Aggressive Lymphoma Patients Research Articles

Characterization of lymphopenia and correlating the risk of cytopenias with dose and BM volume irradiated in aggressive B-cell lymphoma patients bridged with radiation therapy for CAR-T cell therapy

IntroductionThe impact of bridging radiation therapy (bRT) for CAR T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown. MethodsWe retrospectively reviewed adults with relapsed/refractory aggressive large B-cell lymphoma (LBCL) who received bRT prior to CD-19 CAR-T between 11/2017-4/2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. PFS, DSS, and OS were modeled via Kaplan-Meier. ResultsFifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5cm). The median bRT dose was 30Gy (range: 4-48Gy); 26 patients (51%) received ≥30Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range: 0-50%). At a median follow-up of 10.3 months (95% CI: 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI: 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of ≥Grade 3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy (CC) timepoint. There was no correlation between post-RT Grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30Gy bRT, or bRT to ≥15% of BM (all p>0.2). Among patients with Grade 0-2 lymphopenia pre-RT, increased conversion to Grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30Gy bRT, but these factors did not impair ALC recovery at CC. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (p>0.25), DSS, PFS, or OS (p>0.3). ConclusionsLymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk following bRT is not associated with bRT to ≥30Gy, ≥15% of BM, or comprehensive coverage. While bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens.

The Experience of Timisoara Hematology Clinic on the Management of Aggressive Non-Hodgkin Lymphoma Patients

Objectives. One of the most prevalent types of malignant lymphoproliferative disorders is non-Hodgkin lymphoma (NHL), which has shown an increased frequency worldwide of roughly 168% since 1975, coinciding with a decline in the age at diagnosis. Despite a ten-year improvement in overall survival, NHL accounts for approximately 3% of all cancer-related deaths. Delays in diagnosis and the emergence of related comorbidities are caused by the diverse symptomatology and symptoms associated with NHL. Thus, the purpose of this study was to assess patients treated at Timisoara's Clinical Emergency Municipal Hospital who had been diagnosed with aggressive HNL. Material and methods. This cross-sectional study comprised 76 patients diagnosed with aggressive NHL between January 2020 and June 2023 who were admitted to Timisoara's Clinical Emergency Municipal Hospital. Biopsy along with histopathologic examination served as the basis for the diagnosis. As part of the first assessment, bone marrow biopsy and imaging studies (PET/CT) were carried out in addition to laboratory tests. The NHL was staged using the Ann Arbour classification. The present protocols were followed in the establishment of the treatment. PET/CT was used to assess the response to treatment. Results. In this study cohort 72% were stage 4 of NHL at the diagnosis, 16% were stage 3, 5% were stage 2, while only 2% were stage 1. B symptoms were present in 69% of cases. In patients with 4th stage of NHL, bone marrow represents the most frequent extranodal site. 57 patients finished minimum a complete chemotherapy line, from which 90% of the patients had complete (63%) or partial (24%) remission after first-line treatment. Conclusion. The importance of this study was to emphasize the heterogeneity of NHL and to evaluate the treatment response and survivance of aggressive NHL patients.

Clinical observation study of recombinant human thrombopoietin in the prevention of chemotherapy-induced thrombocytopenia in patients with aggressive lymphoma.

e19056 Background: Recombinant human thrombopoietin (rhTPO) has demonstrated efficacy in elevating platelet counts in lymphoma patients suffering from chemotherapy-induced thrombocytopenia. However, the optimal timing for its administration remains to be established. Methods: This prospective, observational, non-randomized, multicenter study aimed to identify the optimal timing for rhTPO intervention in patients with aggressive lymphoma experiencing chemotherapy-induced thrombocytopenia. Participants aged between 18 and 70 years, diagnosed with aggressive lymphoma and chemotherapy-induced thrombocytopenia, were divided into three groups based on their baseline platelet counts. Group 1 received rhTPO when platelet counts fell below 50×109/L but remained above 25×109/L; Group 2 was treated with rhTPO at platelet counts ≥ 50×109/L and < 75×109/L; and Group 3 received rhTPO treatment for platelet counts ≤ 25×109/L. Treatment was discontinued once platelet counts reached ≥ 100×109/L. The primary endpoint was the proportion of patients achieving normalization of platelet counts, the secondary outcomes including platelet nadir values, the incidence of platelet transfusions, and adverse events. Results: Eighty-eight patients were enrolled, with 36 in Group 1, 22 in Group 2, and 30 in Group 3. The groups were comparable in clinical manifestation of age, gender, comorbidities, lymphoma classification, and bone marrow involvement. Normalization of platelet counts was achieved in 69.44%, 81.82%, and 36.67% of patients in Groups 1, 2, and 3, respectively, with Groups 1 and 2 showing significantly higher rates than Group 3 (P<0.05). The mean platelet nadir values were significantly higher in Groups 1 and 2 (28.39±10.19×109/L and 43.23±14.97×109/L, respectively) compared to Group 3 (11.13±6.21×109/L, P<0.01). The incidence of platelet transfusions was notably lower in Groups 1 and 2 (19.44% and 13.64%, respectively) than in Group 3 (70.00%, P<0.01). There were no significant differences in adverse event rates across the groups. Conclusions: Early administration of rhTPO significantly enhances platelet recovery and reduces the need for platelet transfusions in aggressive lymphoma patients with chemotherapy-induced thrombocytopenia.

