Shimony, Shai

Abstract The incidence of venous thromboembolism (VTE) in patients with acute lymphoblastic leukemia (ALL) receiving asparaginase-based induction is high despite primary thromboprophylaxis. Our aim was to derive and externally validate a VTE risk prediction model in patients with ALL receiving asparaginase-based induction. We conducted a multicenter retrospective cohort study of patients (aged ≥18 years) with newly diagnosed ALL receiving asparaginase-based induction. The derivation and external validation cohorts included 306 and 94 patients, respectively. Primary outcome was VTE at any site. A cause-specific Cox proportional hazards model stratified by thromboprophylaxis and center was performed to identify VTE risk factors in the derivation cohort. A risk prediction model for VTE at 30 days was derived using variables with P value < .05 in the multivariable model and was tested in the validation cohort. VTE risk factors on multivariable analysis in the derivation cohort included D-dimer ≥1 μg fibrinogen equivalent unit per mL (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.07-6.5) and hemoglobin (HR for each 1 g/dL increment, 1.19; 95% CI, 1.06-1.34) at ALL diagnosis. A VTE risk score based on these variables distinguished between a 4% (95% CI, 0.72-12) and 20% (95% CI, 14-27) 30-day cumulative incidence of VTE in the derivation cohort, with similar findings in the validation cohort (area under the curve, 0.56). The negative predictive value for VTE at 30 days was 96% and 93% in the derivation and validation cohorts, respectively, and the positive predictive value was 20% in both. We derived and validated a model using D-dimer and hemoglobin, which stratifies VTE risk in patients with ALL receiving asparaginase-based induction.

ABSTRACTOverviewBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic neoplasm that involves multiple organs, including the skin, bone marrow and blood, lymph nodes, and central nervous system. Violaceous tumors or plaques appearing in sun‐exposed areas are characteristic and present in most patients. The disease typically affects adult men aged 60–70 years, although children and younger adults may also be affected.DiagnosisDiagnosis is based on biopsy of an involved site and is typically based on the identification of blastoid cells displaying the classical immunophenotypes CD123, CD4, and CD56 in addition to specific pDC markers.PrognosisThe median overall survival is 18–24 months. Potential risk factors for shortened survival include older age, overt bone marrow involvement, and genetic abnormalities.Therapy and ManagementEither chemotherapy‐based regimens or tagraxofusp, a CD123‐directed interleukin 3 conjugated with diphtheria toxin, may be used for upfront therapy. Eligible patients are recommended to be consolidated with hematopoietic allogeneic stem cell transplantation. Assessment and treatment of the central nervous system is mandatory, and careful monitoring of skin disease in conjunction with dermatology is essential.

