Era Of Chemoimmunotherapy Research Articles

EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2024 update on the diagnosis, risk-stratification, and management.

Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an aggressive B-cell lymphoma associated with EBV infection included in the WHO classification of lymphoid neoplasms since 2016. Although historically associated to poor prognosis, outcomes seem to have improved in the era of chemoimmunotherapy. The diagnosis is established through meticulous pathological evaluation. Detection of EBV-encoded RNA (EBER) is the standard diagnostic method. The ICC 2022 specifies EBV+ DLBCL, NOS as occurring when >80% of malignant cells express EBER, whereas the WHO-HAEM5 emphasizes that the majority of tumor cells should be EBER positive without setting a defined threshold. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, among others. The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. Therefore, inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

Monitoring Response and Resistance to Treatment in Chronic Lymphocytic Leukemia.

The recent evolution in chronic lymphocytic leukemia (CLL) targeted therapies led to a progressive change in the way clinicians manage the goals of treatment and evaluate the response to treatment in respect to the paradigm of the chemoimmunotherapy era. Continuous therapies with BTK inhibitors achieve prolonged and sustained control of the disease. On the other hand, venetoclax and anti-CD20 monoclonal antibodies or, more recently, ibrutinib plus venetoclax combinations, given for a fixed duration, achieve undetectable measurable residual disease (uMRD) in the vast majority of patients. On these grounds, a time-limited MRD-driven strategy, a previously unexplored scenario in CLL, is being attempted. On the other side of the spectrum, novel genetic and non-genetic mechanisms of resistance to targeted treatments are emerging. Here we review the response assessment criteria, the evolution and clinical application of MRD analysis and the mechanisms of resistance according to the novel treatment strategies within clinical trials. The extent to which this novel evidence will translate in the real-life management of CLL patients remains an open issue to be addressed.

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Efficacy of carboplatin–etoposide rechallenge after first-line chemo-immunotherapy in ES-SCLC: an international multicentric analysis

Background and objectives: Second-line treatment for small-cell lung cancer (SCLC) is primarily guided by the time elapsed since the last platinum dose. Rechallenge with carboplatin and etoposide has demonstrated superior outcomes compared to topotecan if the platinum-free interval (PFI) is longer than 90 days and is considered the standard of care. However, these findings predate the chemo-immunotherapy era. This study investigates the effectiveness of the rechallenge strategy after chemo-immunotherapy in a real-world setting. Design and methods: We retrospectively reviewed patients with the extensive stage (ES)-SCLC who received rechallenge with carboplatin and etoposide after first-line chemoimmunotherapy between September 2020 and August 2023 in nine European centres. Demographic and clinical data were collected and analysed. Results: A total of 93 patients were included. Sixty-six (71%) patients had a PFI between 3 and 6 months. Consolidation thoracic radiotherapy and prophylactic cranial irradiation had been administered in 31 (33.3%) patients and 20 (21.5%) patients, respectively. Overall response rate was 59.1%. Median progression-free survival (PFS) was 5 months (95% confidence interval (CI) 4.3–5.7) and median overall survival (OS) was 7 months (95% CI 5.7–8.3). Notably, PFS and OS were not different according to PFI (3–6 m vs > 6 m). Conclusion: Rechallenge with carboplatin and etoposide is a valid second-line option in patients with ES-SCLC whose disease progresses after first-line chemoimmunotherapy. Our analysis shows similar results to previous studies. Furthermore, outcomes were consistent across patients with different PFIs, confirming its efficacy in patients with a PFI longer than 3 months.

Association of Measurable Residual Disease with Progression-Free Survival in Patients with Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis in the Era of Novel Agents