Long-Term Results of IFRT vs. ISRT in Infradiaphragmal Fields in Aggressive Non-Hodgkins’s Lymphoma Patients—A Single Centre Experience

(1) Background: This study aimed to examine the difference in efficacy and toxicity of involved-field (IFRT) and involved-site radiotherapy (ISRT) fields in infradiaphragmal aggressive non-Hodgkin lymphoma patients. (2) Methods: In total, 140 patients with infradiaphragmal lymphoma treated between 2003 and 2020 were retrospectively evaluated. There were 69 patients (49%) treated with IFRT, and 71 (51%) patients treated with ISRT. The median dose in the IFRT group was 36 Gy, (range 4–50.4 Gy), and in the ISRT group, it was 30 Gy (range 4–48 Gy). (3) Results: The median follow-up in the IFRT group was 133 months (95% CI 109–158), and in the ISRT group, it was 48 months (95% CI 39–57). In the IFRT group, locoregional control was 67%, and in the ISRT group, 73%. The 2- and 5-year overall survival (OS) in the IFRT and ISRT groups were 79% and 69% vs. 80% and 70%, respectively (p = 0.711). The 2- and 5-year event-free survival (EFS) in the IFRT and ISRT groups were 73% and 68% vs. 77% and 70%, respectively (p = 0.575). Acute side effects occurred in 43 (31%) patients, which is more frequent in the IFRT group, 34 (39%) patients, than in the ISRT group, 9 (13%) patients, p > 0.01. Late toxicities occurred more often in the IFRT group of patients, (10/53) 19%, than in the ISRT group of patients, (2/37) 5%, (p = 0.026). (4) Conclusions: By reducing the radiotherapy volume and the doses in the treatment of infradiaphragmatic fields, treatment with significantly fewer acute and long-term side effects is possible. At the same time, efficiency and local disease control are not compromised.

Multi-Center Study of COVID-19 Infection in Elderly Patients with Lymphoma: On Behalf of Jiangsu Cooperative Lymphoma Group (JCLG)

Objective: To survey the vaccination status, lymphoma status, characteristics and outcomes of COVID-19 infections in elderly patients with lymphoma in Jiangsu Province of China. Methods: Elderly patients with lymphoma (age≥60 years) in Jiangsu Province was investigated by questionnaire and telephone follow-up during December 2022 to June 2023. Basic information, Lymphoma status, comorbidities, vaccination, severity and outcome of COVID-19 infection were collected. Results: A total of 402 patients were followed up in this study, 364 were confirmed with COVID-19 infection during December 2022 to June 2023. Among these patients, median age was 70 years (range 60-92), Of which 50.25% (202/402) were over 70 years old. Most patients (85.9%,313/364) were symptomatic at COVID-19 diagnosis. 45.6% (166/364) and 54.4% (198/364) was defined as mild COVID-19 and severe COVID-19 infections according to Diagnosis and treatment plan for COVID -19（trial version 10）in China, all patients with severe COVID-19 infection were hospitalized. 56.0% (204 /364) of patients were aggressive lymphoma and 43.4%(158 /364) were indolent lymphoma. Only 43.9% of the patients had received two or more doses of SARS-CoV-2 vaccine at the onset of COVID-19. In univariable analysis, age >70 years(OR 1.88;95% CI 1.24-2.85,p=0.003), the presence of comorbidities (OR 1.41;95% CI 1.41-1.11,p=0.005), active hematological disease(progressive disease or relapsed/refractory disease, OR 2.02;95% CI 1.53-2.67,P<0.001), ≥2 prior treatment(OR 1.88,95% CI 1.42-2.47,p<0.001), and time from anti-lymphoma treatment to COVID-19 (OR 1.90,95% CI 1.53-2.36,p<0.001) were associated with severe COVID-19 infection in the entire cohort. For anti-lymphoma treatment, anti-CD20-based treatments within the last 6 months was associated with severe COVID-19 infection in the aggressive lymphoma patients (OR 2.17,95% CI 1.21-3.88, p=0.009) as well as in the indolent lymphoma patients (OR 5.67,95% CI 1.97-16.29, p=0.001). Of note, among the indolent lymphoma subsets, only anti-CD20-based maintenance therapy might be a risk factor for exacerbating COVID-19 infection (OR 4.42,95% CI 1.15-17.03,p=0.031), while continuous BTK inhibitors might be protective effect on the outcome when compared with other targeted drugs(OR 0.44,95% CI 0.20-0.97,p=0.043). Overall, 7.7% of patients (28/364) ceased，among them 57.4% (16/28) was due to COVID-19 infection,14.9% (4/28) was due to lymphoma deteriation, 17.9%(5/28) due to COVID-19 infection concurrent with lymphoma progression and 10.7%(3/28) with heart failure . Mortality rate increase by lymphoma status [ Controlled disease: 8.67%(15/173) ; Stable disease: 9.80%(5/51);Active disease:16,67%(6/36), p=0.006)], prior lines of anti-lymphoma therapy [1 prior: 7.14%(13/182)；2 prior: 5.26%(3/57);≥3 prior: 25%(9/36), p<0.001] and anti-lymphoma therapy within one month of COVID-19 infection[>1 months: 8.52%(11/129) ;<1 months: 16.67%(17/102); p=0.002]. Conclusions: Elderly patients with lymphoma have a low rate of COVID-19 vaccination and a high rate of severe COVID-19 infection. Patients with active disease, multiple lines of prior therapy, advanced age, multiple comorbidities, and anti-CD20-based treatments within the last 6 months was associated with severe COVID-19 infection..