Background: Patients with acute lymphoblastic leukemia (ALL) receiving L-asparaginase (ASP) based induction therapy have a high risk of venous thromboembolism (VTE). Studies investigating universal thromboprophylaxis strategies have yielded sub-optimal results. Risk prediction models are needed to identify high-risk patients who would be candidates for intensification of thromboprophylaxis, and lower risk patients who are unlikely to benefit. Aims: Derive and externally validate a risk prediction model for VTE in patients with ALL receiving ASP therapy. Methods: We conducted a multicenter, international, cohort study of patients with newly-diagnosed ALL receiving ASP-based induction therapy (≥18yrs). The derivation and external validation cohorts included 306 and 97 patients without VTE prior to ASP therapy, respectively. Patients on therapeutic anticoagulation at index were excluded. Patients were followed from date of first ASP dose for 100 days post ALL diagnosis or until VTE, therapeutic anticoagulation or death. Candidate predictors were documented at ALL diagnosis and included demographics, disease and treatment characteristics, VTE history, comorbidities, thromboprophylaxis, complete blood count, fibrinogen and d-dimer. D-dimer was only analyzed within the 7 derivation cohort centers who routinely tested this at ALL diagnosis with <20% missing values. Primary outcome was VTE at any site (centrally confirmed). Secondary outcomes included major bleeding by ISTH criteria. Cause-specific Cox proportional hazard regression was performed to identify VTE risk factors in the derivation cohort while treating death as a competing event. Variables with p-value <0.1 on univariable analysis were included in a multivariable model and subsequently used in the risk model if p-value <0.05. Lastly, the derived VTE risk prediction model was tested in the external validation cohort for association with time to VTE using cause-specific Cox proportional hazard model. All analyses were stratified by center and use of low molecular weight heparin prophylaxis (at any dose on the date of first ASP dose). Results: The cumulative incidence of VTE in the derivation cohort was 17% at 30 days (95% confidence interval [CI] 13% - 21%) and 22% at 90 days (95% CI 17% - 27%). The multivariable model included hyperlipidemia (hazard ratio [HR] 1.35; 95% CI 0.56 - 3.27), body mass index ≥ 25 kg/m² (HR 1.49; 95% CI 0.75 - 2.95), platelet count ≥ 25 x 10⁹/L (HR 1.42; 95% CI 0.67 - 3.00), increasing hemoglobin per 1 g/dL (HR 1.17; 95% CI 1.03 - 1.32) and d-dimer ≥ 1 µg FEU/mL (HR 2.68; 95% CI 1.08 - 6.66). Hemoglobin as a continuous variable and d-dimer ≥ 1 µg FEU/mL were included in the final model and used to create a risk score which was weighted by estimated log-HR sum of these risk factors. The lowest risk quartile (risk score below 2.1) successfully differentiated between a lower 30-day cumulative VTE incidence (4%, 95% CI 0.72% - 12%) compared with the other quartiles (20%, 95% CI 14% - 27%; HR 4.40, 95% CI 1.54 - 12.5) which were defined as high risk (score ≥2.1). The risk score's negative predictive value (NPV) for VTE at 30 days was 96% and positive predictive value (PPV) was 20%. The validation cohort (n=97 from 3 external cohorts with routine d-dimer measurement) included 16 (16.5%) patients in the low-risk group and 81 (83.5%) in the high-risk group, with a 30-day VTE incidence of 6.3% (95% CI 0% - 17%) and 21% (95% CI 12% - 30%), respectively (HR 6.22; 95% CI 0.85 - 45.8; p = 0.073)). The NPV (93.7%) and PPV (21%) were comparable to the derivation cohort. The 30-day incidence of major bleeding was 0% (95% CI NR - NR) in low-risk patients (HR 1.36; 95% CI 0.27 - 6.77) and 2.0% (95% CI 0.55% - 5.4%) in the high-risk group. Conclusion: Patients with ALL receiving ASP induction therapy have a 17% VTE risk at 30 days. We derived and externally validated a VTE risk prediction model based upon d-dimer and hemoglobin. This model successfully identifies at least 16.5% of patients with ALL who have a low VTE risk after ASP treatment. Using this model, novel prevention strategies which may be associated with cost and risk could now be tailored to patients with higher risk. Prospective studies are needed to validate the model's performance and role in VTE risk management.

Background In 2014, the IMWG updated the criteria for diagnosing multiple myeloma (MM) and added three additional criteria to the traditional CRAB criteria. The new criteria called the SLiM criteria, include clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (rFLC) ≥100 (involved FLC must be ≥ 100 mg/L), and > one focal lesion on MRI studies (each lesion ≥ 5 mm). These criteria were deemed myeloma-defining events (MDE) in the absence of CRAB criteria. Autologous stem cell transplantation (ASCT) has been used for treating MM for over three decades and is safe and efficacious. We report on outcomes of outpatient ASCT in a cohort of patients with MM where therapy was initiated solely based on SLiM criteria. Methods We conducted a retrospective study of all patients diagnosed with MM based on SLiM criteria at Mayo Clinic, Rochester, MN. We compared this cohort to a matched cohort of newly diagnosed MM patients whose MDE was CRAB and who underwent an ASCT. For every patient whose MDE was SLiM, we matched two patients whose MDE was CRAB. The matching was done by age, gender, and melphalan dose. Results Between 2013 and 2022, 30 patients received an ASCT due to SLiM criteria at Mayo Clinic, Rochester (Durie Salmon Stage IA). The median age of our cohort was 63 (range 46-75) years, and 60% had an ISS of 1. Seventeen percent of the cohort was treated with DVRd induction. The median time from diagnosis to ASCT was 6.5 months (IQR 6-7), and all but one received full intensity conditioning with melphalan 200 mg/m2. 53% of patients completed the ASCT without requiring hospitalization, and 47% (n=14) of patients required hospitalization with a median duration of hospital admission of 6 days (IQR 5-14). Bacteremia was confirmed in 7 patients (23%). The matched cohort included 60 patients. Baseline characteristics were similar, with the exception of lower hemoglobin levels in the control group, as expected (13.1 vs 12, P=0.0017). No differences were seen in the number of cells collected (3.4 vs 3.67 X106 cells/kg, P=0.19) or the use of Plerixafor (80% vs 78%, P=0.8). The SLiM cohort had a shorter median time to neutrophil (15 vs 16 days, P=0.049) and platelet (15 vs 17 days, P=0.0004) engraftment. Similar hospitalization and bacteremia rates were seen. The overall response rate was 100%, with a complete response or better (sCR/CR) seen in 30% of patients. The matched cohort had an ORR of 98%, with sCR/CR of 37%. The MRD- rate was the same in both groups. More patients in the SLiM cohort achieved VGPR (50%) than in the CRAB cohort (27%). None of the patients died within 100 days of transplant. The 36-month OS was 100% in the SLiM group and 93.3% in the control group (95% CI 83.1%-97.4%), with a trend towards higher OS in the SLiM cohort (P=0.065). The 36-month PFS was 91.61% in the SLiM cohort (95% CI 69.93-97.87%) and 65.95% in the control group (95% CI 52.31%-76.53%). There was no difference in the PFS between the cohorts (P=0.414). Conclusion ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Improved MRD- and longer PFS were not seen despite lower ISS stage disease in the SLiM group.