Introduction: Achieving undetectable measurable residual disease (uMRD) following treatment has shown significant prognostic value in several hematological malignancies. In chronic lymphocytic leukemia (CLL), uMRD is associated with improved outcomes in the era of chemoimmunotherapy (CIT). However, the role of measurable residual disease (MRD) in the context of novel agents such as Bruton tyrosine kinase inhibitors (BTKi) and/or BCL2 inhibitors (e.g. venetoclax) is uncertain. To address this question, we conducted a systematic review of the literature and performed a comprehensive meta-analysis of trials that included novel agents to evaluate the association between MRD status after treatment and PFS in patients with CLL. Methods: We conducted a comprehensive search of PubMed, EMBASE, Scopus, and Web of Science focusing on CLL trials reporting MRD and its association with PFS. Results were independently screened by two reviewers. Inclusion criteria included prospective phase 3 trials involving a novel agent in one of the treatment arms, while studies with incomplete information on MRD status related to PFS, reviews, abstracts, and retrospective analyses were excluded. The initial search identified 185 studies in PubMed and 402 studies in EMBASE. After applying prespecified criteria, a total of 10 phase 3 trials were included in our analysis. We extracted sample size, patient age, follow-up time, time point and tissue of MRD assessment, MRD cut-off and rate, performance status and molecular status when available. We only considered treatment arms with complete MRD information. The comparison involved patients who achieved uMRD with those exhibiting detectable MRD. When available, hazard ratios (HR) and confidence intervals (CI) were used to evaluate the relationship between MRD status and PFS. If not, we used Kaplan-Meier (KM) curves from both uMRD and MRD subgroups and extracted the coordinates points of the curves using DigitizeIt software (version 2.5.10, I. Bormann) and using the number at risk provided we estimated the HRs and CIs. A meta-analysis was performed using a random effects model from the R package metafor (Viechtbauer, W. (2010). Conducting meta-analyses in R with the metafor package. Journal of Statistical Software, 36(3), 1-48). The pooled hazard ratio estimates, and the corresponding 95% CI and prediction intervals (PI) were reported. Funnel and Baujat plots were generated to assess study heterogeneity and bias. All analysis was performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). Results: A total of 10 phase 3 trials, encompassing 14 treatment arms and involving 3152 patients, met the stringent inclusion criteria. All but one study used a uMRD cut-off of < 0.01%. Detailed information on the treatment arms and key trial characteristics is presented in Table 1. Notably, ten treatment arms were derived from first-line treatment trials, while the remaining arms pertained to the relapsed/refractory population. Only two trials (4 treatment arms) assessed MRD using next generation sequencing (NGS), while the rest used multicolor flow cytometry (MFC) (9 treatment arms) and allele-specific oligonucleotides polymerase chain reaction (ASO-PCR) (2 treatment arms). All but 3 trials assessed MRD in both bone marrow (BM) and peripheral blood (PB). One trial (2 treatment arms) was excluded from the met-analysis due to higher MRD cut-off. All studies included in the meta-analysis measured uMRD (<0.01) versus MRD. The PFS pooled HR estimate for achieving uMRD at 0.01 cut off from the meta-analysis was 0.32 (95% CI [0.22, 0.45]), with minimal bias observed on the Funnel Plot. Conclusions: In this comprehensive meta-analysis, comprising 9 phase 3 trials, achieving uMRD was strongly associated with PFS. These findings further establish the prognostic role of MRD in CLL management and its potential use as a surrogate marker in clinical trials. As the body of evidence on MRD in CLL continues to grow, it becomes imperative to standardize the optimal time point, methodology, and tissue for MRD assessment. Substantial heterogeneity in these aspects underscores the necessity for unified guidelines to ensure the accurate and consistent evaluation of MRD status in clinical practice.

Intrathoracic Progression Is Still the Most Dominant Failure Pattern after First-Line Chemo-immunotherapy in Extensive-Stage Small-Cell Lung Cancer: Implications for Thoracic Radiotherapy.

This study aimed to compare the failure patterns before and after the introduction of immunotherapy and to determine the role of thoracic radiotherapy (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) treatment. We retrospectively reviewed 294 patients with ES-SCLC, of which 62.2% underwent chemotherapy alone, 13.3% underwent chemotherapy followed by consolidative TRT (TRT group), and 24.5% underwent chemotherapy with immune checkpoint inhibitor (ICI group). We performed propensity-score matching (PSM) to compare each treatment group. The median follow-up duration was 10.4 months. At the first relapse, in the cohort showing objective response, the proportion of cases showing intrathoracic progression was significantly lower in the TRT group (37.8%) than in the chemotherapy-alone (77.2%, p < 0.001) and the ICI (60.3%, p=0.03) groups. Furthermore, in the subgroup analysis, TRT showed benefits related to intrathoracic progression-free survival (PFS) in comparison with ICI in patients with less than two involved extrathoracic sites (p=0.008) or without liver metastasis (p=0.02) or pleural metastasis (p=0.005) at diagnosis. After PSM, the TRT group showed significantly better intrathoracic PFS than both chemotherapy-alone and ICI groups (p < 0.001 and p=0.04, respectively), but showed no significant benefit in terms of PFS and overall survival in comparison with the ICI group (p=0.17 and p=0.31, respectively). In ES-SCLC, intrathoracic progression was the most dominant failure pattern after immunotherapy. In the era of chemoimmunotherapy, consolidative TRT can still be considered a useful treatment strategy for locoregional control.

