bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results of a first-in-human study on ESG206, a novel anti-BAFF-R monoclonal antibody, in relapsed or refractory B-cell malignancies.
Authors: Song Yuqin , Lin Ningjing , Liu Hui , Zhou Qing , Xing Xiaoyan
Published: June 2024

e19000

Background: B-cell-Activating Factor-Receptor (BAFF-R), predominantly expressed on the surface of the mature B cells, including malignant B cells, serves as an attractive therapeutic target for the diseases where CD19 or CD20-targeted therapies encounter challenges, such as loss of therapeutic targets or development of resistance. No BAFF-R targeting agent has been approved yet for clinical use to date. ESG206, a recombinant humanized anti-BAFF-R monoclonal antibody modified by glycoengineering for enhanced ADCC effects, is being developed as a treatment for relapsed or refractory (R/R) B-cell malignancies. Preclinical investigations have successfully validated the antitumor effects of ESG206 across a spectrum of malignant B cell disease models, including lymphoma xenografts which were resistant to Rituximab, and Ibrutinib. This report provides preliminary clinical safety, PK, PD, and efficacy results from an FIH study of ESG206 in patients with R/R B-cell malignancies. Methods: This Phase I, open-label, multicenter dose-escalation study enrolled patients with R/R B-cell malignancies resistant to standard therapy. Dose escalation utilized accelerated titration (1 mg/kg) and Bayesian Optimal Interval design (3, 6, and 9 mg/kg). ESG206 was administered intravenously every 2 weeks, with a 4-week cycle, until disease progression or intolerable toxicity. DLT was assessed in the first 28 days. Safety was evaluated per CTCAE 5.0. Tumor assessments every 8 weeks, and peripheral CD20-positive B cell counts as a PD marker were evaluated. Results: As of Jan 30th, 2024, data cut-off date, 6 pts (3 follicular lymphoma (FL), 3 diffuse large B-cell lymphoma (DLBCL)) were enrolled, with a median age of 56 years, 83.3% female; median 2 prior lines of therapy (range 1-3). No DLTs were observed up to 6 mg/kg Q2W. Treatment-related adverse events (TRAEs) included anemia (n=2), decreased white blood cell count (n=1), hyperlipidemia (n=1, grade 2), elevated bilirubin (n=1), diarrhea (n=1), infusion reactions (n=1, grade 2), upper respiratory infections (n=1, grade 2), etc. No grade≥3 TRAEs occurred. Among 6 evaluable patients, 1 FL patient (3 mg/kg Q2W) and 1 DLBCL patient (3 mg/kg Q2W) achieved partial response. After 2 cycles of treatment, there was a 39.5% size reduction in the brain lesions of an FL patient who had intracranial metastases in baseline, suggesting that ESG206 may have a therapeutic effect on brain metastases. A significant decrease in the peripheral CD20+B cells was observed at both 1 and 3 mg/kg Q2W dose levels. ESG206 exposure increased with dose escalation across the 1–3 mg/kg dose range. Conclusions: Preliminary data indicates ESG206 is well-tolerated with promising efficacy signals in R/R B-cell malignancies. These encouraging results warrant continued clinical evaluation as the Phase I study progresses. Clinical trial information: NCT05263739 .
Outcome of patients with primary CNS lymphoma treated with methotrexate based regimens: A retrospective study.
Authors: Teklie Yeshanew , Myint Zaw Win , Ranganathan Raghuveer , Poei Darin , Parker Graham Blake , Ye Shirley
Published: June 2024

e19051

Background: Primary central Nervous system Lymphoma is an aggressive Non-Hodgkins Lymphoma with 5-year survival of only 30 percent. Few studies have addressed the comparison of induction treatment regimens with various risk stratification groups with no consensus on the optimal methotrexate dose for best complete overall response and survival outcome. Our retrospective study compares induction treatment regimens, identifies different risk stratification factors, and provides insight into the best induction treatment regimen with determination of optimal methotrexate dose. Methods: Design: Retrospective Primary Outcomes: Complete response rate, overall survival rate with risk stratification based on histology, Ki-67, and initial albumin level. Results: 77 patients 18 years of age and older with PCNSL at NCC and LAC between June 2015 and July 2022 were included in the study. Overall, 50% of patients were treated with CALGB50202 induction regimen,19% with R-MPV,12 % with De-Angelis regimen. CALGB 50202 has the highest survival rate of 63.4% followed by R-MPV with 22% survival rate followed by De-Angelis regimen with 0% survival rate with chi-square test P-value < 0.001 during the study period. Similarly, CALGB 50202 has the highest CR rate of 61.9% followed by R-MPV with CR rate of 16% followed by De-Angelis regimen with the lowest CR rate of 2.4%.CR rate comparison is statistically significant with P-value of < 0.0001. The study assessed optimum methotrexate dose. The mean and median total methotrexate dose in patients who were alive during the study period was 74.3 grams and 81.7 grams respectively as compared to mean value of 34.2 grams and median of 19.3 grams in patients who died with a p-value of 0.0019.Comparing survival based on histology as germinal center versus non-germinal center PCNSL, the later has higher mortality rate of 64.7 % as compared to 11.8 % in patient with germinal center PCNSL.Ki-67 was assessed as >80% and <80%.Among patients who were alive during the study period,48.8% have Ki-67 > 80% as compared to only 12.2%.On the other hand, among the patients who died,47.1% of patients have Ki-67 <80%,indicating lower ki-67 associated a lower survival outcome as depicted on the Kaplan Meier curve with P-value of 0.004. Patients with normal initial albumin have a higher chance of survival (78%) vs 22% in the group with low albumin level with p-value of 0.0005. Conclusions: CALGB 50202 had the highest CR and survival rates followed by R-MPV regimen in patients with primary CNS lymphoma. The total dose of methotrexate patient receives was an important factor for survival and CR and the optimal total methotrexate dose was 70-80 grams. Normal initial albumin, high Ki-67, and germinal center histology favored better survival.
Clinical observation study of recombinant human thrombopoietin in the prevention of chemotherapy-induced thrombocytopenia in patients with aggressive lymphoma.
Authors: Yang Lei , Wang Ting , Li Zhenling , Deng Qi , Yang Wei , Zhou Hebing , Jing Hongmei , Sun Changyong , Wang Liru , Bao Li , Ye Fang , Bai Jie , Si Lu , Wang Jingwen , Liu Hui
Published: June 2024

