Multiple Lines Of Therapy Research Articles

Assessing outcomes for patients receiving chemotherapy in the intensive care unit.

190 Background: Despite the low in-hospital mortality rate (9%) for Intensive Care Unit (ICU) stays in the US, outcomes for patients with cancer undergoing chemotherapy in the ICU remains unclear. We aimed to assess survival in patients with cancer (liquid, solid tumor and allogeneic stem cell transplant (alloSCT) receiving chemotherapy at our institution and identify patient characteristics for enhanced chemotherapy stewardship. Methods: We analyzed pharmacy data for patients with confirmed malignancies who received chemotherapy while admitted to the ICU at our institution from 1/1/21 to 12/31/23, excluding non-cancer patients and those on home oral regimens. Primary endpoints included 14-day, 30-day, and 90-day survival. Secondary analyses examined survival differences by age, ECOG performance status, and treatment history. Survival differences among patient subtypes were evaluated using Z-tests. Results: We identified 74 unique patients who received chemotherapy for cancer. 54 had liquid tumors, 5 were post-alloSCT, and 15 had solid tumors. The 90-day survival rate was 47% overall: 46% for the liquid tumor group, 80% for the alloSCT group, and 40% for the solid tumor group. When further stratified by tumor type, higher 90-day survival was variable; see Table 1 for details). In patients with lung cancer, 90-day survival was worse for non-small cell lung cancer without tumor mutations (0%, n=2) than those with targetable mutations (50%, n=4) or small cell lung cancer (33%, n=3). An ECOG performance status of 3-4 showed poorer 90-day survival in liquid tumors (23%) compared to ECOG 1-2 (74%; 95% CI 0.26 , 0.76). Solid tumors showed no significant ECOG differences (50%, 40%). Treatment-naive status showed higher 90-day survival in liquid tumors (59%) compared to treatment-resistant tumors (18%; 95% CI 0.17, 0.65), but not in solid tumors (50%, 20%). Conclusions: Our findings suggest generally unfavorable 90-day outcomes for ICU chemotherapy patients, especially those aged over 75, with multiple therapy lines, or ECOG status 3-4. Survival rates varied significantly across tumor types. We are currently broadening our study to include all solid tumor cancer patients. While this is a limited sample, this underscores the need for careful chemotherapy stewardship and advanced care planning in ICU settings. 90-day survival of solid and liquid tumor patients receiving chemotherapy in the ICU by select cancer diagnoses. Cancer Diagnosis n 90-Day Survival (%) AML 20 45 DLBCL 16 33 APML 6 83 Multiple myeloma 5 60 Other liquid tumors 1 11 45 Lung cancer 9 44 Germ cell tumor 2 100 Hormone-sensitive breast cancer 1 100 Other solid tumors 2 3 0 1 T-cell lymphoma, ALL, CNS lymphoma, Castleman, MPN, and plasmablastic lymphoma. Note, patients with allogenic stem cell transplants not included. 2 Carcinoma of unknown primary, colon adenocarcinoma, multiple solid tumors.

Epstein-Barr virus-positive, primary cutaneous marginal zone lymphoma, with transformation: Case report and review of the literature.

We report a patient with EBV positive PCMZL with subsequent transformation to plasmablastic lymphoma and review the literature for transformed PCMZL to assess clinical and pathologic characteristics. In the case we describe, the patient presented with multifocal PCMZL, developed large B cell transformation with plasmacytic differentiation, followed by plasmablastic transformation (PBL), and ultimately died of disease progression despite multiple lines of therapy. Past history was significant for psoriatic arthritis (multiple prior lines of immunomodulatory therapy). The lymphomas and non-involved bone marrow share the same somatic DNMT3A and TET2 mutations, suggesting clonal relatedness and an association with clonal hematopoiesis (CH). Eighteen cases complied the cohort (seventeen cases from the literature and the case reported herein). Nearly half of the eighteen cases of PCMZL with transformation died of progressive disease (44%). Transformed cases were more commonly seen in patients with >2 sites at initial diagnosis. EBV was assessed in 5 patients, 3 were positive (all died of disease). Two patients with NGS studies demonstrated TET2 and DNMT3A mutations. Transformation of EBV positive PCMZL appears to be a poor prognostic indicator, with our reported case being the first well defined case transformed to PBL, suspected to arise from myeloid-CH.

A Systematic Review of Modeling Approaches to Evaluate Treatments for Relapsed Refractory Multiple Myeloma: Critical Review and Considerations for Future Health Economic Models.

