LDH Levels Research Articles

Prognostic factors and mortality predictive scale in patients treated with in-hospital extracorporeal cardiopulmonary resuscitation

Abstract Background Extracorporeal cardiopulmonary resuscitation (ECPR) is a rescue option in cardiac arrest (CA) refractory to advanced life support. Patient selection is challenging, evidence is limited and randomized studies are lacking regarding in-hospital CA. Purpose Our objective was the identification of factors associated with survival in in-hospital ECPR. Methods Retrospective analysis of consecutive cases of venoarterial extracorporeal membrane oxygenator (VA-ECMO) for ECPR indication in a referral center. The ECPR alert includes in-hospital cardiologist/intensivist, on-call interventional cardiologist/cardiac surgeon for cannulation, and on-call perfusionist. We analyzed baseline variables related to CA and ECPR technique and studied their relationship with in-hospital survival. Results Out of 207 VA-ECMO implants between 2014-feb 2023, we selected the ECPR cases: N=59 (28.5%). Baseline, admission and ECPR characteristics are collected in the table. ECMO-VA support intention was bridge to recovery in 68% of cases, transplant 5%, ventricular assist device 5% and decision 22%. The most frequent access was percutaneous femoro-femoral, and ECPR was unsuccessful (no flow, no rhythm, or impossibility of cannulation in 11.8% of cases). All patients underwent temperature control at 36ºC with ECMO. Overall in-hospital survival was 18.6% (n=11) (cerebral performance cathegory 1-2), and the most frequent causes of death were refractory shock/multiple organ failure (49%) and anoxic encephalopathy (25%). The patients who died were significantly younger, had peripheral vascular disease (PAD), higher creatinine, LDH and lactate levels, longer CA duration, and its ECMO implantation was more frequent during on-call hours (table). Lactate >10.05 predicted mortality (AUC 0.693, Sens 67,3%, Esp 80%). The time under VA-ECMO support and mechanical ventilation, and the use of adrenaline infusion were more frequent in the survivors (table). At multivariate analysis, a longer CA duration (HR 0.947, CI95% 0.900-0.977, p0,040) was the only factor independently associated with in-hospital mortality. We developed a predictive scale including factors related to survival (lactate >10.05, >60 minutes CA, PAD, on-call time) which predicted 100% with 3 or more factors (p<0.001) (figure 2). Conclusions In-hospital ECPR is an option for refractory cardiac arrest, with high mortality. CA duration was the only factor independently associated with in-hospital mortality. Three or more adverse factors (lactate >10.05, >60 minutes CA, PAD, on-call time) predicted 100% mortality. Randomized studies are needed to determine a better selection of patientsBaseline, admission and ECPRMortality predictive scale after ECPR

Peculiarities of pharmacological prevention strategy of pancreatic complications after endoscopic papillosphincterotomy for choledocholithiasis

The most frequent complication of endoscopic papillosphincterotomy (EPST) is acute pancreatitis. This complication is supposed to be based on mechanical, chemical, hydrostatic, enzymatic and thermal impact on pancreatic ducts and parenchyma. According to different literature data, the incidence of post-EPST pancreatitis (PEP) varies from 30 to 40%, and the mortality rate is 2–10%. The aim of the investigation was to expand information about peculiarities of early diagnostics and prevention of post-EST pancreatitis at the present stage. To reach the set goal we analyzed 559 case histories of patients with diagnosed cholelithiasis, 319 of them underwent EPST. During the study it was found out, that elevated neutrophils/ lymphocytes ratio over 4.96 (p = 0.001), high LDH level over 250 IU/ml (p = 0,010), as well as C-reactive to albumin index over 0,180 (p = 0.001) are reliable markers of early diagnosis. Also, indirect diagnostic markers of PEEP are biochemical signs of cholestasis and cytolysis of hepatocytes, as well as hyperglycemia combined with glucosuria. We consider the inclusion of intraoperative injections of papillotomy wound margins with epinephrine in combination with subsequent Somatostatin administration in combination with rectal diclofenac and intravenous hydration with Reamberin to be the most effective strategy for PEP prevention. Thus, we can conclude that despite the ongoing research and the search for effective algorithms for the prevention and early diagnosis of PEP, their data often contradict each other or simply do not confirm their effectiveness. The problem of prevention and diagnosis of PEP remains complex and requires further study. There are discrepancies, sometimes significant ones, in the current literature, which provides grounds for the development and research of new methods of early diagnosis and prevention.

МНОЖЕСТВЕННАЯ МИЕЛОМА: ОСОБЕННОСТИ ТЕЧЕНИЯ И ОТВЕТА НА ТЕРАПИЮ У ПАЦИЕНТОВ РАЗНЫХ ВОЗРАСТНЫХ ГРУПП

Background: Multiple myeloma (MM) remains an incurable disease with the development of relapses, sometimes with an uncontrolled course leading to death regardless of the age of the patient. The use of new schemes and methods of treatment has not only significantly improved outcomes in younger MM patients but also improved the quality of life and survival in people over 65 years of age. Objective: to determine the clinical features of the course of the disease and response to therapy in patients of different age groups with newly diagnosed multiple myeloma. Material and Methods: An analysis of the data of 139 patients with newly diagnosed MM was carried out. The median follow-up was 25 months, with a maximum of 58 months. Patients were divided into study groups depending on age at the time of diagnosis: the first group - age up to 65 years (n=65); the second group - age from 65 years and older (n=74). The material of the study was clinical and anamnestic data, the results of laboratory blood tests: biochemical analysis and immunochemical analysis. All the patients underwent the whole body CT scan, diffusely weighted whole body MRI and bone marrow aspiration biopsy with immunophenotypic study. As an induction therapy, according to international recommendations, courses of chemotherapy were used using various regimens containing bortezomib, depending on age and comorbidity. Results. The MM variant with IgA secretion occurred 1.76 times more often in the first group (p=0.128). In the first group hypercalcemia was somewhat more common (2.4 times, p=0.099) and an excess of LDH levels (2.9 times, p=0.072). In contrast, the presence of infectious complications (by 1.2 times, p=0.392), excess of the level of β2-microglobulin > 3 mg/l (by 1.6 times, p=0.086) and kidney damage (by 1.45 times, p=0.037) were more common in the second group, and in the latter case the differences were statistically significant. Disease stage (p=0.0001), excess of β2 microglobulin level (p=0.004), excess of LDH level (p=0.03), presence of anemic syndrome (p=0.003), hypercalcemia (p=0.02), presence of infectious complications (p=0.01) at the time of diagnosis were predictors of worse survival in the general group of MM patients. Conclusion. The active use of new therapeutic strategies and regimens improves treatment outcomes not only in patients under 65 years of age, but also in older patients. New studies are needed to identify prognostic factors in individuals of different age groups in order to start personalized therapy and improve treatment outcomes.

Design, synthesis, and evaluation of n-butylphthalide and ligustrazine hybrids as potent neuroprotective agents for the treatment of ischemic stroke in vitro and in vivo

A series of novel NBP-TMP hybrids with neuroprotective effects were designed and synthesized for the treatment of ischemic stroke. The anti-cerebral ischemic activity of these compounds was screened by evaluating their neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell injury model in vitro. Nine compounds 7e, 7h-7i, 7k, 7m-7p and 7r showed better activities on cell viability and LDH levels compared to NBP at the concentration of 6.25 μM. Among them, compound 7m showed the best potency with a percentage of protection 90.2 % compared to NBP (69.2 %) and other compounds. Preliminary structure-activity analysis revealed that the introduction of iodine and N-methylpiperazine groups could significantly improve the neuroprotective effect. Further mechanism research showed that compound 7m could reduce the damage to neuronal mitochondria caused by OGD/R by reducing ROS and increasing mitochondrial membrane potential (MMP), and reduce the apoptosis and necrosis of neurons to play a neuroprotective role. In addition, 7m could regulate the levels of mitochondrial apoptosis pathway-related proteins Bcl-2, Bax, and caspase 3. Finally, in vivo experiments showed that the compound 7m significantly inhibited ischemia-reperfusion injury and cerebral blood flow in rats, and showed a more significant neuroprotective effect than the positive drug NBP at a dose concentration of 20 mg/kg. In conclusion, our results suggest that 7m may be used as a novel lead compound for the future development of anti-cerebral ischemic agents.