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.
Clinical features and outcomes of patients with follicular lymphoma grade 3A: A real-world study in single center.
Authors: Ye Xingnong , Yu Wenjuan , Wei Juying , Tong Hongyan , Jin Jie
Published: June 2024

e19058

Background: Follicular lymphoma (FL) was classified into three grades based on the number of centroblasts (FL1-2, FL3A, and FL3B). Guidelines suggest that FL1-2 should be treated according to the treatment recommendations for classical FL. FL3B is usually treated as diffuse large B-cell lymphoma (DLBCL).There is no consensus yet on the management of FL3A. In order to explore the relationship between clinical features and outcomes of FL3A, we conducted this study. Methods: We conducted a retrospective study of newly diagnosed FL patients who were admitted to our hospital from January 2013 to December 2022. The data were collected from the hospital electronic medical record system, including but not limited to: demographic characteristics, pathological information, clinical features at diagnosis, treatment, and efficacy evaluation. The survival curve was calculated through Kaplan-Meier method and compared with Log Rank test.The prognostic factors of PFS was compared by COX regression analysis. Results: There were 253 FL3A patients admitted, accounting for 27.55% of all FL patients. After screening, a total of 223 FL3A patients were included in this study. Among 223 patients, the male to female ratio was close to 1:1; The median age is 57 years old. At diagnosed, 33 patients in early stage and 190 in advanced stage. Among advanced patients, 144 had no treatment indications according to the GELF criteria. 86.1% (192/223) of patients received systemic treatment, with the majority of rituximab contained regimens. The overall response rate (ORR) was 96%, and 62.9% of patients who responded to chemotherapy received maintenance therapy with CD20 monoclonal antibody. A median follow-up of 41 months, with an estimated 5-year OS of 91.3% and 5-year PFS of 73%. The PFS of advanced FL patients treated with RCHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was significantly longer than that of non-RCHOP regimen patients (P<0.05). The PFS of patients receiving maintenance treatment was better than that of those not (P<0.05). Conduct prognostic analysis on advanced FL3A patients. Univariate analysis showed that treatment plan selection, maintenance of treatment, PET scan of FDG metabolic maximum uptake value (SUVmax), Ki-67, lactate dehydrogenase (LDH), white blood cell count (WBC), IgA, IgM, all significantly affected PFS; Multivariate analysis shows SUVmax ≥ 15 and platelet count<100 × 109/L and LDH>210U/L are all correlated with poor PFS. Conclusions: This study found that FL3A accounts for 27.55% of all FLs, with a median age of 57 years old and mostly in the advanced stage. FL3A has a long survival period, with a 5-year PFS of 73%. COX regression analysis showed that SUVmax, platelet count, and LDH were all associated with PFS in advanced FL3A patients.Those may explore new clinical prognosis prediction models.
Quantitative systems pharmacology (QSP) model to predict combination activity of CD19-targeted antibody drug conjugate (loncastuximab tesirine) co-dosed with a CD20/CD3 T-cell bispecific (epcoritamab) in patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Boni Joseph P. , Li Yuezhe , Wilkins A. Katharina , Davis Jimena , Knab Tim
Published: June 2024

