Citations

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

Abstract In the United States, over 2 million individuals openly identify with a gender that differs from their sex assigned at birth. A cancer diagnosis is physically and psychologically taxing—and, in some, traumatic. However, for transgender and gender‐diverse (TGD) people, many of whom have experienced discrimination in myriad health care settings, the challenges may be even greater. These recommendations focus on how best to deliver quality cancer care to transgender men (individuals who identify as men but were assigned female sex at birth), transgender women (individuals who identify as women but were assigned male sex at birth), and people who identify somewhere beyond this gender spectrum as nonbinary or using other terms, based on the available, albeit sparse, literature. This review broaches: (1) the epidemiology of cancer in TGD individuals, including the incidence of cancer and cancer‐related mortality; (2) cancer center practices that are welcoming and affirming to TGD patients; (3) the need for awareness and intentionality in the spaces of diagnosis and treatment for cancer; (4) the inevitable conclusion that gender differences exist but much more needs to be learned about the impact of gender‐affirming therapy, consisting of gender‐affirming surgeries and gender‐affirming hormone therapy, on cancer therapy; and (5) the efficacy and perceived safety of antineoplastic therapy and gender‐affirming hormone therapy.

ABSTRACT Background Tricuspid valve‐in‐valve (TVIV) implantation has traditionally included post‐procedure overnight in‐hospital observation with next‐day discharge. Recently, our practice has shifted toward same‐day discharge for most patients after vascular access site hemostasis and adequate recovery from anesthesia. However, data on the safety of this approach remains scarce. Aims Our study aims to describe our practice change and to identify factors that may lead to overnight observation post‐TVIV. Methods We retrospectively reviewed medical records of patients who underwent uncomplicated TVIV implantation as an outpatient procedure at Mayo Clinic between 2011 and 2023. Results Of the 83 patients who underwent TVIV from 2011 to 2023, 65 (78%) were included in the study. The first 39 patients in our institutional series were observed overnight as standard practice. 18 (69%) of the most recent 26 patients in our series were discharged the same day; three patients who remained in the hospital overnight were because of provider preference and/or patient preference without any specific medical concern. Of all 47 patients who were observed overnight, one patient was treated for fluid overload, one patient had non‐sustained ventricular tachycardia on telemetry that resulted in adjustment of antiarrhythmic therapy, two patients had continued bleeding from the access sites and was observed for another day. Among the two of them, one also developed atrial tachyarrhythmias requiring initiation of additional antiarrhythmic therapy. Out of 18 patients discharged the same day, one patient had an ED presentation within 24 h due to access site bleeding which was resolved promptly. There was no mortality or procedural‐related readmission. Conclusion Same‐day discharge may be considered for adult patients who have undergone uncomplicated TVIV with adequate hemostasis and recovery after anesthesia.

Background: Hypomethylating agents (HMA) with venetoclax (VEN) have shown encouraging clinical efficacy in single arm clinical trials for patients with myelodysplastic syndrome (MDS) (Garcia JS et al. ASH 2023, Zeidan AM et al. Am J Hematol. 