Outcome of COVID-19 in Egyptian living-donor kidney transplant recipients and relation to maintenance immunosuppressive drugs: a pilot study

Coronavirus disease 2019 (COVID-19) in kidney transplant recipients is a subject of much debate and became of interest to nephrologists amidst the pandemic. The main concerns are the influence of the chronic use of immunosuppressive drugs, the viral-related risk of acute rejection, and the long-term outcome of allograft function. This single-center prospective study included kidney transplant recipients with COVID-19 infection. Patients were maintained on immunosuppressive regimens. The severity of disease was defined as oxygen saturation < 94%, the need for hospitalization and/or hemodialysis, the occurrence of acute kidney injury (AKI), and mortality. Seventeen patients (54.8%) required hospital admission, four patients needed hemodialysis (12.9%), twelve patients (38.7%) had AKI, and three patients died (9.7%). Oxygen saturation < 94% showed a positive correlation with the presence of diabetes (p value 0.031) and a negative correlation with the maintenance steroid dose (p value 0.046). A negative correlation existed between the need for hemodialysis and average Cyclosporin level (p value 0.019) and between the need for hospitalization and average Tacrolimus level (p value 0.046). Severity of disease was associated with the presence of lymphopenia (p value 0.042), the cumulative steroid dose (p value 0.001), increased serum levels of LDH (p value 0.010), Ferritin (p value 0.020), AST (p value 0.047), and ALT (p value 0.006) and D-dimer levels more than 0.5 mg/L (p value 0.038). This study highlighted that the immunocompromised state of renal transplant recipients may not be regarded as a disadvantage in the setting of COVID-19 infection. Studies on a larger scale are needed to validate these results.

Clinical Pathology Characteristics of 221 Pediatric Anaplastic Large Cell Lymphoma-3 Years Follow up and Experience from China Net Childhood Lymphoma(CNCL)

Objective: To investigate the clinical-pathology characteristics, risk factors, necessary for VBL maintenance therapy，through summarize the clinical data of 221 cases of pediatric Anaplastic Large Cell Lymphoma (ALCL), treated with CNCL-ALCL-2017 witch is modify from BFM-ALCL-99 (±vincristine maintenance therapy) in China Net Childhood Lymphoma (CNCL). Methods: Data were collected on 221 children with ALCL enrolled from CNCL at time between April 2017 to March 2023, including: numbers of cases enrolled in each single center, gender and age at the time of initial diagnosis, the first initial symptom, a delay diagnosis, the misdiagnosis disease , the site of involvement, the level of blood uric acid, the level of blood lactate dehydrogenase, the bone marrow and CNS status, tumor complication, complicated with HLH, staging and treatment subgroups, pathological subtypes, CD3 expression in tumor tissue, bone marrow and peripheral blood ALK gene expression at initial diagnosis (qPCR + FISH), and treatment outcomes, treatment strategy(vincristine maintenance or not), time from initial diagnose to relapse, second-line treatment regimen after relapse, and treatment outcomes after relapsed. Statistical analysis was conducted using SPSS 21.0 software. Results: 221 cases were from 22 hospitals in China. Male = 144 cases, female = 71 cases, age range from 1-16 years (median age 8.9 years), duration from initial symptoms onset to diagnosis was 0.3-11 months (median time 1.0 months), delayed diagnosis was present in 51(23%) children (45 children were misdiagnosed with infectious diseases). Pathological subtypes were: common sub type = 150(67.8%), small cell sub type = 19(8.5%), histiocytic variant subtype = 9(4%), ALK negative subtype = 12(5.4%).others = 31(14%). CD3 expression in tumor: negative = 119, positive = 91. ALK positive by qPCR in peripheral blood at the time of the initial diagnosis = 77, ALK positive by qPCR in bone marrow = 78, bulky disease= 21, mediastinal invasion = 84, CNS invasion = 17, skin invasion = 32. tumor related HLH = 25, normal LDH level at initial diagnosis = 133, 1-fold elevated = 45, 2-3-fold elevated = 39, 4-fold elevated = 2, &amp;gt;4-fold elevated = 2, stage I = 5, stage II = 24, stage III = 70, stage IV = 120 , leukemic stage = 2 . Grouping: group A = 1, group B = 21, group C = 191, group D = 8. Vincristine maintenance = 121. Median follow-up time was 35.4 months (0.5-74.9 months), OS at 3 years = 95.1±1.5% (95% CI = 90%-97.3%, Fig. 1), EFS at 3 years = 84.7±4.5% (95% CI = 79%-89.9%, Fig. 2), and there were a total of 23 patients with events, median time was7 months. There were 10 patients died, 5 of them quit to the treatment, median time was 5 months, and 13 patients who had an event but still alive after second line treatment. Univariate results of the 3 years EFS are detailed in Table 1, with statistically significant including (&amp;lt;0.05): tumor related HLH before treatment, LDH levels higher than 4 times normal and MDD positive at the beginning of the disease, and treated without VBL. The event patients are 23 cases ,the detailed in Table 2, which showed that the earlier the event occurs, the higher the mortality rate. Conclusion:Pediatric ALCL in China is mostly found in school-age boys, and it is easy to be diagnosed as infectious diseases at the time of initial diagnosis due to high fever and elevated CRP. 87% of patients were diagnosed as late stage or high-risk group. The application of the CNCL-ALCL-2017 protocol showed a 3-year OS 84.7% and 3-year EFS 95.1%, indicating that the efficacy was significantly better than that of various centers before the multi center cooperation. The overall survival time is significantly better than the event free survival time, indicating that most patients with progression and recurrence still have a chance of re remission after second line treatment. Adverse prognostic factors include a significant increase in LDH levels at initial diagnosis, initial onset of HLH, positive MDD before treatment, and no use of vinblastine maintenance therapy. Recurrent children: The median recurrence time is 7 months, and the prognosis of early progression and recurrence is worse than that of late recurrence. Key words: Anaplastic large cell lymphoma, Pediatric, Clinical-pathology features, Prognosis

A Retrospective Analysis of COVID-19 Coagulopathy in Hospitalized and Intensive Care Patients with Sickle Cell Disease

Purpose/Objective: The implications of COVID-19 induced hypercoagulability in patients with sickle cell disease (SCD) remain largely unknown. Both COVID-19 and SCD have independent pathophysiological mechanisms which impact each aspect of Virchow's triad to induce a hypercoagulable state (Saxena and Muthu., 2023), however the joint impact of COVID-19-SCD on venous thromboembolism (VTE) remains understudied. As such, our primary objective involved investigating the incidence of VTE events in SCD patients with COVID-19. Our secondary objective involved assessing parameters of COVID-19 infection severity in SCD patients. Methods: We conducted a retrospective cross-sectional study at New York City Health and Hospitals, Kings County involving SCD, sickle cell trait (SCT) and the general population of COVID-19 patients (non-sickle). Data was collected from the onset of the pandemic on March 1, 2020 to December 31, 2021 for hospitalized and intensive care patients. We collected information on incidence of VTE, type of VTE (deep vein thrombosis or pulmonary embolism), age, sex, comorbidities, VTE prophylaxis, D-dimer, ferritin, LDH, BMI, sickle cell phenotype, transfusion requirements, COVID-19 management, SCD management, and outcomes. Data was analyzed on GraphPad PRISM, using one-way ANOVA and odds ratios. A p-value of &amp;lt;0.05 was considered statistically significant. Results: The study included three patient cohorts, consisting of 24 SCT, 26 SCD and 675 non-sickle patients (non-SS) to study incidence of VTE. Additional information regarding infection parameters was obtained on 146 non-sickle patients, and all SCT and SCD patients. We found that there was no significant difference between VTE risk in the SCD and non-sickle patients (OR=0.3736, 95% CI 0.0223 to 6.2675) or SCT and SCD patients (OR=0.2956, 95% CI 0.0115 to 7.6121). There was no significant difference in mortality (OR=0.4909, 95% CI 0.0606 to 3.9736) or intensive care requirements (OR=0.4137, 95% CI 0.1171 to 1.4608) between SCD and non-SS patients (Table 1). We also investigated markers of infection and hypercoagulability and found that there was no significant difference between D-dimer or LDH levels between the three cohorts, however ferritin was significantly increased in the SCD group compared to the non-sickle cohort (Figure 1, p=0.0123). Conclusions/Implications: Current ASH guidelines recommend use of prophylactic dose anticoagulation for critically ill COVID-19 patients and therapeutic dose anticoagulation for acute, but not critically ill patients (Cuker et. al., 2022). There are currently no formal recommendations regarding VTE prevention for hospitalized SCD patients with COVID-19. Our data supports prior reports on VTE in SCD (Singh et. al., 2022) which note that SCD patients with COVID-19 do not have an increased risk of VTE compared with uninfected SCD patients. Similarly, our data suggests that there is no statistical difference in VTE incidence in SCD-COVID-19 patients compared to the general population affected by COVID-19. Given no differences in VTE incidence, we recommend that anticoagulation parameters for the general population of hospitalized and intensive care patients be applied to SCD patients.