Trends in Survival Outcomes for Mantle Cell Lymphoma in the Era of Novel Therapies

Introduction Mantle Cell Lymphoma (MCL) is a rare malignancy, associated with aggressive features and poor outcomes. Previous treatment paradigms for MCL involved chemoimmunotherapy and stem cell transplant (SCT), though this has evolved in recent years with the introduction of novel treatments, including bruton's tyrosine kinase (BTK) inhibitors, chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents such as lenalidomide. Additionally, the incorporation of rituximab maintenance therapy following SCT has demonstrated improved progression-free (PFS) and overall survivals (OS) for MCL patients (pts). While the majority of these novel agents and treatments were FDA approved by demonstrating improved PFS, the benefits of these new treatments on OS trends for MCL pts are not well described. Therefore, to determine whether these advances have translated to OS improvement in the real-world setting, we performed a national analysis of OS trends through multiple treatment eras. Methods The National Cancer Database was used to identify pts diagnosed with MCL from 2004-2020. For pts receiving treatment, the use of front-line single or multiagent therapy, and upfront SCT was compared. Kaplan-Meier and Cox regression analysis was used to compare OS for all MCL pts. Survival was compared by year of diagnosis, with diagnosis in 2004-2013 considered to be managed in the era of chemoimmunotherapy, 2014 and later associated with the introduction of BTK inhibitors, and 2017 and later with the adoption of maintenance rituximab following SCT. Results A total of 31,284 pts with MCL were identified. The mean age at diagnosis was 67 years (yrs) [SD ±12], 93% of pts were White, and 70% had stage IV disease at diagnosis. Pts were increasingly more likely to have ≥2 comorbidities at MCL diagnosis (6.2% from 2004-2013, 8.6% from 2014-2016, and 10.8% from 2017-2020) and were increasingly managed at academic centers (40%, 44%, and 46%, respectively). Rates of pts managed with active surveillance significantly increased over time (4.7% from 2004-2013, 6.7% from 2014-2016, and 8.7% from 2017-2020). Regarding treatment, the rate of upfront multi-agent chemotherapy use decreased over time (67.7% from 2004-2013, 45.2% from 2014-2016, and 38.9% from 2017-2020), corresponding with an increase in single agent treatment (7.9%, 28.2%, and 32.4%, respectively). Notably, the rate of pts receiving SCT following front-line treatment remained similar in each time period (13.6%, 15.4%, and 14.1%, respectively). With a median follow-up of 3.5 yrs, the median OS for all pts with MCL from 2004-2020 was 5.9 yrs (95% CI 5.8-6.0 yrs). The median OS was significantly increased when comparing pts who were diagnosed between 2004-2013 (5.5 yrs) to those diagnosed 2014-2016 (6.8 yrs), and median was not reached for pts diagnosed 2017-2020 (all p&amp;lt;0.001). The median 1-, 3-, and 5-year OS significantly increased following the availability of novel agents after 2014 (2004-2013: 1-year 80%, 3-year 63%, 5-year 52% vs. 2014-2016: 1-year 82%, 3-year 67%, 5-year 58%, p&amp;lt;0.001). Whereas, pts diagnosed from 2017-2020 had similar OS trends as pts diagnosed from 2014-2016 with 1-year 82%, 3-year 66%, 5-year 51% OS, respectively. When adjusted for age and comorbidity burden, the most recent time periods were associated with decreased risk of death (2014-2016: HR 0.81 [95% CI 0.78-0.85], and 2017-2020: HR 0.82 [95% CI 0.78-0.86]) when compared to 2004-2013 (all p&amp;lt;0.001). Conclusions: To our knowledge, this is the largest retrospective review evaluating treatment trends and OS outcomes in pts with MCL in recent decades. These data show that OS has significantly improved for pts diagnosed in the most recent time periods. We hypothesize this is due to the introduction of novel agents such as BTK inhibitors, which is supported by the increased rate of single agent treatment over time, which may be related to BTK inhibitors supplanting chemoimmunotherapy in the front-line setting. We also found that no additional OS improvement was observed during the time period following the adoption of rituximab maintenance after transplant, which may be due to the limited number of pts receiving SCT through each time period. With more follow-up data, future studies may determine whether treatments such as CAR-T (FDA approved in 2020 with data not included in this cohort) have further improved OS outcomes for this incurable malignancy.