2023). Many centers have started utilizing HMA-VEN in the clinical management of MDS due to unmet need, pending results of the ongoing phase 3 randomized clinical trial (VERONA) using this combination. However, real world studies with large sample size investigating the use of these agents in MDS, practice patterns and clinical outcomes are lacking. Methods: This is a multicenter retrospective study of 13 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS who were treated with upfront combination of HMA-VEN, upfront HMA monotherapy, or VEN added after inadequate response or progression on HMA (post-HMA failure VEN). Outcomes analyzed includes clinical response, adverse events (AE) of interest, dose administration and survival. Descriptive statistics were used for baseline characteristics. Overall survival and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05. Results: Among 454 patients included, 258 patients received VEN in combination with HMA [upfront HMA-VEN (n=175), post-HMA failure VEN (n=83)] and 196 patients received HMA monotherapy. Median age was 69 (59-77) years and majority of patients had MDS with excess blasts (75%), high risk (31.9%) or very-high (41.8%) risk disease by IPSS-R, 23.7% had therapy related disease, 33% had deletion17p or TP53 mutation and 40.9% underwent allogeneic stem cell transplantation. VEN was predominantly started in outpatient setting (78.6%) with tumor lysis syndrome (TLS) prophylaxis and VEN doses ranged from 70-400mg, adjusted for concomitant antifungal drugs. Incidence of TLS was minimal (No TLS- 92.9%, lab-only TLS 6.2%, 1 pt with clinical TLS). Neutropenic fever was the main AE noted [upfront VEN-HMA (34.2%), HMA monotherapy (22.5%), post-HMA VEN (44.5%)]. In the upfront setting, response rate was significantly higher with HMA-VEN than HMA monotherapy (CR: 33% vs 12%; marrow CR: 40% vs 27%, p<.001). VEN given in the post HMA failure setting also resulted in encouraging response rates (CR 10%, marrow CR 32%). After adjusting for covariates in multivariable analysis, patients treated with HMA-VEN in the upfront setting had significantly improved event free survival as compared to HMA monotherapy (HR 0.59, HR 0.44-0.78, p<0.01), but overall survival did not reach statistical significance (overall survival HR 0.77, 95%CI 0.57-1.04, p=0.08). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that VEN in combination with HMA resulted in encouraging clinical outcomes and was effectively administered in the outpatient setting with minimal TLS. Infection risk management and supportive measures would be important to improve the ability to use this treatment widely, pending results of the ongoing phase 3 randomized clinical trial. Updated results with additional variables will be available at the main meeting.

Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age < 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p<0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p<0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease > 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS >1 7% vs 13%, p<0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent disease with a median overall survival (OS) of more than 10 years, although a proportion of patients may develop aggressive histology transformation. In a previous report from this large, international dataset, the 10-year cumulative incidence of transformation was 17% (95% 13-21) and in another study of 186 patients, the 10-year cumulative incidence was 14%Click or tap here to enter text.. In this report, we focus on risk factors for transformation as well as clinical characteristics and outcomes of transformed SMZL (tSMZL). Patients and methods: Adults diagnosed with SMZL in 2000-2018 were identified through regional or nationwide population-based registries or from hospital registries. Only patients likely to have SMZL as defined by Matutes et al. were included. Those with discordant lymphoma and/or transformation at diagnosis were excluded. Medical records were reviewed by local clinicians with experience in hematology/oncology, and detailed information on clinical characteristics, treatment lines, and outcomes was collected. Only histologically confirmed high-grade transformations (HT) were included. OS was defined as the time from transformation to death or censoring at last follow-up. Additional analyses stratified by treatment exposure prior to HT and treatment of HT were conducted. Multivariable Cox analyses were performed to determine clinicopathological features associated with transformation and OS. Results: Out of 940 patients with SMZL, 111 developed HT during a median follow-up of 9.1 years. The median time from diagnosis to HT was 3.4 years with an interquartile range of 1.6-7.4 years. Median age at