The Impact of Pausing Bruton Tyrosine Kinase Inhibitor Therapy and Responsiveness of Vaccination in Blood Cancer Patients: Primary Outcome Result for the Randomised Improve Trial

Background: Patients with CLL have profound immunosuppression, higher mortality rates from COVID-19 infection and poorer responses to vaccination. Patients taking continuous Bruton Tyrosine Kinase inhibitor (BTKi) therapy demonstrate the poorest responses to vaccination, despite booster COVID-19 doses. BTKi therapy is taken continuously and is non-selective, inhibiting B cell receptor signalling in healthy B cells, as well as CLL cells. As covalent BTKi therapies have a short half-life and BTK receptor occupancy increases on stopping drug, a temporary pause in BTKi around the time of vaccination may improve immunity. Aim: To assess whether a temporary three-week pause of daily BTKi treatment around COVID-19 vaccination improves the immune response in people with Chronic Lymphocytic Leukaemia (CLL) whilst maintaining disease control. Methods: Patients with CLL in CR/stable PR taking either acalabrutinib or ibrutinib for 1 year or more were recruited to the open-label, prospective, 2-arm, parallel group, multicentre IMPROVE trial (ISRCTN 14197181) at 11 NHS UK hospital sites, prior to their COVID-19 booster vaccination. Participants were randomised (1:1) to either pause BTKi therapy for 3 weeks, starting 6 days before vaccination, or to continue BTKi therapy as usual. Researchers doing the laboratory analyses were blinded to group assignment. The primary outcome was SARS-CoV-2 Spike receptor binding domain (RBD) antibody titres 3 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to treat population. Results: Between Oct 10, 2022 and June 30, 2023, 99 participants with CLL were randomly assigned to continue BTKi (n=49) or pause BTKi (n=50). Mean age of participants was 70.5 years and 71/99 (72%) were male. 63/99 (64%) were on first line CLL therapy, and 51 (52%) were taking Ibrutinib, with the remaining participants taking Acalabrutinib. Participants had a median of 6 previous COVID-19 vaccinations prior to their booster (IQR 4-6). 84 (85%) were given the Bivalent Pfizer booster vaccination, 6 (6%) the Moderna Bivalent, 7 (7%) Sanofi, 1 (1%) unknown and 1 (1%) did not receive a vaccination. The proportion of participants deficient in IgG (&amp;lt;6 g/L); IgA (&amp;lt;0.8g/L) and IgM (&amp;lt;0.6g/L) were similar in both groups at baseline. At baseline, the geometric mean anti-spike RBD antibody titre was 71.6 U/mL (SD 101.3) in the suspend BTKi group and 132.9 U/mL (SD 82.2) in the continue BTKi group. The numbers of participants with no prior response to vaccination (≤ 0.4 U/mL) were 18/50 (36%) in the pause BTKi group and 14/49 (29%) in the continue BTKi group. After 3 weeks, 5/47 (11%) in the pause group and 1/48 (2%) in the continue group, seroconverted. The geometric mean anti-spike RBD antibody titre at 3 weeks was 150.4 U/mL (SD 100.9) in the suspend BTKi group and 151.8 U/mL (SD 109.6) in the continue BTKi group, with a geometric mean ratio (GMR) of 1.830 (95% CI 0.820 - 4.083; p = 0.140; mixed-effects model). There were no intervention-related serious adverse events reported. 4 patients withdrew from study. 2 patients in the pause arm and no patients in the continue arm sought NHS advice during the 3 week vaccination period. 2 patients in the pause arm and 1 patient in the continue arm commenced steroids during the 3 week period. No difference was observed in full blood count parameters between baseline and 3 weeks' in the 2 arms. LDH levels were 191.4 (SD 44.6) and 196.5 (SD 47.4) at baseline and 195.7 (SD 81.8) and 217 (SD 99.7) at 3 weeks' in continue Vs pause arm respectively. Participants self-reported no new or swollen lymph nodes at baseline in either arm, but 4 (8%) reported new or swollen lymph nodes in the pause arm compared with 0 in the continue arm. Compliance was self-reported; 48/49 in the continue group and 47/50 in suspend group confirmed compliance to allocated arm. Interpretation: A 3 week interruption in BTKi around the time of vaccination may improve seroconversion rates in people with CLL but does not boost antibody titre responses overall. Further analysis of secondary endpoints including neutralisation and cellular immunity is ongoing.

Biomarker Analyses in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Crovalimab and Eculizumab: Results from the Phase III Randomized COMMODORE 2 Trial

Introduction PNH is a hematopoietic stem cell disorder characterized by hemolytic anemia, hemoglobinuria, and increased risk of thromboembolic events, and is associated with bone marrow failure. Crovalimab (crova) is a novel complement C5 inhibitor engineered with recycling technology, with a long half-life and high solubility that enables low-volume subcutaneous (SC) administration every 4 weeks (q4w). The global Phase III COMMODORE 2 study (NCT04434092) in C5 inhibitor-naive patients (pts) with PNH demonstrated non-inferiority of crova vs eculizumab (ecu) for hemolysis control, transfusion avoidance, breakthrough hemolysis, and hemoglobin stabilization, and a safety profile that was consistent between crova and ecu (Röth EHA 2023; #S181). Here we report results of the exploratory biomarker analyses in COMMODORE 2. Study Design and Methods In COMMODORE 2, C5 inhibitor-naive pts were randomized 2:1 to receive a weight-based tiered crova regimen or ecu. Regimens included loading doses, followed by maintenance dosing (crova: SC injection q4w; ecu: intravenous infusion every 2 weeks). Co-primary efficacy endpoints were proportion of pts with hemolysis control (central lactate dehydrogenase [LDH] ≤1.5×upper limit of normal [ULN]) from Week (W)5 through W25 and proportion of pts with transfusion avoidance from baseline through W25. Exploratory biomarker analyses included terminal complement activity per 50% hemolytic complement (CH50) liposome immunoassay, free hemoglobin, additional exploration of LDH levels, and flow cytometry of the PNH clone size/C3d levels. Additional descriptive analyses of hemoglobin data compared pts with and without transfusions. All biomarker data were assessed from baseline to W25. Results Data forCH50 and LDH were available for all 204 randomized pts (crova: 135; ecu: 69) and data for free hemoglobin, PNH clone size and C3d were available for 126 pts (crova: 85; ecu: 41). At baseline, mean (standard deviation [SD]) LDH levels were 7.6×ULN (3.4) in crova pts and 7.8×ULN (3.5) in ecu pts. 77% of crova pts and 74% of ecu pts had ≥1 packed red blood cell transfusion ≤12 months before screening. 39% of crova pts and 38% of ecu pts had a history of aplastic anemia; 4% and 9% had myelodysplastic syndrome, respectively. Inhibition of complement activity (per CH50) to below the lower limit of quantification was reached at W2 (first post-dose pharmacodynamic sample) in 93% and 46% of pts in the crova and ecu arms, respectively, and in 90% and 73% at W25 (post-dose) (Figure). With regards to intravascular hemolysis markers, the proportion of pts with LDH ≤1.5×ULN was 81% at W5 and 78% at W25 in crova pts, and 84% at W5 and 77% at W25 in ecu pts. Free hemoglobin, another intravascular hemolysis marker, showed a similar initial decrease from baseline in both arms; however, crova pts consistently showed numerically lower levels than ecu pts from W13 to W25. Mean (SD) increase in hemoglobin level from baseline to W25 was 1.2 g/dL (2.0) in the crova arm (baseline: 8.7 g/dL [1.4]) and 0.8 g/dL (1.9) in the ecu arm (baseline: 8.9 g/dL [1.4]). In both arms, a greater increase in mean hemoglobin level from baseline was observed in pts who achieved transfusion avoidance vs those requiring ≥1 transfusion up to W25 (crova: 1.7 g/dL [SD, 1.8; n=88] vs 0.2 g/dL [SD, 1.9; n=40]; ecu: 1.3 g/dL [SD, 1.6; n=47] vs −0.4 g/dL [SD, 2.1; n=20]). Both arms showed a similar increase from baseline to W25 in the mean (SD) percentage of C3d-positive PNH erythrocytes (crova: 0.7 [1.5] at baseline to 20.8 [19.1] at W25; ecu: 0.6 [0.9] to 22.3 [15.0]). Conclusions Treatment with crova or ecu reduced terminal complement activity effectively, with a higher proportion of crova than ecu pts having undetectable terminal complement activity. However, this did not translate into significant differences in other biomarkers (LDH and free hemoglobin) or in the clinical efficacy between crova and ecu arms. Hemoglobin levels increased in both crova and ecu arms. This improvement was more pronounced in pts not receiving a transfusion from baseline to W25; additional analysis is needed to elucidate the impact of bone marrow failure status. Similar increases in C3d level in each arm were expected, as this is a C5 inhibitor class phenomenon. Overall, biomarker data from COMMODORE 2 support the non-inferior efficacy of crova vs ecu in patients with PNH. Further analyses correlating additional biomarkers with clinical outcomes is warranted.

