Chemoimmunotherapy Research Articles

Evaluating the potential of immunotherapy and chemoimmunotherapy in the treatment of elderly non-small cell lung cancer patients: A real-world study

BackgroundImmune checkpoint inhibitor (ICI) has become the standard therapy for metastatic non-small cell lung cancer (NSCLC) patients. However, no robust evidence on the efficacy and safety of ICI in elderly NSCLC patients has been established. Materials and MethodsThis retrospective study aimed to assess the efficacy and safety of ICI in elderly NSCLC patients. NSCLC patients treated with ICI monotherapy or chemoimmunotherapy (CIT) between 2016 and 2022 were divided into two cohorts according to the age: the Elderly cohort (patients aged ≥ 75 years) and the Nonelderly cohort (patients aged < 75 years). The progression-free survival (PFS), tumor response, and frequency of immune-related adverse events (irAEs) were compared between the two cohorts. ResultsA total of 111 NSCLC patients were included in this study (41 patients in the Elderly cohort and 70 patients in the Nonelderly cohort). The PFS (5.6 months vs. 6.3 months, P = 0.98), response rate (36.6% vs. 44.9%, P = 0.51), and disease control rate (80.5% vs. 76.8%, P = 0.83) were not significantly different between the two cohorts. In a subgroup analysis, stratified according to PD-L1 expression (low vs. high) and ICI treatment mode (ICI monotherapy vs. CIT), the PFSs of both cohorts were also not significantly different, regardless of PD-L1 expression. Moreover, the frequency of irAEs did not significantly differ between elderly and nonelderly NSCLC patients (21/41 [51.2%] vs. 38/70 [54.3%], P = 0.91). ConclusionThe efficacy and safety of ICI in elderly NSCLC patients were not inferior to those in younger patients.

A systematic review evaluating the efficacy of autologous hematopoietic transplantation for diffuse large B cell lymphoma-type Richter syndrome.

Chronic lymphocytic leukemia (CLL) can transform into fast growing lymphoma for diffuse large B-cell lymphoma (DLBCL) called Richter's syndrome (RS), which is commonly related to an existence of large B-cells with equal or larger size than macrophage nuclei or more than twice those of normal lymphocyte. We conducted a systematic review of the existing literature to assess the clinical efficacy of auto-HCT for patients with RS. We searched 4 main databases; EMBASE, Google Scholar, Scopus, PubMed and Web of Science and was done on December 26, 2021. All analyses in this study were performed by Stata software and this review was reported in accordance with PRISMA 2020. Data was extracted from 4 articles; the total number of patients was reported to be 110. Based on the meta-analysis findings, pooled overall survival rate was 56.36% (95%CI= (46.98-65.31). In figure 2, the forest plot of combined results is shown. Despite the use of common treatment regimens such as chemo immunotherapy and the availability of novel therapies including B-cell receptor inhibitors and rituximab-cyclophosphamide-hydroxydaunorubicin-Oncovin-prednisone (CHOP-R) regimen, the status of disease progression and recovery in RS cases is still not strong enough.

Time to second treatment can be used to predict overall survival in chronic lymphocytic leukemia: identifying risk factors to help guide treatment selection

Targeted therapies have largely replaced chemoimmunotherapy (CIT) in first-line treatment of chronic lymphocytic leukemia (CLL). We aimed to develop a prognostic model to determine who would benefit from first-line CIT vs target therapy. In follicular lymphoma, time from diagnosis to second treatment (TT2T) correlates better with overall survival (OS) than time from diagnosis to first treatment (TT1T). We hypothesized that TT2T is a potential surrogate for OS in CLL. In a model-building cohort (n = 298), we evaluated potential predictors for TT2T and derived a risk score, which we validated in an external cohort (n = 1141). Our data demonstrated that TT2T and OS were more strongly correlated than TT1T and OS. Our risk score model consisted of three predictors (unmutated IGHV, β2-microglobulin >297 nmol/L, and Rai stage I–IV), and was prognostic for TT2T and OS. TT2T is a promising surrogate for OS in CLL, but further validation is needed to establish this association.

Treatment of Richter's syndrome

Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). Outcomes are generally poor, with complete remission (CR) rates of only about 20% and less than 20% long-term survival with chemoimmunotherapy (CIT). RS is biologically heterogeneous, and in 80% of patients with CLL who develop DLBCL, the disease is clonally related to the CLL. Clonally unrelated cases are genetically and immunologically distinct from clonally related DLBCL-RS, have more favorable responses to CIT, and are best treated as de novo DLBCL. Relatively favorable outcomes with CIT are also seen in patients who have never previously received treatment for CLL and who lack TP53 mutation or deletion. For the remaining patients, treatment on a clinical trial is optimal. Fortunately, numerous agents are now in clinical development that show encouraging results. Here we review clinical data for some of the most promising approaches. DLBCL-RS tumor cells frequently express programmed cell death 1 protein (PD-1), and several studies have demonstrated activity for PD-1 inhibitors, especially in combination with ibrutinib. The BCL2 inhibitor venetoclax in combination with R-EPOCH CIT achieved CR in 50% of patients, and a study of venetoclax-R-CHOP is ongoing. The noncovalent Bruton's tyrosine kinase inhibitor pirtobrutinib has achieved responses in approximately two-thirds of heavily pretreated patients and, given its favorable toxicity profile, appears ideally suited to combining with other active agents. Finally, we review available data for bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy, which, after revolutionizing the treatment of DLBCL, are now being evaluated in RS.

Divergent paths: management of early relapsed follicular lymphoma

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and Western Europe. Overall outcomes for patients with FL have continued to improve over the last several decades-most notably, with the addition of the CD20 monoclonal antibody rituximab to the treatment armamentarium. More recently, we have seen advances in the management of patients with relapsed/refractory FL with the approval of several new treatments including lenalidomide, axicabtagene ciloleucel, copanlisib, umbralisib, and tazemetostat. Unfortunately, there remains a group of patients for which treatment outcomes, especially overall survival (OS), are suboptimal. This group has been identified as patients who relapse within 24 months (POD24) of completion of chemoimmunotherapy (CIT). Data indicate that patients who relapse within this window have a 5-year OS of around 50%, compared to 80% for those who remain in remission beyond 24 months. POD24 patients have been included and evaluated in the studies of the novel agents mentioned. While not specifically designed to treat this high-risk group, early data suggest that outcomes are not significantly impacted by this designation, unlike CIT. While to date the optimal management of POD24 patients has not been elucidated, the future appears bright with the continued use of the approved agents and several others in clinical development.

Necroptosis-dependent Immunogenicity of Cisplatin: Implications for Enhancing the Radiation-induced Abscopal Effect.

Cisplatin is increasingly used in chemoimmunotherapy and may enhance the T cell-dependent radiation-induced abscopal effect, but how it promotes antitumor immunity is poorly understood. We investigated whether and why cisplatin is immunogenic, and the implications for the cisplatin-enhanced abscopal effect. Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce type I IFN (IFN-I) and extracellular ATP, danger signals of ICD. The hypothetical role of necroptosis and associated damage-associated molecular patterns for cisplatin-induced ICD was investigated by inhibitors and knockout cells in vitro and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed. Cisplatin enhanced the abscopal effect more strongly than oxaliplatin or carboplatin. This correlated with higher induction of IFN-I and extracellular ATP by cisplatin, in a necroptosis-dependent manner. Cisplatin triggered receptor-interacting protein kinase 3 (RIPK3)-dependent tumor cell necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway and IFN-I secretion promoting T-cell cross-priming by dendritic cells (DC). Accordingly, tumor cell RIPK3 or mtDNA deficiency and loss of IFN-I or ATP signaling diminished the cisplatin-enhanced abscopal effect. Cisplatin-treated tumor cells were immunogenic in vaccination experiments, depending on RIPK3 and mtDNA. In human tumor transcriptome analysis, necroptotic features correlated with abundant CD8+ T cells/DCs, sparse immunosuppressive cells, and immunotherapy response. Cisplatin induces antitumor immunity through necroptosis-mediated ICD. Our findings may help explain the benefits of cisplatin in chemo(radio)immunotherapies and develop clinical trials to investigate whether cisplatin enhances the abscopal effect in patients.