Ultra-Hypofractionated Involved Site Radiation Therapy (ISRT) As Salvage or Bridging Therapy in Aggressive Non-Hodgkin Lymphomas

Introduction: Conventional fractionated radiation treatment (RT) to a total dose of 40-50 Gy in 20-25 fractions is typically recommended in the ‘definitive’ intent treatment of aggressive chemorefractory non-Hodgkin lymphoma. However, during the time of COVID-19, recommendations for hypofractionated courses (5-13 fractions) arose (Yahalom et al Blood 2020) as modern radiation techniques should allow similar total doses to be delivered safely in far fewer fractions. Our aim is to evaluate the outcomes and toxicities of ultra-hypofractionated (</=5 fractions) ‘definitive’ ISRT in aggressive non-Hodgkin lymphomas to see if this may be an acceptable alternate recommendation beyond COVID-19. Methods: We conducted an IRB-approved, retrospective review of all aggressive non-Hodgkin lymphoma patients treated at our institution with ‘definitive’ intent (40-50 Gy EQD2 with an α/β of 10) ultra-hypofractionated ISRT between April 2020 and July 2023. Demographic, disease-specific, and treatment-related variables were collected. Primary outcomes include objective response rate (ORR), defined as complete (CR) or partial response (PR) on post-RT positron emission tomography (PET) scans using the Lugano classification, local failure (LF), and radiation-related toxicity per CTCAE v5. Secondary outcomes include overall disease control and survival. Results: 26 ultra-hypofractionated radiation treatments were identified from 23 unique patients who were treated with ‘definitive’ intent ISRT (39.1% salvage, 30.4% early-salvage post CAR-T, and 30.4% bridging to SCT or CAR-T). The most common dose was 30 Gy in 5 fractions (96%); all patients were treated with IMRT with SBRT-type immobilization and image guidance as clinically indicated. The most common diagnosis was DLBCL (91%). 10/23 (43%) patients were female, the majority (82%) were ECOG 0-1 performance status, and the average age at time of RT was 68.9 years. 39% had all FDG-avid sites at the time of radiation treated. The median follow-up was 8.3 months (range 0.3-27.9 months). 26% of patients had acute radiation related toxicities, which were all grade 1-2 with the most common being fatigue (30%). There were no grade 3-4 toxicities, and no subacute or long-term toxicities. Initial local ORR was 20/21, or 95% (86% CR and 10% PR), while initial overall ORR was 12/21, or 57% (52% CR and 5% PR). At time of last follow up, only 1/24 (4%) of irradiated sites had local failure (2 data points N/A), with a TTLF of 1.5 months. 62% of patients had disease progression, with median time to disease progression of 1.5 months. At time of last follow up, 48% were dead, with a median time to death of 6.6 months. Conclusions: Ultra-hypofractionated ISRT in the ‘definitive’ intent treatment of aggressive non-Hodgkin lymphomas has excellent local tumor control and appears to be safe with minimal acute and subacute toxicities. In addition to patient convenience and cost effectiveness, short-course ISRT allows patients to quickly move on to next-line therapy when indicated. Prospective studies and long-term follow up are needed to further validate this as an alternative radiation treatment option.

Cytogenomic features of Richter transformation

BackgroundRichter transformation (RT) is the development of aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This rare disease is characterised by dismal prognosis. In recent years, there has been a deeper understanding of RT molecular pathogenesis, and disruptions of apoptosis (TP53) and proliferation (CDKN2A, MYC, NOTCH1) has been described as typical aberrations in RT.ResultsA single-institution cohort of 33 RT patients were investigated by karyotyping, fluorescence in situ hybridization and single nucleotide polymorphism/copy number (CN) arrays. Most of RTs were typically manifested by diffuse large B-cell lymphoma, not otherwise specified, among the remaining cases one was classified as high-grade B-cell lymphoma with 11q aberrations. The most frequent alterations (40–60% of cases) were represented by MYC rearrangement/gain, deletions of TP53 and CDKN2A, IGH rearrangement and 13q14 deletion. Several other frequent lesions included losses of 14q24.1-q32.33, 7q31.33-q36.3, and gain of 5q35.2. Analysis of 13 CLL/SLL-RT pairs showed that RT arised from the CLL/SLL by acquiring of 10 ~ 12 cytogenetic or CN lesions/case, but without acquisition of loss of heterozygosity regions. Our result affirmed the higher genetic complexity in RT than CLL/SLL and confirmed the linear features of RT clonal evolution as predominant.ConclusionsCytogenomic profile was concordant with the literature data, however the role of IGH rearrangement, 14q deletion and 5q35.2 gain need to be explored. We anticipate that further characterization of RT lesions will probably facilitate better understanding of the RT clonal evolution.

A Prospective Observational Study Evaluating Extracellular Water to Total Body Water Ratio By Using the Bioelectrical Impedance Analysis in Elderly Patients with Hematologic Malignancies