Radiotherapy Consolidation Reduces Risk of Relapse in Diffuse Large B-Cell Lymphoma Patients with Bulky Disease in Complete Response after Frontline Immunochemotherapy: Results from a Retrospective Single Center Study

INTRODUCTION: The role of radiotherapy (RT) consolidation upfront in patients with diffuse large B-cell lymphoma (DLBCL) and bulky disease at diagnosis is controversial, especially in those in complete response (CR) after immunochemotherapy. METHODS: All patients with DLBCL diagnosed between January 2010 and June 2021 at AOU Città della Salute e della Scienza di Torino and treated frontline with RCHOP-like regimens were retrospectively selected. Patients with primary mediastinal lymphoma were excluded. Clinical and biological features as well as treatment and survival data for the whole population were collected. All patients with bulky disease (defined as ≥6 cm) at diagnosis who obtained CR (defined as PET/TC Deauville score ≤ 3) at the end of systemic treatment were further selected. Progression free survival (PFS) and overall survival (OS) were compared between patients receiving consolidative RT on initial bulky mass and those who did not. RESULTS: A total of 453 patients with DLBCL were identified. Median age was 68 years (IQR 58-77), 56% were males, 74% stage ≥3, 52% IPI ≥3. 140/451 (31%) had bulky disease at diagnosis. Median follow-up was 5 years. 5-year PFS and OS for the whole cohort were 59% and 66%, respectively. Bulky disease correlated with a significantly lower 5-year PFS (bulky 50% vs no bulky 64%, p = 0.0005) and OS (bulky 68% vs no bulky 60%, p = 0.01). 82 out of 140 patients with bulky disease (68/82 with a bulky ≥7 cm) were in CR after immunochemotherapy: 19/82 (23%) received RT (16/19 on bulky ≥7 cm), 63/82 (77%) did not (55/63 with a bulky ≥7 cm). There were no significant differences between the two groups regarding age, stage, ECOG PS, LDH levels, extranodal involvement and IPI. RT dose was 30 Gy in most patients (17/19); two patients received 36 Gy and 40 Gy. The 5-year PFS was 95% in the RT cohort and 58% in the no-RT cohort (p = 0.004); the 5-y OS was 95% in the RT cohort and 69% in the no-RT cohort (p = 0.038) (figure 1). A propensity score matching analysis confirmed the benefit of RT on PFS (HR 0.1, 95% CI 0.01-0.68, p = 0.019), and showed a non-statistically significant trend of better OS (p = 0.06). 14/24 relapses in the no-RT cohort occurred on the site of bulky disease. CONCLUSIONS: With the limit of a non-randomized retrospective study, our data showed a benefit of RT consolidation on bulky disease in patients with DLBCL in RC after frontline immunochemotherapy, significantly prolonging PFS and with a trend of improved OS in a propensity score matching analysis.

Frailty Impact on Outcomes of Patients Undergoing Chimeric Antigen Receptor T-Cell (CAR T) Therapy at Princess Margaret Cancer Centre: A Prospective Pilot Study

Introduction Princess Margaret Cancer Centre is 1 of 3 adult centres in Ontario, Canada providing Chimeric Antigen Receptor T-Cell (CAR T) therapy as a standard of care treatment for adult patients with relapsed and refractory B-cell lymphomas. There is no upper age limit for treatment consideration, and frailty may be an important factor in assessing fitness for treatment. This study aims to determine if frailty assessments pre-CAR T can predict those at higher risk for acute toxicities, PFS, and OS, as well as evaluate changes in frailty over time. Methods We performed a cohort study of consecutive patients with lymphoma undergoing CAR T cell therapy at our institution, from April 2021 to date. Frailty was evaluated using the Clinical Frailty Scale (CFS), Grip Strength, Gait Speed, Mini-Cog, Edmonton Symptom Assessment System (ESAS) and Patient Health Questionnaire (PHQ-2 and PHQ-9) at 5 time points: baseline (clearance visit), and 1, 3, 6 and 12 months post-CAR T. At baseline, additional assessments were completed to further characterize frailty including the Vulnerable Elders Survey (VES-13), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and Cumulative Illness Rating Scale (CIRS). We present data on patients enrolled to date. Results Fifty-two patients have had their data analyzed thus far. Mean age is 57.9 ± 12.7 years and 54% are male. 50% have de novo diffuse large B-cell lymphoma, 24% transformation from follicular lymphoma,14% HGBCL, 6% PMBCL and 6% FL. Most patients (83%) received axi-cel. Median follow-up is 3.80 months (IQR 0.56-24.7 mo). All 52 patients completed assessments at baseline, 44 completed 1 month, 25 completed 3 month, 12 completed 6 month and 11 completed 12 month assessments. Median scores (and IQR) for the HCT-CI, CIRS, VES-13 and CFS at baseline were 1.5 (0-5), 3.0 (0-13), 1.0 (0-7), and 3.0 (1-7) respectively. There were clinically significant changes observed in CFS over time ( p=&amp;lt;0.001), with mean scores of 3.3 at baseline, 3.7 at 1 month, 2.8 at 3 months and 2.1 at 12 months. There were no significant changes ( p=0.051; p=0.078) between timepoints for either of the physical assessments of grip strength or gait speed. Sixteen patients (31%) experienced immune effector cell neurotoxicity syndrome (ICANS) (4% Grade 4, 4% Grade 3, 8% Grade 2, 15% Grade 1) and forty-nine patients (94%) experienced cytokine release syndrome (CRS) (2% Grade 3, 65% Grade 2, 27% Grade 1), during the 30 days following cell re-infusion. Seven patients (13%) were admitted to the ICU, with a median in-hospital length of stay for all 52 patients of 12.5 days (IQR 7.0, 99.0). None of the variables tested (age, sex, bridging therapy, LDH, CRP and frailty assessments) were significantly associated with the development or grade of CRS or ICANS. There have been 21 progression events and 18 deaths (6 without progression); 9 pts remain alive post-progression (Figure 1). On univariable analysis of baseline data, ECOG performance status, LDH level, and the VES-13 score were predictive of PFS, while ECOG, LDH, CRP, VES-13 score, CFS and the time to walk 4m were predictive of OS. The HCT-CI and CIRS score were not significantly associated with outcomes. On multivariable analysis of PFS, baseline VES-13 score (HR 1.17, p=0.04) and LDH (HR 1.002, p=0.05) remained significant. Multivariable analysis for OS was not performed due to insufficient number of events. Analyses incorporating repeated measures were performed, and on univariable analysis, the CFS, 4m walk test (s), LDH, VES-13 were significantly associated with PFS and the same variables and CRP were associated with OS (Table 1). On multivariable repeated measurements analyses, only the CFS was still associated with PFS, and CFS and LDH with OS (Table 1). Conclusions Conducting serial frailty assessments in patients undergoing CAR T therapy is feasible. The only longitudinal measurement of frailty found to have clinically significant changes between timepoints was the CFS, suggesting an element of reversible functional impairment related to patients' lymphoma. Within the limits of our sample size, baseline measures of frailty were not predictive of CRS or ICANS; the relationship of CFS change over time with PFS and OS may be indicative of lymphoma response. Enrollment is ongoing and data on larger number of patients with longer term follow-up are needed.