HT was 71 years. Patients with HT shared similar baseline characteristics to those without in terms of age at diagnosis (66.4 vs 67.6), f:m ratio (1.5 vs 1.1) and ECOG ³2 (7.2% vs 7.4%). The 5-yr OS from the time of HT was 42% (CI 95%, 32-54). Of the 111 patients with tSMZL, a complete treatment history from SMZL diagnosis until HT was available for 88 included in the following analyses. By the time of HT, 46 had not received any prior systemic therapy (37 only splenectomy, 9 no therapy), 6 patients had received rituximab alone or combined with splenectomy, and 36 patients had received chemotherapy alone or as part of combined modality treatment. In a uni- and multivariable models for HT, we assessed age, treatment at diagnosis, sex, extra-hilar lymphadenopathy, and extranodal involvement. In both the uni- and multivariable model, age >70 (HR 1.9, 95% CI: 1.1-3.4), immediate treatment including splenectomy (HR 2.0, 95% CI: 1.05-3.6), and extra-hilar lymphadenopathy (HR 1.9, 95% CI: 1.1-3.3) were associated with higher HT hazard, while extranodal involvement (HR 0.23, 95% CI: 0.06-0.84) was associated with a lower HT hazard. At the time of first-line treatment, multivariable analysis revealed similar results and with no association between risk of transformation and treatment strategy (i.e splenectomy alone, rituximab monotherapy or chemotherapy with /without rituximab or splenectomy, and other). At the time of HT, patients who had been previously treated with chemotherapy had an inferior 5-year OS of 24% (95%CI: 13-44%) versus 54% (95%CI: 41-71%) for those who had not received chemotherapy prior to HT. In contrast, there was no difference in the survival of patients that transformed less than or more than 24 months from diagnosis with 5-year OS after HT of 35% (95%CI 20-60%) and 45% (95%CI, 33-61%) respectively. In a multivariable Cox regression analyses of age at time of HT, sex, time since last treatment <24 months, chemo-exposure in previous treatment lines and anthracycline-containing therapy (+/-R) at the time of HT, only prior chemo-exposure was borderline associated with poorer OS (HR 1.8, 95%CI: 0.9-3.5). Conclusion: Patients with SMZL face a notable risk of developing tSMZL over time. Patients in need of immediate treatment at first SMZL diagnosis, age >70 and extrahilar lymphadenopathy had a higher risk of tSMZL and outcomes at the time of HT were poor if patients had been exposed to prior chemotherapy after adjustment for age, sex, and time since last treatment.

Introduction: The primary analysis of the phase 3 ECHO trial (NCT02972840) demonstrated that acalabrutinib plus bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) vs placebo plus bendamustine-rituximab (PBR) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang et al. EHA 2024, Abstract #LB3439). Here we present additional efficacy and safety results from the ECHO trial. Methods: Pts aged ≥65 years (y) with previously untreated MCL and ECOG PS ≤2 were randomly assigned 1:1 to receive ABR or PBR. Acalabrutinib (100 mg twice daily) or placebo was administered until progressive disease (PD) or unacceptable toxicity. Induction with BR was administered for 6 cycles followed by rituximab maintenance (A±R maintenance, cycles 7-30) in pts achieving a partial or complete response (PR or CR). Pts progressing on PBR could cross over to receive acalabrutinib monotherapy. PFS (primary endpoint) was assessed by independent review committee. Minimal residual disease (MRD) negativity rate (10-5) was assessed in peripheral blood (every 24 weeks [wks], at CR, and at PD) and bone marrow (at CR) by NGS-based ClonoSEQ assay (Adaptive Biotechnologies). Results: Among the 598 pts randomized to ABR or PBR (299 in each arm), high-risk baseline characteristics included high-risk simplified MIPI score in 24.1% and 24.4%, blastoid histology in 8.7% and 6.7%, pleomorphic histology in 5.0% and 6.0%, centrally tested Ki-67 ≥30% in 46.5% and 49.2%, and known TP53 mutation in 7.4% and 9.7%, respectively. PFS hazard ratios (HRs) for subgroups were 0.78 (95% confidence interval [CI] 0.51-1.19) in pts with high-risk simplified MIPI score, 0.68 (95% CI 0.29-1.58) in pts with blastoid histology, 0.64 (95% CI 0.25-1.66) in pts with pleomorphic histology, 0.69 (95% CI 0.49-0.98) in pts with Ki-67 ≥30%, and 0.88 (95% CI 0.42-1.78) in pts with known TP53 mutation. In the ABR arm, median PFS was 22.2 months (mo) among pts who discontinued acalabrutinib during induction for reasons other than PD or death, 29.4 mo in pts who discontinued acalabrutinib during A±R maintenance (cycles 7-30) for reasons other than PD or death, and not reached in pts who received acalabrutinib for 31 cycles or more. Among evaluable patients who were MRD negative at the end of induction (24 wks), the rate of conversion to MRD positive during maintenance was lower in the ABR arm (5.85%; n=11/188) than in the PBR arm (15%; n=26/171). Conversely, among evaluable pts who were MRD positive at the end of induction (24 wks), 37.5% (n=3/8) in the ABR arm and 20% (n=3/15) in the PBR arm converted to MRD negative during maintenance. Overall rates of AEs were similar in each arm during induction, but were higher in ABR during A±R maintenance (cycles 7-30) and more so in the monotherapy phase (cycle 31+). Grade ≥3 TEAEs (ABR vs PBR) were 70.0% vs 68.7% during induction, 64.9% vs 62.9% during A±R maintenance (cycles 7-30), and 57.0% vs 45.3% during monotherapy (cycle 31+). Similarly, rates of TEAEs leading to discontinuation of acalabrutinib/placebo were 8.1% vs 8.8% during induction, 23.9% vs 19.0% during A±R maintenance (cycles 7-30), and 25.9% vs 13.7% during monotherapy (cycle 31+). Exposure-adjusted incidence rates per 100 person-years reduced the difference between ABR and PBR for clinically relevant TEAE rates (32.6 vs 29.3 for grade ≥3 serious TEAEs; 4.2 vs 4.0 for grade 5 TEAEs; 15.5 vs 12.4 for TEAEs leading to acalabrutinib/placebo discontinuation), possibly due to longer median exposure to acalabrutinib (28.6 vs 24.6 mo). Conclusion: Acalabrutinib in combination with BR provides a significant PFS benefit in pts with previously untreated MCL, including those with high-risk features. Furthermore, the addition of acalabrutinib to BR provided a greater PFS effect among pts in the ABR arm with the longest exposure to acalabrutinib. The PFS improvement may be partially driven by the contribution of acalabrutinib to sustained MRD-negative status and deepened responses after the end of induction. ABR provides this clinical benefit without excess toxicity as shown by attenuated differences between arms in exposure-adjusted incidence rates, suggesting that higher AE rates in the ABR arm are likely due in part to the longer duration of acalabrutinib treatment vs placebo. These data emphasize the benefits of acalabrutinib in frontline MCL treatment in high-risk pts and the additional benefit of continuous therapy.

Introduction: Nodal lymphomas of T-follicular helper cells (n-TFHLs) are considered neoplasms of mature TFH cells and are classified by the World Health Organization (WHO) under one umbrella with three subtypes: angioimmunoblastic-type (n-TFHL-AI), nodal TFHL, follicular type (n-TFHL-F), and nodal TFHL, not otherwise specified (n-TFHL-NOS). TET2 mutations in n-TFHL-AI subtype frequently co-occur with IDH2R172 mutations. Methods: To elucidate the cooperative role of TET2 and IDH2R172K mutation in n-TFHL-AI pathogenesis, we generated a murine model with Tet2 loss and IDH2R172K knock-in mutation in CD4+ T cells (Tet2-/-/IDH2R172K) by crossing Tet2Flox/Flox/IDH2R172K mice with Cd4-Cre transgenic mice. This resulted in Tet2 exon 3 deletion and IDH2R172K knock-in mutation specifically in CD4+ T cells. Murine tumors were comprehensively evaluated through immunohistochemistry and flow cytometry. Transcriptomic (RNA-seq), 5-hydroxymethylcytosine (5hmC), and 5-methylcytosine (5mC) profiling, and genomic (whole exome sequencing [WES]) analyses were conducted on both earlier time points (preneoplastic) and neoplastic cells. Functional validation involved proliferation, T-cell polarization, and Western blotting assays. Results: The transcriptomic analysis (p < 0.05) in n-TFHL-AI (double-mutant) cases showed enrichment of TFH-like signature, IL-12-signaling, NF-ΚB, and downregulation of TH1 cell differentiation (including IFNγ signaling). Evaluation of double-mutant mice revealed an earlier tumor onset than Tet2 mutant mice, with