[Introduction] Body composition assessment is often used in clinical practice for evaluating and monitoring sarcopenia and nutritional status. Bioelectrical impedance analysis (BIA), which uses the conductivity of the body's intracellular and extracellular fluids to respond to cell and tissue functions, has gradually become widely used in clinical practice because of its non-invasiveness, convenience, and low cost. The ratio of extracellular water to total body water (ECW/TBW) measured by BIA has been found to be related to the prognosis of many diseases, but its application value for patients with hematologic malignancies still needs to be further explored. The purpose of this study was to further explore the application value of ECW/TBW measured by BIA in elderly patients with hematologic malignancies. [Patients and Methods] We prospectively analyzed 82 elderly patients aged≥60 years with hematologic malignancies diagnosed at our institution between 2015 and 2018. Appendicular skeletal muscle mass (ASM) and ECW/TBW ratio were measured by using multifrequency BIA (InBody 720). In this study, the ECW/TBW cut off value to predict survival was determined by a receiver operating characteristic (ROC) curve analysis. The ECW/TBW ratio cut offs was 0.397 (sensitivity 67.3% and specificity 54.5%, area under the curve (AUC) 0.586, [95% confidence interval (CI) 0.46-0.711]) for all 82 patients. Patients with ECW/TBW < 0.397 were sorted into the non-overhydrated group (NOH-group) and those with ECW/TBW > 0.397 into the overhydrated group (OH-group). Skeletal muscle index (SMI) was defined as the ratio of ASM divided by height in square centimeters. Sarcopenia was defined according to the AWGS2019 algorithm, in which the patient has low muscle mass, and low muscle strength or low physical performance. The study protocol was approved by the Institutional Review Board of Yokohama Municipal Citizen's Hospital, and it was carried out in accordance with the Declaration of Helsinki. This trial was registered in the UMIN clinical trial registry (UMIN000035834). [Results] Median age at diagnosis was 78 years (60-93 years), with 46 males and 36 females. The diagnosis included non-Hodgkin lymphoma (NHL, n=51), multiple myeloma (MM, n=11), myelodysplastic syndrome (MDS, n=12), and acute myeloid leukemia (AML, n=8). The mean ECW/TBW ratio of all 82 patients was 0.397±0.014. There was no significant difference in the mean ECW/TBW ratio between disease types. Thirty-four patients (41%) were classified as OH-group and 48 patients (59%) were classified as NOH-group. The median age in the OH- and NOH- groups was 83 and 74 years (p<0.001). The mean BMI did not differ between the two groups (22.17 vs. 22.16 kg/m2, respectively, p = 0.99). The prevalence of sarcopenia was 41.4% (34/82). There was no significant difference in overall survival (OS) between the sarcopenia and the non-sarcopenia group (3-year OS, 58.1% vs. 63.3%, p=0.96). On the other hand, patients with OH-group had shorter OS than those with NOH-group (3-year OS, 46.8% vs. 70.5%, p=0.03). We next performed a subgroup analysis of NHL patients. Among 51 NHL patients, 30 (59%) had aggressive lymphoma and 21 (41%) had indolent lymphoma. Twenty patients (39%) were classified as OH-group and 31 patients (61%) were classified as NOH-group. Patients with OH-group had shorter OS than those with NOH-group (3-year OS, 67.1% vs. 90.3%, p=0.02). The prevalence of sarcopenia was 37.3% (19/51) and sarcopenia was not correlated with survival in NHL patients. Among 30 aggressive lymphoma patients, the overhydrated status was closely associated with poor outcome (3-year OS was 57.1% in the OH-group and 88.9% in the NOH-group, p=0.01). On the other hand, there was no significant difference in OS between the OH- and NOH- groups among 21 indolent lymphoma patients. Multivariate analysis showed that the overhydrated status (high-ECW/TBW ratio) was an independent prognostic factor for OS in patients with aggressive lymphoma (HR, 5.30; 95%CI, 1.01-27.7, p=0.04). [Conclusion] The present study demonstrated that high-ECW/TBW ratio was associated with poor outcome in elderly patients with hematologic malignancies. Especially, the overhydrated status was closely associated with poor outcome in elderly aggressive lymphoma patients. Since our results are based on a small-sized analysis, further large prospective studies are warranted to verify this conclusion.

Feasibility and Safety of the First-in-Human Chemotherapy-Light Combination of Rituximab, Polatuzumab Vedotin and Glofitamab in Previously Untreated Aggressive B-Cell Lymphoma Patients Above 60 Years of Age Ineligible for a Fully Dosed R-CHOP - R-Pola-Glo/Ikf-t062, a Study of the Austrian Group for Medical Tumor Therapy (AGMT-NHL-16) and the German Lymphoma Alliance (GLA2022-10)

Background. Diffuse large B-cell lymphoma is the most common aggressive B-cell lymphoma mainly affecting elderly patients. The treatment goal is usually cure, however, older and frail patients typically exhibit a growing number of comorbidities that significantly increase treatment-related morbidity and mortality thus limiting the treatment goal due to switching to less effective treatments. Particular in the frail population there is an urgent medical need to establish highly effective therapies suitable for patients with limited functional organ reserve. To this end, we developed the chemotherapy-light combination therapy R-Pola-Glo, which is composed of the anti-CD20 antibody rituximab in combination with the antibody-drug conjugate polatuzumab vedotin (anti-CD79b) and the bispecific antibody glofitamab (CD20×CD3). Here, we report the safety data report of the run-in phase following treatment of the first 10 patients with this first-in-human chemotherapy-light combination. Methods. R-Pola-Glo (EudraCT No.: 2022-003398-51) is a prospective, bi-national (Germany/Austrian), multicenter, one arm, phase II trial designed to estimate the 1-year progression free survival of the chemotherapy-light combination rituximab, polatuzumab vedotin and glofitamab as the primary endpoint. Previously untreated DLBCL patients above 60 years of age, who are not eligible for a fully dosed R-CHOP-like therapy were eligible for enrollment, including patients with a lymphoma-related ECOG 3 and reduced kidney function. The study treatment plan includes a mandatory prephase with prednisolone or dexamethasone followed by 12 treatment cycles of 3 weeks each (Fig. 1). The step-up cycle (cycle 1) is comprised of intravenous (i.v.) application of obinutuzumab 1000 mg on D1, followed by i.v. application of polatuzumab vedotin 1.8 mg/kg on D2 and i.v. application of glofitamab in escalating doses of 2.5 mg on D8 and 10 mg on D15. This is followed by the target dose phase (cycles 2-6). Each of the 5 target dose cycles included rituximab 375 mg/m 2 and polatuzumab 1.8 mg/kg, both administered i.v. on D1 and i.v. glofitamab 30 mg on D2. The consolidation phase (cycles 7-12) comprises 6 cycles of glofitamab 30 mg administered intravenously on D1. As this is the first in human combination of these antibodies, the initial 10 patients were analyzed in a planned safety run-in phase and are reported here. Results. The median age of the first 10 patients was 79 years (range 69-81), with 70% of patients presenting with stage III/IV disease and elevated LDH; ECOG of all patients was <3 (ECOG 0: 4 patients; ECOG 1: 4 patients; ECOG 2: 2 patients). Extranodal involvement was present in 40%. Overall, 70% patients had a high-intermediate/high-risk IPI representing a high-risk population. The median follow-up time presented here from registration to time of data cut July 20, 2023 is 62 days (range 38-122) and longer follow-up will be presented at the time of the meeting. We observed 34 adverse events (AEs) including infections (6/10 patients; grade 1: 2; grade 2: 2; grade 3:2; no grade 4/5), neuropsychiatric issues (prednisone induced psychosis, fatigue, dysgeusia (4/10; all grade 1), CRS (3/10; all grade 1), cardiovascular side effects (3/10; all grade 2), infusion related reactions (2/10; grade 2), anemia (1/10; grade 2), bleeding (1/10; grade 3), and renal toxicity (1/10; grade 3). Notably, so far neither polyneuropathy nor ICANs were reported. Ten of the AEs occurring in 5 patients over all courses administered so far required hospitalization and were therefore classified as serious AEs and included infections (4 in two patients, peribronchitis and urosepsis) CRS (2), renal toxicity (1), deep vein thrombosis (1) and bleeding (1). Neither of the events were life threatening and no death occurred. Conclusion. R-Pola-Glo is a chemotherapy-light treatment regimen that exhibits an excellent safety profile in a vulnerable patient population. Specifically, no life-threating adverse events, ICANS, high grade polyneuropathy or deaths of any cause occurred, and CRS events were limited to grade 1. Acknowledgements. Study sponsor of R-Pola-Glo (EudraCT No.: 2022-003398-51) is the Institut für Klinische Krebsforschung (IKF) Frankfurt, Germany; financial support is provided by F. Hoffmann-La Roche Ltd. TM and RWK contributed equally as first authors; RG and BC contributed equally as senior authors.

Circulating Tumor DNA Reflects Histologic and Clinical Characteristics of Various Lymphoma Subtypes.

We designed and evaluated the clinical performance of a plasma circulating tumor DNA (ctDNA) panel of 112 genes in various subtypes of lymphoma. Targeted deep sequencing with an error-corrected algorithm was performed in ctDNA from plasma samples that were collected before treatment in 42 lymphoma patients. Blood buffy coat was utilized as a germline control. We evaluated the targeted gene panel using mutation detection concordance on the plasma samples with matched tissue samples analyzed the mutation profiles of the ctDNA. Next-generation sequencing analysis using matched tissue samples was available for 18 of the 42 patients. At least one mutation was detected in the majority of matched tissue biopsy samples (88.9%) and plasma samples (83.3%). A considerable number of mutations (40.4%) that were detected in the tissue samples were also found in the matched plasma samples. Majority of patients (21/42) were diffuse large B cell lymphoma patients. The overall detection rate of ctDNA in patients was 85.7% (36/42). The frequently mutated genes included PIM1, TET2, BCL2, KMT2D, KLHL6, HIST1H1E, and IRF8. A cutoff concentration (4,506 pg/mL) of ctDNA provided 88.9% sensitivity and 82.1% specificity to predict ctDNA mutation detection. The ctDNA concentration correlated with elevated lactate dehydrogenase level and the disease stage. Our design panel can detect many actionable gene mutations, including those at low frequency. Therefore, liquid biopsy can be applied clinically in the evaluation of lymphoma patients, especially in aggressive lymphoma patients.

Telemedicine-supervised cancer therapy for patients with an aggressive lymphoma and metastatic lung cancer in the U.S. Veterans Affairs National TeleOncology Service.

1602 Background: Telemedicine is increasingly used in cancer care but has mostly been applied to surveillance and oral therapy rather than parenteral treatments. In the U.S. Veterans Affairs National TeleOncology service (NTO), patients receive intravenous cancer treatments locally under remote supervision from a disease-specialized oncologist. We analyzed care delivered by the NTO for patients with an aggressive lymphoma (AL) and metastatic lung cancer (mLC). Methods: The demographics of veterans with AL and mLC enrolled in NTO between 2020-2023 were compared to patients receiving in-person care at the VA. From these NTO cohorts, two subsets of patients receiving 1st line therapy for diffuse large B cell lymphoma (DLBCL) and stage IV non-small cell lung cancer (NSCLC) were extracted and compared to control arms of in-person care matched 1:4 by stage, age, PDL1 (NSCLC), and cytogenetics (DLBCL). Fisher’s exact test was used for categorical variables, t test for continuous variables, log rank for survival, and negative binomial for count outcomes. Results: 140 patients with AL or mLC (40 DLBCL, 13 Hodgkin, 2 Burkitt, 61 NSCLC, 24 SCLC) were enrolled in NTO, spanning 12 U.S. states. Compared to in-person care ( n = 7,561), NTO had more rural (56% vs. 34%, p < 0.001) and white patients (89% vs. 77%, p = 0.002). With a median follow-up of 256 days (IQR, 154 - 415), NTO mLC and AL patients had a median of 15 and 17 telemedicine visits, respectively. 13 of 55 AL (24%) and 56 of 85 mLC (66%) patients received systemic therapy of any line, while 38 (69%) of AL were on surveillance. 7 mLC and 2 AL patients were referred externally for care. 11 patients with DLBCL and 30 patients with stage IV NSCLC started 1st line therapy while in NTO, which were compared to matched controls. NTO and matched control had similar mean time from referral to first appointment and from diagnosis to first treatment. There were no significant differences in progression-free survival between NTO and matched controls for NSCLC (HR 1.1, 95% CI 0.7-1.8) or DLBCL (HR 0.5, 95% CI 0.1-2.3). COVID infections in the first 12 months and number of ED visits in the first 3 months of treatment were not statistically different from controls. Conclusions: The NTO service demonstrates the feasibility of infusional chemoimmunotherapy administration under the direction of a remote tele-oncologist. This model has the potential to improve access to specialized oncology care for rural populations and provides a framework for decentralized clinical trials.[Table: see text]