Longitudinal Analysis of Patient Reported Quality of Life in Newly Diagnosed Chronic Lymphocytic Leukemia Stratified By Initial Management Strategy: A Multi-Institutional Prospective Cohort Study

Introduction: The treatment of chronic lymphocytic leukemia (CLL) has evolved over the past two decades, from finite duration chemoimmunotherapy (CIT) to an era of targeted agents such as Bruton Tyrosine Kinase (BTK) inhibitors, BCL2 inhibitors, and anti-CD20 monoclonal antibodies. Little is known about how initial management strategy (watch and wait [W&amp;W] vs. treatment) at diagnosis impacts patient reported outcomes (PROs) in CLL survivors over time, particularly in light of therapeutic advances over the last decade. Methods: Newly diagnosed CLL patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER1) study between 9/1/02 and 6/30/15, and within 6 months of diagnosis in the MER Phase 2 (MER2) study between 7/1/15 and 5/1/20. PROs were measured using the Functional Assessment of Cancer Therapy-General scale (FACT-G), which generates Physical (PWB, range 0-28), Social/Family (SFWB, 0-28), Emotional (EWB, 0-24), and Functional Well-Being (FWB, 0-28) scores and a Total Score (0-108), with higher scores indicating better WB. In both cohorts, FACT-G was measured at enrollment and at years 1, 2, and 3 after diagnosis, while the timing of later assessments varied slightly by study (MER1: 6 yrs and 9 yrs; MER2: 5 years). We employed a generalized linear mixed model to evaluate change from baseline between groups with groups defined by each participant's initial management strategy (W&amp;W vs. upfront systemic treatment). Initial management strategy was determined by the treating physician. The study was approved by the Mayo Clinic IRB. Results: A total of 722 patients were identified in MER1 and 256 patients in MER2. The median age at diagnosis was 63 years in MER1 and 66 years in MER2 (P&amp;lt;0.05); 66% were male in MER1 and 68% were male in MER2 (P&amp;gt;0.05). More patients initiated upfront systemic therapy in MER1 (n=380, 53%) than in MER2 (n=110, 43%). Other baseline clinical characteristics were similar between the cohorts ( Table 1). There was no statistical difference in the mean FACT-G total score at baseline between MER1 (85.0, SD 12.5) and MER2 (85.2, SD 12.7). In the MER1 cohort, statistically significant lower baseline QOL scores were observed in patients initiating upfront treatment compared to W&amp;W on the FACT-G total score (P=0.002) as well as the PWB (P=0.01), EWB (P=0.03), and FWB (P=0.006) subscales. We also observed that over time, EWB and FWB scores were consistently lower amongst those treated upfront compared to W&amp;W. Further, EWB scores steadily improved over time regardless of initial management ( Figure 1), whereas the FWB and PWB subscales were largely stable over time. Mean SFWB scores dropped amongst patients who received upfront therapy at 3 years, which then steadily improved through year 9 but did not recover back to baseline. SFWB scores were stable among W&amp;W patients. In the MER2 cohort, no statistically significant differences in any of the baseline QOL scores were noted between the W&amp;W vs. initial treatment groups. Despite this, we observed consistently lower mean EWB scores among patients who initiated upfront treatment compared to W&amp;W pts over time. No other statistically significant differences in mean QOL scores over time were observed between groups. Similar to MER1, we did observe a drop in mean SFWB scores amongst patients initiating upfront therapy at 3 years of follow-up that remained decreased at year 5. Conclusion: This is the largest longitudinal study of CLL survivors that spanned over 18 years and two treatment eras. We demonstrated that in the novel treatment era, QOL metrics were similar between initial management strategies (W&amp;W vs. treatment), suggesting that initial management had little to no impact on QOL at baseline or over time. In contrast, in the CIT era, we observed differences in QOL metrics at baseline between groups. In both treatment eras, patients with CLL who required upfront therapy demonstrated a decrease in SFWB from baseline at year 3 of follow-up, and the mean EWB scores were lowest at baseline regardless of initial management strategy (W&amp;W vs. upfront treatment) or treatment era (CIT vs. novel agents), but steadily improved over time. These findings suggest opportunities for interventions to improve QOL in patients with CLL, and additional analyses are ongoing. Further follow-up in the era of novel agents is needed.