A Novel Model Combining Circulating Absolute Monocyte Counts and a Four-Gene Monocyte Signature in Leukapheresis Identifies Lymphoma Patients at Very High Risk of Progression after Tisagenlecleucel or Axicabtagene Ciloleucel Therapy

Introduction CD19-directed chimeric antigen receptor (CAR) T can induce durable remissions in a fraction of relapsed/refractory large B-cell lymphomas (R/R LBCL), but 60% of patients (pts) still relapse. Biological mechanisms explaining lack of responses are emerging but they are largely unsuccessful in predicting disease response at the patient level. Aim To address the potential role of lymphocyte features before CAR T manufacturing, we performed transcriptomic and functional evaluations of leukapheresis products (LK) in 95 R/R LBCL pts enrolled in a prospective observational study, to identify correlates of response and survival to tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel). Methods RNA of sorted CD3+ cells from LK was digitally quantified using the nCounter CAR T Characterization Panel (NanoString). Flow cytometry (FCM) was used for CAR T enumeration and monocyte analysis. Disease response at day 90 was assessed by computed tomography (CT) and positron emission tomography-CT (PET/CT) according to Lugano criteria. Statistical analyses were performed by GraphPad Prism v.9.00 and R v.4.1.2. Results We identified a 4-gene transcriptional signature (including MS4A4A, CD86, CD163 and SIGLEC5) able to divide LBCL pts into two groups, [namely Expressors (EXP) and poor-Expressors (poor-EXP)], characterized by significantly different survival probabilities. EXP have shorter PFS (P&amp;lt;0.0001: median PFS for EXP was 61 days and not reached for poor-EXP) (Fig. 1) and are less likely to respond (P&amp;lt;0.01). As the identified genes are highly expressed in monocytes but not in T cells, we sought to define whether monocytes contained in LK have a role in determining post CAR T outcome. In line with the fact that EXP had higher frequencies of monocytes in LK by FCM, we confirmed elevated absolute monocyte counts (AMC) both in LK (P&amp;lt;0.01) and in peripheral blood (PB) (P&amp;lt;0.05) of EXP. We then checked if monocyte levels could influence response and survival. When compared to responders, non-responders (NR) had higher LK AMC (P&amp;lt;0.01), higher percentages of monocytes (P&amp;lt;0.01) but also decreased percentages of lymphocytes (P&amp;lt;0.001), a parameter that was also associated with reduced PFS [HR: 0.97 (CI 0.96 - 0.99) P=0.01]. Consistent with the fact that circulating monocytes significantly correlated with those in LK (r= 0.6621, P&amp;lt;0.0001), NR also had significantly higher AMC (P&amp;lt;0.001) and AMC levels in PB negatively correlated with PFS [HR: 1.8 (CI 1.2 - 2.9) P=0.01]. Additionally, pts with serum C-reactive protein (CRP) and ferritin levels higher than the upper normal limit, displayed significantly higher AMC (P&amp;lt;0.001 for CRP; P&amp;lt;0.05 for ferritin). Accordingly, univariate analysis indicated that high ferritin, CRP and LDH levels at the time of LK were associated with the lack of response, but only high serum ferritin levels correlated with shorter PFS [HR: 2.86 (CI 1.25-6.55) P=0.013]. We next investigated if the combination of the monocyte signature and high ferritin levels and/or high circulating monocytes could better identify a group of pts at high risk of progression, compared to the expression of the 4 genes alone. Remarkably, albeit high ferritin levels and monocyte counts are overall associated with significantly reduced survival, the shortest PFS was achieved in EXP with monocyte counts above the median (P=0.0234: median PFS for EXP with high monocytes was 32.5 days and for EXP with low monocytes 209 days) (Fig. 2), thus supporting the hypothesis that CAR T treatment outcome is influenced by the presence of elevated levels of monocytes expressing the 4 genes. Concatenated monocyte FCM data from 30 pts analyzed with FlowSOM, followed by a consensus clustering algorithm combined with t-SNE (t-stochastic neighbor embedding), indicated that EXP had higher frequencies of CD14hi monocytes co-expressing MS4A4A, CD86, CD163 and SIGLEC5 at the protein level than poor-EXP (P&amp;lt;0.05), and accordingly, the presence of this population was also associated with lack of response (P&amp;lt;0.05). Conclusions Our data suggest that the poor outcome of some LBCL pts receiving CAR T is due to the presence of high monocytes levels expressing a four-gene signature in an inflammatory microenvironment. Additionally, the pre-manufacturing combined analysis of the gene signature and of PB AMC, could be used to plan trials evaluating CAR T cells versus other newly approved therapies such as bispecific antibodies.

Baseline 18f-Fluorodeoxyglucose PET/CT Radiomics Predicts Outcome in Newly Diagnosed Intravascular Large B-Cell Lymphoma

[Introduction] Treatment outcomes of intravascular large B-cell lymphoma (IVLBCL), a rare subtype of extra-nodal diffuse large B-cell lymphoma (DLBCL), have dramatically improved in recent years. However, prognostic factors for IVLBCL are largely unknown. Several studies have explored the potential of the baseline 18F-fluorodeoxyglucose (FDG) PET/CT radiomics features to identify patients with poor prognosis. For example, metabolic tumor volume (MTV) reflects the FDG-avid tumor burden, and the maximum distance between the largest lesion and any other lesion quantifies the dissemination of the tumor, and both factors are inversely related to overall survival (OS) and progression-survival (PFS) in DLBCL. In this study, we explored prognostic impact of FDG PET/CT radiomics features in newly diagnosed IVLBCL. [Methods] We retrospectively evaluated patients with histopathologically proven newly diagnosed IVLBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group (NJHSG). Quantitative analysis of all FDG PET/CT was performed using Metavol (Hokkaido University, Sapporo, Japan), with exclusion of physiological accumulation. MTV was defined as the volume of lymphoma lesions visualized on PET/CT scans with standardized uptake value (SUV) peaks greater than or equal to hepatic SUV peak. To quantify the dissemination of the tumor, we calculated the number of the body areas (head-neck, chest, abdomen, upper-extremities, lower-extremities) having BM lesions with a higher SUV peak than liver SUV peak. Patients with BM lesions spread across 4-5 areas were defined as cases having widely disseminated lesions (WDL). Progression-free survival (PFS) was defined as the time from the start of treatment to the first of progression, relapse, or death from any cause. Patients undergoing upfront autologous stem-cell transplantation (auto-SCT) were censored at the time of transplantation. [Results] We identified fifty-two IVLBCL patients (age 30-89 years, median 65 years; 57.7% male) who performed FDG PET/CT at diagnosis. Twenty-eight patients (54.9%) had poor performance status (ECOG PS ≥2), and 49 patients (94.2%) showed stage III-IV. Forty-nine patients (94.2%) had 2 or more extranodal involvement. Elevated serum LDH level was observed in 49 cases (94.2%) (median, 623.5 IU/L; range, 147-4907 IU/L). The median serum levels of soluble IL-2 receptor (sIL-2R), ferritin, and C-reactive protein (CRP) were 4496.5 IU/mL (range, 321-19900 IU/mL), 655.15 ng/mL (range, 50-6657 ng/mL), and 6.905 mg/dL (range, 0.11-25.86 mg/dL), respectively. The median MTV was 415.527 cm 3 (range, 0-3000 cm 3). ROC analysis revealed that the cutoff value of the MTV &amp;gt; 388 cm 3 could predict progression events within 2 years. Area under curve was 0.71 (95% CI: 0.564-0.857). Twenty-nine patients (55.8%) were classified as having MTV &amp;gt; 388 cm 3 (high MTV). Twenty-three patients (44.2%) had WDL. Fifty-one (98.1%) patients received chemotherapy, all of which was rituximab-containing regimen. Three patients (5.8%) received upfront auto-SCT. Median follow-up duration was 48.8 months (range, 5.8-140.5 months) in survivors. Age, LDH level, number of extranodal lesions, clinical stage, and PS did not affect OS and PFS. Although the high MTV and WDL did not significantly affect OS ( P = 0.095, P = 0.173, respectively; Log-rank), these findings did correlate significantly with poor PFS ( P = 0.011, P = 0.042, respectively; Log-rank). Thus, we defined a high MTV or a WDL as poor PET findings. Thirty-two patients had poor PET findings. Importantly, patients with poor PET findings showed significantly poor OS and PFS compared to patients without (2-year OS: 71.2% vs. 93.3%, P = 0.015, 2-year PFS: 45.5% vs. 93.8%, P = 0.001; Log-rank, Fig. 1, 2). [Conclusion] This is the largest study to assess prognostic impact of FDG PET/CT radiomics features on newly diagnosed IVLBCL. Poor PET findings were significantly correlated with worse OS and PFS.