Multiple myeloma is a rare incurable hematological cancer in which most patients relapse or become refractory to treatment. This systematic literature review aimed to critically review the existing economic models used in economic evaluations of systemic treatments for relapsed/refractory multiple myeloma and to summarize how the models addressed differences in the line of therapy and exposure to prior treatment. Following a pre-approved protocol, literature searches were conducted on 17 February, 2023, in relevant databases for models published since 2014. Additionally, key health technology assessment agency websites were manually searched for models published as part of submission dossiers since 2018. Reported information related to model conceptualization, structure, uncertainty, validation, and transparency were extracted into a pre-defined extraction sheet. In total, 49 models assessing a wide range of interventions across multiple lines of therapy were included. Only five models specific to heavily pre-treated patients and/or those who were refractory to multiple treatment classes were identified. Most models followed a conventional simple methodology, such as partitioned survival (n = 28) or Markov models (n = 9). All included models evaluated specific interventions rather than the whole treatment sequence. Where subsequent therapies were included in the model, these were generally only considered from a cost and resource use perspective. The models generally used overall and progression-free survival as model inputs, although data were often immature. Sensitivity analyses were frequently reported (n = 41) whereas validation was only considered in less than half (n = 19) of the models. Published economic models in relapsed/refractory multiple myeloma rarely followed an individual patient approach, mainly owing to the higher need for complex data assumptions compared with simpler modeling approaches. As many patients experience disease progression on multiple treatment lines, there is a growing need for modeling complex treatment strategies, leading to more sophisticated approaches in the future. Maintaining transparency, high reporting standards, and thorough analyses of uncertainty are crucial to support these advancements.

Comparative survival analysis of patients with HER2-low and HER2-positive metastatic breast cancer with or without brain metastases treated with trastuzumab deruxtecan.

1036 Background: Breast cancer outcomes vary among HER2-amplified and HER2 low-expression patients, particularly in the presence of brain metastases (BM). Trastuzumab deruxtecan (T-DXd) is FDA approved for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low and HER2-positive (HER2+) patients (pts). This study aims to evaluate the impact of T-DXd treatment on overall survival among HER2 low and HER2-positive metastatic breast cancer (MBC) patients with and without brain metastases (BM). Methods: A retrospective analysis was conducted by using de-identified data available from seven US-based health systems part of Guardian Research Network (GRN). Patients treated with T-DXd from December 2019 to December 2023 with a diagnosis of HER2 low (immunohistochemistry [IHC] 1 + or IHC 2+/negative with HER2 FISH non-amplified) and HER2+ (IHC 3+ or HER2+ and FISH amplified MBC were included. Median overall survival (mOS), calculated from the initiation of T-DXd treatment, was assessed using Kaplan-Meier Curve analysis and Log-rank test. Results: A total of 380 MBC pts were identified. Among these 231 (61.1%) were stratified as having HER2 low and 149 (38.9%) HER2+ MBC. Pts with HER2+ disease had a higher prevalence of BM (n=70; 47%) compared to HER2-low pts (n=55;23.8%). The median age at BM diagnosis was 60.5 years, range: 21.6 to 87.1 years. Within the entire BM group (n=125), there were more pts with ER+ disease (81.9%) in the HER2 low group compared to HER2+ group (55.8%, p=0.01). The majority of these patients had multiple prior lines of therapy. HER2+ BM pts had a median overall survival (mOS) of 9.3 months [CI: 6.79-11.88, log rank p <0.001], compared to 4.3 months [CI: 1.89-6.82, log rank p <0.001] in the HER2-low pts. Without BM, HER2+ pts had a mOS of 10.7 months [CI: 0.71-20.82, log rank p <0.001], compared to 6 months [CI: 3.47-8.67, log rank p <0.001] in the HER2-low pts. Conclusions: In this retrospective study of heavily pretreated MBC patients with multiple prior lines of therapy, pts with HER2+ MBC with and without BM had a longer mOS compared to those with HER2- low disease, suggesting HER2 expression as a key determinant of T-DXd efficacy. Poor survival in MBC patients without BM was attributed to pre-treatment with multiple lines of therapy. Future research should explore combination therapies and predictive biomarkers while conducting clinical trials to optimize treatment strategies for HER2+ metastatic breast cancer patients.

Lutetium-177–PSMA-617 experience in Appalachian patients with advanced prostate cancer at West Virginia University Health Science Center.

e17045 Background: Lutetium Lu-177 vipivotide tetraxetan (Lu-177) allowed for improved biochemical and radiographic response rate with relatively low toxicity for metastatic castration-resistant prostate cancer (PC) after multiple lines of therapy. In the 2021 VISION study (DOI: 10.1056/NEJMoa2107322), Lu-177 was reported to have a median overall survival (OS) of 15.3 months in patients (pts) with advanced prostate cancer (PC). We reviewed the result with Lu-177 for the treatment of advanced PC at a rural tertiary academic center at West Virginia University Health Science Center (WVU-HSC). Methods: All PC pts receiving one or more doses of Lu-177 at WVU-HSC were retrospectively reviewed. Pts were followed until death or the last clinic visit. All pts were established patients at WVU-HSC for management of the advanced PC between July 2022 and February 2024. Data was tabulated with descriptive statistics and median survival was calculated from Kaplan-Meier method. Results: Over an eighteen months period 34 pts received 126 doses of Lu-177. 26 pts were referred from outside the WVU-HSC specifically for Lu-177. Demographics from data collection showed predominantly Caucasian pts (91% Caucasian). The time from the initial PC diagnosis to the first dose of Lu-177 was a median of 67 months (range: 10 months-367 months). The median age at the first dose of Lu-177 was 65 years (range: 45-80). 18 patients (53%) remain alive as of Feb 2024. 14 pts (41%) completed 6 cycles of Lu-177 and 11 pts (32%) remain alive. The Kaplan-Meier median OS for these 34 pts starting from the first cycle of Lu-177 was 10 months. Conclusions: A 2022 estimated cost for Lu-177 was $42,500 per dose (excludes administration) so “payors” may have been charged more than $5,000,000 for the Lu-177 for these patients. Lu-177 may be of more benefit earlier in the PC disease spectrum, or perhaps pre-treatment PSMA imaging can better target patients who will benefit from Lu-177. Our observed median OS of 10 months did not match the 15.3 reported in the VISION study (DOI: 10.1056/NEJMoa2107322). Further data evaluation and collection are warranted from different communities to investigate the differences observed in the survival data reported in the literature and observed in the clinic setting. [Table: see text]

