challenge with limited data. We aimed to identify anticoagulation management strategies and evaluate bleeding and thrombosis rates associated with each approach. A retrospective cohort study in Israel and the Netherlands was conducted. Patients with hematological malignancy and atrial fibrillation were indexed when platelets were < 50 × 109/L and followed for 30 days. The cohort included 61 patients of whom 42 (69%) had anticoagulation held at index. On multivariate analysis, holding anticoagulation was associated with age < 65 years and atrial fibrillation diagnosed within 30 days prior index. Clinically relevant bleeding was diagnosed in 7 (16.7%) and 1 (5.3%) of patients who had anticoagulation held and continued respectively, while arterial thromboembolism occurred in 1 patient in each group (2.4% and 5.3%, respectively). All-cause mortality rate was high at 45%. Accordingly, the 30-day bleeding risk may outweigh the risk of arterial thromboembolism in hematological malignancy, platelets < 50 × 109/L and atrial fibrillation.

Thrombin Generation in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The optimal antithrombotic treatment for patients with atrial fibrillation (AF) that undergo percutaneous coronary intervention (PCI) is controversial. Dual therapy (clopidogrel and a direct oral anticoagulant [DOAC]) is safer than triple therapy (warfarin, aspirin, and clopidogrel), while efficacy is unclear. We aimed to evaluate thrombin generation (TG) under dual and triple therapy. METHODS: A noninterventional prospective trial in patients with AF undergoing PCI. Patients received 4 weeks of triple therapy with aspirin, clopidogrel, and a DOAC followed by aspirin withdrawal. TG was measured in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) at 3 five to 21 points, day 1 after PCI (TIME 0), 4 weeks after PCI (TIME 1), and 2 weeks after aspirin withdrawal (TIME 2). RESULTS: Twenty-three patients (18 men, median age 78 years, 83% with acute coronary syndrome) were included. Endogenous thrombin potential (ETP) in PPP was high at TIME 0 compared with TIME 1 (ETP 3,178 ± 248 nM vs. 2,378 ± 222 nM, p = 0.005). These results remained consistent when measured in PRP. No significant difference in ETP was found before (TIME 1) and after aspirin withdrawal (TIME 2) although few patients had high ETP levels after stopping aspirin. CONCLUSIONS: TG potential is high immediately after PCI and decreases 4 weeks after PCI in patients receiving triple therapy. TG remains constant after aspirin withdrawal in most patients, suggesting that after 1 month the antithrombotic effect of dual therapy may be similar to triple therapy.

Health-Related Quality of Life in Patients with Chronic Myeloid Leukemia Treated with First- Versus Second-Generation Tyrosine Kinase Inhibitors.

The life expectancy of patients with chronic myeloid leukemia (CML) approaches that of the age-matched population and quality of life (QOL) issues are becoming increasingly important. To describe patients' characteristics and assess QOL, we delivered a 30-item core questionnaire, a 24-item CML-specific questionnaire, both from the European Organization for Research and Treatment of Cancer (EORTC), and additional health-related items to 350 patients. Among 193 patients who completed the questionnaires, 139 received either imatinib (n = 70, 33%), dasatinib (n = 45, 23%) or nilotinib (n = 24, 12%). Patients' median age was 58 (range: 23 to 89) years and 86 (63%) were males. Stratifying patients by treatment, we recognized two distinct populations. In comparison to patients on dasatinib and nilotinib, patients on imatinib were two decades older, had a longer duration of disease and current treatment, experienced fewer limitations on daily activities (p = 0.02), less fatigue (p = 0.001), lower degree of impaired body image (p = 0.022) and less painful episodes (p = 0.014). Similarly, they had better emotional functioning, were less worried, stressed, depressed or nervous (p = 0.01) and were more satisfied with their treatment (p = 0.018). Not only does age associate with current treatments, but it also predicts how patients perceive QOL. Young patients express impaired QOL compared with elderly patients.

Sequential treatment with FLAG-IDA/treosulfan conditioning regimen for patients with active acute myeloid leukemia.

Sequential protocols combining salvage chemotherapy with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute myeloid leukemia (AML) have been studied more than a decade. Purpose of this retrospective analysis was to evaluate the anti-leukemic efficacy and toxicity of FLAG-IDA protocol (fludarabine, cytarabine, and idarubicin) followed by treosulfan-based conditioning for patients with active AML. From January 2014 to November 2019, a total of 29 active AML patients [median age, 64 years (range, 23-73)] were treated. All patients completed protocol regimen and were transplanted. Five patients (17%) had grade 3-4 toxicities; therefore, treosulfan was substituted with total body irradiation (TBI) non-myeloablative conditioning. Six (20%) patients died within 30 post-transplant days, all from infectious complications. Out of 23 evaluable patients on day 30, 22 (96%) achieved complete hematologic remission with full donor chimerism. Non-relapse mortality (NRM) rates at 1 and 3 years were 22% and 49%, respectively. Median overall survival (OS) was 12 (95% CI, 4-20) months. OS and disease-free survival were 50% and 46% at 1 year and 28% and 17% at 2 years, respectively. Age, gender, disease burden, number of previous lines, and comorbidity score did not predict survival. Sequential strategy combining FLAG-IDA and treosulfan may offer a salvage option for few selected patients with active AML; however, high NRM presents a major obstacle to treatment success. Future efforts should focus on reducing NRM by moderating regimen intensity and by better selection of patients.