Development of a Novel Prognostic Score in Patients with Waldenström Macroglobulinemia Prospectively Enrolled in the Observational NF10 Study of Fondazione Italiana Linfomi

Background. IPSSWM and revised-IPSSWM are the two currently prognostic scores used for survival prediction in symptomatic Waldenström Macroglobulinemia (WM) patients in need of treatment. In addition to age and serum beta-2 microglobulin levels, which are present in both scores, the IPSSWM includes anemia, thrombocytopenia and the concentration of the serum monoclonal component (MC), while revised-IPSSWM includes LDH and serum albumin levels. Both IPSSWM and revised-IPSSWM have been developed in retrospective series and apply only to symptomatic WM patients. Aim. To analyze WM patients prospectively enrolled in the NF10 observational study since 2010 with the aim to define a prognostic score applicable to all WM patients at diagnosis, either symptomatic or asymptomatic. Methods. The progression-free survival (PFS) and overall survival (OS) rate was estimated and plotted using the Kaplan-Meier method, with 95% confidence interval (95% CI), and the effect of covariables on PFS was estimated by means of the Cox proportional hazard (PH) regression. The association with PFS was expressed as hazard ratio (HR) with 95% CI, either in univariable or multivariable regression. All statistical tests were two-sided. The proportionality of risk of the multivariable Cox PH model was checked graphically by means of the scaled Schoenfeld residuals, and the model performance was analyzed using the likelihood displacement method. Starting from a model with 10 variables selected on the basis of clinical and statistical considerations, the final model was selected on considering the Akaike (AIC) and likelihood ratio test. The cut-offs were selected after modelling the covariate with restricted cubic spline in Cox regression. The final model was internally validated using bootstrap techniques to evaluate the discriminant power (C-index), slope shrinkage to check for overfitting, and calibration (comparison between predicted and actual survival). Results. We identified 303 eligible patients from the NF10 study, of whom 185 (60%) needed treatment immediately after diagnosis (42%) or later (18%). These were main patients characteristics: 59% were male, 46% were aged &amp;gt;70 years, 8% had constitutional symptoms, 55% had Hb &amp;lt;12 g/dL, 54% had an absolute lymphocyte count ≥2x10 9/L, 9% had platelets &amp;lt;100x10 9/L, 37% had a serum MC &amp;gt;2 g/dL, 21% had albumin &amp;lt;3.5 g/dL, 23% had LDH &amp;gt; upper limit of normal (ULN), 32% had beta-2 microglobulin &amp;gt;1.5xULN. With a median follow-up of 51 months, 5-year PFS for the entire cohort was 67% (95%CI 60-73%). In univariate analysis, age &amp;gt;70 years (P=0.043), constitutional symptoms (P=0.009), nodal sites (P=0.002), Hb &amp;lt;12 g/dL (P&amp;lt;0.001), absolute lymphocyte count ≥2x10 9/L (P=0.033), serum MC &amp;gt;2 g/dL (P=0.003), high beta-2 microglobulin (P&amp;lt;0.001) and LDH (P=0.001), albumin &amp;lt;3.5 g/dL (P&amp;lt;0.001), C-reactive protein &amp;gt;4 mg/dL (P=0.008) were associated with shorter PFS. In multivariate analysis, age, anemia, hypoalbuminemia and high LDH retained prognostic value and thus entered the final model. Patients were classified into 3 risk groups: low (0-1 factors, 62% of patients), intermediate (2 factors, 24%) or high (3-4 factors, 15%), with a 5-year PFS of 80% (95%CI 70-87%), 49% (95%CI 32-64%) and 25% (95%CI 11-42%), respectively, with C-Harrell=0.744 and robust internal validation and calibration. OS was respectively 96% (95%CI 90-98%), 77% (95%CI 62-87%) and 43% (95%CI 25-60%) for the low, intermediate and high risk group (Figure 1). Conclusions. We developed a prognostic model based on 4 parameters easily attainable in clinical practice, able to predict PFS and OS at diagnosis. This is the first prognostic score for WM developed in a prospective study and applicable to patients presenting either with symptomatic or asymptomatic disease. This prognostic model identifies a subset of high-risk patients with a dismal outcome and a median OS &amp;lt;5 years. External validation in independent cohorts is needed.

Primary and Secondary Plasma Cell Leukemia Risk Stratification By Circulating Plasma Cells

Plasma cell leukemia (PCL) is a rare plasma cell dyscrasia associated with poor outcomes. PCL can present de novo as primary PCL (pPCL) or from preceding multiple myeloma as secondary PCL (sPCL). The International Myeloma Working Group (IMWG) in 2021 updated the diagnostic criteria for pPCL using circulating plasma cells (CPC) to ≥5% instead of ≥20% as both carry similar survival. In this single center retrospective analysis, we compared clinical features and overall survival (OS) for 104 patients: with pPCL ≥5% CPC ( N = 35), sPCL 5-19% CPC (sPCL-A) ( N = 11), sPCL ≥20% CPC (sPCL-B) ( N = 38), and spillover group 1-4% CPC regardless of newly diagnosed or secondary status ( N = 20). Mean ages were 57 - 59 years old for all groups (range: 25 - 84) with no difference in age between groups ( p = 0.90). There was a slight predominance of females (54.8%) over males and blacks (53.9%) over non-blacks. More patients with pPCL were black (65.7%) compared to sPCL and spillover groups, although this difference was not statistically significant ( p = 0.35). pPCL patients presented with the highest mean WBC at diagnosis (23.4 x10 9/L) compared to sPCL-A (5.5 x10 9/L), sPCL-B (12.2 x10 9/L), and spillover (7.2 x10 9/L) groups ( p &amp;lt;0.001). Patients in all groups were anemic (hemoglobin 7.8 - 9.3 g/dL), thrombocytopenic (platelets 60.2 - 101.2 x 10 9/L), and had abnormal renal function (creatinine 1.4 - 2.7 mg/dL), elevated LDH (918.7 - 1515.5 units/L, highest in sPCL-A), and elevated uric acid levels (5.9 - 8.2 mg/dL). sPCL patients and spillover group had more lytic lesions on skeletal survey ( p = 0.009) and positron emission tomography (PET) ( p = 0.02) compared to patients with pPCL. sPCL-A patients had higher incidences of lymphadenopathy ( N = 5/11, 62.5%, p = 0.02) and central nervous system invasion ( N = 4/11, 36.4%, p = 0.02) compared to other groups. There was no difference in incidence of extramedullary disease ( p = 0.29) between groups. Over 90% of patients with PCL had high-risk cytogenetics with 63% carrying a complex karyotype. Hypodiploidy was seen more often in patients with pPCL and sPCL-B compared to sPCL-A and spillover ( p = 0.005). There was no difference between groups in incidence of deletion 17p ( p = 0.53). All patients benefited in terms of OS from daratumumab (HR 0.44, 95% CI 0.25 - 0.76; p = 0.004), IMiDs (HR 0.13, 95% CI 0.08 - 0.23; p &amp;lt;0.001), PIs (HR 0.43, 95% CI 0.25 - 0.75; p = 0.003), chemotherapy (HR 0.56, 95% CI 0.32 - 0.98; p = 0.04), and autologous hematopoietic stem cell transplantation (HR 0.33, 95% CI 0.16 - 0.71; p = 0.004). DVT-PACE type regimens (dexamethasone-bortezomib-thalidomide-cisplatin-doxorubicin-cyclophosphamide-etoposide) are used for pPCL and may be less effective in sPCL and spillover patients who have been heavily pretreated. We noted no benefit in OS for all patients including pPCL, sPCL-A, sPCL-B, and spillover groups who received DVT-PACE (HR 0.97, 95% CI 0.62 - 1.50, p = 0.88). The lack of OS benefit in pPCL patients receiving DVT-PACE persisted on multivariate analysis when adjusting for PCL group alone (HR 0.79, 95% CI 0.50 -1.26; p = 0.33) and PCL group, age, platelet count, and presence of high-risk cytogenetics (HR 1.11, 95% CI 0.63 - 1.94; p = 0.72). After median follow-up of 6.70 months, median OS was 7.14 months for the entire cohort with 92.3% ( N = 96) deceased. On univariate analysis, male sex, age &amp;gt;58 years old, high-risk cytogenetics, LDH &amp;gt;604 units/L, creatinine &amp;gt;1.40 mg/dL, hemoglobin &amp;lt;8.3 g/dL, platelets &amp;lt;53.5 x10 9/L, lytic lesions on skeletal survey and on PET, extramedullary disease on PET, and plasmacytoma were associated with inferior median OS (Table 1). pPCL had higher median OS (13.1 months) compared to sPCL-A (3.1 months, p = 0.03) and sPCL-B (3.5 months, p = 0.003) (Figure 1). There was no statistically significant difference in median OS between pPCL (13.1 months) and spillover patients (10 months) ( p = 0.48) as well as sPCL-A (3.1 months) and sPCL-B (3.5 months) ( p = 0.80). Although the spillover group was associated with a trend towards better OS compared to sPCL-A and sPCL-B groups, this was not statistically significant, which may be due to low N which is a limitation of the study. Further research is required to better understand the clinical features, treatment responses, and outcomes of pPCL, sPCL, and spillover group (1-4% CPC).