OCEANIA: real-world study of ovarian cancer treatment patterns across multiple lines of therapy in Argentina and Brazil.

Aim: To evaluate real-world data on treatment patterns in Argentina and Brazil in patients with ovarian cancer.Methods: This study evaluated de-identified antineoplastic exposure data from a private healthcare provider in Argentina and health claims database (Orizon) in Brazil from 2010 to 2019 and 2015 to 2020, respectively.Results: Platinum-based chemotherapy was the most common first-line therapy (Argentina: n=311 [87.6%]; Brazil: n=1142 [79.3%]). The proportion of patients receiving platinum-based chemotherapy declined across both populations from first- to second-line, while use of non-platinum-based, targeted, and hormone therapies increased. Duration of platinum-based treatment and time to next treatment decreased from first- to fourth-line.Conclusion: There is an unmet need for effective therapies that can prolong time to next treatment in ovarian cancer in Argentina and Brazil.

Front-line Management of Follicular Lymphoma

Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) in Western countries. Most patients have an indolent disease course with 10-year survival estimates of 80% among all patients in the rituximab era. However, risk stratification schema can identify subgroups of patients at higher risk of early death and/or progression following front-line therapy. In addition, histologic transformation to an aggressive NHL occurs in approximately 2% of patients per year. Many patients can initially be observed, but ultimately, most will be treated with multiple lines of therapy during their lifetimes. Current Health Canada-approved systemic treatment options include chemoimmunotherapy and lenalidomide plus rituximab. Phosphoinositide 3-kinase (PI3K) inhibitors were initially approved but were later withdrawn because of toxicity considerations. Newer therapies likely to impact care in Canada include bispecific T cell engagers (BiTEs) and chimeric antigen receptor (CAR)-T cell therapy.

Perspective: rethinking therapeutic strategies in oncology.

Immuno-oncology has revolutionized cancer care, drug development, the design of clinical trials, standard treatment paradigms, and the evaluation of response to therapy. These are all areas, however, that have not fully incorporated principles of tumor immunology. Insufficient emphasis is put on the effect drugs have on the immune system, and specifically, the impact that multiple lines of therapy can have on the functioning of the immune system, hindering a robust anti-tumor immune response. A paradigm shift in how we approach the development of novel immunotherapeutic agents is necessary to facilitate the effective improvements in patient outcomes.