EP13.03-12 Prophylactic Cranial and Consolidation Thoracic Radiation in Extensive Stage Small Cell (ES-SCLC) Lung Cancer in the Chemo-immunotherapy Era

EP13.03-12 Prophylactic Cranial and Consolidation Thoracic Radiation in Extensive Stage Small Cell (ES-SCLC) Lung Cancer in the Chemo-immunotherapy Era

2001P Consolidative thoracic radiotherapy of extensive-stage small cell lung cancer in the era of chemoimmunotherapy: A retrospective analysis concerning patients from southern Italy

2001P Consolidative thoracic radiotherapy of extensive-stage small cell lung cancer in the era of chemoimmunotherapy: A retrospective analysis concerning patients from southern Italy

The Impact of Prophylactic Cranial Irradiation and Consolidative Thoracic Radiation Therapy for Extensive Stage Small-Cell Lung Cancer in the Transition to the Chemo-Immunotherapy Era: A Single Institution Series

IntroductionExtensive-stage small-cell lung cancer (ES-SCLC) continues to have poor survival due to its aggressive behavior, despite improvements with incorporation of immunotherapy with standard chemotherapy. Controversy exists regarding the role of consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) in ES-SCLC due to high recurrence rates. We report our institutional result of the benefit of PCI and TRT in ES-SCLC. MethodsPatients with ES-SCLC without intracranial metastasis at diagnosis (N = 163) were included. All patients completed systemic therapy with or without immunotherapy based on time of standard of care. Cohorts were divided by systemic therapy use and further subdivided by treatment with PCI and TRT. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method with log-rank test for comparison. The effects of TRT and PCI were estimated by multivariable (MVA) Cox regression. ResultsSeventy-four patients (45.4%) received TRT, and 33.1% (n = 54) received PCI. The median follow-up was 11 months (3-85 months). PCI improved median OS to 15 months from 10 months, P = .02) and median PFS to 8.5 months from 5 months (P = .02) which remained significant on MVA, P = .02 and P = .02, respectively. TRT improved OS on UVA (P = 0.002) but was not significant on MVA. TRT did not improve PFS. ConclusionThis study including chemotherapy and chemo-immunotherapy suggests improved outcomes with addition of PCI in patients with ES-SCLC while TRT did not show benefit to either OS or PFS. A future trial is needed to evaluate the role of TRT and PCI in the era of chemo-immunotherapy.

Role of consolidative thoracic and prophylactic cranial radiation in extensive stage small cell lung cancer in chemo-immunotherapy era.

8595 Background: The role of consolidative thoracic and prophylactic brain radiation in extensive stage small cell lung cancer patients is controversial. We investigated the factors associated with the use of any radiation therapy (RT) and whether Radiation has a benefit to overall survival (OS) in the total patient group and whether this benefit is the same if Chemotherapy (CT) only is used, or chemo-immunotherapy (CT-IO) is used. Methods: The NCDB database was queried from years 2017-2019. Patients receiving systemic therapy- STX (CT or CT-IO) had to have at least 6 months of follow-up and have no brain metastases at diagnosis. All RT patients had to receive upfront systemic therapy, were treated 2 to 6 months from diagnosis, and if treated to the brain received 25Gy in 10 fractions only. Multi-variate analyses (MVA) were used to determine factors associated with OS and selection for any radiation. Propensity matching for factors affecting OS were used to generate Kaplan-Meier OS curves. Log-rank tests were used to determine differences in Kaplan Meier survival curves for the effects of RT on OS. Results: The total number of patients receiving RT or systemic therapy alone as well as their median follow-ups(months(mn) were (981, 33.02mn) and (8909, 30.59mn). The median time to the start of STX and RT were 22days and 135 days respectively. MVA noted that RT had a greater effect on OS (Thoracic, Brain, Both – HRs = 0.78, 0.75, and 0.68) than other interventions including IO (HR 0.87) and palliative care without RT (HR 1.07). Selection for radiation depended significantly upon factors affecting OS(HR) including liver metastases (0.59), females (1.21), age/10yr(0.78) and Charlson co-morbidity index of &gt; 3(0.66), but did not depend upon insurance status, race, or county income/high school graduation rates. Propensity score matched OS curves noted the same effects of RT on OS whether CT or CT-IO was given. The lowest HRs were noted when both thoracic and brain RT were given (see table). Conclusions: The patient with extensive stage small cell lung cancer who reach candidacy and receive RT may have a significant improvement in OS compared to the patients treated only with CT or CT-IO. Combined thoracic and prophylactic brain RT seems to be better than either one alone. The impact of radiation whether given to one or two sites may be more beneficial than immunotherapy added to chemotherapy. [Table: see text]

Relationship between BCL2 mutations and follicular lymphoma outcome in the chemoimmunotherapy era

How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS, and MYC, in 199 newly diagnosed grade 1 and 2 FLs. BCL2 mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04–8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02–2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05–3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.