A comprehensive assessment of lymphocyte subsets, their prognostic significance, and changes after first-line therapy administration in patients with chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), changes in the peripheral blood lymphocyte subsets play an important role in disease progression and infectious complications. The impact of chemoimmunotherapy (CIT) on these changes has not been extensively studied METHODS: We used multi-color flow cytometry, to prospectively measure absolute and relative numbers of CD4+ and CD8+ T-cells and their subsets in 45 patients with indolent untreated CLL, 86 patients indicated for first-line treatment, and 34 healthy controls. In 55 patients, we analyzed the impact of CIT RESULTS: CLL patients had a significant increase in most cell populations in comparison to controls. Progression of CLL was characterized by significantly elevated counts with the exception of a lower percentage of naïve T-cells. After treatment, the percentage of naïve T-cells further decreased at the expense of effector memory T-cells (TEM). In patients with indolent CLL, higher percentages of naïve CD4+ (p= 0.0026) and naïve CD8+ (p= 0.023) T-cells were associated with a longer time to first treatment (TTFT). The elevation of CD4+ central memory T-cells (TCM) (p= 0.27) and TEM (p= 0.003) counts and a higher percentage of CD4+ TEM (p= 0.0047), were linked with shorter TTFT. In treated patients, increased regulatory T-cells count was associated with shorter time to next treatment (TTNT) (p= 0.042), while higher CD4+ TCM count with shorter TTNT (p= 0.035) and shorter overall survival (p= 0.041). Our results indicate that naïve cell depletion and CD4+ TCM and TEM increases are detrimental to CLL patients' prognosis.

Expression profile of immunophenotypic marker molecules on B-lymphocytes in patients with chronic lymphocytic leukemia at the stages of immunochemotherapy

Purpose of the study. To study the expression of immunophenotypic marker molecules on B-lymphocytes of patients with chronic lymphocytic leukemia at the stages of immunochemotherapy while monitoring minimal residual disease.Patients and methods. 20 patients with CLL were examined, who in the period 2019–2022 underwent 6 courses of immunochemotherapy (ICT) in the RB/FCR mode at the National Medical Research Centre for Oncology, Rostov-on-Don. Before, after 3, 6 courses of ICT, bone marrow immunophenotyping was performed by flow cytometry. The data is evaluated in Statistica 13.0.Results. Before treatment, 3 groups of patients were identified depending on the expression of prognostic markers (CD38, ZAP‑70, CD11c, CD25, FMC7). I (2 people) – without expression of CD38, ZAP‑70, CD11c, CD25, FMC7 on tumor B-lymphocytes. II (14 people) – with variable expression of CD25, CD38 (0.4–47.6 % and 0.0–57.5 %, respectively), lack of expression of ZAP‑70, CD11c, FMC7. III (4 people)– with high expression of CD38 (57.5–69.2 %), ZAP‑70 (36.6–48.3 %), CD11c (20.0–96.5 %), CD25 (64.9–92.7 %), FMC7 (13.6–88.6 %). After the 3rd course of ICT, the minimum residual disease (MRD): 0 % in group I, 0.48 ± 0.13 % in group II, 33.5 ± 7.84 % in group III. After the 6th course of ICT MRD: 0 % in group I, 0.42 ± 0.09 % in group II, 33.2 ± 8.07 % in group III. The expression of immunophenotypic markers in groups II and III remained unchanged after 3, 6 courses of ICT. According to the criteria for assessing the response to therapy (IWCLL, 2018), patients of groups I, II after the 6th course of ICT have complete remission, 3 patients of group III have partial remission, 1 patient has stabilization of the process. Preliminary data have been obtained indicating that the absence or increased expression of CD38, CD25, ZAP‑70, CD11c, FMC7 on B-lymphocytes of CLL patients before treatment may predetermine the hematological response to therapy according to RB/FCR regimens.Conclusion. Initially, increased expression of all prognostic antigens simultaneously: CD38, CD25, ZAP‑70, CD11c, FMC7 on the tumor population of B-lymphocytes in patients with CLL is associated with an unsatisfactory response to treatment, which seems promising from the point of view of studying the effect of the analyzed marker molecules on achieving a hematological response at the stages of immunochemotherapy.

Real-World Outcomes with First-Line Ibrutinib (Ibr) Versus Chemoimmunotherapy (CIT) in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Final Analysis Results from the InformCLL Registry

Background: The therapeutic landscape for CLL/SLL has rapidly evolved with the introduction of novel agents such as Ibr. The informCLL registry (PCYC-1134; NCT02582879) is the largest US-based prospective, observational registry of patients (pts) initiating FDA-approved treatment for CLL/SLL in the era after approval of Ibr. Here, we report real-world (RW) outcomes in pts with CLL/SLL receiving first-line (1L) therapy, including comparison of 1L Ibr versus CIT, from the final analysis of informCLL. Methods: Pts with CLL/SLL who initiated FDA-approved treatment (within ±45 days of enrollment) were enrolled between 10/2015 and 6/2019. Pts were primarily enrolled from community-based practices (comprising 93% of sites). Data were collected for baseline characteristics, treatment patterns, and safety. Time to next treatment (TTNT) was estimated by Kaplan-Meier method and for comparison of outcomes with 1L Ibr versus CIT, by Cox proportional hazards regression analysis in weighted cohorts. Inverse probability of treatment weighting (IPTW) was performed to balance the baseline characteristics between cohorts. Adverse events (AEs) were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Of the 1459 eligible pts enrolled, 854 were treated in the 1L setting (59%). In the overall 1L cohort, median age was 70 years (≥75 years in 33%); 90% had ECOG performance status of 0 or 1; 47% had Rai stage III/IV (among n=547 with Rai staging); median Charlson Comorbidity Index (CCI) score was 1 (range 0-12) with CCI ≥3 in 16%; median time from initial diagnosis to 1L treatment was 19 mo. FISH testing data were available in 57% of pts in the 1L cohort; among these pts, 12% had del(17p). The most common 1L therapies were Ibr (45%; single-agent Ibr in 43% of all 1L therapies) and CIT (43%: most commonly BR, 24%); immunotherapy was given in 11% while chemotherapy (0.9%) and other novel agents (0.7%) were rare. With a median follow-up of 31.8 mo in the 1L cohort, median TTNT was not reached (NR); estimated proportions of pts without next-line therapy (NLT) were 79% at 24 mo, 71% at 36 mo, and 64% at 48 mo. The 1L cohort included 383 pts treated with Ibr and 363 pts treated with CIT; median follow-up was 31.4 mo for the Ibr cohort and 34.3 mo for CIT. Compared with the CIT cohort, pts in the Ibr cohort were older, had longer time from diagnosis to treatment, were more likely to have a history of other malignancy, and were more likely to have del(17p) or TP53 mutation (Table). Baseline characteristics in the weighted cohorts were balanced. In the IPTW-adjusted cohorts, median TTNT was NR for Ibr and 56.5 mo for CIT; TTNT was improved with Ibr relative to CIT (hazard ratio 0.744; 95% CI, 0.563-0.981) (Figure). Estimated proportions free of NLT in the weighted Ibr cohort were 75% at 36 mo and 69% at 48 mo; rates in the weighted CIT cohort were 66% and 57%, respectively. Median duration of index treatment was 24.0 mo for 1L Ibr and 4.7 mo for CIT. In the Ibr cohort (n=383), serious AEs occurred in 144 pts (38%), most commonly (≥3% of pts) pneumonia (n=23; 6%) and atrial fibrillation (Afib; n=21; 5%); AEs led to discontinuation of Ibr in 135 pts (35%), most commonly Afib (n=19; 5%) and fatigue (n=12; 3%). In the CIT cohort (n=363), serious AEs occurred in 85 pts (23%), most commonly febrile neutropenia (n=13; 4%) and pneumonia (n=11; 3%). AEs led to discontinuation of CIT in 61 pts (17%), and no single AE term led to discontinuation in ≥3% of pts (most common was anemia, 2%). EAIRs per 100 pt-mo for serious AEs were 1.93 with Ibr and 4.55 with CIT. EAIRs per 100 pt-mo for AEs leading to discontinuation were 1.53 with Ibr and 3.09 with CIT. Conclusion: In this large RW registry of pts with CLL/SLL, results from IPTW-adjusted analysis showed that 1L Ibr was associated with longer TTNT than CIT, with sustained benefit up to 4 years of follow-up. Pts receiving 1L Ibr therapy tended to be older, more often had a history of other malignancy, and more often had high-risk genomic features (del(17p) or TP53 mutation among those tested) than pts treated with CIT. The spectrum and frequency of AEs observed with these 1L regimens appear consistent with data from clinical studies and other RW studies. When adjusted for exposure, rates of AEs leading to discontinuation and serious AEs were lower with Ibr than CIT. Future analyses examining the impact of factors such as age/comorbidity and race are warranted to further our understanding of RW outcomes in pts with CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Karyotypic Complexity and Translocations Are Adverse Prognostic Features in Patients with Chronic Lymphocytic Leukemia without TP53 Aberrations Treated with Venetoclax-Based Time-Limited Combinations