Efficacy of folinic acid rescue following MTX GVHD prophylaxis: results of a double-blind, randomized, controlled study.

The use of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis is associated with increased rates of organ-specific toxicities. Despite limited data, the European Society for Blood and Marrow Transplantation-European LeukemiaNet working group recommend the use of folinic acid (FA) rescue to reduce MTX toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). In a multicenter, double-blind, randomized, controlled trial, we explored whether FA rescue reduces MTX-induced toxicity. We enrolled patients undergoing allo-HCT with myeloablative conditioning with peripheral blood stem cell grafts, with GVHD prophylaxis consisting of cyclosporine and MTX. Patients were randomized to receive FA or placebo starting 24 hours after each MTX dose and continuing over 24 hours in 3 to 4 divided doses. The primary end point was the rate of grades 3 and 4 oral mucositis. After enrollment of 52 patients (FA, n = 28; placebo, n = 24), preplanned interim analysis revealed similar rates of grade 3 and 4 (46.6% vs 45.8%; P = .97) and grades 1 to 4 (83.3% vs 77.8%; P = .65) oral mucositis. With a median follow-up of 17 (range, 4.5-50) months, there was no difference in the rates of acute and chronic GVHD, disease relapse, nonrelapse mortality, and overall survival. These interim results did not support continuation of the study. We conclude that FA rescue after MTX GVHD prophylaxis does not decrease regimen-related toxicity or affect transplantation outcomes. This study was registered at clinicaltrials.gov as #NCT02506231.

Epidural/spinal anesthesia during delivery in women with factor XI deficiency, a single center experience.

INTRODUCTION: The safety of neuro-axial anaesthesia (epidural/spinal) at labour of women with partial factor XI (FXI) deficiency is uncertain. Although FXI deficiency is frequent in Ashkenazi Jews, it is not routinely measured before labour. Our institute serves a large Ashkenazi population. We assumed that 10% of them have undiagnosed FXI deficiency. AIM: Assess the incidence, bleeding tendency and coagulation status among Jewish Ashkenazi women with FXI deficiency that underwent neuro-axial anaesthesia at delivery. METHODS: Jewish Ashkenazi women who underwent neuro-axial anaesthesia at labour completed the SSC ISTH bleeding assessment tool (BAT) and had blood drawn for coagulation tests, FXI and thrombin generation after labour. Estimation for 10 years was calculated from the 1-year sample. RESULTS: We recruited 261 women during 12 months. Among them, 39 (15%) had FXI deficiency (<70%) with median FXI levels of 63% (range: 33%-70%). Around 50% of them underwent amniocentesis in the current pregnancy and prior neuro-axial anaesthesia with no bleeding complications. BAT score and thrombin generation did not differ between women regardless of FXI status. aPTT was longer in women with partial FXI deficiency (median - 28.6 sec vs 26.3 sec, P < .001, Table 2), although within the normal range in all women. No bleeding complications after neuro-axial anaesthesia at delivery were reported in our centre in the last decade though, and according to our estimation, at least 2150 women had partial FXI deficiency. CONCLUSIONS: A significant number of Jewish Ashkenazi women with undiagnosed partial FXI deficiency undergo neuro-axial anaesthesia at labour without bleeding complications.

Early detection of infectious complications during induction therapy for acute leukemia with serial C-reactive protein biomarker assessment.

Febrile neutropenia (FN) and blood stream infections (BSI) are major complications of induction treatment for acute leukemia. We assessed the predictive utility of C-reactive protein (CRP), an acute phase reactant, for FN and BSI during induction. CRP levels and dynamics were analyzed in 138 consecutive patients. FN and BSI occurred in 110 (80.3%) and 10 (7.5%) patients, respectively. Median peak CRP level in the 24-hours preceding FN was 7.5 mg/dl (0.2-38.1) vs. median peak CRP level of 5.11 mg/dl (0.2-23.1, p = .009) in patients without FN. CRP levels preceding BSI were 13.1 mg/dl (6.9-27.9) vs. 6.3 mg/dl (0.16-38.14, p = .011). CRP increase prior to event (ΔCRP) was higher among patients with BSI vs. patients without BSI (p = .013). CRP was predictive for FN (p = .009) and BSI (p = .01) on ROC curve analysis and was also independently associated with FN on multivariate analysis. In conclusion, CRP is a sensitive biomarker that precedes FN and BSI.