Molecular and Cytogenetic Evaluation in Systemic Mastocytosis

Systemic mastocytosis (SM) is a rare hematological neoplasm characterized by pleomorphic symptoms, related to mediators release from pathological mast cells. Tissue infiltration of liver, spleen, gastro-intestinal (GI) tract and osteolysis are present in aggressive disease. As KIT D816V mutation can be found in approximately 80% of patients, several additional somatic mutations of prognostic significance have been detected in a subset of patients. We report on clinical, cytogenetic and molecular characteristic of 160 patients with SM diagnosed in the last 15 years at our center. Fourteen (8.9%) patients had cutaneous mastocytosis, 85 (53.5%) had indolent SM (ISM), 12 (7.5%) had smoldering SM (SSM), 27 (17%) had aggressive SM (ASM), 17 (10.5%) had SM with an associated hematological neoplasm (AHN-SM) and 1 (0.6%) had mast cell leukemia. Symptoms were mostly related to mediators release: itching and blistering (69, 43%), anaphylaxis (49, 30%), diarrhea/bloating (19, 12%), osteoporosis/bone fracture (10, 6%), constitutional symptoms (8, 5%), bone pain and myalgia (16, 10%), anaphylaxis from Hymenoptera venom (24, 15%). While SM patients were mostly treated with antihistamines and membrane stabilizers, 29 patients needed a disease modifying therapy. Four patients with ISM were treated with Interferon (IFN) for bone lytic alterations, while 1 patient with ISM started midostaurin for uncontrolled symptoms. Other 11 patients with ASM were treated with midostaurin: 4 responded, while 7 needed multiple lines of therapy including allogeneic transplant in 4 cases. Eleven patients with ASM were treated with tyrosin kinase inhibitors (TKI) before midostaurin became available, while 2 elderly patients were treated with low dose cytarabine and TKI for concomitant acute leukemia. KIT D816V mutation was found in 111 of 131 (85%) evaluable patients with SM. Cytogenetics was normal in all but 2 patients with AHN-SM in which a chromosomal gain was reported. Among 6 patients with ISM, KIT mutation was found in only 2 cases. One patient had isolated KIT mutation and was treated with IFN for skin symptoms and bone fracture, and another patient had a DNMT3A associated mutation and was treated with imatinib. Moreover, 1 patient presented both DNMT3A and TET2 mutations and was treated with IFN for bone fracture. Among 12 ASM patients, 1 was negative for significant mutations: no disease control was achieved after target therapy, and bone marrow function slowly recovered after allogeneic transplant. The most frequently recorded mutations were SRSF2 and TET2: they were present in 4 patients each and recorded together in 3 cases. Two patients with SRSF2 and TET2 mutations died after multiple lines of therapy: 1 patient for infection and graft versus host disease after allogeneic transplant and 1 for progressive disease. Moreover, the latter had additional RUNX1 mutation. Two patients with concomitant SRSF2 and IDH1 mutations and TET2 mutation respectively responded to midostaurin, while 1 with DNMT3A mutation received multiple lines of therapy and died for pneumonia. One patient with ASXL1 mutation responded to chemotherapy after 2 previous lines of treatment. Among 4 patients with isolated KIT mutation, 2 responded to midostaurin, 1 obtained a partial control of symptoms after 4 lines of treatment and 1 suddenly died after achieving stable disease after 2 lines of therapy. Among 3 patients with SM associated to myelodyplastic syndrome, 1 was negative for KIT but positive for TP53 mutations and died for natural event after symptoms directed therapy and continuing recombinant erythropoietin. The other 2 KIT positive patients presented multiple concomitant mutations. Additional TET2 and SRSF2 mutations were recorded in a patient who died few weeks after diagnosis, while additional TET2, SRSF2, RUNX1 and KRAS mutations were recorded in a patient treated with midostaurine and 2CDA before successful allogeneic transplant. Molecular characterization of SM has uncovered a complex landscape of somatic mutations other than KIT D816V. Although the prognostic significance of some recurrent mutations has been reported, prospective correlation with clinical response may highlighted their role in the pathogenesis of disease and possibly elucidate mechanism of resistance to treatment. On the other hand, cytogenetics might no be considered mandatory except for AHN-SM

B-Cell Maturation Antigen (BCMA) Expression and Clinical Features of Plasmablastic Lymphoma (PBL)

Introduction: Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of large B-cell lymphoma with plasmacytic differentiation. Although limited-stage (LS) PBL has a favorable outcome, extensive-stage (ES) PBL has a poor prognosis, with a median survival of 12-18 months. Patients with relapsed/refractory (r/r) PBL have limited treatment options and most die from the disease. B cell maturation antigen (BCMA) - directed cellular and immunotherapies are highly effective in MM. The data on BCMA expression in PBL is limited. Literature review identified one report including 7 PBL cases all of which expressed BCMA. We studied all patients with a diagnosis of PBL who presented to Moffitt Cancer Center in Florida, USA from Jan. 2006 to Apr. 2023, and retrospectively performed BCMA immunohistochemistry (IHC) staining on the available archived FFPE biopsy samples. Methods: Progression-free survival (PFS) was calculated as time from disease progression or last follow up to treatment start date. Overall survival (OS) was calculated as time from death or last follow up to date of PBL diagnosis. Association of BCMA expression with PFS or OS was evaluated using logrank test, with continuous variables converted to categorical by classifying as above or below median. All analyses were done using SAS 9.2. Results: A total of 32 PBL patients were identified. The median age was 59 years (range 31-83 years); 21 (65.6%) had stage III/IV (ES); 9 patients (28.1%) were HIV positive; and 57.1% of evaluated cases were EBV positive by EBER. Treatment data was available for 30 patients. The most common frontline therapies were EPOCH and CHOP with or without rituximab; four patients received bortezomib combined with EPOCH; 7 patients (23.3%) received autoSCT in 1 st remission (Table 1). Median follow-up was 77.6 months calculated using the reverse Kaplan-Meier method. Consistent with previous reports, patients with ES PBL had worse outcome than those with LS PBL, with 3-year OS rates of 24% and 100%, respectively, p=0.01 (Table 1). Among the 20 patients with ES PBL and known treatment responses, 11 did not achieve CR after frontline therapy. Ten of these 11 patients died due to disease progression, 9 within 2 years and 1 within 3 years. Two patients received CD19 CAR-T after multiple lines of therapy. Both died within 30 days, one from disease progression and the other from multiple treatment complications. Out of the 18 cases with tissue available for IHC study, 17 (94.4%) had positive BCMA expression (Figure 1). The median percentage of BCMA+ cells was 75% (Table 1). Eleven (61.1%) cases had intermediate to strong BCMA staining. Neither BCMA+ cell percentage nor BCMA expression level was associated with disease stage, response rate, PFS, or OS (p>0.10 for all tests). Discussion: In our study the majority of our PBL cases tested positive for BCMA, and the percentage of BCMA+ cells seemed comparable to MM cases.To our knowledge, this is the largest and the first report that systemically evaluated BCMA expression in PBL. Our results provide evidence to explore BCMA as a potential target in PBL. Currently two anti-BCMA CAR-T products and an anti-BCMA/CD3 bispecific T-cell engager have been approved for r/r MM. A BCMA-targeting antibody-drug conjugate (ADC) Belantamab mafodotin-blmf was initially granted accelerated approval by FDA for r/r MM but was later voluntarily withdrawn from the market. Given the expression of BCMA in PBL and the lack of effective treatment of r/r PBL, these patients could be considered in trials evaluating the BCMA-targeting therapies. In fact, in a case report recently published, one patient with refractory PBL achieved CR after one infusion of BCMA CAR-T and remained in CR after 14 months. Ten of our 11 ES patients who did not achieve CR after frontline chemotherapy died from the disease, emphasizing the importance of clinical trials for this condition. We did not find an association of BCMA expression with clinical outcomes as oppose of MM, in which higher BCMA expression was associated with shorter PFS and OS. The lack of association in our study may be due to the small sample size, or, it may reflect a difference in biological role of BCMA in PBL from MM. Our results will need to be corroborated with other series to confirm our findings. Translational studies need to evaluate the dynamics of BCMA protein expression on PBL cell membrane and the activity of BCMA-targeting agents in vitro and in animal models of PBL.