Background: The presence of ≥3 (complex karyotype, CKT) and specifically ≥5 (high-CKT, hCKT) chromosomal aberrations (CA) is associated with a poor prognosis in patients (pts) with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT). Studies on the prognostic impact of CKT with targeted agents are not only heterogeneous in size and methodologies but also conflicting, with reports on both negative impact (venetoclax [ven] + rituximab [RVe] and ibrutinib monotherapy) and no impact (ven + obinutuzumab [GVe], ven + ibrutinib, idelalisib + rituximab) on progression-free (PFS) and overall survival (OS). Here, we prospectively evaluate the impact of CKT in a large cohort of pts treated with ven-based time-limited combinations within the GAIA/CLL13 trial. Methods: The phase 3 GAIA/CLL13 trial compared 3 different time-limited ven-based combinations against CIT in fit, treatment-naïve pts with CLL. Pts with TP53 aberrations were excluded. Pts were randomized to CIT (FCR in pts ≤65y; BR in pts >65y), RVe, GVe, or GVe plus ibrutinib (GIVe). Chromosome banding analyses were performed following IL-2/CpG-stimulation, karyotypes were analyzed according to ISCN 2020. No CKT (nCKT) was defined as ≤2, CKT as ≥3, intermediate CKT (iCKT) as 3-4 and hCKT as ≥5 CA. Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10 000 leukocytes measured by 4-color flow cytometry. Results: Chromosome analysis was successfully performed at baseline in 895 of 926 pts. Of these, 672 (RVe: 231; GVe: 218; GIVe: 223) were in the pooled ven population (pooled ven) and 223 in the CIT arm. nCKT was present in 79.4%, 81.0%, 83.5%, and 87.9%, iCKT in 13.5%, 14.7%, 11.5%, 9.4% and hCKT in 7.2%, 4.3%, 5.0% and 2.7% of pts treated with CIT, RVe, GVe and GIVe, respectively. Male gender, del(11q), del(6q) and trisomy 12 were associated with CKT. No correlation was observed between IGHV status or CLL-IPI and CKT. With CIT, uMRD rates in peripheral blood at month 15 were lower in pts with CKT compared with nCKT (37.0% vs 57.1%; OR 0.44, p=0.016). In none of the ven arms, uMRD rates were significantly different between pts with CKT and nCKT (RVe: 52.3% vs 56.7%, GVe: 86.1% vs 86.3%, GIVe: 92.6% vs 92.3%). Across all treatment arms, pts with ≥5 CA had significantly shorter PFS than pts with <5 CA (Figure 1). With CIT, also iCKT was associated with shorter PFS (vs nCKT: HR 2.49, p=0.003), while in none of the ven arms there was a significant PFS difference between iCKT and nCKT (RVe: HR 1.35, p=0.376; GVe: HR 0.94, p=0.912; GIVe: HR 0.38, p=0.341). Pts harboring translocations (TL) (CIT: n=52 [23.4%], pooled ven: n=160 [24.1%]) had inferior PFS compared to pts without TL irrespective of the treatment arm (Figure 2). Focusing on the ven-treated population, this difference was mostly driven by unbalanced TL (vs no TL: HR 3.83, p<0.001) however balanced TL still conferred inferior PFS compared to pts without any TL (HR 1.66, p=0.035). Pts with CKT but without TL had comparable PFS to nCKT (HR 0.53, p=0.217) whereas pts with CKT and TL had significantly shorter PFS (HR 2.79, p<0.001). In pooled ven, particularly pts with TL involving 8q (n=22) or 18q (n=29) showed significantly shorter PFS (HR t(8q;x) 3.94, p<0.001; HR t(18q;x) 2.48, p=0.006), while with CIT numbers were too small for reliable conclusions (n=5 and n=6, respectively). In a multivariate analysis, CKT was identified as an independent prognostic factor for PFS with CIT, while in pooled ven, only hCKT and TL were identified as independent adverse factors for PFS. OS was shorter for CKT vs nCKT with CIT (HR 3.25, p=0.044), but not in the ven arms. At progression (PD), karyotyping data was available in 88 of 161 (54.7%) pts. With CIT, 7 of 20 (35.0%) pts with nCKT at baseline acquired CKT at PD, in the pooled ven group this fraction was substantially smaller (6/45, 13.3%). With CIT, the number of CA increased between baseline and PD (mean, 2.0 to 3.4) while it remained stable after ven (2.1 to 2.0). Conclusions: In pts lacking TP53 aberrations, hCKT (≥5 CA) but not iCKT (3-4 CA) was associated with shorter PFS following treatment with time-limited ven combinations. While this study confirms the adverse impact of CKT with CIT, it identifies hCKT as an adverse prognostic factor in the context of ven-based combination treatment in CLL. Presence of translocations was associated with inferior PFS in all treatment arms. Karyotyping at relapse shows increased genomic complexity after CIT as opposed to ven-based treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes with Immunochemotherapy Plus Radiation Versus Immunochemotherapy Alone in Stage I Diffuse Large B-Cell Lymphoma: A Retrospective Study

Introduction Diffuse Large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with a prognosis highly dependent on the stage of the disease. The mainstay of front-line therapy for limited-stage DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP-like immunochemotherapy (IC). The impact of combined modality therapy (CMT) with radiation therapy (RT) after IC remains uncertain in the rituximab era. In the pre-rituximab era, studies comparing the efficacy of chemotherapy with or without RT showed heterogenous results. To date, only a few single institutional studies have compared IC versus CMT. The aim of this study is to evaluate the efficacy of standard IC compared to CMT in patients with stage I DLBCL in the rituximab era. Methods Adult patients with stage I DLBCL diagnosed between 2002 to 2015 and seen at Mayo Clinic Rochester were identified. Data were obtained from medical records. All patients were treated with IC (R-CHOP or R-CHOP-like), or IC followed by radiation (CMT). The student's t-test or the Wilcoxon rank-sum test was used to analyze between-group differences, as appropriate. Chi-square or Fisher's exact test was used for categorical variable comparisons. Progression-free survival (PFS) was defined as the time from the date of diagnosis to the date of relapse, death or the date of the last follow-up and was analyzed using the Kaplan-Meier method. Overall survival (OS) was defined as the time from the date of diagnosis to the date of last follow-up or death. Response to treatment was evaluated by treating physicians. Results The study included 123 patients diagnosed with stage I DLBCL with a median follow-up time of 65.9 months for IC arm and 56.2 months for CMT arm. Overall, 78 patients were treated with six cycles of IC, and 45 patients were treated with 2-4 cycles of IC followed by involved-site radiation (2 cycles in 4 patients, 3 cycles in 25 patients, 4 cycles in 16 patients). There were no significant differences in age, sex, or extranodal involvement. In the IC group, 59 patients had cell of origin data available: 44 (56.41%) were GCB subtype and 15 patients (19.23%) were non-GCB subtype. In the CMT group, 21 patients (47%) and 9 patients (20%) had GCB and non-GCB subtypes, respectively. Double-hit lymphoma (defined as rearrangement of MYC together with rearrangement of BCL2 and/or BCL6) was reported in 4 out of 78 patients in the IC arm and 2 out of 45 patients in the CMT arm. There was no significant difference in response rates to frontline treatment between groups. In the IC group, the overall response rate (ORR) was 92% (n=72), and the rate of complete response (CR) was 87% (n=68), partial response (PR) was 5% (N=4), stable disease (SD) was 5% (n=4), and progressive disease (PD) was 5% (n=4). In the CMT group, the ORR was 96% (n=43, all CR); 2 patients achieved SD (4%) and no patients had a PR or PD. With a median follow-up time of 65.9 months for IC arm, 14 patients had died. With a median follow-up of 56.2 months for the CMT arm, 14 patients had died. Median PFS was not reached in the IC group while PFS was more than 10 years in the CMT group (p=0.7851) [Figure 1]. There was no significant OS difference observed in both groups (p=0.2561) [Figure 2]. Conclusion Our study showed no significant difference in OS and PFS between patients with stage I DLBCL treated with IC or CMT. Future research on a larger patient population is needed to evaluate the role of consolidation radiotherapy in early stage DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