A Unique Case of Large Pelvic Non-Hodgkin Lymphoma

Introduction: Non-Hodgkin lymphoma (NHL) represents a diverse group of malignancies arising from lymphocytes and lymphoid tissues. It encompasses multiple subtypes, including the aggressive diffuse large B-cell lymphoma (DLBCL), which is the most common type of NHL in adults. DLBCL typically presents as a rapidly growing mass in the lymph nodes or extranodal sites. While DLBCL can affect various regions of the body, its occurrence in the pelvic region is infrequent and poses unique diagnostic and therapeutic challenges. Case Description: We present a rare and intriguing case of a 51-year-old female admitted for acute on chronic microcytic anemia, with accompanying symptoms of decreased oral intake due to nausea, and vomiting, significant weight loss, night sweats, and lower quadrant abdominal pain. Additionally, she reported decreased urinary frequency, urgency. CT imaging of the abdomen and pelvis revealed a large soft tissue mass measuring 7.6 x 4.6 x 5.7 cm in the posterior right pelvic region, resulting in severe hydroureteronephrosis, along with bilateral iliac chain adenopathy, retroperitoneal lymph node enlargement, and severe splenomegaly. CT chest revealed several small lung nodules indicating distant metastasis. Additionally, the patient exhibited elevated levels of LDH, CA 199, and CRP, and decreased hemoglobin levels, indicating the presence of systemic disease. A CT-guided biopsy of the right pelvic mass confirmed the diagnosis of non-Hodgkin malignant lymphoma, specifically of the diffuse large B-cell type. Immunohistochemistry and flow cytometry demonstrated CD20 positivity in the proliferating large cells, consistent with DLBCL, and revealed a kappa-restricted B-cell population expressing CD19, CD20, and kappa surface immunoglobulin light chains. The PET scan showed prominent splenomegaly, adenopathy, and retroperitoneal involvement, corroborating the lymphoma diagnosis. The patient was discharged for outpatient follow-up with oncology with a treatment plan of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) administered every 3 weeks, omitting rituximab during the first cycle. Discussion: This case stands out due to the unusual presentation of a large DLBCL in the pelvic region, which is a relatively rare occurrence. The localization of DLBCL in the pelvis poses a diagnostic challenge, as symptoms may overlap with various other conditions. Moreover, the extensive involvement of the retroperitoneal lymph nodes and splenomegaly added complexity to the management of the disease. The rarity of DLBCL in the pelvis highlights the importance of considering lymphoma in the differential diagnosis of patients presenting with non-specific pelvic symptoms and acute anemia. Early recognition of such cases is crucial for timely intervention and optimal treatment planning. Understanding the immunophenotypic characteristics of the tumor is essential for tailoring effective therapeutic strategies. This unique case sheds light on the need for further research and evidence-based guidelines for managing NHL in uncommon anatomical locations, promoting better patient outcomes and quality of life.

Differences in Clinical Outcomes between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients

Previous retrospective studies have revealed that a substantial portion of PV patients experience resistance to hydroxyurea (HU-R) and intolerance to HU (HU-I). Currently, the therapeutic options for both groups of patients do not differ, and most clinical trials investigating second-line therapies have enrolled patients with HU-R or HU-I without considering potential clinical distinctions between the two groups. Direct comparisons between patients with HU resistance and HU intolerance have not been conducted, and prognostic factors related to clinical outcomes, such as thrombosis, bleeding, disease progression, and survival, remain unclear for patients experiencing HU resistance or intolerance. A total of 90 patients with HU-R/I were retrospectively anlyzed in this study. Among them, 44 and 46 patients fulfilled the ELN criteria defining resistance or intolerance to HU, respectively. Patients with HU-R were older at the time of diagnosis of PV (66.7 ± 13.2 years, vs. 59.8 ±11.2 years in the HU-I group, P = 0.016), had longer times to developing HU-R/I, and thus, were older at the time of HU-R/I development compared with those with HU-I. The majority of the study patients continued HU treatment with dose modification or intermittent discontinuation with anagrelide added to control platelet counts until disease progression or death because of limited second-line treatment options during the observed period. The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). The type of thrombosis did not differ between the two groups (P = 0.628). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio = 5.57, 95% CI: 1.22 - 25.54, P = 0.027). The patients in the HU-R group had significantly lower PFS (40.2% vs. 66.1% in the HU- I group, P &amp;lt; 0.01). They also showed a trend toward lower TFS (51.0% vs. 62.1% in the HU-I group; P = 0.055) and lower OS (57.5% vs. 67.7% in the HU-I group; P = 0.060) compared to patients with HU-I. The mortality at seven years was 42.5% in the HU-R group and 32.3% in the HU-I group (P = 0.06). Higher LDH levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. These findings suggest that HU-resistant patients have a higher risk of hematological transformation but a comparable risk of thrombosis to HU-intolerant patients. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

Patterns of Cytokine Release Syndrome with Teclistamab in Relapsed/Refractory Multiple Myeloma with or without Prior T-Cell Redirection Therapy

Introduction: Numerous therapeutic options with novel mechanisms of actions are currently available for treating patients with relapsed/refractory multiple myeloma (RRMM). Teclistamab (Tec) is a first-in-class BCMA X CD3 bispecific T-cell engager antibody that was recently approved for patients with RRMM who have received at least 4 lines of therapy (LOT). In the landmark MajesTEC-1 study, cytokine release syndrome (CRS) with Tec was reported at a rate of 72% (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022); however, patients who were previously treated with T-cell redirection therapies (TCRT) were excluded from the study [TCRT: chimeric antigen receptor (CAR) T-cells and/or other bispecific antibodies]. Given this knowledge gap, we investigated whether prior TCRT exposure impacts CRS rates with Tec in a real-world setting. Methods: Our institutional plasma cell disorders database was queried to identify RRMM patients who received commercial Tec from November 2022 to July 2023. Patients who completed the Tec step-up dosing phase (first step-up, second step-up and first full doses) were divided into two cohorts based on prior TCRT exposure before treatment with Tec (prior TCRT exposure: cohort 1 and no prior TCRT exposure: cohort 2). Data collection included patient demographics, disease characteristics, prior LOT, and rates/grades of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). The Chi-square/Fisher exact test was used to compare differences in CRS rates between the two cohorts. Univariate and multivariate logistic regression analyses were performed to assess impact of prior TCRT exposure on CRS rates with Tec. The results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). For cohort 1, the Mann-Whitney U-test was used to compare the median time elapsed from the last prior TCRT dose until the first Tec step-up dose between patients who developed CRS with Tec compared to those who did not. All statistical analyses were performed using SPSS software (version 29). Results: 50 patients (cohort 1: 25 and cohort 2: 25) were included in the final analysis. Baseline characteristics were comparable between the two cohorts except for prior LOT, where patients in cohort 1 represented a more heavily pretreated population (Table 1). The CRS rates were significantly lower in cohort 1 (40%, n=10) compared to cohort 2 (76%, n=19, p=0.02; Figure 1). CRS grades 1 and 2 occurred in 32% (n=8) and 8% (n=2) of patients in cohort 1 and 48% (n=12) and 28% (n=7) of patients in cohort 2, respectively (p=0.40). Among the CRS events, 60% (6/10) and 68% (13/19) occurred following the first Tec step-up dose in cohorts 1 and 2, respectively. In univariate logistic regression analysis, no prior exposure to a TCRT was associated with about a 5-fold increase in the incidence of CRS with Tec (OR= 4.8, 95% CI: 1.5-17.1.2, p=0.02). After adjusting for age, extramedullary disease (EMD) and elevated LDH levels, the impact of prior exposure to TCRT remained significant with an OR of 4.5 (95% CI: 1.3-18.6, p=0.01). In cohort 1 (prior TCRT exposure), the median time elapsed between the last TCRT dose and the first Tec step-up dose was 321.5 days (range: 50-808 days) in patients who developed CRS with Tec compared to 265 days (range: 41-1617 days) in those who did not (p=0.90). Conclusion: In our study, prior exposure to a TCRT was associated with a significantly lower incidence of CRS during the Tec step-up dosing phase, which may be suggestive of T-cell exhaustion. This observation will allow for optimization of CRS prophylactic strategies for RRMM patients receiving Tec treatment.

Pre-Treatment Pulmonary Assessment Have Limited Utility in B-Cell Lymphoma Patients Treated with Autologous Anti-CD19 CAR T-Cell Therapy

Introduction Pulmonary function tests (PFT) play a pivotal role in hematopoietic cell transplantation (HCT), with routine evaluation in HCT candidates. However, their predictive value in chimeric antigen receptor T-cell (CAR-T) therapy outcomes remains uncertain. To address this gap, we conducted a retrospective analysis of PFT metrics and pulmonary comorbidity definitions, following the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), in B-cell lymphoma patients treated with autologous CD19-CAR-T cell therapy. Patients and Methods In this retrospective analysis, we included adult patients (age ≥ 18 years) with B-cell lymphoma who received treatment at a tertiary medical center with commercially available or point-of-care (POC) anti-CD19 CAR T-cell therapy (Kedmi et al., Transplant Cell Ther. 2022) as their 3rd line of treatment or above, between 2017 and 2022. Patients underwent routine PFT assessment before CAR-T cell therapy, as part of institutional practice, including spirometry, body plethysmography, and single-breath diffusing capacity for carbon monoxide (DLCO). Patients were categorized into three pre-treatment pulmonary comorbidity groups (normal, moderate, severe) based on HCT-CI definitions for forced expiratory volume in 1 second (FEV1) and DLCO expressed as precent of predicted value (&amp;gt;80%, 66-80%, &amp;lt;66%, respectively). Results A total of 192 patients (median age, 60 [range 46-69]) were included. Aggressive B-cell lymphoma was the predominant diagnosis (n=166, 86%) followed by indolent B-cell lymphoma (n=18, 9.4%), and Mantle cell lymphoma (n=8, 4.2%). Most patients had a good performance status (KPS ≥ 90, 78%), although with high-risk disease features (pre-lymphodepletion LDH was elevated in 108 [56%]). Seventy-eight (41%) patients received bridging therapy. POC CAR-T were used in 56%, while 44% received commercial CAR-T (26% axi-cel, 18% tisa-cel). Pre-CAR-T smoking history was documented in 25% of patients. The median pre-treatment measured-to-predicted DLCO and FEV1 were 96% and 92%, respectively. Seventy-four percent of patients had normal DLCO, and 77% had a normal FEV1. The calculated normal, moderate, and severe pulmonary comorbidity levels, per the HCT-CI, were 64%, 23%, and 13%, respectively. With a median follow-up of 17.6 months (IQR 8.5-29.7), the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 7.6 months. There was no correlation between pulmonary comorbidity level and the best overall response rate. Categorical PFT results (FEV1 and DLCO) and pulmonary comorbidity (per-HCT-CI) were not associated with reduced OS (p=0.3, p=0.4, p=0.6, respectively) or reduced PFS (p=0.058, p&amp;gt;0.9, p=0.2, respectively) in a univariable Cox regression analysis. However, FEV1 as continuous measure and FEV1 categorized into 2 levels (normal vs. moderate-severe) were associated with reduced PFS ( Figure 1). FEV1 (as a continuous metric) association with PFS remained consistent (HR 0.99 [95% CI 0.98-1], p=0.007) in a multivariable Cox regression adjusted for pre CAR T KPS score, elevated LDH level, and co-stimulatory CAR-T domain. Nevertheless, this association is minor, with unclear clinical significance. No association was observed between pulmonary function measures and immune-toxicities, including cytokine release syndrome grade &amp;gt;2 or immune effector cell-associated neurotoxicity grade &amp;gt; 2. Conclusions To the best of our knowledge, this is the first study evaluating the relationship between PFTs and the outcomes of CAR T-cell treatment. Our results indicate that among standard measures of pulmonary assessment, only FEV1 was predictive of poor PFS, though with minor association, with unclear clinical significance. We did not observe any association with overall survival. These findings suggest that pre-CAR-T pulmonary assessment may have limited utility in evaluating CAR-T candidates. Nevertheless, further validation in a multicenter setting is required.

Golidocitinib in Treating Refractory or Relapsed Peripheral T- Cell Lymphoma: Full Analysis of the Multinational Pivotal Study Results (JACKPOT8)

Introduction: Golidocitinib is the first JAK1 selective inhibitor to enter into pivotal clinical development for the treatment of relapsed/refractory peripheral T cell lymphoma (r/r PTCL). Preliminary analysis of the JACKPOT8 study (NCT04105010) has shown promising antitumor efficacy and a manageable safety profile of golidocitinib. Here we reported the full analysis of the phase 2 multinational pivotal study JACKPOT8 Part B. Methods: This study enrolled r/r PTCL patients who had undergone at least one line of systemic therapies. All patients received golidocitinib at 150 mg once daily (QD) until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was a CT-based objective response rate (ORR) assessed by an independent review committee (IRC) per Lugano 2014 criteria. Other efficacy endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The efficacy analysis set included patients whose pathological diagnosis of PTCL has been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at the baseline assessed by IRC. The safety analysis set included all dosed patients. Results: A total of 88 efficacy evaluable patients with r/r PTCL were included in the analysis. The median age was 57.5 years, and the majority (64.8%) were male. The major pathological subtypes included PTCL NOS (56.8%), AITL (18.2%), and ALCL (11.4%). At the baseline, 54.5% of patients had ECOG PS of 1, 52.3% had elevated LDH levels, and 21.6% had bone marrow involvement. The median prior lines of therapies were two. All patients had been treated with chemotherapies, 50% had been treated with histone deacetylase inhibitors, and 10.2% had received CD30 targeted therapy. Per IRC assessment based on CT imaging, 39 patients achieved tumor response, with an ORR of 44.3% (95% CI: 33.7%, 55.3%), and 26 patients (29.5%) achieved complete response. The primary endpoint met the pre-defined target with statistical significance ( p &amp;lt; 0.0001). Tumor response was observed in various subtypes, irrespective of age, gender, baseline bone marrow involvement, and ECOG PS. With a median follow-up time of 10.4 months for DoR, 59% of responders were still event-free. The median DoR has not been reached, with an estimated 12-month DoR rate of 70.2%. With a median follow-up time of 9.6 months for PFS, the median PFS was 5.6 months. The longest PFS was 20 months, and the patient was still responding. Per investigator assessment, 34 patients achieved tumor response (ORR: 38.6%). The DoR and PFS by investigator assessment were similar to that of IRC assessed results. With a median follow-up time of 15.1 months for OS, approximately 60% of patients were still alive, with an estimated median OS of 19.2 months. A total of 112 patients were included in the safety analysis set. The median relative dose intensity was 100%. A total of 62 patients (55.4%) reported ≥ grade 3 treatment-emergent adverse events (TEAEs). The most common drug-related ≥ grade 3 TEAEs were hematological adverse events in nature, including neutropenia (25%), leukopenia (23.2%), and lymphopenia (18.8%). The majority of TEAEs were reversible and clinically manageable. Treatment-related AEs leading to dose interruption, reduction, and discontinuation were reported in 36.6%, 7.1%, and 8% of patients, respectively. Conclusions: This pivotal study met its primary objective, suggesting golidocitinib can be an effective treatment option with a manageable safety profile for patients with r/r PTCL. The updated data will be presented at the conference.