Abstract Introduction: Though originating from different cell origins, several reports have described patients with the coexistence of chronic myeloid leukemia (CML) and paraproteinemias, mostly in patients treated with tyrosine kinase inhibitors (TKIs). Objective : To determine whether the prevalence of paraproteinemia in a large cohort of chronic phase (CP-) CML patients is higher than expected in the general population. Methods: We conducted a cross-sectional study among out-patient CP-CML patients treated in a tertiary medical center. Between February 2019 and May 2021 consecutive CP-CML patients who consented to the study, performed the following tests: quantitative immunoglobulin (Ig) levels, serum-free light chains (sFLC), serum protein electrophoresis (SPEP), and if abnormal also serum protein immunofixation (IFIX). The primary outcome was the prevalence of paraproteinemia among this cohort of CML patients. We conducted further analyses to evaluate whether various patient, disease and treatment-related variables are predictors of paraproteinemia within our cohort. Results: One hundred patients, 50% males, with a median age of 63.5 (range 26-91.6) years were recruited for the study. The median time from CML diagnosis to enrollment was 6.3 (range 0.1-23.5) years. Cohort's characteristics are depicted in table 1. Monoclonal (M-) protein was detected on SPEP and IFIX in eight patients (8%), whose median age was 66.8 (range 46-74) years. Among them, two patients had an abnormal sFLC, elevated IgG or IgA levels, on a bone marrow biopsy over 10% monoclonal plasma cells were present, and in the absence of myeloma defining events they were diagnosed with IgG-kappa and IgA-kappa smoldering multiple myeloma (SMM), respectively. The other six patients had normal sFLC ratio and characteristics compatible with low-risk monoclonal gammopathy of undetermined significance (MGUS). Six patients with a detectable M-protein were treated with a TKI [imatinib (n=2), dasatinib (n=3), bosutinib (n=1)] and two were in treatment-free remission (TFR). All continue observation for their paraproteinemia. None of the patients in our cohort was diagnosed with active MM. The presence of anemia was predictive of paraproteinemia, albeit with borderline statistical significance in both univariate (p=0.053) and multivariate analysis (p=0.069). Apart from anemia, no predictors for paraproteinemia were found among various other patient and disease related variables. Conclusions: This is the largest study describing the prevalence of paraproteinemia among CML patients. We found the prevalence of MGUS in CP-CML patients (6%) to be higher than in the general population above the age of 50 (3.2%), and a non-negligible prevalence of SMM (2%). Based on these data, we recommend considering screening for paraproteinemia coexistence in CML patients. Further studies and extended follow-up are needed to elucidate the true clinical significance of our findings. Figure 1 Figure 1. Disclosures Leader: Bayer: Honoraria; Leo Pharma: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Honoraria.