FLIPI24: An Improved International Prognostic Model Developed on Early Events in Follicular Lymphoma

Background: Early events are associated with inferior outcomes in follicular lymphoma (FL) and increased risk of death due to refractory FL. Risk prediction of early events prior to the start of therapy may enhance clinical management and research strategies. We report the FL International Prognostic Index model developed specifically to predict the risk of event within 24 months (EFS24) of starting first-line immunochemotherapy (IC) (FLIPI24). Methods: Modeling was performed using individual patient data from 10 observational cohorts from Europe, North America, and Australia. Eligible patients were diagnosed with grades 1-3A FL and initiated frontline R-CHOP, R-CVP, R-bendamustine (B-R), or like therapies. Event-free survival (EFS) was defined as time from start of IC to progression, retreatment, transformation, or death due to any cause. Model development utilized a truncated Cox model stratified on IC type and cohort with a time-dependent adjustment for maintenance therapy. Multiple imputation was implemented to address missing data. Functional forms of variables were assessed using splines. Model selection was based on model performance, clinical relevance, and parsimony. Gradient boosting machines were evaluated as a complementary approach and used to inform model selection. Model building was performed on an 80% split sample with 20% held for internal testing. External validation occurred in an independent cohort. FLIPI24 risk scores assumed B-R or R-CHOP based chemotherapy and 50% likelihood of maintenance. Results: 4485 patients initiating frontline IC between 2002 and 2018 were utilized in the analysis; 3577 patients were utilized for model building and 908 for internal model testing. Median age at diagnosis in the model build dataset was 61 years (IQR 53-69) and 51% were male. FLIPI was 21%, 32%, and 48% for low, intermediate, and high risk, respectively. IC type was 1874 R-CHOP or like (52%), 730 B-R or like (20%), and 973 R-CVP (27%); 2164 received CD20 antibody maintenance (61%). At median follow-up of 77 months (IQR 48-115), EFS24 estimate was 81% (95% CI: 79-82) and 835 patients (23%) died. 5-year survival after an early (non-death) event was 46% (95% CI: 42-50). The FLIPI24 model utilizes 5 continuous variables: age (linear 60-90 years with inflection at age 75), hemoglobin (linear 8-17 g/dL), white blood cell count (linear 4-11 109/L), normalized lactate dehydrogenase (linear 0.5-5), and beta-2-microglobulin (linear 1-10 mg/L). Linear variables and valid ranges were utilized based on close examination of functional forms across potential models. Continuous FLIPI24 risk scores were grouped for visualization in K-M curves as follows: very low risk (0-0.10), low risk (0.10-0.15), average risk (0.15-0.20), high risk (0.20-0.40), very high risk (>0.40), Figure 1. Internal validation was performed on the 20% holdout set (N=908). The FLIPI24 had superior concordance (c-stat) for EFS24 (c-stat=0.666) compared to FLIPI (c-stat=0.630) and PRIMA-PI (c-stat=0.590) models, Table 1. Importantly, FLIPI24 also improved prognostic ability for 10-year OS following IC (c-stat = 0.672) vs FLIPI (c-stat=0.629) or PRIMA-PI (c-stat=0.595). External validation was performed in a prospective cohort of 1438 newly diagnosed patients with FL (558 treated with IC) enrolled in the multicenter US LEO Cohort between 2015 and 2020. The FLIPI24 had superior c-stats compared to the FLIPI and PRIMA-PI for EFS24 (0.671 vs 0.600 vs 0.602) and OS (0.732 vs. 0.652 vs 0.635) in IC treated patients and for OS (0.785 vs 0.703 vs 0.662) when assessed in all patients. Conclusion: The FLIPI24 model provides an individual risk score at diagnosis for the likelihood of experiencing an event within 24 months from starting IC. The FLIPI24 was rigorously developed, tested, and externally validated using large harmonized and pooled international observational cohorts from the IC era. The FLIPI24 utilizes objective variables easily and reliably measured at diagnosis. A novel feature of the model is the significance of established blood-based measurements in the model, which appears to capture underlying tumor and host biology. Model performance for FLIPI24 was superior to standard clinical models for prediction of both EFS24 and OS in internal and external validation sets. Elevated FLIPI24 risk represents a patient population for further biologic studies and who should be considered for novel frontline therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Indirect Comparisons of the Efficacy of Subcutaneous Epcoritamab Vs Chemoimmunotherapy in Patients with Relapsed or Refractory Large B-Cell Lymphoma

Background: Epcoritamab is a novel, subcutaneous (SC) CD3xCD20 bispecific antibody that has been shown to be efficacious in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) as monotherapy. The phase 1/2 EPCORE NHL-1 (NCT03625037) study evaluated epcoritamab in patients with R/R LBCL who received at least 2 prior lines of systemic therapy. Patients in the trial were heavily pretreated with a median of 3 (range, 2-11) prior lines of therapy, 39% had prior chimeric antigen receptor T-cell (CAR T) therapy, 61% had primary refractory disease, and 83% were refractory to the last line of therapy. With a median follow-up of 10.7 months, the overall response rate (ORR) by independent review committee based on Lugano criteria was 63%, with a complete response (CR) rate of 39%; median overall survival (OS) was not reached (Thieblemont et al, EHA 2022). No head-to-head data have compared SC epcoritamab with chemoimmunotherapy (CIT). This study conducted an unanchored, matching-adjusted, indirect comparison of the efficacy of SC epcoritamab as reported in the EPCORE NHL-1 trial with that of CIT as reported in the SCHOLAR-1 study (Neelapu et al, Blood Adv 2021), which is the largest reported outcomes study in patients with R/R LBLCL treated with CIT. Methods: Published OS data for CIT from SCHOLAR-1 and ORR and CR rate based on investigator-assessed International Working Group criteria were used to conduct this matching-adjusted, indirect treatment comparison versus epcoritamab. Patients with prior exposure to CAR T therapy enrolled in EPCORE NHL-1 were excluded in this analysis because the SCHOLAR-1 study only included patients without prior exposure to CAR T therapy. Analysis was conducted by adjusting for imbalances in the following baseline characteristics between individual patient-level data from EPCORE NHL-1 and aggregate data from SCHOLAR-1: age 65 years or older, sex, primary refractory disease, disease refractory to at least 2 consecutive lines of therapy, Eastern Cooperative Oncology Group performance status, relapse within 12 months of autologous stem cell transplant, and disease stages III and IV. Propensity score weights resulting from the adjustment were applied to estimate differences in risk for ORR and CR rate for epcoritamab versus CIT, and weighted Cox proportional hazards models were used to estimate the OS HR between the 2 comparators. Adjustment weights were truncated at 1% and 99% of their distribution to reduce occurrence of extreme weights. Results: Patients without prior exposure to CAR T therapy enrolled in the EPCORE NHL-1 trial (N = 96) were mostly 65 years and older, men, had stage III or IV disease, had a history of primary refractory disease, and were refractory to at least 2 consecutive lines of therapy (Table 1). After adjustment, imbalances of these baseline characteristic variables between EPCORE NHL-1 and SCHOLAR-1 were mitigated (Table 1). Before adjustment, the ORR, CR rate, and OS HRs for epcoritamab were 68.8%, 41.7%, and 0.443 (vs CIT), respectively, for patients naive to CAR T therapy (Table 2). After adjustment, compared with CIT, patients receiving epcoritamab had a higher adjusted ORR (74.5% vs 34.1%; difference in risk, 40.4%; P < 0.001) and CR rate (52.4% vs 12.1%; difference in risk, 40.4%; P < 0.001). After adjustment, patients treated with epcoritamab also had improved OS versus CIT (HR 0.283, 95% CI: 0.161-0.497; P < 0.001). The median OS for CIT was 5.4 months, whereas the median OS of epcoritamab had not yet been reached with a median follow-up of 10.7 months. Limitations: Although this study adjusts for confounding variables between trials, outcomes are still subject to a higher level of uncertainty than what would have occurred if epcoritamab and comparators were studied within a randomized controlled trial. In addition, adjustments are based on the aggregate proportions of patient characteristics so that the associations between survival and baseline factors on the study level may be different than they would have been on the patient level. Conclusions: Findings from this cross-study analysis suggest that epcoritamab demonstrated significantly better efficacy in a highly refractory LBCL population versus CIT. Despite lack of an available head-to-head comparison, this study contextualizes the epcoritamab data and underscores the therapeutic potential of epcoritamab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genetic Markers and Front Line FCR/BR Vs. Rve, Gve and Give Treatment - Outcome Results from the CLL13/GAIA Trial