e19059

Background: Loncastuximab tesirine-lpy (Lonca) is an antibody-drug conjugate comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin. Epcoritamab-bysp (Epco) is a CD20×CD3 T cell-engaging bispecific antibody (bsAb) that redirects T-cells to eliminate malignant B-cells. Epco and Lonca target different B-cell surface antigens and combining both is expected to have additive or synergistic efficacy. Previously, a novel QSP model for Lonca was developed (Utsey K et al. Clin Pharmacol Drug Dev. 2023;12:123-125) and validated with clinical data from patients with R/R DLBCL (Caimi P et al. Blood. 2022;140:9548-9550). A combination QSP model for Lonca with Epco in R/R DLBCL was described to predict potential anti-tumor synergies in proposed clinical trials. Methods: The model reduced previous Lonca model complexity while maintaining core functionality and was combined with a published QSP model for T-cell bsAbs (Hosseini I et al. Npj Syst Bio Appl. 2020;6(1):1-11) to predict tumor dynamics after Lonca and/or Epco treatment. Assumptions included: 1) Lonca or Epco induce healthy and malignant B-cell killing; 2) tumor comprises malignant B- & T-cells; 3) tumor volume is based on malignant B-cell count; 4) T-cells can enter or leave tumor as with other tissues; 5) CD19-/low CD20+ B-cells account for tumor heterogeneity from cells insensitive to Lonca treatment. Results: Tumor growth inhibition (TGI) was predicted to plateau by Cycle (C) 2 with Epco monotherapy. By end of C3, however, predicted median normalized tumor volume reduction with co-dosing Lonca and Epco was approximately 1 log order greater than Epco alone. Maximum activity of Lonca and Epco therapy was not observed until C4 or later as depth of tumor regression increased with additional treatment cycles. Since patients with DLBCL may present with low T-cell counts (Hutchings et al. Lancet. 2021) the effect of T-cell count at baseline was evaluated. A 50% decrease at baseline from 2000-1000 T-cells/µL significantly reduced antitumor effect with Epco alone but made no difference with Lonca in combination. Conclusions: These results resemble predictions for Lonca in combination with other bsAbs (Lonca plus mosunetuzumab or glofitamab; abstract submitted to AACR 2024). By end of C3, Lonca plus Epco was predicted to promote substantially more TGI than Epco or Lonca alone. While increased doses of Lonca from 90-150 µg/kg in combination had limited additional therapeutic benefit, combination treatment beyond C3 was predicted to increase depth of tumor regression. Response from Lonca and Epco co-dosing was predicted to be less affected by suppressed T-cell counts at baseline compared to Epco alone; a feature that may enhance responsiveness when T-cell level is moderate.
Effect of AVM0703 treatment on the limitations of R-CHOP and survival in a model applicable to ABC subtype DLBCL.
Authors: Deisher Theresa , Mittal Sandeep , Sawas Spencer , Michiels McKenzie , Jarzyna Peter
Published: June 2024

e19060

Background: The current treatment regimen for DLBCL consisting of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (RCHOP), is challenged by molecular and prognostic characterization of DLBCL. Activated B-cell (ABC) lymphoma has a significantly worse prognosis (5 yr OS rate: 45% - 56%) than germinal center B-cell (GCB) lymphoma (78% - 80%) after RCHOP treatment. Around 40% of patients ultimately relapse and/or develop primary refractory disease, cardiotoxicity and long-term secondary malignancies. Efforts are being made to improve the RCHOP backbone by including dose intensification and by the addition of new agents to increase the efficacy and reduced toxicity of RCHOP (McKelvey EM Cancer 1976; Wilson WH Blood 2002; Molina TJ JCO 2014; Coiffier B Hematology 2016). AVM0703, an immunomodulatory drug, mobilizes bispecific γδ and inv-TCR double-positive novel T and NKT cells. In a previous study employing an aggressive, immune resistant A20 mouse lymphoma model (Bascuas T J Transl Med. 2016), neoadjuvant AVM0703 was additive/synergistic, when cyclophosphamide/fludarabine (CyFlu) was dosed 3 and 24 hr later, with no additional toxicities. In the present study we combined AVM0703 with RCHOP to evaluate the efficacy in A20 mice model. Methods: 10 week old Balb/c mice were injected with 2x106 murine A20 B-cells in the flank and were randomized (1:1 male: female) into 1) Placebo 2) 3 cycles RCHOP 3) 3 cycles AVM0703 (18mg/kg HED) 4) 3 cycles AVM0703+RCHOP, when tumor size reached ~100 mm3. Mice who achieved complete remission (CR) were re-challenged at 21-25 wks later. Pre and post re-challenge, presence of memory cells was analyzed using flow cytometer. All mice were monitored continuously as per the IACUC protocol. Results: Mice treated with the combination of AVM0703+RCHOP achieved superior CR compared to RCHOP alone, which was not curative in any mice. In first phase of the study, 3 out of 11 AVM0703 +RCHOP treated mice showed CR after only 1-cycle. In second phase, 2 of 12 mice survived in CR for >150 days after 3 cycles, whereas no RCHOP mice survived beyond 2 cycles. AVM0703+RCHOP treated mice in long-term CR, had memory cells (CD44hi-Cd62low) pre- and post re-challenge, and no A20 engraftment, suggesting strong immunological memory induced by AVM0703+RCHOP. Conclusions: AVM+RCHOP demonstrated anti-tumor activity in A20 lymphoma mice, with reduced toxicity, compared to RCHOP. Larger preclinical studies are underway to confirm the activity of AVM0703+RCHOP against RCHOP resistant ABC DLBCL, and the potential to reduce total RCHOP exposure to only 3 cycles while maintaining or improving efficacy. [Table: see text]
Demographic and survival data of patients with primary diffuse large B-cell lymphoma of the head and neck: A single center experience.
Authors: Kidi Mehmet Mutlu , Biter Sedat , Aydinalp Camadan Yasemin , Yaslikaya Sendag , Koseci Tolga , Bayram Ertugrul , Disel Umut , Sahin Berksoy , Kara Ismail Oguz
Published: June 2024