Improvements in Overall Survival in Older Patients with Mantle Cell Lymphoma Are Driven By Improvements across Multiple Lines of Therapy

Introduction Survival rates for people with mantle cell lymphoma (MCL) have improved in recent years. Among the potential factors accounting for this improvement is the approval of multiple new therapies over the past two decades, including bortezomib, bendamustine, ibrutinib, lenalidomide, acalabrutinib, and zanubrutinib. We hypothesized that the availability of multiple agents with non-overlapping mechanisms of action would result in significant improvements in overall survival following first-line therapy. Methods Patients diagnosed with MCL between 2002 and 2017 were identified using the SEER-Medicare linked database. Selected patients were >65 years of age at the time of diagnosis with MCL. Lines of therapy were determined using billing codes, with inpatient/outpatient claims used for traditional agents and Medicare Part D dataset used for oral agents. Next lines of therapy were defined based on claims for new anticancer agents separated from the end of the prior line by some certain number of days. Sensitivity analyses were performed varying the number of days between therapies. Overall survival (OS) was defined as initiation of initial therapy to death, while OS2 was defined as time from initiation of second-line therapy to death. Time to next therapy 1 (TTNT1) was defined as time from start of first-line therapy to death or start of second-line therapy, whichever came first. Cox models and Kaplan-Meier (KM) survival curves were generated for time-to-event analyses. Analyses were stratified by categories of years of first- and second-line therapies corresponding to eras of key drug approvals (e.g., 2002-2005, 2006-2009, 2010-2013, >2013). Results In total, 4,832 patients were included, among whom 3,840 patients (79.5%) had claims for first-line regimens and 1,648 (34.1% of total and 42.9% of patients with first-line regimens) had second-line regimens. Of the 4,832 patients, the majority were male (67.4%), White (94.6%), and non-Hispanic (94.7%), with good performance status (74.8%) and a Charlson Comorbidity Index <2 (64.8%). The median age at diagnosis was 75 (IQR 70-81). Patients with first- and/or second-line regimens did not differ significantly from the entire population of 4,832 patients with MCL in terms of baseline characteristics. In the first-line setting, use of bendamustine-rituximab (BR) increased from 2.3% of patients treated in 2006-2009 to 49.5% in 2014-2017. Similarly, use of single-agent BTK-inhibitors (BTKi) increased from nonexistent in patients treated in 2010-2013 to 13.8% in 2014-2017. In the second-line setting, use of single-agent BTKi similarly increased from 2.6% of those treated in 2010-2013 to 44.9% in 2014-2017. Median OS for the 3,840 patients with fist-line regimens was 4.4 years (95% CI, 4.1-4.5); median OS for those receiving first-line therapy in 2002-2005 was 3.5 years (3.1-3.9), compared to 3.7 (3.4-4.0), 4.5 (4.2-5.0), and not reached (4.8-NR) among those treated in 2006-2009, 2010-2013, and 2014-2017, respectively. Patients treated in 2014-2017 had significantly improved OS compared with those in 2002-2005 (log rank p<0.0001). Median TTNT1 overall was 2.5 years (2.4-2.6); median TTNT1 was 3.2 years (2.9-3.5) vs 2.3 years (2.1-2.6) for patients who received first-line therapy in 2014-2017 compared to 2002-2005 (log rank p<0.0001) ( Figure A). In addition, there was a significant difference across KM curves for OS2 stratified by categories of years of second-line therapy, with median OS2 of 2.5 (2.0-3.2) in patients treated in 2014-2017 compared to median OS2 of 2.1 (1.7-2.5) in 2010-2013 ( Figure B). Discussion In this analysis, we observed improvements survival of MCL patients over time, along with similar improvements in outcomes following first-line therapy, which may correlate with increased BR and BTKi use as first-line agents. Unexpectedly, improvements in survival following first-line therapy were considerably more modest. Potential explanations include lack of data from recent years during which we expect continued increased utilization of oral therapies vs unique impact of repeated therapies in the elderly. Overall, these data support the need for ongoing development of first- and subsequent-line therapies in MCL.