BACKGROUND: Genomic aberrations, IGHV mutation status and recurrent mutations in genes such as TP53 are established prognostic factors in CLL in the context of chemoimmunotherapy (CIT). For time limited treatment with venetoclax in combination with Rituximab (RVe), Obinutuzumab (GVe) and Obinutuzumab and Ibrutinib (GIVe) the role of these factors is less-well established. METHODS: The phase 3 GAIA/CLL13 trial compared 3 different time-limited venetoclax-based combinations against CIT in fit, treatment-naïve patients with CLL without del(17p) or TP53 mutations detected via Sanger sequencing. Patients were randomized to receive CIT (FCR for patients ≤65y; BR for patients >65y), RVe, GVe or GIVe. Co-primary endpoints were PFS and MRD in peripheral blood at month 15 via 4-colour flow. Genomic aberrations were assessed at enrolment by FISH, IGHV by sequencing with a threshold of 98% homology and mutations via amplicon-based targeted NGS for TP53, NOTCH1, SF3B1, MYD88, KRAS, NRAS, BRAF, EGR2, NFKBIE, RPS15, XPO1 and BIRC3 in 913 of 926 patients (98.6%) of the full trial cohort. RESULTS: The incidences of genomic aberrations based on the hierarchical model were del(11q) 17.5%, +12 16.2%, mono-allelic del(13q) 44.6% and normal karyotype 21.7%. IGHV was unmutated (U-IGHV) in 55.9% and mutated (M-IGHV) in 41.0% of patients (ITT). Subset#2 accounted for 50 patients equally distributed among U-IGHV and M-IGHV. The incidence of gene mutations was SF3B1 22.6%, NOTCH1 20.5% (exon 34 and 3'UTR), NFKBIE 13.6%, BIRC3 11.8%, BRAF/KRAS together 9.6%, XPO1 7.9%, EGR2 5.6%, RPS15 5.5% and MYD88 4.2%. Minor mutations with a variant allele fraction (VAF) of 1.5% to 10% were frequent in BIRC3 and NFKBIE (59.6% and 56.0% of all variants, respectively), while minor mutations in TP53 not previously detected by Sanger sequencing were rare (2.0%). Undetectable MRD (uMRD) was not associated with any genetic subgroup in the pooled analysis of GVe/RVe/GIVe. Single arm analysis revealed NOTCH1 mutation associated with lower rate of uMRD with GVe (74.4% vs 88.6%, p=0.02) and higher uMRD rate in +12 cases with RVe (73.5% vs. 52.2% in del(13q), p=0.03). With CIT a significantly lower uMRD rate was found in U-IGHV (42.0% vs. 66.3% in M-IGHV, p<0.01) and del(11q) (39.0% vs. 58.4% in del(13q), p=0.04) while mutated MYD88 associated with a higher uMRD rate (92.3% vs 50.2%, p=0.02). At a median follow-up of 38.8 months, there were 188 PFS events in the ITT population. For CIT U-IGHV (HR 4.47, p<0.01), del(11q) (HR 2.68, p<0.01) and mutated NOTCH1 with VAF>10% (HR 2.01, p=0.01) associated significantly with shorter PFS in univariate analysis. In the combined analysis for RVe/GVe/GIVe U-IGHV (HR 2.29, p<0.01), mutations in NOTCH1 (HR 1.76, p<0.01) and BRAF/RAS (HR 2.45, p<0.01) were associated with significantly shorter PFS and del(13q) (HR 0.67, p=0.03) with longer PFS. A separate analysis for each venetoclax arm identified mutated NOTCH1 (GVe: HR 2.2 p=0.04 and GIVe: HR 2.2, p=0.05), BIRC3 (GIVe: HR 3.6 p<0.01), BRAF/KRAS/NRAS (RVe: HR 3.6, p<0.01 and GIVe: HR 3.7, p<0.01) NFKBIE (GVe: HR 3.0, p<0.01), del(13q) (GVe: HR 0.4, p=0.01) and U-IGHV (GVe: HR 2.6, p=0.03 and GIVe: HR 2.7, p=0.03) as prognostic factors for PFS. Subset 2 was not associated with shorter PFS, also not among M-IGHV patients. In multivariable analysis including all clinical, laboratory and genetic markers significantly associated with PFS, treatment with GVe and GIVe were independent favorable factors (HR 0.42 and 0.33, respectively, both p<0.01) and U-IGHV (HR 2.43, p<0.01), and mutated NOTCH1 (HR 1.46, p=0.03) were confirmed as independent prognostic factors. In a separate multivariable analysis only for CIT, del(11q) (HR 1.89, p=0.03), U-IGHV (HR 3.08, p<0.01), and mutated NOTCH1 >10% VAF (HR 2.12, p=0.01) were verified as independent adverse genetic risk factors. For the combined RVe/GVe/GIVe group, mutated BRAF/RAS (HR 1.87, p=0.01), U-IGHV (HR 1.85, p<0.01), and mutated NOTCH1 (HR 1.54, p=0.04) were confirmed as independent adverse prognostic factors. CONCLUSIONS: Early results from CLL13/GAIA show association of gene mutations with lower rate for uMRD and shorter PFS after CIT or venetoclax-based therapy. IGHV and NOTCH1 mutation retain their prognostic role with both treatment types. Mutations in the RAF/RAS pathway (9.6% overall) were associated with shorter PFS with venetoclax-based therapy, while with CIT an impact on outcome is not apparent at present. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Survival Outcomes for Intensive Versus Standard Chemoimmunotherapy in Primary Mediastinal B-Cell Lymphoma: A Meta-Analysis of 4068 Patients