e19069

Background: Head and neck malignancies account for around 10% of lymphomas, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histologic subtype. Head and neck lymphoma is as the second most pervasive location for extra-nodal lymphoma, following the gastrointestinal system. This study focused on examining the demographic characteristics, main localization distribution, and survival rate of patients with head and neck lymphoma at the Çukurova University Medical Oncology Clinic. Methods: We conducted a retrospective analysis of 97 individuals diagnosed with single-center, head, and neck diffuse large B-cell lymphoma (DLBCL) from 2011 to 2020. Data pertaining to patients was acquired from electronic medical records. The patients were categorized based on anatomical localization, and survival rates and survival data were computed for each primary localization. Results: Out of the total number of patients, 48 (49.5%) were female, and 49 (50.5%) were male. The patients had a median age of 59.5 years. Waldeyer's ring was the most frequent site of primary head and neck tumor localization in patients with DLBCL, accounting for 42.4% of cases. The distribution of anatomical sites was as follows: nasopharynx accounted for 30.8%, nasal cavity accounted for 10.3%, thyroid accounted for 6.2%, parotid accounted for 5.2%, oral cavity accounted for 3.9%, and other anatomical sites accounted for 1.2%. Based on the Ann Arbor staging approach, 65% of the patients were classified as stage I-II. The 3-year survival rate was 71%, while the 5-year survival rate was 61%. The overall survival of individuals with nasopharyngeal lymphoma was considerably shorter when compared to those with non-nasopharyngeal lymphomas (p=0.0372). Conclusions: We conducted a thorough analysis of the data pertaining to lymphomas characterized by diffuse large B-cell lymphoma (DLBCL) occurring in the head and neck region. The study found that when the nasopharynx is affected, it is linked to a worse prognosis and may necessitate more intensive treatment. Our work is a retrospective study conducted at a single center. However, future investigations with a more significant number of participants and a prospective design is necessary.
An institutional experience of a rare diagnosis of subcutaneous panniculitis-like T-cell lymphoma.
Authors: Fort Callie , Raina Rohit , Surapaneni Rakesh
Published: June 2024

e19073

Background: Subcutaneous Panniculitis-like T-cell lymphoma (SPTCL) is a rare diagnosis making up < 1% of Non-Hodgkin lymphomas. Data from Surveillance Epidemiology and End Results (SEER) identified a total of 204 cases from 2000-2020. Clinically, SPTCL presents as subcutaneous nodules and is difficult to distinguish from other more common conditions such as lupus erythematosus panniculitis. Most of our understanding on presentation, diagnosis and treatment on SPTCL is limited to small case series. Methods: Following IRB approval, a multi-center retrospective clinical and pathological review identified patients diagnosed with SPTCL from 1/1/2013-10/24/23. The study was conducted at Baylor Scott & White system (CTX). Inclusion criteria included ≥ 18 years old, SPTCL AB sub-type. Patients were seen for > 2 visits during time of active treatment. Cases of SPTCL y8 sub-type were excluded from the study. A descriptive analysis of the clinical presentation, treatment choice/duration, and clinical outcomes was generated. Results: A total of 5 patients met criteria for inclusion during the previously defined time period. The median age at diagnosis was 39 with a median follow up of 6 years. Patients presented with multiple nodular lesions affecting the chest, trunk, axilla, arms, and legs. Sixty percent of patients received misdiagnosis and experienced delay in appropriate treatment with a maximum delay of 10 years. Histopathology showed panniculitis-like lymphoid infiltrate composed predominantly of T lymphocytes, with areas of adipocyte rimming and a background of fat necrosis. No patients developed hemophagocytic syndrome. Patients were treated with steroids alone or in combination with cyclosporine, methotrexate, and/or romdespin. Sixty percent of patients achieved a complete response, and 40% remain in remission. The 5-year disease specific survival rate was 100%. Conclusions: SPTCL showed an indolent course in the patient population studied. All patients treated with systemic steroids as first line therapy responded favorably. When tolerated cyclosporine and methotrexate controlled disease in patients that showed progression following the completion of steroid taper.
Outcomes of ide-cel in patients with relapsed/refractory multiple myeloma: A single-institution experience.
Authors: Trando Aaron , Ghamsari Farid , Yeung Philip , Costello Caitlin , Saunders Ila M. , Jeong Ah-Reum
Published: June 2024