Abstract Background: Marginal zone Lymphoma (MZL) is the third most abundant lymphoma and it is subclassified into 3 entities: splenic, nodal and extranodal mucosa associated lymphoid tissue (MALT). Positron emission tomography (PET) using 18F fluorodeoxyglucose (FDG) with computed tomography (CT) is increasingly used for staging and response assessment of FDG avid lymphomas, such as diffuse large B cell lymphoma and Hodgkin lymphoma. The role of PET/CT in lymphomas with variable FDG avidity, such as MZL, is still under active research. Aims: The purpose of this study was to evaluate PET/CT as a diagnostic and prognostic tool in patients with MZL. Methods: A retrospective cohort study of patients with newly diagnosed MZL, treated with immunotherapy, chemotherapy regimen, surgery or eradication between 2008 and 2016 in a single tertiary center. Patients who did not undergo pre-treatment PET/CT (P-PET/CT) were excluded. Patients were identified through the hospital's computerized database. Demographic, clinical and laboratory data were collected from patients' files until the latest follow-up available and for at least 12 months after completion of treatment administration. P-PET/CT, interim (I-PET/CT) and end-of-treatment PET/CT (E-PET/CT) studies were centrally reviewed by a nuclear specialist and reported using 3 methods of evaluation: visual assessment, maximal SUV reported and Deauville 5-point score (DS) evaluation (DS only for I-PET/CT and E-PET/CT). PET/CT was interpreted as positive if any of the three evaluation methods was positive. The primary outcome was to evaluate the prognostic role of P-PET/CT, I-PET/CT and E-PET/CT on progression free survival (PFS) and overall survival (OS). Survival curve was calculated using the Kaplan-Meier method, and Cox regression. Models adjusted for age, sex, and stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) was used for the association between PET/CT positivity, PFS and OS. Results: Data of 196 patients with MZL were identified. 86 patients were excluded due to absence of P-PET/CT. Thus, 110 patients were included in this analysis. The most frequent histological type of MZL was MALT (51%). Median patients' age was 67 years (range: 18-93). The median follow-up period was 63 months (range: 3-278). 54/110 (73%) presented with bone marrow involvement and 100/110 (91%) had extranodal involvement. MZL transformed to an aggressive lymphoma in 3% of the patients. The median OS and PFS for the whole cohort were 63 months (interquartile range: 39-85) and 60 months (interquartile range: 37-76), respectively. 77/110 (71.3%) patients had positive P-PET/CT. Among 19 patients that had I-PET/CT, eight studies were positive and 11 negative. 63/110 patients underwent E-PET/CT: 12 studies were positive and 51 negative. P-PET/CT and I-PET/CT were not predictive of PFS or OS. Sub-group analysis of the different types of MZL did not show such a correlation as well. When adjusted for age, sex and stage, positive E-PET/CT was associated with reduced PFS with a hazard ratio (HR) of 4.16 (CI 1.55-11.2, p=0.005) (Figure 1). Conversely, positive E-PET/CT did not correlate with OS maybe due to the low death rate (3 patients). In a univariate analysis, beta 2 microglobulin was prognostic for PFS with and adjusted HR of 1.44 (CI 1.08-1.94, p-0.014). Conclusions: Our study shows that above 70% of MZL are FDG avid. P-PET/CT and I-PET/CT were not predictive of PFS; However, E- PET/CT was predictive of PFS with an adjusted HR of 4.2. Figure 1: The association between E-PET/CT in PFS Disclosures No relevant conflicts of interest to declare.

AbstractWe evaluated the role of 18‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography ([18F] FDG‐PET) with computed tomography (CT) (PET/CT) as a diagnostic and prognostic tool in newly diagnosed marginal zone lymphoma (MZL) patients.This is a retrospective cohort study of patients with newly diagnosed MZL, treated with immunotherapy, chemotherapy regimens, surgery, or Helicobacter pylori eradication between 2008 and 2016 in a single tertiary center. Only patients who had a pretreatment PET/CT (P‐PET/CT) were included. P‐PET/CT, interim (I‐PET/CT), and end‐of‐treatment PET/CT (E‐PET/CT) studies were reviewed. P‐PET/CT results were reported using two methods of evaluation, qualitative and semi quantitative: visual assessment (VAS) and maximal standardized uptake value (SUVmax), and I‐PET and E‐PET results were reported by Deauville 5‐point score (DS) evaluation as well. Avidity of PET/CT was defined as abnormal uptake in any of these methods. The primary outcome was the prognostic role of P‐PET/CT, I‐PET/CT, and E‐PET/CT on progression‐free survival (PFS) and overall survival (OS).Data of 196 patients with MZL were identified, 110 of which had P‐PET/CT and were included in this analysis. Median age was 67 years (range 18‐93). The median follow‐up period was 63 months (range 3‐278). The median OS and PFS for the whole cohort were 63 (interquartile range 39‐85) and 60 (interquartile range 37‐76) months, respectively. The avidity of PET at baseline for the whole cohort was 70% (77/110 patients), for MALT lymphoma, 62.5% (40/64 patients), for NMZL, 76.4% (13/17 patients), and for SMZL, 82.7% (24/29 patients). When adjusted for IPI, sex, and comorbidities, positive E‐PET/CT was associated with reduced PFS with a hazard ratio (HR) of 3.4 (95% CI, 1.27‐9.14, P = 0.02). Positive E‐PET/CT did not correlate with OS. However, there were only three events. P‐PET/CT was not predictive of PFS or OS. Our study demonstrates that above 70% of MZL are FDG avid. Positive E‐PET/CT is a strong prognostic factor for PFS.