Background Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity with a predilection for female adolescents and young adults (AYAs). Due to its rarity, there is a paucity of prospective data and lack of randomized studies to inform on optimal frontline therapy. Expert guidelines from around the globe vary considerably with recommendations ranging from dose-intensive chemoimmunotherapy (CIT) to R-CHOP-21 with consolidative mediastinal radiation (RT). To assess if there are distinct differences in outcome between these approaches, we performed a systematic review and meta-analysis comparing dose-intensive versus standard CIT for the frontline treatment of PMBCL. Methods We performed a comprehensive and specific literature search on the frontline treatment of PMBCL. Studies included in our meta-analysis were prospective or retrospective published datasets that reported treatment outcomes (event free survival, EFS; progression free survival, PFS; overall survival, OS) for specific CIT regimens for PMBCL patients of any age. Standard approach was defined as R-CHOP-21 or CHOP-21, with or without RT. Dose intensive approaches were defined as regimens that increase the frequency, dose or number of systemic agents in comparison to R-CHOP-21. Case reports, small case series (<5 PMBCL patients) and unpublished conference abstracts were excluded. We searched MEDLINE, Embase, and Cochrane CENTRAL via Ovid and Web of science for all published literature on this topic on February 8th, 2022. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the PRISMA extension statement.1 Two independent authors screened all studies to compile a final list of included publications, from which data was extracted. Patient number, trial type, treatment, consolidative RT/autologous stem cell transplant (auto-SCT), EFS, PFS and OS data was collected from each study. Pooled analysis for each efficacy outcome was calculated using percentages and sample size. Linear regression was used to compare treatment modalities for EFS, PFS and OS outcomes. Median follow-up time varied for each study, therefore outcomes were standardized by calculating average yearly event-free percentages. Results Our systematic review generated 1404 articles, which led to the inclusion of 53 publications, encompassing 4068 patients. 2517 patients were treated with dose-intensive approaches compared to 1551 with standard R-CHOP-21 (n=1095) or CHOP-21. Dose intensive approaches are summarized in Table 1. Consolidative RT was administered in 16.9% of the dose intensive arms, compared to 51.3% of R-CHOP regimens. Median follow up across all studies was 56 months. Outcome data is summarized in Table 1. 2234 patients in the dose intensive studies were evaluable for OS, with a cumulative 87.1% reported survival. Standard CIT studies reported 1440 patients with OS data, with a combined 78.9% reported survival. Controlling for differences in median follow up, the average percent per year surviving in the dose intensive CIT arm was 23.2% (95% CI 22.5 - 23.9) compared to 20.4% (95% CI 19.6 - 21.2) for standard CIT (p < 0.001). Aggregate overall survival and percent per year surviving for DA-EPOCH-R patients alone was 91.8% and 31.0% (29.6 - 32.3), compared to 87.3% and 24.8% (23.8 - 25.9; p < 0.001) for R-CHOP-21. Collective data revealed an EFS of 76.1% (n=794) and a PFS of 79.8% (n=1501) for the dose intensive group, compared to 55.7% (n=248) and 70.4% (n=1206) for the standard CIT arm. Improved EFS and PFS in the dose-intensive arm was confirmed with average percent per year event free survival (EFS 16.3% vs. 10.3%, p < 0.001; PFS 20.8% vs 18.7%, p < 0.001) for all patients, as well as the subgroup of DA-EPOCH-R compared to R-CHOP-21 (EFS 21.0% vs 15.6%, p < 0.001; PFS 35.4% vs 18.0%, p < 0.001). Conclusion To our knowledge, this is the largest meta-analysis reported to date of efficacy outcomes for frontline CIT in PMBCL. Pooled and yearly event-free analyses demonstrate that dose intensive approaches have more favorable overall survival, EFS and PFS. Furthermore, fewer patients in the dose intensive arm are exposed to consolidative RT, curtailing chronic toxicity. As we await results of randomized prospective trials, our meta-analysis supports the use of dose-intensive chemoimmunotherapy alone for the initial management of PMBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prediction of Early Disease Progression at 24 Months (POD24) Using Pre-Treatment Biopsies from Patients with Follicular Lymphoma (FL) Treated with Immunochemotherapy (IC)

Background: Gene expression profiling has been successfully used to interrogate FL biology related to overall survival alone or in combination with clinical parameters and mutation profiles such as the M7-FLIPI. However, none of these has ever been specifically trained against the most reproducible and pertinent predictor of excess mortality: early progression of disease by 24 months (POD24). Nor has any assay been validated on a clinical platform for testing patients in a CAP-CLIA environment. We therefore undertook a discovery analysis and also investigated published gene signatures to determine the best method for upfront prediction of POD24 with clinical progression (not transformation). Methods: For model generation, we assembled and harmonized gene expression data from frozen tissues from 377 total FL cases treated with immunochemotherapy (IC) from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP; N=80, unpublished, Affymetrix), British Columbia (N=137, Silva et al, 2018, DASL Illumina), and PRIMA cohorts (N=160, S. Huet et al, 2018, Affymetrix) and performed in silico analysis to identify the most promising candidate genes to predict POD24. In addition to the identified genes, we also included all "IR1/IR2" genes (S. Dave 2004) and "PRIMA23" (Huet) genes and other published genes of interest totaling 144 genes related to tumor, microenvironment, and housekeeping functions. We used these 144 genes as the basis for an nCounter code set (NanoString, Seattle, WA), and then evaluated their expression in formalin-fixed, paraffin-embedded (FFPE) tissues from a training set of 57 matching cases from the LLMPP cohort and an independent set of 59 independent samples from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). Comparing the FFPE NanoString results from the LLMPP training set to their matched fresh frozen Affymetrix results identified, 48 of the 144 candidate genes for which the two platforms showed agreement with correlation > 0.5). Multiple prediction architectures were compared using these 48 genes and optimized via cross-validation on this training set to develop a final locked down POD24 predictor ("CCP-32") based on a linear combination of the expression of 32 selected informative genes and an additional 19 housekeeping genes. Additionally, for comparison, the Huet profiling scores were calculated on the LLMPP training samples and a cut-point, optimized to select patients with POD24 as a dichotomous endpoint. These two predictors were then applied to an independent set of 174 FFPE samples from the MER population-based cohort. Samples with very low signal in the normalization genes were excluded (8/116 training and 17/174 validation). Samples from patients that were event free until they experienced transformation or were lost to follow-up in less than 24 months after IC were treated as censored and were thus excluded (2/116 training, 6/174 validation). Results: When applied to the MER FFPE validation set, the CCP-32 predictor placed 30% in a poor prognosis group with an observed POD24 rate of 56% while the remaining 70% samples had an observed 18% POD24 - an enrichment that was statistically significant (p=2.9x10-5). A training-optimized cut of the Huet profiling score performed similarly on the validation set with 44% placed in the poor prognosis group, with an observed POD24 rate of 48%, while the remaining 56% had an observed POD24 of 15% (p=1.5x10-5) Conclusions: Starting with an agnostic in silico analysis of data from frozen FL tissue to identify predictive genes, also including known gene sets pertinent to FL, we first identified genes that correlated best in FFPE tissues using digital expression profiling to develop an algorithm specifically trained to detect POD24 due to progression (not transformation) on a clinical platform using routinely processed samples. A novel predictor and the Huet profiling score were each able to detect a biological subset that was heavily enriched in the approximately 30-44% of FL patients at risk for POD24. Additional cohort analyses are underway. Integration of gene mutations and other genetic factors will also be explored to determine whether these can improve the predictive value with a long-term goal of creating a combined assay that could be suitable for use in a clinical laboratory to select high risk patients for clinical trials.