Is consolidative thoracic radiotherapy of extensive-stage small cell lung cancer still beneficial in the era of immunotherapy? A retrospective analysis

PurposeExtensive-stage small cell lung cancer (ES-SCLC) carries a dismal prognosis. The benefit of consolidative thoracic radiotherapy (TR) after first-line chemoimmunotherapy with PD-L1 inhibitors in this setting remains unclear. As TR can improve overall survival (OS) after conventional chemotherapy, we retrospectively analyzed OS of an inhouse cohort treated either with TR or with chemoimmunotherapy alone.MethodsA total of 41 patients treated with chemoimmunotherapy with PD-L1 inhibitors (atezolizumab or durvalumab) for ES-SCLC at our hospital since 2019 were analyzed. TR was administered in 10 fractions of 3 Gy. Patient characteristics, number of immunotherapy cycles received, brain irradiation, and presence of hepatic and cerebral metastasis at diagnosis were assessed. Primary endpoint was OS after first diagnosis.ResultsConsolidative TR was associated with a significantly longer OS than systemic therapy alone (1-year OS 78.6% and 2‑year OS 37.1% vs. 1‑year OS 39.7% and 2 years not reached, p = 0.019). With regard to radiotherapy indication, survival at 1 year was 88.9% (log-rank p = 0.016) for patients receiving consolidative TR. For patients receiving TR in case of progression, 1‑year survival was 66.7%. Hepatic and cerebral metastasis at first diagnosis had no significant effect on OS.ConclusionTR was significantly associated with longer OS. The survival benefit of TR was most pronounced for consolidative radiotherapy after initial chemoimmunotherapy compared to TR in case of progression. Although retrospective findings need to be interpreted with caution, in the absence of prospective data, our findings provide a basis for offering consolidative TR in the era of chemoimmunotherapy.

(Peri)Centromeric Rearrangements Are Recurrent Recombination Events in Complex-Karyotype Chronic Lymphocytic Leukemia