Effectiveness of Chemo-Immunotherapy (CIT) and Novel Therapies in Second or Later Line of Therapy (2L+) for Patients with Relapsed/Refractory (R/R) Aggressive Large B-Cell Lymphoma (LBCL)

Aim: Patients with R/R LBCL after first-line treatment have poor prognosis. Multiple novel therapies have been approved for R/R LBCL in recent years, but CIT regimens are still commonly used. This study evaluated the effectiveness of CIT and novel therapies in 2L+ in patients with R/R LBCL and the association between patient clinical characteristics and real-world outcomes. Methods: This was a multi-site retrospective observational study of patients aged ≥18 years with R/R LBCL in the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (patients followed from 1/1/2015 to 2/15/2023) who were treated with CIT or novel therapy in 2L+. CIT regimens included salvage/palliative chemotherapy, lenalidomide, rituximab, or obinutuzumab, used alone or in combination. Novel therapies included polatuzumab vedotin plus bendamustine and rituximab or variations thereof (i.e., pola-based regimen), tafasitamab plus lenalidomide or variations thereof (tafa-based regimen), and loncastuximab tesirine (lonca). Patients' demographic and clinical characteristics were assessed from the first confirmed R/R disease diagnosis and initiation of 2L+ therapy. When multiple lines of therapy (LOTs) were eligible for inclusion in the analysis, one was randomly selected as the index LOT. Real-world outcomes, determined by investigators at each clinical site, including overall response rate (ORR), complete response (CR) rate, duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), and overall survival (OS) were described for all patients in each treatment group and for the subgroup of patients with prior chimeric antigen receptor (CAR) T-cell therapy. Multivariable Cox Proportional Hazards models were used to assess associations between select patient clinical characteristics and real-world outcomes. Results: The study population included patients treated with CIT (N=653), pola-based regimen (N=116), tafa-based regimen (N=55), and lonca (N=42) ( Figure 1A). The median (m) age at date of index treatment initiation across groups ranged from 63 to 74 years. Across groups, most patients had primary refractory disease-i.e., were refractory to the first LOT (69.5% CIT vs. 73.3% pola vs. 58.2% tafa vs. 71.4% lonca), whereas variable proportions had one prior LOT (65.5% vs. 17.2% vs. 43.6% vs. 7.1%) and prior CAR T-cell therapy (5.1% vs. 43.1% vs. 32.7% vs. 47.6%). In the CIT group, ORR was 33.8%, 15.5% of patients achieved CR, mPFS (95% CI) was 1.9 (1.7, 2.1) months, and mOS was 9.1 (8.1, 10.5) months. In the pola group, ORR was 42.2%, 24.1% of patients achieved CR, mPFS was 2.5 (2, 3.2) months and mOS was 7.8 (6.4, 11.8) months. In the tafa group, ORR was 25.5%, 14.5% of patients achieved CR, mPFS was 2.7 (2.1, 4.2) months, and mOS was 8 (5.3, 12.7) months. In the lonca group, ORR was 40.5%, 21.4% of patients achieved CR, mPFS was 3 (2.1, 5.1) months, and mOS was 4.7 (3.7, 10.8) months. Demographics and outcomes for all patients and those who received prior CAR T-cell therapy are summarized in Figure 1A. In the multivariable Cox regression analysis, International Prognostic Index (IPI) risk score ≥3, CIT as the index treatment type, and primary refractory status were significantly associated with time from response to progression/death (P<0.05; Figure 1B). IPI risk score ≥3, CIT as the index treatment type, and primary refractory status were significantly associated with worse PFS. IPI risk ≥3, ≥3 prior LOTs, and primary refractory status were significantly associated with OS. Conclusion: In this large clinical cohort of patients with R/R LBCL with high proportions having primary refractory disease, all common treatments were associated with modest ORR/CR and poor OS. Receiving CIT treatments, higher IPI score, primary refractory status, and higher number of prior LOTs were significantly associated with poor clinical outcomes. A study with larger sample size and longer follow-up may be warranted to further understand the clinical effectiveness of novel treatments. Thus, despite the availability of novel treatments during the study period, these findings highlight the need for more effective treatment alternatives beyond currently available options to improve outcomes.