Outcomes and Prognostic Factors of Transformed Follicular Lymphoma: An Analysis from the LEO Consortium

Introduction: Histologic transformation (HT) from follicular lymphoma (FL) to an aggressive lymphoma is infrequent (rates in the rituximab era, ~ 2% per yr over the first 5 yrs after diagnosis) with unfavorable outcomes. Sarkozy (2019) showed approximately half of lymphoma-related deaths in the first decade following diagnosis follow HT. Reported survival outcomes following HT are heterogeneous, with median survival ranging from 22 to 50 mos. and 5-yr survival ranging from 24-60%. Establishing prognosis at the time of HT would be useful, but previous research efforts have been limited by small sample sizes. Data on factors associated with outcomes following HT have included time to progression, prior therapy, anthracycline exposure, and early HT, but contemporary analyses examining these factors in large, expert-practice datasets is lacking. Herein we utilized the scope of the Lymphoma Epidemiology of Outcomes (LEO) Consortium to examine prognostic factors for and outcomes following HT. Methods: This was a multicenter observational cohort study from the LEO Consortium. The cohort consists of prospectively enrolled patients in the University of Iowa/Mayo Clinic SPORE MER and LEO Cohorts, as well as patients with HT retrospectively identified at LEO centers. Data were collected from medical records by standard protocol with all events verified by lymphoma clinicians. Eligible patients were diagnosed between 2002-2019, had a biopsy proven grade 1-3A FL at diagnosis with a subsequent biopsy showing HT to an aggressive lymphoma (FL 3B, diffuse large B cell lymphoma (DLBCL), or high-grade B cell lymphoma (HGBCL)); patients with a component of FL3B, DLBCL, or HGBCL at diagnosis were excluded. The primary outcome was overall survival (OS), defined as the time from HT until death from any cause. Associations between clinical factors at time of HT and/or diagnosis with OS were evaluated using Kaplan Meier curves and Cox models; cause of death was evaluated using a competing risk approach. Results: 306 patients were identified having a HT event between 2002 and 2021. Histology at diagnosis was FL grade 1-2 in 86% and FL 3A in 14%. Median (IQR) age at time of HT was 63 (56-71) yrs; 39% of patients were female. Median time from diagnosis to HT was 28 (11-60) mos. 65% of patients (n=199) had prior immunochemotherapy (IC), of whom 59% (n=117) received an anthracycline. 20% (n=61) patients had HT prior to any systemic treatment and 53% (n=163) had HT after only 1 line. 69% (n=138) of HT following IC occurred within 24 mos of diagnosis. Transformed lymphoma histologies were predominantly DLBCL (83%), followed by HGBCL (11%) and FL3B (6%). At median follow-up from HT of 86 mos (62-99), 158 patients died, with 114 of 136 known causes of death (84%) lymphoma related. Median OS following HT was 61 mos (95% CI 50-97), and 5-yr OS estimate was 52% (95% CI: 46-58%). Early HT (within 24 mos of diagnosis) was associated with inferior outcomes (5-yr OS 42% vs 59%, HR=1.86 (1.36-2.55)) (Figure 1). Age >70 years was associated with worse OS compared to age<60 (5-yr OS 37% vs 61%, HR=2.19 (1.48-3.23)). No significant association with OS was observed for age 60-69 yrs vs younger patients. Anthracycline exposure prior to HT was associated with worse OS (5-yr OS 41% vs 58%, HR=1.51 (1.10-2.08)). Exposure to IC (5-yr OS 42% vs 67%, HR=1.68 (1.20-2.36)) or any systemic therapy (5-yr OS 46% vs 71%, HR=1.76 (1.15-2.70)) was also associated with inferior OS. Gender, histologic grade at diagnosis, or subtype at HT did not demonstrate association with OS (Table 1). Among patients who died, cause of death was predominantly due to lymphoma-related causes (progression, n=95 (65%); therapy-related, n=14 (10%)) compared to non-lymphoma (n=16, 11%) or missing/unknown causes (n=22, 15%). Cause of death patterns were consistent across all clinical groups evaluated. Conclusions: HT conveys a troubling prognosis for lymphoma patients. These data confirm previous reports of early HT, prior IC, and anthracycline exposure as negative prognostic indicators and extends the observation to any systemic therapy. HT at age >70 adds to inferior OS, but a more refined prognostic model will require more detailed clinical variables from time of diagnosis and HT. These data highlight HT as continued area of unmet need with high lymphoma-related mortality. Further research is needed with additional prognostic factors at the time of HT and the influence of patterns of care on outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1b Trial of Subcutaneous Epcoritamab in Pediatric Patients with Relapsed or Refractory (R/R) Aggressive Mature B-Cell Neoplasms (EPCORE Peds-1)

Background: Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common types of mature B-cell lymphoma (MBL) in children. A majority (90%-95%) of children with these malignancies are cured with initial chemoimmunotherapy (CIT), leaving a small portion of patients with relapsed or refractory (R/R) disease who have a poor prognosis (Cairo et al, J Clin Oncol 2012). R/R MBL is often treated with aggressive CIT regimens such as R-VICI or R-ICE, but a high, unmet need remains (Woessmann et al, Blood 2020). Long-term survival is observed in approximately 20% to 30% of pediatric cases of R/R MBL, with better long-term survival seen in those who attain complete response (CR) with reinduction CIT and reach consolidation with stem cell therapy. Patients with partial response (PR) after reinduction CIT may undergo stem cell transplant but typically have lower long-term survival rates than those experiencing CR (Burkhardt et al, Cancers 2021). Long-term survival or cure in patients with R/R MBL requires an effective therapy that results in CR before stem cell transplant. Epcoritamab is a bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell-mediated killing of malignant CD20+ B cells. The phase 1/2 EPCORE NHL-1 study (NCT03625037) of epcoritamab monotherapy in adult patients with R/R B-cell non-Hodgkin lymphoma established the recommended phase 2 dose (RP2D) and demonstrated safety and promising efficacy, including deep and durable responses (overall response rate [ORR], 63%; CR rate, 39%; preliminary median duration of response [DOR], 12 months) in a population with highly refractory large B-cell lymphoma (n=157) (Thieblemont et al, EHA 2022). Because favorable safety and efficacy data were observed in adults, it is reasonable to investigate use of epcoritamab in children with R/R MBL who fail to achieve CR with reinduction CIT or are unable to receive further consolidation with stem cell therapy after CIT. Study Design and Methods: EPCORE Peds-1 is a single-arm, open-label, phase 1b study (NCT05206357) evaluating the safety, pharmacokinetics, pharmacodynamics preliminary efficacy, and immunogenicity of epcoritamab monotherapy in pediatric and young adult patients with R/R Burkitt lymphoma, Burkitt-like lymphoma/leukemia, DLBCL, or other aggressive CD20+ MBL. Primary endpoints are safety and tolerability, including incidence and severity of cytokine release syndrome, immune cell-associated neurotoxicity syndrome, and clinical tumor lysis syndrome, as well as pharmacokinetic parameters of maximum observed concentration and area under the concentration-time curve from time 0 to last measurable concentration within the dosing interval. Secondary endpoints include CR per International Pediatric Non-Hodgkin Lymphoma response criteria, event-free survival, overall survival, initiation of stem cell transplant/chimeric antigen receptor T-cell therapy, ORR, DOR, duration of CR, and immunogenicity. Exploratory endpoints include the monitoring of pharmacodynamic markers such as cytokines and immunophenotyping of B and T cells. At least 15 patients will be enrolled with a maximum age of 25 years (for those with Burkitt lymphoma), with at least 12 patients 1 year of age or older but younger than 18 years who are evaluable for primary endpoint assessment. Eligibility criteria require that patients have not reached remission with reinduction CIT or are ineligible for further consolidation with cell therapy and have acceptable performance status (Lansky, Karnofsky, or Eastern Cooperative Oncology Group, depending on age). Epcoritamab will be subcutaneously administered using step-up dosing (priming and intermediate doses on days 1 and 8 of cycle 1 [28 days/cycle], followed by 10 weekly full doses from day 15 of cycle 1 through cycle 3; Figure). Additional full doses will be administered every 2 weeks for cycles 4 to 9 and every 4 weeks for cycles 10 and beyond for a maximum of 2 years of treatment. Epcoritamab priming-, intermediate-, and full-dose regimens will be based on weight categories; patients weighing at least 40 kg will receive the adult RP2D. Disease status will be assessed by CT/MRI/PET prior to epcoritamab administration on day 1 and at a minimum at weeks 6, 12, 24, 36, and 48 and at 18 and 24 months. Patients will be followed for at least 3 years after enrollment. Enrollment is ongoing in North America, Asia, Europe, and Australia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Genome-Wide Association Study (GWAS) of Event-Free Survival (EFS) in Follicular Lymphoma Patients Treated with Front-Line Immunochemotherapy: A Lysa, Iowa/Mayo MER, and FIL Study