Healthcare Utilization Disparities of Adolescent and Young Adults Compared to the Older Lymphoma Population

BackgroundAdolescent and Young Adults (AYAs) are an underserved, high-risk population. Identifying health care utilization patterns, and particularly acute care visits, is important as these are high-intensity, expensive services. We investigated whether differences exist in health care utilization between the AYA lymphoma population compared to their older adult counterparts. Materials and MethodsTwo correlated outcomes were used to measure health care utilization: 4 or more acute visits (emergency department or urgent care) and number of nonacute visits (office or telephone visits). We studied 442 patients with aggressive lymphoma patients 15 years or older at time of diagnosis managed at our cancer center within 2 years of their diagnosis. A multivariate generalized linear mixed model simultaneously estimated the effect of baseline predictors on 4 or more acute care visit with robust Poisson regression and nonacute visit counts with negative binomial regression allowing for a within-subject random effect. ResultsAYAs had increased risk of having ≥4 acute visits (RR = 1.96; P = .047) compared to their older counterparts. Obesity (RR = 2.04, P = .015) and living less than 50 miles from the cancer center (RR = 3.48, P = .015) were independently associated with higher risk of acute care usage. Acute care visits for psychiatric or substance use related reasons were significantly higher (P = .0001) among AYA (10/114, 8.8%) vs. non-AYA (3/328, 0.9%). ConclusionDisease-targeted interventions to address high acute health care utilization is needed amongst AYAs. Additionally, early multidisciplinary involvement after cancer diagnosis particularly with psychiatric expertise amongst AYAs and palliative care involvement in both groups is needed.

Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells.

First-line Treatment With Bendamustine and Rituximab for Old and Frail Patients With Aggressive Lymphoma: Results of the B-R-ENDA Trial.

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles bendamustine (BR) in elderly or frail aggressive B-cell lymphoma patients: 39 patients aged >80 years and 29 patients aged 61-80 years with elevated Cumulative Illness Rating Scalescore >6 were included. Progression-free survival (PFS) and overall survival (OS) at 2 years were 45% (95% confidence interval [CI], 28%-61%) and 46% (28%-63%) for the patients age >80, as well 32% (13%-51%) and 37% (17%-57%) for frail patients age 64-80, respectively. In a preplanned retrospective analysis, we found no significant differences in PFS and OS comparing the outcome of the 39 patients age >80 years with 40 patients aged 76-80 years treated with 6xR-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and 2 x rituximab in the RICOVER-60 trial (DSHNHL 1999-1, NCT00052936, EU-20243), yet we detected lower rates of infections and treatment-related deaths in the BR-treated patients. We demonstrate that older and frail patients with aggressive B-cell lymphoma who are not able to receive standard CHOP-based therapy can benefit from anthracycline-free therapy as a feasible and effective therapeutic option.

Orelabrutinib in Combination with Rituximab and Chemotherapy for Newly Diagnosed Aggressive B-Cell Lymphoma: A Multicenter, Single-Arm, Prospective Study

Keywords: Orelabrutinib, B-cell lymphoma, overall response rate Introduction Dysregulated B-cell receptor (BCR) signaling has been identified as an important feature of B-cell lymphomas. Inhibition of Bruton's tyrosine kinase (BTK), downstream of BCR, has demonstrated promising efficacy profiles in B-cell malignancies. Orelabrutinib is a newly developed BTK inhibitor with high selectivity for B-cell malignancies. This study was conducted to evaluate the preliminary efficacy and safety of orelabrutinib in combination with rituximab and chemotherapy for newly diagnosed aggressive B-cell lymphoma. Methods This was a single-arm, multicenter, prospective study in patients with clinical and histopathological confirmed aggressive B-cell lymphoma. The primary endpoints were investigator-assessed overall response rate (ORR) and complete response (CR) rate. Adverse events (AEs) were assessed in accordance with NCI CTCAE v4.03. Results A total of 42 patients with newly diagnosed aggressive B-cell lymphoma were enrolled from October 2020 to May 2022, including 28 diffuse large B-cell lymphoma (DLBCL), 12 primary central nervous system lymphoma (PCNSL), and 2 patients with high-grade B-cell lymphoma. The median age was 66.5 years (range, 35-86 years), and 23 (54.7%) were male. 66.7% of enrolled patients had stage III-IV disease. The median follow-up was 8.0 months (2.0-20.0 months). All the patients received orelabrutinib combined with rituximab and chemotherapy regimens. At data cutoff, 28 patients completed 6 cycles of treatment and were evaluated for therapeutic efficacy. Next-generation sequencing was performed and the genetic mutations included MYD88, BCL6, BCL2, CD79b, KMT2D, etc. All 42 patients were evaluable for toxicity. The toxic reactions were relatively mild, including grade 3 febrile neutropenia in 2 cases (4.8%), grade 3 neutropenia (2.4%), grade 3 thrombocytopenia (2.4%), and grade 3 leukopenia (2.4%). No other grade 3-4 non-hematologic AEs were reported. There was no dose modification due to AEs. The therapeutic responses were assessed. Among the 30 patients with DLBCL or high-grade B-cell lymphoma, 21 patients completed 6 cycles of treatment at data cutoff, with an ORR of 100%, and 15 (71.4%) patients achieved CR. The estimated 1-year overall survival (OS) and 1-year progression-free survival (PFS) rates were 100% and 94.1%, respectively. In addition, subgroup analyses were performed. Seventeen patients were non-GCB subtype, with a CR rate of 84.5%. Among the included DLBCL patients, 13 patients had MYC/BCL2 protein dual expression (DE), and the ORR and CR rate were 100% and 90.9%, respectively. Twenty-two patients were extra-nodal DLBCL, with a CR rate of 86.7%. The estimated 1-year PFS rate was 93.8%. Among them, 13 patients were non-GCB subtype, and 11 of them received 6 courses of treatment, with a CR rate of 81.8%. We further analyzed the treatment response of PCNSL patients. A total of 12 patients with newly diagnosed PCNSL were included in this study, with a median age of 57 years (range, 35-75 years) and 7 (58.2%) patients were male. Ten (83.3%) patients were non-GCB subtype. Seven patients completed 6 courses of treatment, with an ORR of 100%, and 4 patients achieved CR. Conclusions The preliminary results of this study suggested that orelabrutinib in combination with rituximab and chemotherapy may be a well-tolerated and effective regimen in newly diagnosed aggressive B-cell lymphoma patients. A larger sample size and longer follow-up time are needed in the future to validate this conclusion. Next-generation sequencing results are expected to provide additional explanations for differential treatment responses. Disclosure: No relevant conflicts of interest to declare.