e19500

Background: Idecabtagene vicleucel (ide-cel) is a novel CAR T-cell therapy that targets B-cell maturation antigen (BCMA). This single-center retrospective study reports the real-world clinical outcomes of ide-cel therapy in patients with relapsed/refractory multiple myeloma (RRMM) with the additional goal of investigating host predictive factors for therapy performance. Methods: We conducted a retrospective review of adult patients with RRMM who received ide-cel between 2021 and 2023 at University of California San Diego Health and had at least six months of follow-up data available. Data on baseline characteristics, efficacy responses, and adverse reactions (including CRS and ICANS grading per ASTCT) were obtained. Treatment responses were recorded according to the International Myeloma Working Group criteria. Survival analyses were based on Kaplan-Meier and Cox proportional hazards methods. Results: A total of 25 patients with RRMM were included. The median age was 65 (range, 50-79). 48% of patients were male. Patients received a median of six lines of prior therapy with 12% of patients receiving prior BCMA-targeted therapy. Six patients (24%) had confirmed high-risk cytogenetics while twelve patients (48%) had extramedullary disease. The median follow-up was 11.4 months. The objective response rate was 84%; sCR was seen in 56% of patients, VGPR in 16%, PR in 12%, and PD in 16%. Four patients in sCR have since relapsed. Five deaths were observed (20%), all due to progressive disease. Median PFS for the cohort was 13.9 months (95% CI, 9.21 – NR); among responders, PFS was 20.6 months (95% CI, 11.9 – NR). Median OS was NR (95% CI, 19.3 month – NR). The respective PFS and OS at 12 months was 57% (95% CI, 37% – 86%) and 83% (95% CI, 69% – 100%). Of 11 patients who had relapsed/refractory disease to ide-cel, six were alive at time of last follow-up; three are responding to teclistamab, two to talquetamab, and one to radiation. The incidence of CRS and ICANS was 92% (grade 3-4: 4%) and 12% (grade 3-4: 8%), respectively. Univariate and multivariate analysis did not reveal any significant predictive markers of superior PFS or OS, including age, ECOG, mSMART classification, high-risk cytogenetics, extramedullary disease, median number of lines of prior therapy, prior BCMA-targeted therapy, and triple/penta-class refractory disease. Conclusions: Despite our patients having a high median number of prior lines of therapy, our response and toxicity rates were similar to the findings in the current literature, including those observed in the landmark KarMMa-1 trial. We did not find any significant predictive factors of PFS or OS with the caveat of a small sample size. Further research remains necessary to identify potential predictors that may discriminate responders from non-responders, which will improve the application of CAR T-cell therapy in patients with RRMM.
Analysis of real-world (RW) pomalidomide (pom) dosing patterns in patients (pts) with multiple myeloma (MM) from the Flatiron database.
Authors: Dhakal Binod , Godara Amandeep , Medvedova Eva , Naik Seema , Nooka Ajay K. , Parekh Trilok V. , Hadley David , Kansagra Ankit J. , Anderson, Jr Larry D.
Published: June 2024

e19508

Background: Pom is an immunomodulatory drug commonly used in combination with other antimyeloma therapies for the treatment (tx) of pts with MM. However, there is a paucity of data on RW dosing patterns with pom and associated tx outcomes. We report RW pom dosing patterns and effectiveness using RW data to inform potential pom dosing strategies as part of combination tx regimens. Methods: RW pom data in pts with MM were derived from the US Flatiron Health deidentified electronic health record (EHR) database (Jan 2011–Nov 2021). Pom starting dose (1, 2, 3, or 4 mg) and line of therapy (LOT) were identified from EHRs. Tx patterns were captured per LOT; pts could receive >1 pom-containing tx regimen/LOT. Pts receiving pom were followed until Dec 2023 for outcome analysis. Overall survival (OS) and time to next tx (TTNT) were estimated using the Kaplan-Meier method and analyzed by log-rank testing. Results: Of 15,378 pts with MM, 2,034 had an order for pom, of whom 1,344 received pom and 880 had LOT data. The most common initial pom dose was 4 mg (50%), followed by 2 mg (30%), 3 mg (16%), and 1 mg (4%). The most common pom-containing tx regimens were: daratumumab + pom + dexamethasone (d; 29%), pom + d (18%), and carfilzomib + pom + d (14%); 6% of pts received pom monotherapy. Retreatment with pom was infrequent, with 84% of pts receiving only 1 pom-containing LOT. Most pts (n=652, 74%) remained on the initial pom dose received; of these, 367 pts remained on an initial dose of 4 mg. Among pts who changed dose (n=227, 26%), 36% changed from 2 mg and 36% changed from 4 mg. Of pts who received an initial dose of 4 mg and changed dose (n=81), 43%, 51%, and 6% reduced to 3, 2, and 1 mg, respectively. Of pts who received an initial dose of 2 mg and changed dose (n=82), 17% reduced to 1 mg. Among pts who received an initial dose of <4 mg and changed dose, dose escalation was common (67% of pts with a 3 mg initial dose increased to 4 mg; 33% and 50% of pts with a 2 mg initial dose increased to 3 and 4 mg, respectively). Outcome analysis of pts with LOT and available follow-up data suggest that initial pom dose had no impact on OS and TTNT (Table). Log-rank analysis of OS and TTNT between the initial doses of 2 and 4 mg showed no significant difference among all pts ( P=0.32) or in pts who changed dose ( P=0.29). Conclusions: RW analyses show that most pts remain on the initial pom dose received, but some pts changed doses. Pom, most commonly used in combination regimens, can be used across an initial dose range with no impact on efficacy in pts with MM. Optimal pom dosing may vary across pts and combination regimens; pom dosing should be tailored to pt needs per disease and tx factors. [Table: see text]
Survival shifts in multiple myeloma: Evaluating the impact of therapeutic advances and racial disparities after a decade of change.
Authors: Hebishy Ahmed , Zweigle Joshua Walter , Hussain Ali , Muzaffar Mahvish
Published: June 2024

e19509

Background: Multiple myeloma (MM) is the second most common hematologic malignancy and is considered an incurable disease. However, the last two decades have witnessed the emergence of new therapies that have improved overall survival by several folds. In the current study, we are examining the evolving trends in age-adjusted incidence and relative survival among myeloma patients over the last 20 years, specifically focusing on discerning disparities in these trends based on racial classifications. Methods: We performed a retrospective cohort study using the SEER Plus Data, 12 registries, Nov 2022 Sub (1992-2020) to calculate the age-adjusted incidence and relative survival rate (RSR) of MM in the US in two specific time intervals 2001-2010 & 2011-2020 consistent with changes in MM treatment during 2011-2020 including the emergence of immunomodulatory drugs (IMiDs). The year of diagnosis, sex, and race data were available for each case. We excluded cases diagnosed before 2001 and after 2020. Patients were stratified by sex and categorized into two racial groups: White and Black. The 60-month (5-year) and 116-month (used as a 10-year estimate) RSR and age-adjusted incidence rate were calculated for the cohort and each racial group. We calculated survival utilizing the Kaplan-Meier method. Using the log-rank test, we also found hazard ratios (HR), with the corresponding CI for each racial group stratified by sex. Results: We investigated MM incidence and survival rate trends over two decades while considering gender and race. The age-adjusted incidence rate showed a significant overall increase from 6.5 to 7.4 per 100,000, with changes in gender-specific rates. Higher incidence rates among Black populations were noted. Cohort relative survival analysis revealed improved median survival (53 to 83 months) and increased relative survival rate both at five years (46.4% to 56.3%) and at ten years (28.8% to 40.8%). An investigation based on race revealed substantial improvements among both White and Black populations. The HR (Table) emphasized the improved survival outcomes for patients diagnosed in period two across genders and races. Conclusions: The study highlights the changes in the incidence and survival rates of MM. Notably, MM incidence has seen a significant rise in the last decade, particularly among the Black population. The survival of patients diagnosed between 2011 and 2020 revealed statistically significant improvement at both the 5- and 10-year mark compared to patients diagnosed between 2001 and 2010. [Table: see text]
Incidence of thromboses and secondary cancers in patients with multiple myeloma after lenalidomide-based induction followed by maintenance as first-line therapy: A systematic review and meta-analysis.
Authors: Mahadevia Himil , Gaur Rishabh , Shaddarsanam Phanisri , Gutta Neha , Wang Xi , Cheng An-Lin , Shrestha Anuj
Published: June 2024

e19510

Background: Lenalidomide, an immunomodulatory drug (IMiD) is one of the backbones of standard first-line induction regimen for multiple myeloma (MM). Lenalidomide maintenance is associated with improved progression-free survival, especially after bone marrow transplantation. The optimal duration of maintenance therapy is unknown. In our study, we evaluated the incidence of any thrombosis, venous thrombosis (VTh) and arterial thrombosis (ATh) as well as any secondary cancers, secondary solid and hematologic cancers in patients with MM who received lenalidomide-based first-line induction followed by lenalidomide maintenance for at least 6 months. Methods: This systematic review identified pertinent clinical trials from MEDLINE, Embase, and CENTRAL databases from inception to December 31, 2023. After two rounds of review by 4 authors independently, 25 clinical trials in patients with MM met the above eligibility criteria. The number of cases with any thrombosis, VTh, ATh, any secondary cancers, secondary solid and hematologic cancers along with the total number of patients in the arms with lenalidomide-based therapy were extracted from each trial. The incidence meta-analysis was performed using the “meta” package version 6.2-0 of R version 4.2.2 via a random-effects model. Pooled incidence and its associated 95% confidence interval (CI) were reported for each outcome. I² statistic was used to determine the heterogeneity of the studies. Results: 10743 patients were reviewed from 25 clinical trials. The pooled incidence rate of any thrombosis was 4% (0.04; 95% CI: 0.03 to 0.06, I2=91%). The pooled incidence rate of arterial thrombosis and venous thrombosis was 1% (0.01; 95% CI: 0.00 to 0.02, I2=77%) and 4% (0.04; 95% CI: 0.02-0.09, I2=94%) respectively. The pooled incidence rate of any secondary cancer was 5% (0.05; 95% CI, 0.04 to 0.07, I2=93%). The pooled incidence rate of secondary hematological malignancies was 2% (0.02; 95% CI, 0.01 to 0.03, I2=90%) and secondary solid cancers was 4% (0.04; 95% CI, 0.03 to 0.06, I2=76%). Conclusions: IMiDs are one of the backbones of the MM regimen. Our meta-analysis showed lenalidomide-based regimen increased the risk for thromboses – higher for VTh (4%) and slightly higher for ATh (1%). It also showed a higher rate of secondary cancers – both solid (4%) and hematologic cancers (2%). However, our study showed considerable heterogeneity. These events become clinically important as patients with MM live longer. MM patients on lenalidomide maintenance could benefit from an active surveillance, monitoring and early treatment program for these long-term adverse effects. VTh prophylaxis based on the type of regimen is already standard. Secondary cancer surveillance may need to be individualized for MM patients in remission.
Association of posterior reversible encephalopathy syndrome with proteasome inhibitors approved for multiple myeloma: Analysis of FAERS database.
Authors: Singh Harkarandeep , Kaur Uttamjot , Neupane Niraj , Kharel Himal , Saeed Hassan , Gill Prabhsimrat , Shrestha Asis
Published: June 2024

e19515

Background: Proteasome inhibitors (PI) are a class of drugs that are used in the treatment of Multiple Myeloma. There are currently three PIs (Bortezomib, Carfilzomib, and Ixazomib) approved by FDA for this indication. Peripheral neuropathy has been described as one of their most common side effects but the association with another life-threatening neurological disorder, Posterior Reversible Encephalopathy Syndrome (PRES), remains poorly understood. Methods: We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System database to analyze the risk of PRES associated with various Proteasome Inhibitors. We employed disproportionality signal analysis and calculated the reporting odds ratio with a 95% confidence interval. Results: A total of 79,450 adverse events were found within the FAERS database that were associated with the three FDA approved PIs. PRES accounted for 274 cases, of which 165 cases were in females and 71 cases in males. Majority of patients were adults, with 119 cases between 18-64 years of age, 88 cases above 65 years, and 50 cases with age not specified. Death was reported in 70 cases while 74 cases were marked as having life threatening illness, and 152 cases needed hospitalization. Bortezomib accounted for most cases (202 cases, ROR 6.03, 95% CI 5.3-7.1), followed by Carfilzomib (68 cases, ROR 7.2, 95% CI 5.7-9.1), and Ixazomib (9 cases, ROR 0.99, 95% CI 0.5-1.7). Conclusions: The study helps to shed light on the incidence, and hospital outcomes of PRES associated with various proteasome inhibitors. Significant safety signals were found for Bortezomib, and Carfilzomib. Females were almost 2.5 times more likely to develop PRES compared to males. These findings highlight the importance of keeping a high index of suspicion for PRES while evaluating patients on PIs who present with concerning neurological symptoms.
Improving clinical outcomes in multiple myeloma: Weight maintenance strategies to reduce complications during autologous hematopoietic transplantation.
Authors: Shah Anvay , Bradshaw Danielle , Shah Vishrut , Dalgetty Mark , Athota Sruthi , Boghani Faizan , Stokes Michael , Branham Zachery , Mian Mohammad , Keruakous Amany R. , Chauhan Ayushi , Cortes Jorge E. , Bryan Locke Johnson , Jillella Anand P. , Kota Vamsi
Published: June 2024

e19533

Background: Multiple myeloma (MM) is the second most prevalent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for younger patients has dramatically changed treatment outcomes. Monitoring daily weights has been well documented in Acute promyelocytic leukemia (APL) induction, though little has been documented in myeloma patients receiving ASCT. Monitoring daily weights can be a useful tool in maintaining patients' euvolemic status and can help to facilitate appropriate resuscitation of patients who are otherwise prone to sepsis and fluid overload. At our center over the last few years, we have standardized an approach to monitoring and maintaining the weights of MM patients at or near their pre-admission level with fluids and diuresis, as needed. We report outcomes of weight monitoring on morbidity and mortality during ASCT for MM. Methods: We conducted a retrospective chart review of MM patients receiving ASCT at our center between January 2019 and December 2022. Patients whose weights were monitored and maintained within 3 kilograms of admission weight were identified. We looked at the length of stay (LOS) and ICU transfers during this time. We reviewed the records of 205 patients induced at our center. Results: The mean age was 62 years at the time of transplant (34-78). 119 of the 205 patients identified as men (58%). Out of 205 patients, 152 patients did not have their weights maintained. Of these 152 patients, 7 were transferred to ICU. 53 patients had weights maintained, of which 1 patient was transferred to ICU (OR 0.089 (95% CI 0.018-0.6725) (p = 0.019)). The mean LOS for all patients was 12.97 days. Mean LOS was 12.41(n = 53) and 13.18(n = 152) days for patients whose weights were and were not followed, respectively (mean difference of 0.77 days) (95 % CI of -0.15 to 1.68) (p = 0.0992). 3 of the 205 patients died during admission. In these patients, weights were not maintained before ICU transfer. (OR = 0.4072 (0.0207-8.0136) (p = 0.55)). Conclusions: Fluid overload and sepsis are significant concerns in the treatment of MM. Our findings suggest that maintaining euvolemia can effectively manage patients on the floor and limit and in some cases prevent ICU transfers. Although there are limitations to our study due to its retrospective, single-center nature, the cost-effectiveness and noninvasive means of maintaining euvolemic status support its potential application to standard treatment protocols. Further prospective studies are warranted to validate these findings. [Table: see text]
Survival outcomes in patients with primary plasma cell leukemia treated with novel therapies at University of California San Diego Health: A single institution experience.
Authors: Ghamsari Farid , Trando Aaron , Jeong Ah-Reum , Saunders Ila M.
Published: June 2024