A Phase Ib Open-Label Study of MRG001 in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL)

Background: Patients with R/R DLBCL who fail multi-agent chemoimmunotherapy have a poor prognosis and a need for more treatment options. MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE). MRG001 has been evaluated in a first-in-human phase Ia study and determined 1.8 mg/kg Q3W as RP2D. Here we present results from phase Ib study of MRG001 in patients with R/R DLBCL who had failed established therapies for the safety and preliminary antitumor activity evaluation. Methods: Patients aged ≥18 years with ECOG PS 0-1, histologically diagnosed R/R DLBCL who had failed ≥ 2 prior therapies (a prior anti-CD20 antibody treatment was necessary) were enrolled in this single-arm, open-label phase Ib study. All patients received MRG001 1.8 mg/kg IV Q3W until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was overall response rate (ORR) assessed by investigators according to the Lugano response criteria, duration of response (DoR) and safety. Results: At data cutoff (Jul 28, 2023), 35 patients were enrolled and received ≥1 dose of MRG001; 29 (82.9%) had discontinued the treatment and 6 (17.1%) were ongoing. Median age was 62 years (34-76), 24 (68.6%) patients were male, 24 (68.6%) had an ECOG PS of 1. The median antitumor systemic prior lines was 3 (2-7), and most patients (62.9%) had ≥3 prior lines of therapy. 3 patients received prior ASCT, and 7 patients received prior CAR-T. Median follow-up (range) was 6.8 months (0.7-18.0) for all patients. Among the 34 evaluable patients, ORR by investigator review was 38.2% (95% CI, 22.2-56.4), with 6 patients (17.6%) having a CR and 7 (20.6%) having a PR; 10 patients (29.4%) had SD, and disease control rate (DCR) was 67.7% (95% CI, 49.5-82.6). Median DoR for the 13 responders was 10.5 months (95% CI, 6.5-NE). For patients with a CR, mDoR was 13.7 months (95% CI, 10.5-NE). Treatment related adverse events (TRAEs) occurred in 33 (94.3%) pts, most commonly reported were leukopenia (68.6%), neutropenia (65.7%), anemia (45.7%), AST increased (40.0%), and lymphopenia (31.4%). Grade 3/4 TRAEs occurred in 20 (57.1%) pts, most commonly reported were neutropenia (40.0%), leukopenia (17.1%), and lymphopenia (11.4%). Discontinuation due to a TRAE occurred in 2 (5.7%) patients. Patients all successfully recoverd from these TRAEs through the implementation of clinical supportive care. Grade 1/2 treatment-related peripheral neuropathy occurred in 22 (5.7%) patients; no grade 3/4 AEs occurred. No dose reduction occurred due to TRAE. No infusion reaction or tumor lysis syndrome due to treatment occurred and no pts died because of TRAEs. Conclusion: Phase Ib results show that MRG001 had clinically meaningful antitumor activity in patients with R/R DLBCL who progressed after multiple lines of therapy. Additionally, the safety profile was manageable and patients tolerated treatment well. Clinical trial information: NCT05155839.

Favorable Outcomes of Splenic Marginal Zone Lymphoma in an International Study of 934 Patients with Long Follow-up

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb <12g/dL for women or <13g/dL for men) in 58%, LDH >UNL in 46%, lymphocytosis (>5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Efficacy of anlotinib in Chinese patients with metastatic breast cancer: A retrospective observational study.

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.

Equecabtagene Autoleucel: First Approval.

Equecabtagene autoleucel (Fucaso®), an autologous anti-B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy that uses lentivirus as a gene vector to transfect autologous T cells, is being developed by IASO Biotechnology and Innovent Biologics, Inc. for the treatment of multiple myeloma (MM) and autoimmune diseases of the nervous system, including neuromyelitis optica spectrum disorder (NMOSD). Equecabtagene autoleucel was granted conditional approval in China in June 2023 for the treatment of adults with relapsed or refractory MM (RRMM) who have progressed after ≥ 3 lines of therapy (≥ 1 proteasome inhibitor and an immunomodulator). This article summarizes the milestones in the development of equecabtagene autoleucel leading to this first approval in patients with RRMM who have progressed after multiple lines of therapy.

Real-world Management of CML: Outcomes and Treatment Patterns.

Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Analysis of Real‐World Treatment Patterns and Outcomes Among Patients With Relapsed/Refractory Follicular Lymphoma Including POD24 Patients

