Changing Patterns of Symptomatic Myeloma after the Implementation of the 2014 IMWG Diagnostic Criteria and Reduced Early Mortality

In 2014, the IMWG updated the diagnostic criteria for symptomatic myeloma and in addition to classical "CRAB", implemented "biomarkers of malignancy" (BoM) (FLC ratio>100, more than 1 focal lesion in MRI and bone marrow infiltration of at least 60%). As a result, a subset of patients previously considered as having "smoldering myeloma" were characterized as symptomatic and were eligible to start therapy; these criteria are also adopted in clinical trials. However, the impact of the 2014 IMWG criteria in the overall clinical presentation of symptomatic myeloma patients who start therapy or in the outcomes of patients who present only with biomarkers of malignancy, has not been fully appreciated. We evaluated the characteristics and outcomes of patients who started therapy in the past 5 years, when the 2014 IMWG criteria were implement in our clinical practice and compare their characteristics and outcomes with those of patients that started in an earlier period. To adjust for advances in diagnosis and especially imaging, the analysis included 1007 consecutive patients who started therapy in the Department of Clinical Therapeutics between 1/1/2010 and 31/12/2020. Our prospectively maintained database includes all consecutive patients who start therapy for myeloma. The patients were divided in two cohorts: those that started therapy after 1/1/2015 (after 2014 IMWG criteria implementation) and those that started therapy between 1/1/2010 and 31/12/2014. In these two chronological periods, methods for the assessment of disease were similar except for wider use of ldWBCT after 2013 and more frequent use of conventional CT before 2013. In the 2010-2014 period, 393 patients started therapy vs 614 that started between 2015-2020. Patients in the two groups had similar age (mean 67 vs 66.3, p=0.399) and similar b2-microglobulin levels (7.39 vs 7.33 mg/L, p=0.907) but hemoglobin (mean 10.2 vs 10.6 gr/dl, p=0.016), platelet counts (mean 230 vs 246 x10 9/L, p=0.021), serum albumin (3.6 vs 3.8 gr/dl, p=0.003) were higher in the 2015-2020 era. Although it did not reach statistical significance, mean bone marrow infiltration in trephine biopsy (60.5% vs 57.3%, p=0.056) and eGFR (mean 66.6 vs 62.3 ml/min/ 1.73 m2, p=0.057) were higher and mean serum calcium levels lower (9.9 vs 10.2 mg/dl, p=0.073) in 2015-2020 group, while, serum LDH >ULN (19.6% vs 21.4%, p=0.513) and high risk cytogenetics (20.4% vs 20.8%) were found in similar rates. Accordingly, ISS and R-ISS stage distribution was similar (p=0.496). Per CRAB criteria, hemoglobin < 10 gr/dl was present in 48.9% of patients in the 2010-14 period vs 43.6% in the 2015-2020 (p=0.1), hypercalcemia in 18.2% vs 15% (p=0.185), serum creatinine ≥2 mg/dl in 22% vs 18% (p=0.124) and lytic bone disease in 76.9% vs 76.8%, p=0.973). At least one CRAB was present in 96.4% vs 94% of patients in the two periods (p=0.603). Even in the era before the publication of the 2014 IMWG criteria, 3.6% of patients that started therapy did not fulfill the CRAB criteria of that time; in retrospect, most had at least one BoM present. In the 2015-2020 period, 6% of new patients were considered as symptomatic based on the presence of BoM only. The median follow-up of the 2010-2014 cohort is 63 months and is 25 months for the 2015-2020 group; the 1- and 2-year OS is 83% vs 90% and 75% vs 79% respectively (p=0.057) for the two groups; early mortality (within 3 months from start of therapy) was 7.4% vs 3.9% (p=0.016) respectively. The OS of patients starting therapy based on the presence of BoM only is not reached (3-year OS 87%) vs 59 months (3 year OS: 65%) for patients presenting with CRAB (p=0.051). Because there may be a lead time bias, we also compare the OS of patients with biomarkers of malignancy only vs those with CRAB and ISS-1 disease: OS was similar although with a trend towards better OS for those with BoM. In conclusion, the implementation of the 2014 IMWG diagnostic criteria has resulted in about 6% of newly diagnosed patients starting therapy based only on the presence of BoM. Although the implementation of the criteria has resulted in slightly better clinical presentation (less severe CRAB) and reduced early mortality, most patients still present with disease complications. These data point to the need to develop tools that can identify myeloma patients earlier during their disease course, before they develop devastating complications, in order to further improve their outcomes and quality of life. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Genesis: Honoraria; GSK: Honoraria; Amgen: Honoraria. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria.

Dynamics and Management of CAR-T Cells Associated Cytopenias: A Single-Center Experience