e19538

Background: Plasma Cell Leukemia (PCL) is a rare, but aggressive and devastating disease for which there is a paucity of data regarding the efficacy and safety of modern therapies to guide management. Data prior to the use of modern therapies showed abysmal overall survival (OS) of approximately 4-12 months. There is generally agreement that novel therapies have improved outcomes, but data supporting this is sparse due to the rarity of the disease. As such, there is currently no standard of care agreed upon by experts, and the specific approach for treatment currently varies by provider. Methods: In this single-center retrospective study, we review the outcomes of patients diagnosed with primary plasma cell leukemia (pPCL) from 2008 to 2023 who received at least one of the novel therapies of immunomodulatory drugs (IMiD), protease inhibitors (PI), and/or anti-CD38 antibodies at University of California San Diego Health. Baseline characteristics and efficacy outcomes were collected. Results: A total of 11 patients were identified who met the inclusion criteria. The median age at time of diagnosis was 50. The median circulating plasma cells at diagnosis was 34%. All but 2 patients had > 20% circulating plasma cells. The remaining two had circulating plasma cells of 10% and 14% meeting the newly re-worked definition of plasma cell leukemia. One patient had a single extramedullary plasmacytoma at the time of diagnosis. High risk cytogenetics, defined as having t(4;14), t(14;16), t(14;20), Del17p, Gain1q, were characterized for all patients. 4 had one high risk mutation, 3 had two mutations. Only one patient’s first line did not include any of the novel therapies. 81% of patients’ first line of therapy included a form of cytotoxic chemotherapy (of which 55% of those were cisplatin, doxorubicin, cyclophosphamide, etoposide (PACE)). The most common first line of therapy was bortezomib (V), dexamethasone (D), PACE, +/- thalidomide (T) or lenalidomide (R), and +/- stem cell transplant (SCT). The other 19% of first line therapies contained exclusively novel therapies; namely VTD and daratumamab-RVD. Seven patients underwent SCT. One patient who underwent allogeneic transplant as part of their first line therapy has not yet relapsed 5 years post-transplant. Median OS was 28.8 months (95% CI 17.3 –not reached (NR)). First progression free survival (PFS) was 5.7 months (95% CI 2.3 – NR). For patients with available data, overall response rate (ORR) to 1st line of therapy was 60%. Conclusions: Our results demonstrate that the outcomes of patients with PCL have greatly improved with the use of novel therapies. The small sample size and heterogeneity of the treatments prohibited correlative statistical analysis. Prospective studies are needed to determine the best treatment option for this high-risk population which is excluded from most myeloma trials.
A phase 1 single-arm, open-label study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in patients (pts) with acute myeloid leukemia (AML) in complete response (CR) with measurable residual disease (MRD).
Authors: de la Fuente Burguera Adolfo , Cerchione Claudio , Scholl Sebastian , Middeke Jan Moritz , Nitika Nitika , Lane Maureen E , Zhao Wanying , Angelides Steven , Roemeling Reinhard von , Platzbecker Uwe
Published: June 2024

TPS6587

Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these 3 onco-proteins by emavusertib may address the unmet need for novel therapies in AML. Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses in pts with relapsed or refractory AML (Metzeler 2022). Azacitidine + venetoclax (aza+ven) is an approved therapy for newly diagnosed pts with AML, unfit for intensive chemotherapy. Pre-clinical studies have demonstrated that emavusertib in combination with aza+ven has synergistic and antileukemic effects. In the VIALE-A study, composite CR (CRc) (CR, CRh, or CRi) in the absence of MRD of <1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS) compared with AML pts who achieved CRc but were MRD+ (Pratz, 2022). Therefore, adding emavusertib to aza+ven in CR or CRh, MRD+ pts may convert MRD status without significant toxicity and become a potential new regimen in front-line therapy. Methods: This is a single-arm, open-label Phase 1 study of emavusertib in combination with first line aza+ven in AML pts ≥60 years of age who achieved CR or CRh with MRD+ status based on local testing. The primary objective is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include determining the MRD conversion rate, pharmacokinetics, DOR, and OS. The study will enroll approximately 24 pts at 5 to 10 sites globally. Pts will have received aza+ven as first line therapy and achieved CR or CRh after 1-6 cycles of aza+ven. If MRD status remains positive, emavusertib will be added to the existing aza+ven regimen. Key exclusion criteria include residual toxicities and significant comorbidities. In the first cohort, the starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. The duration of emavusertib treatment will extend to 14 and 21 days, in subsequent cohorts. The pts will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- after 6 cycles of treatment. Enrollment to cohort 1 began in December 2023. (EU CT Number 2023-505828-58). Clinical trial information: 2023-505828-58.