Introduction: Although follicular lymphoma (FL) is an indolent disease, there is much heterogeneity in outcomes. Patients with early relapsed disease within 24 months (POD24) have been reported to be a poor prognostic subgroup, although this finding has not been confirmed in several recent real-world studies. This study describes treatment patterns, prognostic factors, and outcomes in patients with relapsed/refractory (R/R) FL, including those who progress through multiple lines of therapy (LOTs). Methods: This study was conducted using the COTA database, which is comprised of electronic health records drawn from academic centers (50%) and community practices (50%) in the US. Patients included in this study had a confirmed diagnosis of FL (index date) between 1 January 1990 and 31 December 2022, were ≥18 y of age at index date, were administered treatment for FL, and were followed >3 months after first-line (L) treatment initiation. The utilization of novel treatment options was captured progressively throughout the study period. Patients who progressed from 1L chemoimmunotherapy (CIT) within 24 months were identified as POD24 patients. A landmark approach was taken to assess the overall survival (OS) of the POD24 patients who had at least 24 months of follow-up from 1L CIT versus non-POD24 patients as described in previous studies (Casulo et al., Blood 2022). Patient demographics, treatment patterns, and OS were also assessed by LOT. Results: Overall, 3568 FL patients met inclusion criteria. Among these, 2465 received 1L CIT, with 459 (18.6%) identified as POD24. Of these POD24 patients, 264 had ≥24 months of follow-up from 1L CIT and were included in the landmark analysis. This sub-group of POD24 patients had a median age of 64 y at diagnosis and 86.6% had stage III/IV disease. Non-POD24 patients (n = 2006) had a median age of 61 y at diagnosis and 81.4% had stage III/IV disease. POD24 patients had worse OS (hazard ratio [HR] 2.24; 95% confidence interval [CI] 1.79, 2.80) versus non-POD24 patients. Of the 3568 1L FL patients, 862 continued to 2L, 328 continued to 3L, 146 continued to 4L, and 59 continued to 5L+ treatment. Across all LOTs, the most common therapy was rituximab or obinutuzumab + chemotherapy. The utilization of novel treatments (ie, kinase inhibitors, CAR T-cell therapy, tazemetostat) increased through LOTs, with 6.4% utilization at 3L, 9.6% at 4L, and 20.7% at 5L. Patients who progressed through successive LOTs experienced worsening OS (Figure 1). The research was funded by: This study was funded by Genmab A/S and AbbVie Inc. Keywords: Cancer Health Disparities, Late Effects in Lymphoma Survivors Conflicts of interests pertinent to the abstract. L. H. Sehn Consultant or advisory role: AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, Takeda A. Wang Employment or leadership position: AbbVie Stock ownership: AbbVie J. Yu Employment or leadership position: AbbVie R. Kamalakar Employment or leadership position: AbbVie K. Sail Employment or leadership position: AbbVie Stock ownership: AbbVie W. Sinai Employment or leadership position: AbbVie Stock ownership: AbbVie D. Arnette Employment or leadership position: AbbVie S. Yang Employment or leadership position: Genmab A. Mutebi Employment or leadership position: Genmab Stock ownership: Genmab F. R. Navarro Employment or leadership position: Genmab G. Salles Consultant or advisory role: AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, Takeda

Real-world patient characteristics and treatment patterns associated with tucatinib therapy in patients with HER2+ metastatic breast cancer.

1051 Background: Tucatinib (TUC) is an oral HER2-targeted therapy approved by the FDA in Apr 2020 for use in combination with trastuzumab and capecitabine (TRA+CAP) for patients with previously treated HER2+ metastatic breast cancer (MBC). In the randomized HER2CLIMB trial, median (95% CI) overall survival (mOS) and progression-free survival (PFS) for patients receiving TUC with TRA+CAP were 21.9 (18.3, 31.0) and 7.8 (7.5, 9.6) months, respectively. Median duration of therapy was 7.3 months. HER2CLIMB used a standard of care comparator arm and included patients with active and stable brain metastasis (BM). HER2CLIMB was conducted prior to approval of fam-trastuzumab deruxtecan (T-DXd) so did not assess the impact of TUC-based therapy following T-DXd. Objective: Describe patient characteristics, treatment patterns, and clinical outcomes for TUC-based treatment in the real-world setting. Methods: This retrospective study included patients in the Komodo Health dataset (aggregating data from patient administrative health claims in the United States) diagnosed with MBC between Jan 1, 2017 and Sep 3, 2022 and initiating TUC post- approval in Apr 2020. Patient characteristics were described in the baseline period (≤6 months from TUC initiation). Key outcomes were time to next treatment (TTNT; as a proxy for PFS), time to discontinuation (TTD), and persistence (proportion continuing treatment at each timepoint) in all TUC-treated patients, and in patients receiving TUC immediately following T-DXd. Results: Of 16,990 patients identified with HER2+ MBC, 528 received TUC-based treatment. Of these, 57 (11%), 164 (31%), 154 (29%), and 153 (29%) received TUC in first-line (1L), second-line (2L), third-line (3L), and fourth-line or later (4L+), respectively. Median follow-up from TUC initiation was 9 months. Overall, 400 patients (76%) had BM prior to initiating TUC (43 [75%], 138 [84%], 111 [72%], and 108 [71%] in 1L, 2L, 3L, and 4L+, respectively). Median (95% CI) TTNT was 10.7 (9.4, 13.1) months overall and 11.5 (9.6, 14.4) in patients receiving TUC in 2L or 3L. Median (95% CI) TTD was 8.5 (7.2, 9.3) months overall, and 9.1 (7.7, 9.9) in patients receiving TUC in 2L or 3L. TUC persistence in the overall cohort was 46% (91/200) at 12 months and 35% (40/115) at 18 months. Sixty-one patients (12%) received TUC immediately following T-DXd (median 4L; 12 in 2L/3L, 49 in 4L+); of whom 36 (59%) had BM prior to initiating TUC. TTNT and TTD for patients treated with TUC following T-DXd were 7.5 (5, 13.3) and 7.3 (3.2, 9.5) months, respectively. Conclusions: In the real-world setting, a higher proportion of patients receiving TUC had BM compared with the HER2CLIMB patient population. TUC-based treatment in the real world is used in multiple lines of therapy and is associated with a similar TTNT and TTD to PFS observed in HER2CLIMB, inclusive of a cohort of patients who received TUC following T-DXd therapy.