290P Use of PEG G-CSF is associated with decreased myelotoxicity in dexrazoxane-used aggressive non-Hodgkin lymphoma patients

Dexrazoxane (DXZ) is indicated as a cardioprotective agent for elderly aggressive lymphoma receiving doxorubicin. Several studies reported an apparent increase in the severity of myelosuppression when dexrazoxane was used. Prophylactic use of pegylated granulocyte colony stimulating factor (PEG G-CSF) is known to reduce the incidence of both neutropenia and febrile neutropenia. We conducted a retrospective study to evaluate prophylactic effect of PEG G-CSF in elderly aggressive lymphoma treated with CHOP-based regimen and cardioprotective dexrazoxane.

CT-016 Prognostic Role of Lymphocyte-to-Monocyte Ratio in Patients Treated With CAR-T for Aggressive Lymphoma

Low absolute lymphocyte-to-monocyte ratio (ALC/AMC) predicts decreased survival in aggressive lymphoma (NHL) patients (pts) receiving chemotherapy and autologous stem cell transplantation (ASCT). We report the clinical significance of ALC/AMC and associated cellular phenotype changes in pts receiving chimeric antigen receptor T-cell (CAR-T) therapy. We conducted a retrospective chart review of all pts who received axicabtagene ciloleucel for NHL at Mayo Clinic, Rochester, between 6/2016 and 12/2020. ALC and AMC were obtained from clinical labs before lymphodepletion chemotherapy (LD). A receiver operator curve was generated using nominal logistic regression on ALC/AMC to predict complete remission (CR). Survivals were calculated using the Kaplan-Meier method. Blood immune phenotypes were assayed by multiparametric flow cytometry. Low ALC/AMC (≤0.8, n=29) prior to LD was associated with a lower CR rate (AUC=0.68, P=0.0004). Baseline characteristics were similar between the low and high ALC/AMC groups (>0.8, n=52), except for the use of prior ASCT and bridging therapy. The low ALC/AMC group also had higher C-reactive protein (CRP) on the day of CAR-T infusion and was associated with shorter event-free survival (EFS) and overall survival (OS) (EFS: 2.6 vs. 6.4 months, P<0.0001; OS: 5.3 months vs. not reached, P=0.0006). The prognostic association remained statistically significant in multivariate analysis that included prior ASCT, bridging therapy, and CRP. Compared with the high ALC/AMC group, the low ALC/AMC group had decreased CD4 effector memory T cells and increased CD16+CCR2+ monocytes (n=26). In addition, when comparing pts who achieved CR initially and relapsed versus those who maintained durable CR for 6 months or longer, there was a difference in these phenotypes as well as the number of CD27+CD45RA+CD62L+ CD8 T cells and PD-1+TIGIT+ T cells. ALC/AMC is a clinically accessible test that is strongly associated with CAR-T response and survival. Immune characterization revealed that the biologic effect is not just associated with cell numbers. Phenotypes, such as monocytes with inflammatory capacity and T-cell subsets, may further distinguish between primary refractory disease, early relapse, and durable response. These data could inform future therapeutic strategies to improve clinical outcomes with CAR-T.

CT-009 Prognostic Role of Lymphocyte to Monocyte Ratio in PTS Treated With CAR-T for Aggressive Lymphoma

Low absolute lymphocyte to monocyte ratio (ALC/AMC) predicts decreased survival in aggressive lymphoma (NHL) patients (pts) receiving chemotherapy and ASCT. We report the clinical significance of ALC/AMC and associated cellular phenotype changes in pts receiving chimeric antigen receptor T-cell (CART) therapy. We conducted a retrospective chart review of all pts who received axicabtagene ciloleucel for NHL at Mayo Clinic, Rochester between 6/2016 and 12/2020. ALC and AMC were obtained from the clinical lab before lymphodepletion chemotherapy (LD). The receiver operator curve was generated using nominal logistic regression on ALC/AMC to predict complete remission (CR). Survivals were calculated using the Kaplan- Meier method. Blood immune phenotypes were assayed by multiparametric flow. Low ALC/AMC (≤0.8, n=29) prior to LD was associated with a lower CR rate (AUC=0.68, p=0.0004). Baseline characteristics were similar between the low and high ALC/AMC group (>0.8, n=52), except for the use of prior ASCT and bridging therapy. The low ALC/AMC group also had higher CRP on the day of CAR-T infusion and was associated with shorter EFS and OS (EFS: 2.6 vs. 6.4 months, P<0.0001; OS: 5.3 months vs. not reached, P=0.0006), respectively. The prognostic association remained statistically significant on multivariate analysis that included prior ASCT, bridging therapy, and CRP. Compared to the high ALC/AMC group, the low ALC/AMC group had decreased CD4 Tem and increased CD16+CCR2+ monocytes (n=26). In addition, when comparing patients who achieved CR initially and relapsed versus those who maintained durable CR for 6 months or longer, there was a difference in these phenotypes as well as the number of CD27+CD45RA+CD62L+ CD8 T cells and PD-1+TIGIT+ T cells. ALC/AMC is a clinically accessible test that is strongly associated with CAR-T response and survival. Immune characterization revealed that the biological effect is not just associated with cell numbers. Phenotypes such as monocytes with inflammatory capacity and T cell subsets may further distinguish between primary refractory disease, early relapse, and durable response. These data could inform future therapeutic strategies to improve clinical outcomes with CAR-T.

Emerging Therapies for the Management of Richter Transformation.

Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with underlying chronic lymphocytic leukemia/small lymphocytic lymphoma. Aside from a small subgroup of patients with clonally unrelated and previously untreated chronic lymphocytic leukemia, the disease responds poorly to standard therapies and prognosis is dismal. Recent developments in the understanding of the biology of RT and the advent of several targeted agents may result in improved outcomes for these patients. The purpose of this review is to analyze recent data on the pathogenesis and treatment of RT. We reviewed studies addressing the pathophysiology of RT and analyzed the data for frontline chemoimmunotherapy and emerging targeted therapies likely to play a significant role in the future management of RT. Several biologic and clinical factors may help identify those who are unlikely to respond to conventional chemoimmunotherapy; where possible, these patients should be managed with a novel approach. Emerging therapies for the management of RT include chimeric antigen receptor T-cell therapy, noncovalent Bruton tyrosine kinase inhibitors, and T-cell-engaging bispecific antibodies. The use of less toxic and more effective targeted therapies may result in improved outcomes. Larger, prospective clinical trials are required to confirm efficacy and safety of novel agents for the management of RT, particularly when used in combination with other targeted therapies and in addition to chemoimmunotherapy regimens.

S210: CAR T-CELLS ASSOCIATED ACUTE TOXICITY IN B-CELL NON-HODGKIN LYMPHOMA: REAL-WORLD STUDY FROM THE DESCAR-T REGISTRY

Background: Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are common immune-related toxicities associated with chimeric antigen receptor (CAR)–T-cell therapy. Their clinical manifestations can be severe and potentially life threatening. Aims: Here, we report the French experience of CAR-T toxicity, we specifically addressed the modifiable risk factors for toxicity and we assessed management toxicity in real-world population. Methods: We conducted a study in a large cohort of R/R aggressive B-cell lymphoma patients (pts) treated with commercial products. All data were collected through the French DESCAR-T registry. CRS/ICANS were graded prospectively (ASTCT grade scale). Regarding previously validated predictive score of CRS and ICANS in the literature, EASIX score (LDHxCreatinine/Platelets), modified-EASIX score (m-EASIX: CRPxCreatinine/Platelets) and simplified-EASIX score (s-EASIX: LDH/Platelets) (Pennisi et al., 2021) were assessed in our cohort. Results: A total of 705 pts were included for the analysis of toxicity with a median follow-up of 12 months (range: 0.2-39). Notably, 74 pts (11%) pts had an ECOG/PS ≥ 2 before lymphodepletion. CRS of any grade occurred in 587 pts (83.3%) including 62 (10.5%) with grade 3 or higher (grade 3+). The median time from the infusion to the onset of CRS was 2 days (range: 0-34); the median time to resolution was 6 days (range: 1-30). ICANS of any grade occurred in 289 pts (41%) including 78 (27%) with grade 3+. The median time from the infusion to the onset was 6 days (range: 0-379); the median time to resolution was 7 days (range: 1-100). Most patients (94.5%) with ICANS had previously experienced CRS. Only 89 pts (29.9%) required admission to intensive care unit. Tocilizumab was the most common treatment for toxicity (411 pts, 68%) and 272 pts (45%) received corticosteroids. Interestingly, 38% of patients with CRS grade 1, 53 % with grade 2 and 65% with grade 3+ developed ICANS subsequently. In multivariate analysis, the parameters which retained statistical significance to predict any CRS were Axi-cel ([OR] = 2.79, 95% CI 1.75-4.45; p <0.0001) and elevated LDH (>upper limit normal; [OR] = 1.69, 95% CI 1.03-1.63; p = 0.03). Bulky mass > 5 cm ([OR] = 2.95, 95% CI 1.60-5.45; p = 0.0005), age <65 years ([OR] = 0.42, 95% CI 0.20-0.86; p = 0.01) and higher s-EASIX score ([OR] = 1.38, 95% CI 1.15-1.67; p = 0.0005) increased the risk of developing grade 3+ CRS. Parameters which retained statistical significance to predict any ICANS were Axi-cel ([OR] = 3.95, 95% CI 2.57-6.06; p <0.0001), ECOG ≥2 ([OR] = 2.10, 95% CI 1.26-3.51; p= 0.004), age ≥65 ([OR] = 3.17, 95% CI 2.10-4.79; p <0.0001) and higher s-EASIX score ([OR] = 1.20, 95% CI 1.03-1.40; p= 0.01). Axi-cel ([OR] = 13.1, 95% CI 3.98-43.3; p <0.001), ECOG ≥2 ([OR] = 0.04, 95% CI 1.007-4.38; p= 0.04) and higher s-EASIX score ([OR] = 1.35, 95% CI 1.08-1.67; p= 0.0067) increased the risk of developing grade 3+ ICANS. No survival impact (OS and PFS) was detected for pts who experimented any grade or grade 3+ of ICANS or CRS (Figure 1). Importantly, cumulative dose and duration of tocilizumab or corticosteroids were not significantly associated with adverse PFS or OS. Image:Summary/Conclusion: In this large study, robust biological and clinical predictive factors of CRS and ICANS were identified. A propensity-score matched comparison of axi-cel and tisa-cel for toxicities will be performed for the EHA congress. Neither grade 3+ CRS, ICANS, nor Tocilizumab or corticosteroids use for CAR-T toxicity had negative impact on survival.