* Martín-Rojas RM and Bailén R equally contributed to this work. INTRODUCTION CAR-T cell therapy is approved by the European Medicines Agency (EMA) and the Federal Drugs Administration (FDA) for the treatment of adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy and for children and adults up to age 25 with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Prolonged cytopenias have been reported in up to 30-60% of patients undergoing CAR-T cell therapy, but information about its pathophysiology, dynamics and clinical impact is scarce. METHODS We conducted a retrospective study of consecutive patients undergoing commercial CAR-T cell therapy in our center between June 2019 and March 2021. We analyzed peripheral blood cell counts pre-lymphodepletion, at admission and during the first year of follow-up. This information was correlated with clinical data and analytical parameters. This study was approved by our institutional Ethics Committee and it was performed in compliance with the Declaration of Helsinki. Data were analyzed using IBM SPSS Statistics version 24 and GraphPad Prism version 8.4.3. RESULTS A total of 40 patients were included, 37 with diagnosis of R/R DLBCL and 3 with B-ALL (Table 1). 6-month overall survival was 71% for patients with lymphoma and 33.3% for patients with B-ALL. The dynamics of neutrophil and platelet counts is shown in Figure 1. Median hospitalization duration was 25 days (range: 11-241) and, during this period, 10 patients (25%) required transfusion of 5 or more red cell concentrates (18.9% lymphoma vs. 100% B-ALL; p=0.002), 11 patients (27.5%) required 5 or more platelet transfusions (21.6% lymphoma vs. 100% B-ALL; p=0.003) and 6 patients needed 5 or more doses of G-CSF (13.5% lymphoma vs. 33.3% B-ALL; p=0.3). On day +28 post CAR-T cell therapy, 26 patients (65%) showed persistent profound cytopenias not related with marrow infiltration (absolute neutrophil counts ≤500/μL and/or platelets ≤50000/ μL): a total of 4 patients (15.4%) had neutropenia, 8 patients (31%) thrombopenia and 14 patients (54%) both. 100% of patients with B-ALL maintained aplasia at day +28, with no evidence of disease. Due to persistent cytopenias at discharge, 22 patients (64.7%) received outpatient treatment with G-CSF (20 lymphoma vs. 2 B-ALL; p=0.41), 13 patients (38.2%) received erythropoietin (11 lymphoma vs. 2 B-ALL; p=0.16) and 12 patients (35.3%) were treated with thrombopoietin analogues (10 lymphoma vs. 2 B-ALL; p=0.13). One patient with B-ALL received a boost of selected CD34+ cells from her donor (Table 1). On day +90 post CAR-T cell therapy, 7 patients (26.9%) showed profound cytopenias and, on day +180 it increased to 9 patients (47.4%). None of the 9 patients who were alive at one year follow-up, presented profound cytopenias at this point (Figure 2). Profound cytopenias on day +28 were related to bridging therapy (p=0.04), bone marrow infiltration at diagnosis (p=0.05), higher lymphodepletion doses (p=0.05), evidence of a bulky mass pre-lymphodepletion (p=0.007), development of cytokine release syndrome (CRS) (p=0.012), ICU admission (p=0.07), infectious complications (p=0.008) and having less than 2000/ μL neutrophils pre-lymphodepletion (p=0.04). A multivariate analysis using logistic regression identified higher doses of lymphodepletion (OR 7.57; 95% CI 1.14-50.4; p=0.03) and bone marrow infiltration at diagnosis (OR 7.31; 95% CI 0.97-54.95; p=0.05) as the only independent predictors factors of these cytopenias. Profound cytopenias on day +180 were related to bone marrow infiltration at diagnosis (p=0.02), having received bridging therapy (p=0.05) and lower pre-lymphodepletion lymphocyte counts (p=0.04) and folate levels (p=0.05). None of these variables reached statistical significancy on the multivariate analysis. CONCLUSIONS Profound cytopenias not associated with progression or relapse were a frequent complication after commercial CAR-T cell therapy, with 65% of cases on day +28, being the lymphodepletion dose and bone marrow infiltration at diagnosis independent predictors for its development. Beyond day +28, up to 47% patients showed profound cytopenias. A higher number of patients and longer follow-up are needed to confirm our findings and identify other potential prognosis factors for these cytopenias. Figure 1 Figure 1. Disclosures Martín-Rojas: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Assessment of the role of 18F-FDG PET CT in detection of bone marrow infiltration in comparison to the Bone Marrow Aspirate in Lymphoma patients

Background 18-F-2-Deoxy-D-Glucose Positron Emission Tomography [FDG-PET], combined with multidetector helical Computed Tomography [PET/CT] has emerged as a one of the most important prognostic tools for lymphoma management. Previous studies have indicated that PET/CT is a convenient method for bone marrow assessment in patients with lymphoma. A blind Bone Marrow Biopsy [BMB] has been traditionally used as the golden standard in marrow evaluation despite its invasiveness. Objective is to compare the results of PET/CT with BMB regarding bone marrow infiltration [BMI] in patients with Hodgkin's Lymphoma [HL] and Non-Hodgkin's Lymphoma [NHL] and to characterize the visual bone marrow FDG uptake pattern by PET-CT Methods A cross sectional study including 27 cases of Lymphoma, conducted at Ain Shams University hospitals, the patients were investigated using PET-CT scan and BMB ,the period was between December 2018 till the end of May 2019. Results Our study included 27 histologically proved Lymphoma patients, 14 (51.9%) were males and 13 (48.1%) were females, with age ranging from 17 to 69 years (mean 45 years). Among the total cases, 17 (63%) patients had NHL, while 10 (37%) patients had HL. All the patients were evaluated at first by BMB (taken from the dorsal portion of the iliac crest) for initial staging, then the patients underwent PET/CT scan. The study revealed 12 patients (44.4%) had BMI detected by PET/CT imaging; however, only 7 patients (25.9%) were detected by BMB. BMB and 18F-FDG PET/CT scans were concordant for BMI detection in 22 patients (81.5%): positive concordance in 7 patients and negative in 15. Of the 5 discordant cases, four had a focal marrow intense FDG uptake detected by PET/CT and were upstaged as their BMB results were false-negative, one patient had intense diffuse marrow uptake by PET/CT while its BMB was negative (revealed only hyper cellularity with mild dysplasia). The sensitivity, specificity, PPV, and NPV of PET for identifying BMI was 100%, 75%, 58.3%, 100% respectively with a diagnostic accuracy 81.5% with a (p value < 0.05). Conclusion 18F-FDG PET-CT imaging is more sensitive than bone marrow biopsy for bone marrow infiltration detection in Hodgkin's Lymphoma and Non-Hodgkin's Lymphoma staging.