Background: Few studies have evaluated the role of host (germline) genetics in predicting outcome in follicular lymphoma (FL) patients. Using patients treated with rituximab (R) based immunochemotherapy (IC) from 3 clinical trials and one prospective observational study, we conducted the first genome-wide association study (GWAS) of prognosis in FL patients to identify germline genetic predictors of event-free survival (EFS) overall as well as failure within the first 24 months after treatment initiation (EFS24). Methods: We conducted a GWAS study of FL patients (n=1,054) treated in first-line therapy with R-CHOP (n=726, 69%), R-CVP (n=255, 24%) and R-FM (fludarabine and mitoxantrone) (n=73, 7%) from the following studies: PRIMA (n=391) and RELEVANCE (n=205) of the Lymphoma Study Association; FOL05 (n=199) of the Fondazione Italiana Linfomi; and the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) (n=259). After IC, 437 patients (41%) received R-maintenance. Genotyping was performed using Human Core exome (PRIMA, RELEVANCE, FOL05) and 660 Quad (MER) BeadChips. Minimac4/1000G was used to impute additional SNPs. After stringent quality control measures, 1,287,537 SNPs across the 4 cohorts with a minor allele frequency (MAF) >0.05 were evaluated. Association testing was conducted assuming a log-additive genetic model. We calculated the hazard ratios (HR) by Cox regression analysis for EFS. Results were adjusted for FLIPI score, sex, cohort, principal component analysis of population stratification, treatment (R-CHOP/R-FM vs. R-CVP), and use of R-maintenance (modeled as a time-dependent variable). To identify early clinical failures, we conducted a GWAS using a piecewise Cox model to find SNPs associated with events within the first 24 months (EFS24) vs after 24 months. Because of the heterogeneity of our prognostic cohorts, we utilized a cross-validation statistical technique to identify robust findings that replicate across cohorts. The data were iteratively analyzed in discovery and validation blocks using a "leave-one-cohort-out" (LOCO) strategy: in each round, one cohort was left for validation while the other three cohorts were combined for discovery. Top SNPs were selected from each discovery block of three cohorts with an inclusive p<0.0001 threshold to move to validation in the remaining cohort. SNPs were considered validated with a p<0.1 threshold and a consistent HR direction between discovery and validation blocks. Validated SNPs were then combined into a final pooled analysis and were ranked based on p-value and number of cross validations in the context of standard pooled GWAS results. Results: In the final analysis for EFS prediction, the top SNP was rs72625024 at 3q27.3 (MAF=0.11; HR=0.62, p=9.37x10-8), which was discovered and validated in all 4 LOCO rounds. Figure 1 shows this and other top SNPs from the LOCO analysis mapped onto traditional pooled GWAS results. This SNP also predicted overall survival (OS) in a model independent of FLIPI and other prognostic factors (HR=0.69, p=0.013). rs72625024 is near FETUB (fetuin B), which is involved in the inactivation of the PI3K/AKT signaling pathway. The other top SNPs for EFS were at 3q21.1 and 8p23.2, but they did not reach statistical significance and showed weak validation in the LOCO design. In the analysis of EFS24, rs114695031 at 14q32.13 predicted events during the first 24 months and was discovered and validated in all 4 LOCO rounds (MAF=0.20; HR=0.58, p=1.93x10-8) (Figure 2). This variant is an intronic SNP localized in T Cell Leukemia/Lymphoma 6 gene, a long non-coding RNA and putative tumor suppressor. Suggestive associations for early failure were observed for rs12824955 at 12q24.11 (MAF=0.27; HR=0.60, p=1.46x10-7) and validated in 3 of 4 LOCO rounds, while rs333302 at 3q21.1 (MAF=0.42; HR=1.61, p=1.15x10-6) did not reach statistical significance. For events after 24 months, no SNPs were statistically significant. Conclusions: In this large GWAS study, a locus at 3q27.3 (near FETUB) was associated with EFS after adjustment for other prognostic factors and treatment. Furthermore, a genome-wide significant locus (p<5x10-8) at 14q32.13 (near TCL6) predicted EFS24, suggesting a specific role in early failures. These results, requiring additional external validation, support a role for inherited susceptibility impacting outcomes in IC-treated FL and that may vary by timing of failures. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Significance of Interim PET/CT in Follicular Lymphoma Treated with Frontline Chemoimmunotherapy

Introduction: Despite being the prototypical indolent non-Hodgkin lymphoma, follicular lymphoma (FL) is a heterogeneous disease with a subset of patients experiencing early progression or histological transformation and poor overall survival. Upfront identification of these high-risk patients remains an area of unmet need. Interim positron emission tomography/computed tomography (iPET) is commonly used to identify suboptimal response while on therapy but data supporting this practice in FL are limited. We aimed to evaluate the prognostic impact of iPET response assessment using the Deauville 5-point scale (DS) in FL patients treated with frontline chemoimmunotherapy (CIT). Methods: Patients with FL (grade 1-3A) who underwent iPET after 2-4 cycles of frontline CIT at a single academic center from 2008-2020 were identified. Patients treated with prior radiotherapy or rituximab monotherapy were excluded. Baseline, interim and end-of-treatment (EOT) PET scans were re-read by a nuclear medicine specialist using the DS. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards model was used for multivariate analysis. Results: 143 patients were included. The median age was 64 (range 28-86). Forty patients (28%) had grade 3A FL and 126 patients (88%) had stage 3-4 disease. FLIPI score was low for 20%, intermediate for 34% and high for 46% of patients. The CIT used were R-CVP (68%), BR (17%) or R-CHOP (15%) and 59% of patients received rituximab maintenance. Most iPETs (90%) were performed after 3-4 cycles. iPET DS was 1-2 for 59%, 3 for 13% and 4-5 for 28%. Six patients changed therapy based on progression on iPET; four of them had a confirmed histologic transformation. EOT PET was available for all other 137 patients with EOT DS of 1-2 for 72%, 3 for 4% and 4-5 for 24%. During follow up, 63 patients (44%) relapsed or progressed, including 14 patients (10%) with a biopsy-proven transformation in aggressive lymphoma, and 25 patients (17%) died. Progressive lymphoma was the most common cause of death (n=15; 10 of these were from histologic transformation), followed by other malignancy (n=5, including one case of treatment-related AML), cardiovascular cause (n=3) and one treatment-related mortality (liver failure related to hepatitis B reactivation). With a median follow up of 67 months, the median PFS was 70 months (95% CI 22- 119) and median OS was not reach for the entire cohort with a 2-yr PFS of 70% (95% CI 62-77) and 5-yr OS of 85% (95% CI 77-90). IPET was a significant predictor of PFS and OS with a 2-yr PFS 89% vs 64% vs 35% (p=<0,001) and 5-yr OS of 95% vs 63% vs 75% (p<0,001) for DS 1-2 vs 3 vs 4-5 respectively (figure 1) EOT PET was also a significant predictor of PFS and OS with a 2-yr PFS of 92% vs 80% vs 18% (p<0,001) and a 5-yr OS of 94% vs 75% vs 65% (p<0,001) for DS 1-2 vs 3 vs 4-5 respectively. In the multivariate analysis, adjusting for FLIPI and histological grade at diagnosis, iPET DS of 4-5 was an independent factor for worse PFS (HR 5,1 95% CI 2,9-9,1) and OS (HR 6,6 95% CI 2,3-19,3). Patients with iPET DS 3 had a non-significant worse PFS (HR 1,7 95% CI 0,8-3,8) but a significant worse OS (HR 9 95%CI 2,8-29,5) than those with iPET DS1-2. However, most deaths in patients with iPET DS 3 were not related to the underlying lymphoma. Conclusion: In this cohort of FL patients treated with frontline CIT, an iPET DS of 4-5 was predictive of inferior PFS and OS, independently of FLIPI and initial histological grade. A DS of 3 was seen in few patients and had lower predictive value. Whether outcomes can be improved by response-adapted therapy remains to be determined and studies are needed to inform optimal care in this setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal