Subsequent Lines Of Therapy Research Articles

Patterns of Care and Resource Use Among Elderly Relapsed/Refractory Follicular Lymphoma Patients: US Medicare Claims Analysis

Background: Follicular lymphoma (FL)is the second most common type of non-Hodgkin lymphoma (NHL) and most common indolent NHL. Rituximab-based chemotherapy is highly effective and considered the mainstay first-line (1L) treatment for FL, though many patients relapse and continue through successive lines of therapy. These relapsed/refractory (R/R) patients experience worse outcomes and represent an unmet need for more effective treatment approaches. This study examined treatment patterns, health care resource utilization (HCRU), and costs among R/R FL patients initiating third line (3L) therapy between 2011 and 2020. Methods: This retrospective, observational study used Center for Medicare and Medicaid fee-for-service Medicare data. The sample included treated patients with FL (identified via 1 inpatient or 2 outpatient claims) aged ≥66 years who initiated 1, 2, and 3L therapy between January 1, 2011, and December 31, 2020. Patients were required to have continuous coverage in the 12 months pre-FL diagnosis and 3 months post-diagnosis and were followed until discontinuation of enrollment or death. Line of therapy (LoT) was calculated until the end of treatment, death, or transformation to diffuse large B-cell lymphoma. Outcomes included patient characteristics, treatment patterns, health care costs and HCRU. R esults: This analysis identified 8737 1L, 1847 2L, and 410 3L treated FL patients. Median age at the start of each LoT was 75 years at 1L, 77 at 2L, and 79 at 3L. Of R/R FL patients initiating 3L, the most common baseline Charlson comorbidities included diabetes without chronic complications (23%), chronic pulmonary disease (22%) and renal disease (20%), 32% were defined as having progression of disease within 2 years of 1L (POD24), and 30% were defined as double refractory to both an anti-CD20 agent and an alkylating agent. Treatment utilization rates were similar across LoTs; the most used regimens were rituximab/obinutuzumab (R/O) (used 35% of the time in 1L, 33% in 2L, and 31% in 3L) and bendamustine + R/O (39% in 1L, 33% in 2L, and 21% in 3L). Mean duration of 1L treatment was longer for patients who only initiated 1L (10.1 months) vs. those with R/R FL who went on to initiate 2L and 3L (7.5 and 7.4 months, respectively). As R/R FL patients who initiated 3L moved through LoTs, increases were observed in the number of patients with at least 1 inpatient admission (17% in 1L and 31% in 3L) and with at least 1 emergency room visit (27% in 1L and 41% in 3L). Mean total all-cause costs per-member per-month (PMPM) also increased with each subsequent LoT ($15,917 in 1L, $17,767 in 2L, and $18,266 in 3L). In addition, mean total all-cause costs of R/R FL patients defined as POD24 and double refractory were higher in 3L; $20,172 PMPM and $21,724 PMPM, respectively). Conclusions: In this elderly R/R FL population, similar therapies were used across multiple LoTs. With each subsequent LoT, treatment duration shortened and notably, costs and HCRU increased. Additionally, patients defined as POD24 and double-refractory experienced higher costs. This research highlights a substantial unmet need in R/R FL for novel therapeutic options that can provide better outcomes and reduce HCRU.

High Responses Rates with Single Agent Belantamab Mafodotin in Relapsed Systemic AL Amyloidosis

Introduction: Systemic AL amyloidosis, a rare incurable plasma cell disorder, has no approved treatments at relapse. Belantamab mafodotin is an antibody-drug conjugate which targets BCMA antigen approved for relapsed refractory myeloma. We report our results using belantamab mafodotin monotherapy for the treatment of patients with relapsed refractory AL amyloidosis including those traditionally excluded from clinical trials (eGFR<30 ml/min/1.73m 2 and cardiac Mayo stage IIIb disease). Methods: All patients treated with belantamab mafodotin monotherapy at standard dose (2.5 mg/kg) or dose reduction between April 2021 - July 2023. Standardised assessments including measurement of cardiac biomarkers, clonal parameters and imaging were performed and disease assessment was reported as per International Society of Amyloidosis consensus criteria. Results: Twenty-seven patients were included. The median age at was 65 years (range 41-76) and eight (30%) patients were aged >70 years. Eighteen (67%) had λ AL-type and nine (33%) κ AL-type. A median of two organs were involved at baseline (range 1-4) with renal and cardiac involvement in 20 (74%) and 15 (56%) respectively (3 each for Mayo stage IIIa and stage IIIb). The median time from AL amyloidosis diagnosis to first administration of belantamab mafodotin was 69 (range 5-174) months (~6 years) with a median of 3 prior lines of treatment (range 2-6). Prior drug class exposure included proteasome inhibitors (100%), immunomodulatory drugs (81%) and anti-CD38 antibody (81%) therapy. Ten patients (37%) had undergone prior melphalan-conditioned autologous stem cell transplantation. At the time of first belantamab mafodotin dose, the median involved free light chain concentration was 118mg/l (range 31-1778), eGFR was 40 ml/min (range 7 - 120) and a third (9/27) with an eGFR <30 ml/min/1.73m 2. NT-proBNP was 845 ng/l (range 99-70,000). At data cut-off, a median of 5 (range 1-11) doses of belantamab mafodotin were delivered. Of those with evaluable disease, best haematological overall response rate (partial response or better) was 80% (20/25) at a median time to best haematological response of 2 months (95% CI 1-4, range 1-17). Complete response (CR) or very good partial response (VGPR) was achieved in 64% (16/25). Two patients have only had 1 cycle and too early to perform response assessment. Reasons for treatment discontinuation (n=12) were: inadequate response/progression (n=7), keratopathy (n=1), grade 3 thrombocytopenia (n=1), physician choice (n=3: discontinued due to treatment for unrelated metastatic squamous cell carcinoma but remains in CR; facilitation of renal transplant; prior to BCMA-directed CAR-T in VGPR). At a median follow-up of 13 months follow-up (95% CI 4-18, range 1-27) from belantamab mafodotin initiation, 15 patients (56%) remain on therapy. Two patients died (1 due to progressive disease, 1 unrelated) and seven patients progressed and had subsequent line of therapy at a median time of 6 months (95% CI 2-4) in those that had a next line of therapy. Median treatment-free survival or death was 27 months (10-NR), and 1-year treatment-free survival/death was 69% (95% CI 41-86). Median overall survival (OS) is not reached. 1-year OS is 88% (95% CI 59-97). Bilateral microcystic corneal keratopathy, the most frequent adverse event, was seen in 19 (70%) patients (5%; 1/19 grade 4).Ocular adverse events improved in all patients after treatment delay. Only one patient required treatment cessation due to ocular toxicity (despite achieving PR after one dose). Thrombocytopenia was reported in 3 (11%) (grade 3: 1; grade 2: 1). Only two patients remained on the standard dose of 2.5mg/kg for >3 cycles. Nine patients had eGFR <30ml/min and 6/9 started at a dose of 1.25mg/kg with no unexpected side effects (1 patient had grade 3 keratopathy). One patient post-renal transplantation (on tacrolimus and mycophenolate) had no significant toxicity and achieved a CR after cycle 3. No treatment-related deaths, cardiac or renal toxicities observed in our cohort. Conclusion: Belantamab mafadotin has high efficacy and good tolerability in multiply relapsed AL amyloidosis including efficacy in patients otherwise excluded from clinical trials. Treatment-emergent adverse events (especially keratopathy) do not preclude delivery of drug with appropriate dose reductions.

Outcomes of CAR-T Cell Therapy for Large B Cell Lymphoma in Patients of 70 Years and Older: Multicentric Experience on Behalf of Geth-TC/Geltamo

Background: Median age at diagnosis of diffuse large B cell lymphoma (DLBCL) patients is 66 years; 40% of patients are diagnosed at an age greater than 70 years. CAR-T cell therapy is approved for the treatment of relapsed/refractory DLBCL patients; however, a deeper understanding of outcomes in patients older than 70 years is needed. Our aim was to analyze outcomes of CAR-T cell therapy in this population and compare them to those obtained in younger patients in the real-world setting. Methods: A subgroup analysis of our real life experience report (Kwon, Iacoboni et al. Haematologica 2022) was performed. Data from consecutive patients treated in Spain with commercial CAR-T products were retrospectively collected on behalf of GETH-TC (Spanish Group of Stem Transplantation and Cell Therapy)-GELTAMO (Spanish Group of Lymphoma and Autologous Stem Cell Transplantation). Patients infused between November-2018 and August-2021 were included. Last update of the cohort was performed in June 2023. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) were graded using the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Results: Characteristics of the patients are summarized in Table 1. A total of 307 patients underwent apheresis for CAR-T cell therapy as 3 rd or subsequent line of therapy. Fifty-four (18%) patients were 70 years or older. There were no differences between groups regarding product selection, proportion of patients infused, production failure and rate of bridging therapy. There were more patients with HCT-CI score ≥3 and a trend of higher proportion of patients with ECOG >2 at apheresis in the older group (31% vs. 19%, p=0.047; 9% vs. 5%, p=0.054); the remaining baseline characteristics did not differ. A similar proportion of patients were infused. Among the infused population (n=261), median time from apheresis to infusion was 49 days for patients ≥70 years (n=45) and 47 for younger patients (n=216) (p=0.824). A similar proportion of patients developed any grade of CRS and ICANS (88% vs. 80%, p=0.132 and 31% vs. 29%, p=0.843) and grade 3-4 events (11% vs. 6.5%, p=0.277 and 18% vs. 10%, p=0.146). Median duration of CRS (4 and 5 days, p=0.150), ICANS (4 and 5 days, p=0.540) and hospitalization length (20 days for both groups, p=0.995) did not differ between groups. There were not significant differences in the proportion of patients admitted to ICU (24% vs. 18%, p=0.284); however, the proportion of patients developing infection in the first 6 months after infusion showed a trend to be higher in the older group (42% vs. 29%, p=0.099). Non-relapse mortality was similar between groups (13% vs. 7%, 9=0.24). With a median follow-up of 19.2 months from infusion, both 12-m PFS (30% vs. 38%, p=0.281) and 12-m OS (49% vs. 54%, p= 0.473) were similar between older and younger patients (Figure 1). In the multivariate analysis of the whole population including CAR-T type, disease characteristics (primary refractory, progressive disease, disease stage, R-IPI and high LDH at apheresis), ECOG ≥2 and age ≥70, high LDH (HR 2.1, p=0.001), disease stage III-IV (HR 1.8, p=0.038) and ECOG ≥2 (HR 2, p=0.025) were risk factors for EFS. Age ≥70 (HR 1.5, p=0.054) and progressive disease at lymphodepletion (HR 1.8, p=0.055) were nearly significant risk factors. In the multivariate analysis for OS, high LDH (HR 1.7, p=0.013), high R-IPI (1.2, p=0.039), ECOG ≥2 (HR 2, p=0.014) and progressive disease at lymphodepletion (HR 1.9, p0.042) were risk factors for OS, while age had no impact (HR 1.1, p=0.674). Conclusions: In our real-life experience, CAR-T cell therapy showed a similar efficacy and safety in younger and older patients (>70 years). Consequently, this latter group should receive CAR-T cell therapy if treatment criteria are met.

A Real-World Evidence Study of the Temporal Evolution in Treatment Patterns and Outcomes for Chronic Lymphocytic Leukemia

CONCLUSIONS Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in North America. Treatment of CLL is currently indicated only for patients with disease-related symptoms or organ compromise, such as cytopenias, with no evidence of survival benefit for the treatment of asymptomatic patients. Patients with CLL are not cured with conventional therapy and typically require repeated treatments over their lifetime. Median overall survival (OS) is difficult to estimate given recent advances in therapy options but is dependent upon disease features, patient characteristics, and treatment choice. Since the recent introduction of targeted therapy for CLL, there has been limited Canadian data on the evolution of management approaches in a real-world setting. Data are needed to improve the current understanding of the treatment landscape of CLL. This retrospective observational cohort study used real-world, population-level data to describe the baseline characteristics, treatment patterns, clinical outcomes, and healthcare resource use of individuals diagnosed with CLL in Alberta, Canada. The study cohort included all individuals in Alberta over 18 diagnosed with CLL between 2010-2020 and who subsequently initiated systemic therapy. Data were collected through electronic health records and administrative databases. OS was defined as the date of diagnosis to death from any cause or last known contact with the health care system. A total of 890 individuals diagnosed with CLL between 2010-2020 who initiated first-line (1L) systemic therapy were included in the analyses. The mean age at initiation of 1L therapy was 69 years, and 68% were male. Among individuals who initiated 1L therapy in 2020+, the primary form of 1L systemic therapy was ibrutinib monotherapy (IBR) (29%), followed by bendamustine plus rituximab (BR) (21%). A considerable number of individuals did not initiate subsequent lines of therapy, with a drop of approximately 40-45% between each successive line. The treatment landscape changed over time, particularly with respect to decreased use of 1L fludarabine, cyclophosphamide, and rituximab (FCR; 40% in 2010-2013 vs. 9% in 2020+) and increased use of 1L IBR (6% in 2014-2017 vs. 29% in 2020+). Individuals treated at an academic centre were more likely to receive 1L IBR than those treated at a community centre. The median duration of 1L therapy was considerably longer for patients treated with targeted therapy (IBR: 9.8 months) compared to chemoimmunotherapy (BR: 5.6 months, FCR: 5.6 months). The majority of individuals did not initiate therapy immediately after diagnosis, with a median time from diagnosis to initiation of 1L therapy of 24 months (recognizing that the population described includes only those who initiated 1L therapy such that time to first therapy would be much longer for the entire CLL population). The time to next line of therapy (from the start of each line to the start of the subsequent line) was 17 months from 1L to second-line (2L), 14 months from 2L to third-line (3L), and 12 months from 3L to fourth-line. Median OS from initiation of 1L was 104 months, 2L was 70 months, and 3L was 64 months. On average, individuals had 39 healthcare encounters within the first year of initiating 1L systemic therapy, with an average of one hospitalization, six ambulatory care encounters, 25 non-cancer practitioner encounters, and seven cancer physician visits. The mean number of healthcare encounters within the first year of front-line therapy tended to decrease over time, which may be attributable to the changing treatment landscape. These findings highlight the rapid changes in CLL therapy that have occurred over the last decade. Our results demonstrate the significantly smaller cohorts of real-world patients receiving 2L or later therapies compared to 1L and highlight declining survival with subsequent lines of therapy, and a decreasing trend of healthcare resource use over time.

Acute Leukemias of Ambiguous Lineage Have Durable Response to Hypomethylating Agents Plus Venetoclax in Older Patients

Background: The standard of care for frontline therapy of acute leukemias of ambiguous lineage (ALAL) remains controversial due to their rarity; however, outcomes are generally poor. Intensive chemotherapy (IC) regimens are standard, with evidence suggesting that acute lymphoblastic leukemia regimens are more effective than those used for acute myeloid leukemia (AML). Strategies for treating older or frail patients are limited. Although treatment with a hypomethylating agent plus venetoclax (HMA/Ven) is standard therapy for IC-ineligible AML patients, the role of HMA/Ven in ALAL remains poorly characterized. We performed a retrospective chart review of patients at our institution with Philadelphia-negative ALAL, comparing the outcomes of those treated with HMA/Ven and those who received IC. Method: Patients ≥ 18 years treated at Weill Cornell Medical Center with newly diagnosed, pathologically confirmed acute undifferentiated leukemia (AUL), T/myeloid, or Philadelphia chromosome-negative B- and B/T-myeloid leukemia were included. Frontline HMA/Ven was defined as Ven plus azacytydine, decitabine, or oral decitabine/cedazuridine (one patient had initial HMA monotherapy followed by HMA/Ven). Intensive chemotherapy included patients who received variations of standard ALL or AML IC regimens (hyper- or mini-hyper-CV[A]D, cytarabine plus daunorubicin or idarubicin, or cladribine plus idarubicin and cytarabine) with or without Ven. Tyrosine kinase inhibitors including midostaurin or gilteritinib were added for patients with fms-like tyrosine kinase 3 ( FLT3) mutations. Baseline and disease characteristics were collected as well as disease response, subsequent lines of therapy, whether the patient proceeded to allogeneic hematopoietic cell transplantation (HCT), rate of morphologic complete remission (CR), and overall survival (OS). Results: Of 16 patients, 7 received frontline HMA/Ven. B/myeloid was the most common disease type (n=8), followed by T/myeloid (n=4), AUL (n=3), and 1 patient with B/T/myeloid disease. The median age was 74 years (interquartile range [IQR] 62-80). Patients who received HMA/Ven were older than those who received IC, with median ages of 79 (IQR: 77-82) and 62 (IQR: 56-70; p = 0.01), respectively. Baseline white blood cell, hemoglobin, platelet counts, and lactate dehydrogenase, as well as blast percentages in both peripheral blood and bone marrow were similar between the groups. Although not validated in ALAL, markers of adverse myeloid disease as per the ELN 2022 schema were prevalent in both groups, including mutations in RUNX1, ASXL1, SRSF2, and TP53 (Figure A). One HMA/Ven patient and 3 IC patients underwent HCT. Of evaluable patients, 83% and 88% of HMA/Ven and IC patients achieved CRs, respectively. At 2 years, both groups had 50% overall survival (95% CI 22.5-100 in both). Among HMA/Ven recipients, overall survival ranged from 10-56 months, not including two patients with ongoing follow-up at 3 and 46 months (Figure B). Discussion: The treatment of ALAL remains a challenge, particularly in older patients who may be unfit for intensive treatment strategies. In our study, patients who received HMA/Ven had similarly durable disease control to younger patients who received IC in the frontline setting. Prolonged responses were seen in both AUL and MPAL. Multicenter registry and prospective analyses are needed; however, given the rarity of these diagnoses, our findings suggest that HMA/Ven should be considered as a frontline therapy for unfit patients with ALAL.

Real-World Outcomes Among 2L+ Patients with Chronic Lymphocytic Leukemia (CLL) By Line of Therapy (LOT)

Introduction: The chronic lymphocytic leukemia (CLL) treatment landscape is rapidly evolving, and real-world (rw) outcomes of patients receiving 2L+ therapy in the current treatment paradigm are incompletely understood. This study examined the rw outcomes of patients with CLL/ small lymphocytic lymphoma (SLL) receiving 2 or more lines of therapy (LOTs) using a large, contemporary rw dataset. Methods: Patients meeting the study criteria were identified in the COTA real-world, clinical database: Aged ≥ 18 years at diagnosis with CLL/SLL who initiated 2L therapy between January 1, 2014 and June 30, 2021. The initial index date for the study was the date of 2L initiation and was updated to the start of each subsequent LOT for LOT-specific analyses. The following time to event outcomes were evaluated for the study population and by LOT using the Kaplan-Meier method: time to next treatment (TTNT: time from index to the initiation of the next LOT or death), time to treatment discontinuation (TTD: time from index to treatment discontinuation for any reason, including end of therapy as prescribed/indicated), rw duration of response (rwDOR: time from the first clinician-documented CR or PR to the first assessment of progressive disease or the initiation of next LOT among responders), rw progression-free survival (rwPFS), and rw overall survival (rwOS). For all time-to-event endpoints, patients were censored at the date of last visit. Rw overall response rate (rwORR) was the proportion of patients who had a clinician-documented PR or CR as the best response to a LOT among all patients who received that LOT. Results: A population of 1,102 patients was identified from the COTA database meeting the study criteria. Key patient and clinical characteristics included: median age at diagnosis of 64 years, 60.9% male, 88.1% treated in a community setting, 74.1% diagnosed in 2014 or earlier, 9.3% positive for TP53 mutation (55.0% unknown), and 7.8% with del(17p) mutation (66.2% unknown). Median TTNT among patients who received 2L (n=1102) was 29.3 months (95% CI: 27.3, 32.6), and median DOR to 2L (n=863) was 31.9 months (95% CI: 27.5, 36.4). Generally, median TTNT and DOR decreased across LOT 2-4. Median TTNT from 3L (n=468) and 4L (n=201) initiation were 21.4 (95% CI: 18.2, 25.1) and 15.1 months (95% CI: 11.5, 20.2), respectively, and median DOR among 3L (n=333) and 4L (n=130) responders were 22.6 (95% CI: 18.3, 26.2) and 15.1 months (95% CI: 11.7, 22.9), respectively. More than three-quarters (78.3%) of 2L patients experienced a physician-documented CR or PR, and rwORR decreased over subsequent LOTs (71.2% in 3L and 64.7% in 4L). Median TTD varied by treatment type. Patients who received continuous therapy with Bruton's Tyrosine Kinase inhibitors (BTKis) experienced longer median TTD, while patients who received fixed-duration therapies experienced shorter median TTD. Median TTD among patients who received ibrutinib (n=391), acalabrutinib (n=54), or venetoclax + rituximab (n=48) in 2L was 24.8, 32.6, or 23.5 months, respectively, while median TTD among patients who received BR (n=194) or rituximab monotherapy (n=67) was 4.0 or 0.9 months, respectively. Finally, median rwPFS and rwOS decreased by LOT for patients who received 2L-4L. Median rwPFS for 2L, 3L, and 4L were 31.4 (95% CI: 28.6, 35.5), 22.8 (95% CI: 19.1, 26.4), and 16.5 (95% CI: 13.6, 22.6) months, respectively, and median rwOS were 79.0 (95% CI: 68.9, 85.3), 56.3 (95% CI: 51.6, 64.5), and 51.9 months (95% CI: 33.8, Not Reached), respectively. Conclusions: In this real-world, contemporary database analysis, median TTNT and DOR exceeded 2 years among 2L patients. Although the adoption of novel therapies has changed the CLL/SLL treatment paradigm and patients who received 2L BTKi therapy experienced numerically greater TTD relative to those who received other treatment types, patients with relapsed/refractory (R/R) disease continue to experience poor rwPFS and rwOS relative to patients in clinical trials. This study demonstrates the continued unmet need for this rw patient population and highlights the need for continued innovation, namely new therapeutic agents leveraging novel mechanisms of action, to improve rw outcomes for patients with R/R CLL/SLL.

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.

Optimal Therapeutic Strategies in Relapsed/Refractory AML with Prior Exposure to Venetoclax Based Therapy

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from immature myeloid progenitors with notoriously poor outcomes, particularly in the elderly. Venetoclax (Ven) plays an essential role in acute myeloid leukemia (AML) directed therapy as it is approved for frontline therapy in combination with azacitidine (Aza), decitabine (Dec), or low-dose cytarabine (LDAC) for patients aged 75 years and older, or those with significant comorbidities. However, venetoclax-based therapy is not curative, and the ideal salvage regimen is unclear in these patients. We performed a retrospective review that analyzed a single center's venetoclax-based regimens to identify rational subsequent lines of therapy after failing venetoclax. Methods: We conducted a retrospective review of adult patients at Roswell Park Comprehensive Cancer Center who had a confirmed AML diagnosis and received a venetoclax-based regimen as upfront therapy between January 2015-February 2023. Demographics, prior hematological disorders, ELN risk stratification, Eastern Cooperative Oncology Group (ECOG) performance status, treatment received in upfront vs relapsed/refractory settings, date of remission/relapse, disease-specific variables [molecular data, cytogenetics], and outcomes [duration of response, time to progression, MRD status, and overall survival] were collected. Of note, in patients who received upfront venetoclax regimen, the subsequent salvage therapy was grouped by targeted (Gliterinib, Enasidenib, Ivosidenib), low-intensity (single agent hypomethylating therapy, gemtuzumab, ozogamicin), or intensive groups (CLAG-M) and analysis was performed for progression-free survival (PFS). The patient demographics and clinical characteristics were summarized by group (i.e. response, regimens) using the Mann-Whitney U and Fisher's exact test. Survival functions were described by the Kaplan-Meier method and compared with the Log-rank test. Analyses were performed in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: The retrospective study analyzed 97 patients. In the upfront analysis, the median age was 73.4 years (range: 51.4-89.8) and 64 (66.0%) of the patients were male. 65 patients (67.0%) received Aza/Ven, 26 (26.8%) Dec/Ven, and 6 (6.2%) LDAC/Ven. Per ELN 2022 criteria, 13.3% of patients were stratified as favorable,12.2% as intermediate, and 74.4% as adverse risk. Of the adverse risk patients, 67/97 (69.1%) patients received Aza/Ven. Median survival time for all upfront induction regimens was 15.8 months (95% CI: 8.1-22.6), greatest median survival with Aza/Ven of 19.1 months (95% CI:10.4-23.6). Median PFS by all induction regimens was 8.9 months (95% CI: 5.0-13.9) with the greatest median PFS being Aza/Ven at 10.9 months (95% CI: 6.6-20.2); p=0.045). Overall, 29 out of 97 (29.9%) patients received salvage therapy. These included 19 (65.5%) males with 93.1% of patients being Caucasian. The majority of patients (81.5%) had adverse ELN risk stratification (Table 1). Total 1-year survival rate is 0.050 (0.31-0.67), with intensive 0.050 (0.16-0.67), low intensity 0.67 (0.35-0.86), targeted 0.39 (0.18-0.60). Total 3-year survival rate is 0.19 (0.06-0.38) with intensive 0.17 (0.02-0.46), low intensity 0.30 (0.08-0.56), and targeted 0.20 (0.05-0.41). Patients receiving subsequent salvage therapy after upfront venetoclax regimen showed the greatest PFS after receiving low-intensity therapy compared to targeted or intensive regimens with a median survival of 13.9 months (95% CI: 0.0-35.9); p<0.001) (Figure 1). Median survival after intensive therapy was 1.3 months (95% CI:0.5-3.9) and targeted therapy 5.8 months (95% CI: 2.8-10.0). Total OS 14.9 (95% CI: 6.1-22.7) with a low-intensity median survival of 22.7 months (95% CI:1.4-Not Reached (NR)). Conclusion: In this single-center retrospective review, it was found that a low-intensity salvage regimen after the upfront venetoclax regimen showed the greatest PFS compared to targeted or intensive regimens, however, there is no statistically significant difference in OS. Our study results were limited by a small sample size. Further studies are needed to clearly define the ideal salvage regimen for AML patients failing upfront venetoclax-based therapy.

Allogeneic Stem Cell Transplant and CD30 Directed CART Cell Therapies Are Associated with Improved Survival in Classical Hodgkin Lymphoma Refractory or Intolerant to Brentuximab Vedotin and Anti-PD-1 Therapy: Real World Analysis from 14 U.S. Academic Centers

Background: Patients (pts) with classical Hodgkin Lymphoma (cHL) who become refractory to both BV and anti-PD-1 therapies (double refractory, DR) or intolerant (INT) of BV and anti-PD-1 therapies have limited treatment options. There is limited information regarding optimal treatment approaches in these pts. Rechallenging with BV or anti-PD-1 therapies has been previously described in small cohorts with variable success. Allogeneic stem cell transplantation (alloSCT) remains the only curative approach in multiply relapsed/refractory cHL. This study aims to assess practice patterns and outcomes in a large cohort of pts with DR or INT cHL. Methods: We conducted a retrospective study of adult pts with cHL from 14 U.S. academic medical centers who developed DR or INT cHL between Jan 2011 and Dec 2021. DR was defined as treatment failure (evidence of progression by imaging or biopsy) while on therapy or within 3 months of the last dose of both BV and anti-PD-1 therapy. INT was defined as having toxicity limiting further cycles of BV or anti-PD-1 therapy. Pts with INT were either intolerant to both BV and anti-PD-1 or intolerant and refractory to BV or anti-PD-1. The co-primary endpoints were progression free survival (PFS) and overall survival (OS) in pts with DR/INT cHL. Time-to-event analyses were evaluated by Kaplan-Meier methods and log-rank tests. Results: A total of158 pts were eligible. Clinical characteristics at diagnosis included median age 33 years (yrs, range 16-89), 61% male, 77% white race, 66% nodular sclerosing subtype, 47% stage 4, and 60% primary refractory. DR cHL was observed in 119 pts (75%), while 39 pts (25%) were INT. The median OS from the time of DR/INT was 7.4 yrs (95%CI 4.1-NR). There was no difference in OS by DR and INT pts (log-rank p=0.33). The majority (87%, n=137) received subsequent lines of therapy after DR/INT (median 2, range 0-14). Next line of therapy after DR/INT was BV or anti-PD-1 rechallenge (with or without combination therapy) in 39 pts (29%), conventional cytotoxic chemotherapy in 62 pts (45%), immunomodulatory based therapy (lenalidomide, everolimus) in 16 pts (12%) or other in 20 pts (15%). Any line of therapy after DR/INT included alloSCT in 29 pts (18%) and CD30 directed chimeric antigen receptor T-cell (CART) therapy in 24 pts (15%). Forty pts (25%) were rechallenged with BV based therapies. The majority (88%) were previously refractory to BV. The median time from DR/INT to BV rechallenge was 348 days (range 14-1186). The objective response rate (ORR) was 63%, complete response rate (CRR) was 33%, and median PFS was 183 days (95%CI 108-273). Fifty-nine pts (37%) were rechallenged with anti-PD-1 based therapies. The majority (88%) were previously refractory to anti-PD-1 therapy. The median time from DR/INT to anti-PD-1 rechallenge was 233 days (range 3-1409). The ORR was 54%, CRR was 27%, and median PFS was 182 days (95%CI 127-357). There was no difference in PFS comparing BV and anti-PD-1 rechallenge (p=0.50) and no OS benefit of either BV or anti-PD-1 rechallenge, p=0.19 and 0.80 respectively. In 29 pts treated with alloSCT, the median time from DR/INT to alloSCT was 220 days (range 27-1971). AlloSCT was associated with longer OS compared to pts not treated with alloSCT (p<0.001), Figure 1. 3-year OS estimate was 96% (95%CI 75-99%) with alloSCT and 56% (95%CI 46-65%) without alloSCT. In 24 pts treated with CD30 directed CART, the median time from DR/INT to CART was 255 days (range 76-1600). CD30 directed CART was associated with longer OS compared to pts not treated with CART (p=0.009), Figure 2. 3-year OS estimate was 86% (95%CI 62-95%) with CART and 60% (95%CI 50-69%) without CAR-T. Only 2 pts were treated with both alloSCT and CART after DR/INT indicating that OS benefit was independent of cross over treatment. Conclusion: To our knowledge, this is the largest cohort analyzing treatment outcomes in pts refractory to, or intolerant of BV and anti-PD-1 therapy. Additionally, this study represents one of the largest evaluations of BV or anti-PD-1 rechallenge after prior DR or INT. BV and anti-PD-1 rechallenge were effective with high ORR, but median PFS with rechallenge was less than a year, indicating that rechallenge could be considered as a therapeutic bridge. There was no OS benefit of BV or anti-PD-1 rechallenge. AlloSCT and CD30 directed CART were highly effective and associated with longer OS. Pts with DR/INT cHL should be considered for alloSCT or CD30 directed CART.

Comparison of Time to Next Treatment or Death between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) and Bortezomib, Lenalidomide, and Dexamethasone (VRd) in Transplant Ineligible Patients with Multiple Myeloma

Introduction: Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd. Methods: A retrospective cohort study was conducted for patients with NDMM who initiated FL DRd or VRd in Acentrus (1/1/2018 - 5/31/2023), an electronic medical record (EMR) database from academic and non-teaching hospitals in the United States. Patients were included if they had ≥2 records with an ICD-10-CM diagnosis code for MM, ≥6 months of data availability prior to first record with MM diagnosis (without use of antineoplastic agent), initiated FL treatment (initiation of DRd or VRd; index date) within 12 months of first record of MM diagnosis, and ≥90 days of data availability post-index. Patients with pre-index diagnosis of amyloidosis or other cancers and those who participated in a clinical trial before or during FL treatment were excluded. To limit the analysis to the TIE population, patients who had a record of a stem-cell transplant (SCT) before or during FL treatment and those who were <65 years old (used as proxy to SCT eligibility) were excluded. Patient characteristics were evaluated up to 12-months pre-index (baseline period). Patients were followed from the index date until earliest of date of initiation of a next line of treatment, death, or end of data availability. Medications received within 60 days from the date of the first MM antineoplastic agent were considered as FL therapy regimen. Next line of treatment was identified as initiation of a new antineoplastic agent (excluding corticosteroids) outside of FL therapy or re-treatment of FL after >90-day gap. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between study cohorts, with variables with standardized differences <10% considered balanced. Weighted Kaplan-Meier (KM) curves and a doubly-robust Cox proportional hazards model adjusting for baseline variables remaining imbalanced after IPTW were used compare TTNT or death between study cohorts. Results: Overall, 149 and 494 patients were identified in the DRd and VRd cohorts, respectively. After weighting (N DRd weighted = 302, N VRd weighted = 341), most baseline characteristics in both cohorts were similar, including mean age (DRd: 75.3, VRd: 74.5), female sex (DRd: 48.9%, VRd: 45.8%), white race (DRd: 55.8%, VRd: 58.7%), black race (DRd: 8.8%, VRd: 11.3%), Medicare insurance coverage (DRd: 62.7%, VRd: 65.9%), and mean Quan-Charlson comorbidity index (DRd: 3.8, VRd: 3.6; Table 1). Some imbalances remained for mean age, race, ethnicity, and index year, thus they were additionally adjusted for in doubly-robust Cox model. The median duration of follow-up was 20.2 months and 21.5 months among DRd and VRd patients, respectively. A total of 98 (32.4%) DRd patients and 175 (51.2%) VRd patients received a subsequent line of therapy or died, with the median TTNT or death being 37.8 and 18.7 months in the DRd and VRd cohorts, respectively (hazard ratio: 0.58, 95% CI: 0.35, 0.81; p<0.001; Figure 1). KM estimates for patients remaining on FL therapy were significantly higher for DRd than VRd at 6 months (93.0% vs. 80.1%), 12 months (80.0% vs. 61.0%), 18 months (64.9% vs. 51.3%), and 24 months (60.2% vs. 42.9%). Conclusion: In this retrospective cohort study using EMR data, TIE NDMM patients who initiated DRd had a significantly longer time to next treatment or death than patients who initiated VRd. Results from this real-world study fills an unmet data gap by providing information on the comparative effectiveness evidence for DRd versus VRd among TIE NDMM patients. These findings support the use of DRd as an effective treatment option in the TIE NDMM patient population.

Outcomes in Patients with Classical Hodgkin Lymphoma Refractory or Intolerant to Brentuximab Vedotin and Anti-PD-1 Therapy: Real World Analysis from 14 U.S. Academic Centers

Background: Brentuximab vedotin (BV) and anti-PD-1 therapies (nivolumab and pembrolizumab) have changed the therapeutic landscape for patients (pts) with classical Hodgkin lymphoma (cHL) over the past decade. Although first proven to be beneficial in relapsed and refractory cHL, these therapies have moved earlier in the treatment algorithm given superior response rates and survival compared to cytotoxic chemotherapy alone. However, there is limited data regarding outcomes in pts who progress after both BV and anti-PD-1 therapies (double refractory, DR) or become intolerant (INT) of these therapies. Knowledge of outcomes in this subset of pts is important as BV and anti-PD-1 therapies are increasingly used in front-line treatment and early relapsed cHL. Methods: We conducted a retrospective study of adult pts from 14 U.S. academic medical centers who developed DR cHL or became INT of BV and/or anti-PD-1 therapy between January 2011 and December 2021. DR was defined as treatment failure (evidence of progression by imaging or biopsy) during therapy or within 3 months of the last dose of both BV and anti-PD-1 therapy. INT was defined as any toxicity limiting further cycles of BV or anti-PD-1 therapy. Pts with INT were either intolerant to both BV and anti-PD-1 or intolerant and refractory to BV or anti-PD-1. The primary endpoint was assessment of overall survival from time of cHL diagnosis (OS-1) and from DR or INT (OS-2). Secondary endpoints included description of pt characteristics developing DR or INT cHL, estimate of OS comparing DR versus INT, and estimate of OS stratified by prior autologous stem cell transplant (ASCT) at the time of DR/INT. Time-to-event analyses were evaluated by Kaplan-Meier methodology. INT pts were not included in time to progression (TTP) analysis for initial BV or anti-PD-1 therapy. Results: 158 pts were eligible. Clinical characteristics at diagnosis included median age 33 years (range 16-89), 61% male, 77% white race, 66% nodular sclerosing subtype, 47% stage IV, and 56% with B symptoms. Front-line treatment was ABVD/AVD in 122 pts (77%) and BV or anti-PD-1 therapy in 28 pts (18%). 60% had primary refractory cHL (n=94). Table 1 describes pt characteristics in detail. Initial BV treatment was after a median of 2 lines of therapy (LOT) (range 0-7). The majority (60%, n=94) were treated with BV monotherapy and 15% (n=24) were treated with BV combined with anti-PD-1 therapy. Median TTP of BV refractory pts was 168 days (95%CI 138-190). Initial anti-PD-1 therapy was after a median of 3 LOT (range 0-12). Nivolumab was the most commonly used (72%) anti-PD-1 therapy. Median TTP of anti-PD-1 refractory pts was 223 days (95%CI 166-271). DR cHL was observed in 119 pts (75%), while 39 pts (25%) were INT. The median time from cHL diagnosis to DR/INT was 3.3 years (95%CI 0.5-23.1). At the time of DR/INT, 47% (n=75) had prior ASCT. The majority (87%, n=137) received subsequent LOTs after DR/INT (median 2, range 0-14). Table 1 describes DR/INT in detail. The median OS from the time of cHL diagnosis (OS-1) in all pts was 15.0 years (95%CI 9.4-20.9). There was no difference in OS-1 between DR and INT pts (log-rank p=0.83) or primary refractory and front-line relapsed pts (log-rank p=0.94). Pts who developed DR/INT at any time after ASCT had a significantly longer OS-1 compared to DR/INT without prior ASCT with a median OS of 19.1 years (95%CI 19.1-NR) versus 8.6 years (95%CI 5.3-15.0), respectively (log-rank p<0.001, Figure 1). Comparing pts with prior ASCT and no prior ASCT, the median age at DR/INT was 35 (range 20-75) versus 49 (range 18-90) years, Fisher's exact p=0.01. Adjusting for age at DR/INT did not impact the association between prior ASCT and improved OS, Cox proportional hazard ratio 0.48 (95%CI 0.25-0.90, p=0.02). Median OS from time of DR/INT (OS-2) was 7.4 years (95%CI 4.1-NR). OS-2 was not different between DR and INT pts (log-rank p=0.33). Conclusion: To our knowledge, this is the largest cohort of pts refractory to, or intolerant of BV and anti-PD-1 therapy. OS was longer than anticipated both from diagnosis and from time of DR/INT. Pts who were DR/INT after ASCT had a significantly longer OS. Further investigation is needed to determine if OS differences by ASCT may be due to disease biology or sequencing of therapies. Importantly, OS-2 serves as a benchmark for future clinical trials evaluating DR/INT cHL pts.

Comparative Effectiveness of Ibrutinib Flexible Dosing Treatment Strategies on Time to Next Treatment in a Largely Community-Based Claims Database: A Target Trial Emulation Study

Introduction: Outside of a clinical trial setting, ibrutinib is the most well-characterized of the covalent Bruton's tyrosine kinase inhibitors used in the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the first-line (1L) setting. However, the impact of ibrutinib dose adjustment on clinical outcomes remains to be defined. In this real-world effectiveness study, we compared time to next treatment (TTNT) as a proxy for disease progression for dose adjustment and standard dose treatment strategies in patients with CLL/SLL receiving 1L single-agent IBR. Methods: This study utilized the Komodo Health payer-complete dataset, derived from U.S. health insurance claims from >150 private insurers covering >160 million individuals from 2015-2023; 53% of these patients are from community centers. Adult patients with CLL/SLL were included if they initiated 1L single-agent IBR 420 mg/day between March 2016 - April 2023 (IBR initiation date = index date; 1L single-agent IBR was defined as no other CLL/SLL treatment in the 12-month baseline period or within 28 days after index). A target trial emulation (TTE) approach was utilized to compare TTNT, defined as the time between the index date to the initiation of a next line of therapy (LOT), for two treatment strategies: 1) Dose adjustment strategy, defined as a lead-in IBR treatment at 420mg/day for 3-12 months, followed by dose adjustment to <420mg/day until next LOT or IBR discontinuation; 2) Standard dose strategy, defined as a continuous IBR treatment at 420mg/day without any dose adjustment for >12 months until next LOT or IBR discontinuation. The TTE approach minimizes immortal time bias in a naïve observational analysis as patients in the dose adjustment cohort cannot initiate next LOT before dose adjustment occurs [Hernan et al. Am J Epidemiol. 2016]. To explicitly emulate a target trial, two clones were created for each patient, with one clone contributing person-time and event to each treatment strategy of interest, respectively. A clone was artificially censored when the actual treatment path deviated from the assigned treatment strategy. Selection bias due to artificial censoring was corrected using time-varying inverse probability of censoring weights (IPCW), accounting for post-index time-varying clinical factors related to IBR dose adjustment or IBR discontinuation. TTNT hazard ratio (HR; robust 95% confidence interval [CI]) was estimated using an IPCW-weighted pooled logistic regression model. Alternative lead-in periods with IBR standard dosing (3-6 and 3-9 months) were also evaluated. A subgroup analysis was conducted among patients with high cardiovascular (CV) risk, defined as having a preexisting CV comorbidity or a high CHA 2DS 2-Vasc risk score. Results: 3,342 adults initiated 1L single-agent IBR at 420 mg/day. Mean (standard deviation [SD]) age was 67.5 (10.6) years, 62% were male, and mean (SD) Quan-Charlson Comorbidity Index score was 3.0 (1.5). The median (interquartile range) follow-up duration was 19.6 (7.5, 35.0) months. During the study period, 463 patients (14%) initiated a subsequent LOT. The high CV risk subgroup consisted of 2,640 (79%) patients. In the overall study population, 608 (18%) patients experienced a dose adjustment after the index date. Of those, the dose adjustment occurred ≤3 months, ≤6 months, and ≤12 months post-index in 159 (26%), 300 (49%), and 440 (72%) patients, respectively, with dose used at the first reduction of 70 mg, 140 mg, or 280 mg in 4 (1%), 85 (14%), and 519 (85%) patients, respectively. The dose adjustment strategy (420 mg/day for 3-12 months followed by a reduced dose) was not associated with increased risk of initiating next LOT (adjusted HR [95% CI] 0.95 [0.80, 1.14]) compared to the continuous standard dose strategy; results for the alternative lead-in periods and the high CV risk subgroup were consistent with the primary scenario. Conclusions: In this real-world comparative effectiveness study with the majority of patients from community centers, dose adjustment of 1L single-agent IBR treatment for CLL/SLL is not associated with an increased risk of initiating next LOT when compared to continuous standard dose treatment. These findings suggest that a flexible dosing approach with IBR may be an effective option to maintain an optimal balance of clinical therapeutic efficacy and safety for patients with CLL/SLL in the 1L setting.

Evolving treatment patterns and improved outcomes in relapsed/refractory mantle cell lymphoma: a prospective cohort study

Over the last two decades, the frontline therapy for mantle cell lymphoma (MCL) has evolved. However, the impact of subsequent lines of therapy on survival outcomes has not been well characterized. In this study, we investigated the treatment patterns and survival outcomes in patients with relapsed/refractory (R/R) MCL treated with second-line (2 L) therapy. Adult patients with newly diagnosed MCL from 2002 to 2015 were enrolled in a prospective cohort study. Clinical characteristics, 2 L treatment details, and outcomes were compared between patients who received 2 L treatment between 2003–2009 (Era 1), 2010–2014 (Era 2), and 2015–2021 (Era 3). 2 L treatment was heterogenous in all eras, and there was a substantial shift in the pattern of 2 L therapy over time. The estimated 2-year EFS rate was 21% (95% CI, 13–35), 40% (95% CI, 30–53), and 51% (95% CI, 37–68) in Era 1–3 respectively, and the 5-year OS rate was 31% (95% CI, 21–45), 37% (95% CI, 27–50), and 67% (95% CI, 54–83) in Era 1–3, respectively. These results provide real-world evidence on evolving treatment patterns of 2 L therapy based on the era of relapse. The changes in 2 L treatment correlated with improved EFS and OS, suggesting that treatment advances are associated with improved outcomes in patients with R/R MCL.

The choice of treatment for chemorefractory colon cancer

Metastatic colorectal cancer (mCRC) is a major challenge in the treatment of malignant neoplasms. However, with the development of cytotoxic chemotherapy, targeted therapy and local therapies, survival rates have improved significantly. Treatment of patients with CRC in the third and subsequent lines of therapy suggests the use of regorafenib / TAS102, as well as a return to previously used chemotherapy. Late-line treatment with anti-EGFR antibodies (cetuximab, panitumumab) is the choice for mCRC as it has been shown to improve survival rates. BRAF inhibitor and an anti-EGFR antibody is effective in BRAF mutations. A feature of the HER2 / neu mutation is the requirement for dual blockade with trastuzumab + lapatinib or pertuzumab + trastuzumab. For MSI-high, anti-PD therapy (nivolumab, pembrolizumab, or nivolumab + ipilimumab combination therapy) is highly effective. Adagrasib and sotorasib have demonstrated their value in the treatment of CRC with the KRAS G12C mutation. Two inhibitors are approved for NTRK-positive colorectal cancer — larotrectinib and entrectinib. It is also worth noting that one of the local options for the treatment of mCRC is stereotactic radiation therapy. This article presents the current possibilities of therapy for chemoresistant CRC.

Progress in systemic therapy for advanced-stage urothelial carcinoma.

Despite recent advances, advanced-stage urothelial carcinoma (aUC) remains incurable, with 5-year survival rates of approximately 10%. Platinum-based chemotherapy has a major role as first-line therapy for most patients with aUC. The approval of the anti-PD-L1 antibody avelumab as maintenance therapy for patients without initial disease progression on platinum-based chemotherapy is an important development that has improved the survival outcomes of patients with this disease. Otherwise, the use of first-line immune-checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 has been restricted to patients who are ineligible for platinum-containing chemotherapy regimens. Other important developments include the FDA-accelerated approval of first-line enfortumab vedotin plus pembrolizumab for patients ineligible to receive cisplatin and the availability of FGFR inhibitors, enfortumab vedotin and sacituzumab govitecan for subsequent lines of therapy. Several research questions remain unaddressed including the lack of adequate biomarkers, how to assign priority to the different treatment options for individual patients and which agents can be effective as monotherapies. The future is promising with the emergence of modalities such as antibody-drug conjugate-like drugs, next-generation ICIs, bispecific antibodies and cellular therapies. In this Review, we summarize the evolution of systemic therapy for patients with aUC and provide insights into the unmet needs.

Establishing an esketamine clinic in Australia: Practical recommendations and clinical guidance from an expert panel.

Major depressive disorder (MDD) can have severe impacts on function and quality of life. Up to one third of patients will have an inadequate response to their first line of treatment, with subsequent lines of therapy associated with lower remission rates and higher relapse rates. Recently esketamine has become available for Australian patients, and this agent provides an additional treatment option for those with MDD who have had an inadequate response to two or more antidepressant therapies during the current moderate to severe depressive episode. This paper provides an expert panel's practical recommendations and clinical guidance for establishing esketamine clinics in Australia. An expert panel (n = 11) comprising psychiatrists, mental health care nurses, pharmacists, and individuals with experience establishing esketamine clinics was convened in Sydney. The panel developed practical recommendations and clinical guidance, which were then further refined. Five key areas were identified: practical considerations for esketamine clinic set-up, including multidisciplinary care considerations; patient selection; administering esketamine; adverse event management and long-term follow-up. Guidance presented in this paper should assist Australian clinicians to set up an esketamine clinic, and provide practical advice on the infrastructure and clinical requirements for treatment of patients with this agent.

Durable Transfusion Independence in Lower-Risk Myelodysplastic Syndrome (LR-MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database

CONCLUSIONS Red blood cell (RBC) transfusions are commonly used to treat patients with LR-MDS and anemia. RBC transfusion dependence (TD) is an impairment on patients' quality of life and associated with worsened survival (Lemos et al. Sci Rep. 2021). The few approved therapeutic options for LR-MDS have limited efficacy and durability. In this study, the baseline RBC-TD before first-line (1L) and second-line (2L) of therapy, durability of transfusion independence (TI), and associated survival among patients with LR-MDS treated with current standard-of-care therapies were assessed in a large US health insurance claims database. Optum Clinformatics ®, a large single-payer database of administrative health claims for members of large commercial and Medicare Advantage health plans, includes approximately 17-19 million annual covered lives, for a total of >76 million unique lives over a 9-year period. Patients with LR-MDS were identified through 5 relevant International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes (D46.0, D46.1, D46.9, D46.A, and D46.B) between Oct 2015 and Jun 2022 and were required to have no MDS/acute myeloid leukemia (AML) diagnosis and no use of higher-risk MDS or AML medication before their respective index diagnosis dates. As revised International Prognostic Scoring System or other risk score classification information was not available in the database, ICD-10 diagnosis codes were used as a proxy for the identification of LR-MDS; these codes have been used previously in published studies (Zeidan et al. Leuk Lymphoma. 2019). Lines of treatment were determined based on claims for MDS treatments contained in the database: erythropoietin stimulating agents (ESAs; darbepoetin, epoetin alfa), hypomethylating agents (HMAs; azacitidine, decitabine, decitabine-cedazuridine), lenalidomide, luspatercept, eltrombopag, and cyclosporine. Outcomes of interest included transfusion burden (RBC units [U] in 8 weeks), proportion of patients who were transfusion independent before and after different lines of treatment, time to 8- and 16-week continuous TI, Kaplan-Meier analysis of real-world progression-free survival (starting a next line of treatment, progression to higher-risk MDS or AML, and death were considered events), and overall survival. The analysis included 5662 patients with LR-MDS (median age, 79 years; 57% male; 76% non-Hispanic White, primarily covered by Medicare Advantage) who received ≥1 line of treatment. Overall, 66% and 17% of patients received frontline monotherapy with ESAs and HMAs, respectively. In the 16 weeks before 1L treatment initiation, 35% of patients received ≥1 RBC transfusion. During 1L treatment, 45% of patients received ≥1 RBC transfusion, of whom 49% received >3 U and 24% received >6 U during any 8-week period. 2L treatment consisted of ESA monotherapy (40%), HMA monotherapy (21%), luspatercept (9%), or a combination thereof (19%). In the 16 weeks before 2L treatment initiation, 49% of patients received ≥1 RBC transfusion, and 55% received transfusions during 2L treatment (Table). Among patients receiving ≥1 transfusion during 2L treatment, 61% and 31% had >3 and >6 U/8 weeks, respectively. Transfusion burden was greater for patients with ring sideroblast-positive disease and increased with subsequent lines of therapy. Among 612 patients who received ≥1 transfusion in the 16-week period before 2L, 33% achieved 16-week TI with subsequent therapies. Median real-world progression-free survival from start of 2L was 20.0 months in patients who achieved 16-week TI and 4.1 months in patients who did not ( P < .0001). The median overall survival from start of 2L was 23.4 months overall, and 37.9 months vs 9.3 months among responders becoming RBC-TI vs nonresponders, respectively ( P < .0001; Figure). Among patients with LR-MDS, 35% and 49% were RBC-TD before 1L and 2L of therapy, respectively. Achievement of TI was associated with improved survival, suggesting that RBC-TD is a modifiable predictor of clinical outcomes in LR-MDS. Despite the currently available therapies, RBC-TD after any line of therapy is associated with poorer outcomes. Our study results show that novel therapies that provide durable TI are expected to yield decreased progression and improved survival.

Limited Utility of Mayo 2012 Cardiac Staging System for Risk Stratification of Patients with Advanced Cardiac AL Amyloidosis - Analysis of a Uniformly Treated Cohort of 1275 Patients

Introduction: Systemic light chain (AL) amyloidosis is a rare incurable disorder caused by extracellular deposition of misfolded light chain protein fibrils causing organ dysfunction. Cardiac involvement is present in approximately two thirds of cases at diagnosis. Survival depends largely on the severity of cardiac involvement as well as haematological response to treatment. Two validated cardiac staging systems, Mayo 2012 (stage I-IV) (Kumar, Dispenzieri et al. 2012) and European modification of the standard Mayo staging system 2004 (stage I-IIIb) (Wechalekar, Schonland et al. 2013, Palladini, Sachchithanantham et al. 2015), stratify patients according to different thresholds of biomarkers markers of disease involvement (NTproBNP, troponin T and, additionally for Mayo 2012, difference between involved and uninvolved free light chain [dFLC]). Patients included in these original models were not treated with a uniform induction protocol and treated with regimens such as oral melphalan dexamethasone, which are now rarely used. There is a need to re-assess the predictive performance and robustness of these staging systems with current treatment approaches. We report here the comparison of cardiac staging in a large cohort of patients with AL amyloidosis uniformly treated bortezomib-containing regimens in the first-line setting from the ALChemy study. Methods: Patients enrolled in a prospective observational study at the United Kingdom National Amyloidosis Centre from 2010-2019 treated with bortezomib-based regimens were analysed. Outcomes were stratified according to Mayo 2012 and the European modified Mayo classification. Written consent was obtained from all patients in accordance with the Declaration of Helsinki. Results: 1275 patients (755 male, 520 female) were included. Median age at presentation was 67 years (range 29-89), with a median of two involved organs (range 1-5); 812 (64%) had cardiac involvement, 892 (70%) had renal and 154 (12%) liver involvement. All patients were treated with first-line bortezomib-based therapy: bortezomib-cyclophosphamide-dexamethasone in 1190 [93%]; bortezomib-dexamethasone in 48 [4%]; bortezomib-thalidomide-dexamethasone in 21 [2%] and 16 others. None were treated with a daratumumab based combination or autologous stem cell transplant (ASCT) upfront; 95 (7%) had ASCT at a subsequent line of therapy. Patients were classified by Mayo 2012 staging as: stage I, II, III, IV in 199 (16%), 329 (26%), 413 (32%) and 334 (26%) cases, respectively and by European modified staging as: stages I, II, IIIa and IIIb in 219 (17%), 436 (34%), 424 (33%) and 196 (15%), respectively. The median follow-up was 47 months (95% CI 45-50), median overall survival (OS) was 59 months (95% CI 51-67) and 3-year OS was 59% (95% CI 56-61). Whilst both Mayo 2012 and European modification models were predictive of overall survival, the European modification discernibly discriminated those with the poorest and best outcomes. Median OS by European staging for stage I, II, IIIa, IIIb was: not reached (NR), 76, 34 and 8 months respectively, compared with Mayo 2012 stage I, II, III, IV: NR, 74, 36, and 26 months respectively. European stage II, IIIa, IIIb had a hazard ratio (HR) for death of: 2.42 (95% CI 1.69-3.49), 4.65 (95% CI 3.27-6.61) and 9.18 (95% CI 6.36-13.25), respectively. Mayo stage II, III, IV had a HR of: 2.54 (95% CI 1.72-3.76), 4.66 (95% CI 3.21-6.76) and 5.99 (95% CI 4.12-8.71), respectively. Conclusion: Advanced stage cardiac involvement remains a prognostic predictor of adverse outcomes. In a cohort of bortezomib-treated patients, the European modification has a stronger predictive value for poorer outcome. The Mayo 2012 staging, utilising additional dFLC, did not discriminate the most advanced disease as well suggesting that treatment markedly impacts the predictive capability of cardiac staging systems. Daratumumab-based treatments may have an even greater impact in ameliorating the adverse prognostic significance of high presenting dFLC. Until cardiac staging is revalidated for the modern treatment era of AL amyloidosis, our data should be taken into consideration when using cardiac staging systems in the clinic as well as for clinical trial design.

Real-World Evaluation of Outcomes in Relapsed/Refractory Multiple Myeloma Patients That Are Triple-Class Exposed after Receiving 2 or More Prior Lines of Therapy

Background: Recent studies have shown that a majority of multiple myeloma (MM) patients (pts) in the United States (US) are triple-class exposed (TCE) after four lines of therapy (LOT), with poor prognosis for TCE patients. As treatment for MM evolves to include more advanced triplet and quadruplet regimens, a growing number of US pts are likely to reach TCE status in earlier lines of treatment. Therefore, we sought to evaluate the frequency of pts reaching TCE status after receiving two or more prior LOT (3L+) and their associated clinical outcomes. Methods: This retrospective studyused de-identified health records from the ConcertAI Patient360 MM EMR database, which consists primarily of data from community-based oncology centers in the US. The primary objective was to compare real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) between 3L+ pts with TCE status to those without TCE status. TCE was defined as exposure to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Eligibility criteria included adult subjects (age ≥ 18) diagnosed with MM between January 1, 2011 and September 30, 2022, who received at least one line of therapy post-diagnosis, did not undergo stem cell transplantation prior to treatment, did not have any other primary cancer diagnosis at baseline (1 year prior to initial diagnosis), and initiated 3L therapy from January 1, 2017, to September 30, 2022. Progression-based LOT was defined using ConcertAI's proprietary regimen-based LOT, modified to advance to a new line only after discontinuation of at least 1 year or a progression event. rwPFS and rwOS by were calculated via Kaplan-Meier method, with differences evaluated using the log-rank test. Pts without physician-documented progression or survival events were censored at the subsequent LOT or latest follow-up for PFS and were censored at the latest follow-up for OS. Results: Overall, 557 pts meeting eligibility criteria initiated 3L therapy in 2017 and beyond were included in the analysis. Of these, 297 had 3 LOT, 146 had 4 LOT, and 114 had ≥ 5 LOT. Median age at diagnosis was 67.0 years (y), 48.1% were female, and 37.3% had transplant post-diagnosis. Most frequently, ECOG status was 1 (30%), eGFR ≥ 60 (40%) and R-ISS stage 3 disease at diagnosis (29%) with 27%, 28% and 34% of data not available, respectively. Median (range) follow-up for survivors from diagnosis was 63 (10 - 141) months. Most pts were treated at community-based centers (78.3%), located in the Southern US region (53.9%), with 74.0%, 20.3%, and 4.3% white, black and Hispanic pts represented, respectively. Overall, 429 (77%) pts were TCE: 32% were TCE prior to 3L initiation, 63% prior to 4L, and 74% prior to 5L. Among TCE pts, the percentage reaching TCE status within 1L, 2L, 3L, 4L, and 5L+ of therapy was 4%, 39%, 40%, 14%, and 3%, respectively. TCE pts were frequently retreated with agents, even after prior refractory status ( Figure A). Median (95% CI, Events n/N) rwPFS in 3L+ was 5.7 (5.2 - 6.4 mo, 358/464) in TCE pts vs 9.8 (8.5 - 11.8 mo, 337/498) in non-TCE pts (p<0.001). Median (95% CI, Events n/N) rwOS from time of 3L initiation was 15.9 (11.3 - 19.2 mo, 106/179) in TCE pts vs 31.5 (27.3 - 43.1 mo, 168/340) in non-TCE pts (p<0.001). Median rwPFS and rwOS were consistently lower in TCE vs non-TCE pts across 3 - 5 LOT ( Figure B). Conclusion: In this real-world cohort from predominantly community-based US oncology centers, approximately 80% of patients were TCE, with 83% reaching TCE status within 3 LOT. TCE pts experienced inferior rwPFS and rwOS compared with non-TCE pts. The inferior survival outcomes and frequent re-exposure to previously used agents after TCE status underscore the need to understand optimal sequencing of anti-myeloma agents, particularly given the advancements in modern immunotherapies.

Statistical Challenges from Trials of Potentially Curative Treatments: Validation of Cure Assumptions When Analyzing Zuma-7 Follow-up Data of Axi-Cel and Standard of Care Therapy

Introduction: ZUMA-7 is the largest randomized controlled trial (RCT) for chimeric antigen receptor (CAR) T-cell therapy which compared axicabtagene ciloleucel (Axi-cel) to standard of care (SoC) including autologous stem cell transplant (ASCT) for the treatment of relapsed or refractory DLBCL. Both arms of ZUMA-7 contained potentially curative treatments; however, differences in the treatment completion rate (94% received axi-cel and 36% received ASCT) and timing to receive definitive treatment led to differences in the extent and timing of cure. Furthermore, 57% of the SoC arm received potentially curative CAR-T therapies in subsequent lines of therapy leading to a delayed cure in that fraction of the population. The resulting event-free survival (EFS) and overall survival (OS) curves can pose challenges in interpretation and extrapolation for the purpose of simulations of long-term treatment effects and cost-effectiveness. Mixture cure modeling (MCM) has been suggested as a superior method to evaluate treatments of a curative nature to allow for part of the population to achieve long-term remission. This method has been shown to be useful both in designing and powering clinical studies of curative therapies but also for extrapolation of long-term outcomes in simulation studies. However previous iterations of this method did not account for differences in timing of curative therapies. ZUMA-7 had two pivotal analyses separated by nearly 2-years of follow-up: a primary EFS (datacut 1) and a primary OS analyses (data cut 2). The aim of this study was to use the two data cuts of ZUMA-7 to validate MCM in 2L LBCL and describe differences that may have arisen due to treatment specific timing and extent of cure. Methods: Overall survival individual patient-level data from the ZUMA-7 trial for axi-cel and SoC from both data cut 1 (median follow-up: 24.9 months) and data cut 2 (median follow-up: 47.2 months) were used in this analysis. Three different parametric modeling approaches were applied and compared in both data cuts: standard parametric model, spline-based model, and MCMs. Modeling approaches were evaluated for plausibility across a range of metrics, across the two data cuts, including visual fit, plausibility of long-term estimates, statistical goodness of fit, inspection of hazard plots, point-estimate accuracy, and conditional survival estimates. Additionality, the ability of the early data cut extrapolation to predict the actual data was assessed by comparing the model predictions with the latest KM estimator in both trial arms. Differences between trial arms were evaluated. Results: Cure-based and spline models provided the best fit based on the percentage inaccuracy of extrapolations fitted with data cut 1 in comparison to 5-year OS Kaplan-Meier estimates confirmed by data cut 2. In the axi-cel treatment arm, the percentage inaccuracy range between 2% and 27% (Figure 1). Based on data cut 1, cure fractions ranged considerably across the MCM extrapolation forms considered for both treatment arms (range: 24-54% [Figure 2] and 35-49% for axi-cel and SoC, respectively). Notably, the range of cure fractions narrowed considerably based on extrapolations performed on the more mature data cut 2 (range: 50-54% [Figure 2] and 41-50% for axi-cel and SoC, respectively). Overall, the uncertainty in the estimate of cure fractions based on MCMs was reduced from data cut 1 to data cut 2 for axi-cel vs. SoC, suggesting clinical input is needed to validate early extrapolations using less mature data cuts. Conclusion: Our analysis suggests that MCMs are helpful in making accurate predictions of survival based on immature data when a plateau in the survival curve is clinically plausible. However, this analysis also highlights the importance of considering clinical plausibility to guide specific curve selection in the presence of immature survival data, as there was a high degree of variability in the early extrapolations which was reduced with the longer-term follow-up. The ability to reliably extrapolate from early data may improve clinical decision making and reduce delays in patient access to potentially lifesaving treatments as more mature follow-up data are being collected.