Background: A retrospective cytogenetic study encompassing 5290 patients with chronic lymphocytic leukemia (CLL) identified complex karyotype (CK) as adverse prognostic factor. In cases with ≥5 chromosomal aberrations (CAs), this finding was independent of TP53 alterations (Baliakas et al., 2019) Which chromosomal rearrangements dominate CK-CLL is insufficiently defined impeding the identification of genomic events responsible for poor prognosis. To delineate cytogenetic aberrations in CK-CLL, we analysed conventional karyotypes from 125 patients classified as high-risk during the era of chemoimmunotherapy. Methods: Chromosome banding (CBA, CpG oligonucleotide and IL-2 stimulation, N=131), SNP-array analysis (Affymetrix 6.0, N=109), DNA methylation analysis (Illumina Infinium HumanMethylation450 BeadChips, N=45) and telomere length measurement (N=122) was conducted on samples taken at enrolment on the CLL2O trial of the GCLLSG/FCLLSG (NCT01392079). This trial encompassed CLL patients (pts) with TP53 alteration (deletion/mutation, TP53alt; treatment-naïve or purine-analogue relapsed/refractory) and TP53intact purine-analogue refractory disease. CBA and TP53 mutation data from the CLL11 trial of the GCLLSG (NCT01010061, N=152) was integrated for multiple linear regression. Results: An informative karyotype was obtained in 125/131 pts (for clinical/genetic features see Table). The total number of CBA-detected CAs was 618 with an average of 4.9 CAs per case (range 0-21). Pts with TP53alt had a significantly higher karyotype complexity than pts without (5.3 vs 2.7 CAs mean, p=0.02). A normal karyotype was found in 2 pts, a non-CK in 32 pts (≤2 CAs; 20 pts TP53alt), a low- or intermediate-CK in 34 pts (3 or 4 CAs, 30 pts TP53alt), and a high-CK in57 pts (≥5CAs, 54 pts TP53alt). Cytogenetic aberrations comprised 341 derivative chromosomes, 131 interstitial/terminal losses, 65 monosomies, 53 balanced translocations, 21 trisomies, 5 inversions, and 2 interstitial gains. Remarkably, 308/618 CAs had at least one breakpoint in the centromere (p10/q10; N=70) or in p11/q11 (N=238) directing our interest towards (peri-)centromeric breakage. Chr17 was most frequently affected linking (peri-)centromeric breakage to TP53 loss. Whole arm translocations (WAT) constituted the most common cause for TP53 loss (N=47 in 39 pts) with chr18 (N=9), chr17 (N=6), chr8 (N=6) and chr15 (N=6) being the most frequent translocation partners. Other cytogenetic events underlying TP53 loss were complex unbalanced rearrangements (N=40 in 39 pts), simple interstitial/terminal deletion (N=22 in 22 pts) and dicentric chromosomes (DIC, N=8 in 8 pts, 6 with breakpoints in p11/q11). In total, 98/117 aberrations causing TP53 loss had breakpoints in (peri-)centromeric cytobands. Mapping chr17 breakpoints based on SNP-array results revealed that more than half (58%) clustered within a 1 Mb region on both sides of the centromere. In contrast, chr17 breakpoints in CK-AML are random suggesting that chr17 (peri-)centromeric instability is specific for high-risk CLL. (Peri-)centromeric rearrangements in form of WAT and DIC were also found to occur without chr17 involvement (N=24 in 20 pts and N=12 in 8 pts, respectively). Chromosome involvement was random pointing towards general (peri-)centromeric instability. Multiple linear regression revealed only karyotype complexity but not TP53alt or prior treatment as significant risk factor for WAT/DIC substantiating the notion that (peri-)centromeric instability is an intrinsic hallmark of high-risk CLL. DNA methylation patterns in regions adjacent to pericentromeric breakpoint clusters located on chr17p and chr18p showed no abnormalities when compared to cases without chr17/chr18 aberrations. Telomere length was significantly shorter in cases harboring at least one (peri-)centromeric rearrangement (p<0.001), but this association could not be confirmed when restricting the analysis to non-CK cases (N=20 vs 13, p=0.08). Conclusions: Karyotype complexity was confirmed as typical feature of high-risk CLL. (Peri-)centromeric aberrations showed up as new hallmark characteristic of CK-CLL and WAT/DIC as otherwise rare events in hematologic malignancies were frequently observed. The underlying reasons for (peri-)centromeric breakage and its prognostic impact beyond karyotype complexity and TP53 alterations require further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of race on treatment outcomes in triple-negative breast cancer at an academic medical center.

e12616 Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and in all but the smallest tumors, neoadjuvant chemotherapy (NACT) is part of the standard of care. Black women (BW) suffer a poorer prognosis than white women (WW) with TNBC, and whether this is due to differences in treatment, disease biology, or socioeconomic variables is not fully known. This study, conducted at a racially diverse academic medical center, aimed to investigate factors associated with unfavorable outcomes in BW with TNBC. Methods: 131 patients with TNBC received NACT from 2008-2017 at Winship Cancer Institute were included in this retrospective study. Descriptive statistics were applied to delineate the relationship with racial disparity. Clinical outcomes include progression free survival (PFS) and distance metastasis free survival (DMFS) and were analysis using Cox proportional hazard model. Results: Among 131 patients with TNBC treated with NACT, 58.5% were BW and median age was 55. BW and WW had similar disease staging at diagnosis and similar pathologic responses to treatment. Yet, BW were less likely to complete NACT compared with WW (80.8% BW completed NACT vs 98.0% WW, p=0.005). BW were more likely to either not complete NACT or to require dose reduction or dose delay (42.5% BW vs. 23.1% WW, p=0.024). Coexisting hypertension (65.8% BW vs. 35.2% WW), elevated BMI (31.7% BW vs. 27.5% WW), or covered by Medicaid (29.3% BW vs. 13.0% WW) were more common among BW. Medicaid insurance was associated with worse progression-free survival (HR 2.49, p=0.015) and distant metastasis free survival (DMFS, HR 2.73, p=0.018). Dose delays were associated with worse DMFS (HR 3.02, p=0.017). Discussion: In this study, we found that BW were less likely to complete NACT than WW, more likely to suffer dose delays, and more likely to require dose reductions. BW were also more likely to have Medicaid insurance, another factor that correlated with inferior outcomes; perhaps because patients with Medicaid insurance are also more likely to suffer from reduced access to transportation, childcare, and other infrastructure critical to maintaining a schedule for NACT. More research is needed to understand the reasons for the dose delays, dose reductions, and failures to complete NACT so that interventions can be designed to address them. Conclusions: As we move into the era of chemoimmunotherapy for TNBC, where drug combinations and treatment schedules are becoming even more complex, a better understanding of the reasons for dose delays, dose reductions, and treatment discontinuations will be key to maintaining optimal outcomes for TNBC patients, regardless of race.

EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk-stratification, and management.

Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the WHO classification of lymphoid neoplasms since 2016. EBV+ DLBCL, NOS, is an aggressive B-cell lymphoma associated with EBV infection, and a poor prognosis with standard chemotherapeutic approaches. The diagnosis is made through a careful pathological evaluation. Detection of EBV-encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for percentage of positive cells has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation, primary effusion lymphoma (PEL), among others. The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. Therefore, the inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

Matching-adjusted Indirect Comparison of the Efficacy of Loncastuximab Tesirine Versus Treatment in the Chemoimmunotherapy Era for Relapsed/Refractory Diffuse Large B-cell Lymphoma

BackgroundLoncastuximab tesirine (Lonca) and chemoimmunotherapy (CIT) have been assessed in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), but direct evidence from head-to-head randomized clinical trials is not available. Materials and MethodsMatching-adjusted indirect comparison (MAIC) was used to evaluate the efficacy of Lonca versus CIT-era treatment in R/R DLBCL. The analysis used individual patient data from the phase II LOTIS-2 trial of Lonca (NCT03589469) and pooled aggregated data from 2 extension studies of the CORAL trial for CIT. The LOTIS-2 trial included 145 patients who had relapsed or progressed following 2 or more multi-agent systemic treatment regimens; the CORAL extension studies included 203 patients who received 2 prior lines of therapy and 75 patients who relapsed after autologous hematopoietic cell transplantation. MAIC analyses were performed to adjust for cross-trial differences in inclusion/exclusion criteria and the distribution of observed baseline characteristics. Overall response rate (ORR) and overall survival (OS) were compared between the balanced trial populations. ResultsA total of 80 patients in LOTIS-2 were included in the analysis. After matching to the characteristics of 278 patients from the pooled CORAL extension studies, the ORR was significantly higher for Lonca compared with CIT-era treatment (53.4% vs. 40.3%, P < .05). Lonca was also associated with a significantly improved OS compared with CIT-era treatment (median OS 10.8 vs. 6.4 months; adjusted hazard ratio: 0.67 [95% CI: 0.48, 0.92], P < .05). ConclusionThis study indicates that Lonca was associated with significantly improved efficacy compared with CIT-era treatments for R/R DLBCL.

Survival, causes of death, and the prognostic role of comorbidities in chronic lymphocytic leukemia in the pre-ibrutinib era: A population-based study.

To evaluate temporal trends in survival and causes of death in patients with chronic lymphocytic leukemia (CLL) in a nationwide study. The cohort consisted of 13,009 Swedish CLL patients diagnosed 1982-2013. Relative survival (RS) and excess mortality rate ratios (EMRR) with 95% confidence intervals (95% CIs) were estimated using flexible parametric survival models. Cause-specific hazard ratios (HRs) were estimated for the linear effect of 10-year increase in year of diagnosis. The excess mortality decreased comparing 2003-2013 to 1982-1992 (EMRR=0.53, 95% CI 0.48-0.58). The 5-year RS increased between 1982 and 2012 for patients >51years at diagnosis and improved for patients ≤51years after 2002. The rate of CLL-specific deaths decreased over time (HR=0.78, 95% CI 0.75-0.81). Compared to patients with no comorbidity, patients with 1 and 2+ Charlson Comorbidity Index points had HR=1.35 (95% CI 1.25-1.45) and HR=1.47 (95% CI 1.37-1.57) for CLL-related mortality, respectively. Survival in CLL patients improved in the era of chemoimmunotherapy, and this was largely explained by reduced CLL-related mortality. The increased rate of CLL-related mortality in patients with comorbidities emphasizes the importance of the newer and better tolerated targeted therapy.

Performance of Standard Prognostic Models in Older Adults Receiving Ibrutinib for Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL): A Post Hoc Analysis of Alliance A041202 Phase 3 Trial

Performance of Standard Prognostic Models in Older Adults Receiving Ibrutinib for Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL): A Post Hoc Analysis of Alliance A041202 Phase 3 Trial