a median survival of 1.3 years compared to 1.7 years (p=0.006), respectively. With chronic stimulation by T cell-dependent antigens (sheep red blood cells [SRBCs]), these mice showed B-cell expansion with a 100% incidence of lymphoid neoplasms, in contrast to PBS-treated mice, where myeloid and lymphoid diseases occurred at an equal ratio. Genomic analysis of murine tumors revealed a unique mutation spectrum in metabolic genes (Ata3d3a, Atp1a3, Ppp4r3a, and Nemf), T- and B-cell interaction (Gnai3), Stat pathway (Jak1), and DNA repair (Zfp451). Transcriptomic analysis of tumors showed downregulation of Tbx21, increased TFH-related genes, and increased expression of Bcl6 with downregulation of its known suppressed genes. Transcriptomic analysis of murine CD4+ T cells isolated at 12 weeks revealed downregulation of genes associated with TH1-cell differentiation and Trp53 signaling, concurrent activation of T-cell receptor (TCR) and MAPK signaling, and API-complex. We demonstrated elevated levels of 2-hydroxyglutarate (2-HG) in double-mutant cells, and enasidenib (IDH2R172 inhibitor) treatment significantly decreased 2-HG levels and increased Tbx21 expression. Mutant cells showed a proliferative advantage in IL-2 and IL-21 in vitro conditions, resulting in enhanced TCR, AKT, ERK1/2, p-65, and inactivation of p-FOXO1 protein. While these cells showed a growth advantage in in vitro culturing with TFH conditions, their growth and polarization were impaired in TH1 conditions, indicating a differentiation block. Tet2-/-/IDH2R172K mice (12-week) with SRBCs treatment revealed a significant induction of B and CD4+ T- cell populations compared to wild-type (WT) mice (p=0.01). In vitro co-culturing experiments demonstrated that Tet2-/-/IDH2R172K mutant CD4+ T-cells confer a substantial proliferative advantage to B-cells (p=0.021). Notably, these double-mutant CD4+ T cells exhibited superior proliferation compared to WT CD4+ T-cells when co-cultured with B-cells isolated from WT or double mutant mice (p=0.004). When Tet2-/-/IDH2R172K neoplastic cells with whole tumor were allografted into NOD scid gamma (NSG) mice, lymphoma developed within three months, but also showed numerous B-cells in the TME. This suggests that the propagation of neoplastic T-cells likely require B cell help. Overall, the TFH program remained intact in transplanted cells, and a global decrease in 5hmC levels and an increase in 5mC levels were observed. Conclusion: Tet2-/-/IDH2R172K murine CD4+ T cells exhibited hyperactive TCR signaling, impaired DNA damage response, and NF-ΚB activation as key oncogenic transitions. Both in vitro co-culturing and the allografting of neoplastic Tet2-/-/IDH2R172K cells showed dependence on B-cells, suggesting that interrupting T- and B-cell interaction could be a therapeutic approach.

Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for both AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network (ELN) blast phase registry reported outcomes of 240 CML-BP pts. They also reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we are undertaking this study through the H Jean Khoury Cure CML Consortium (HJKC3) to study the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution separately and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2024 were included. Categorical variables were compared using the Chi-square test. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Survival probabilities were computed using the Kaplan-Meier method and compared with the log-rank test. Results: Of the 72 pts with CML-BP included in this analysis, 29 (40.3%) were female and 43 (59.7%) were males. At the time of diagnosis, 36 (50%) had CML-CP (chronic myeloid leukemia in chronic phase), 11 (15.3%) pts were diagnosed with CML-AP (accelerated phase CML) and 25 (34.7%) pts with de-novo CML-BP. For the 47 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 26 months (1-207 months). Median age at diagnosis of CML-BP was 54 years (range 21-86 years). EM disease was present in 17 (23.6%) pts (7 myeloid sarcoma, 5 central nervous system and 5 skin) with 3 pts presenting with EM disease only. Blasts were of myeloid phenotype in 41 (56.9%), lymphoid in 29 (40.3%) and mixed in 2 (2.8%) pts. The bcr-abl protein was p210 in 59 (81.9%), p190 in 5 (6.9%) and p230 in 1 (1.4%) pt. Four pts had prior allogeneic stem cell transplant (alloSCT) for CML-CP. Of the pts who had an ABL kinase domain mutation tested, 42.9% (18/42) pts were found to have an ABL kinase domain mutation. The most common TKD mutation was T315I (n=6). Next generation sequencing was performed in 32 pts. The most common mutations were ASXL1 (n=10), RUNX1 (n=4), BCOR (n=2), BCORL1 (n=2), DNMT3A (n=2) and 1 each in CSF3R, KMT2A, EZH2, NF1 and TP53. Of the 72 pts, 68 underwent CML-BP directed therapy. While only 9 (13.2%) pts were treated with TKI alone (4 dasatinib, 2 imatinib, 2 ponatinib and 1 asciminib), 54 (79.4%) pts were treated with a combination of chemotherapy with TKI (24 dasatinib, 13 ponatinib, 9 imatinib, 6 nilotinib, 1 bosutinib and 1 asciminib), and 5 (7.4%) pts were treated with chemotherapy alone. The response rate after CML-BP directed therapy was 72.1% (n=49). Best response was return to CML-CP in 17 pts, CHR with PCyR in 1 pt, CCyR in 11 pts, MMR in 5 pts, MR4 in 4 pts, MR4.5 in 5 pts and MR5 in 6 pts. Rate of response with third and second generation TKI was significantly better than first generation TKI (80% and 77.1% vs 36.3%; p=0.02287). 30 (44.1%) pts proceeded to alloSCT. Of the 49 pts that responded, 16 (32.6%) relapsed. The median time to relapse was 5 months (range 1-46 months). At a median follow up of 57 months, the median OS for all pts was 18 months. There was no difference in OS based on blast phenotype (14 months for myeloid, 21 for lymphoid and 7.5 for mixed; p=0.1185), initial diagnosis (38 months CP-CML, 13 for CML-AP and 16 for de-novo BP pts; p=0.6380), or TKI (13 months for first generation, 20 for second and not reached for third generation TKI; p=0.1729). The OS of pts that were treated with a combination of TKI and chemotherapy was significantly longer compared to pts treated with TKI or chemo alone (28 vs 13 or 4.5 months; p=0.0003). Of the 32 pts that responded, OS for pts that underwent alloSCT was significantly longer compared to pts that did not (not reached vs 14 months; p= 0.0022). Conclusion: CML-BP continues to have a dismal prognosis. Treatment is heterogenous involving various combinations of TKI and chemotherapy. In our analysis, treatment with second or third generation TKI led to better responses. In addition, treatment with chemotherapy in combination with TKI and alloSCT led to improved OS. Updated results from further multi-institution analysis will be presented at the meeting.

Background: Anaplastic large cell lymphomas (ALCLs) represent a heterogeneous group of T-cell lymphomas that currently are classified by the presence or absence of ALK tyrosine kinase (TK) fusion genes (ALK+ or ALK−) and clinical presentation (systemic, cutaneous, or breast implant-associated). Two overarching molecular types of ALCL recently were discovered, defined by the presence (Type I) or absence (Type II) of a gene expression signature highly enriched for JAK-STAT3 activation. Fusions involving non-ALK TK genes occur in some ALK− cases, but the fusion landscape of ALCL remains incompletely characterized. Methods: Expert consensus pathology review was conducted in the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). RNAseq was performed and fusions were identified using FusionCatcher. Here, we focused on recurrent in-frame coding fusions. Previously unreported fusions were validated by RT-PCR. Type I/II was assigned using a previously validated gene expression-based model. Genes with adjusted (adj) P<0.05 were considered differentially expressed. Overall survival (OS) was assessed for systemic ALCL, when available. Results: We evaluated 379 ALCLs (229M/150F; mean age, 56 y). Of 199 candidate fusions (excluding reciprocal events), 28 were recurrent and passed quality metrics. At least 1 of these 28 fusions was present in 150 cases (40%). ALK fusions were present in 106 ALK+ ALCLs (all Type I; P<0.0001). Of these, NPM1::ALK was seen in 68/106 (64%). Alternate partners (X::ALK) included ATIC (N=24) and CTLC, COL1A2, MSN, MYH9, RNF213, SATB1, TFH, TPM3, and TRAF1 (1-3 cases each). X::ALK was associated with older age (mean, 52 y) than NPM1::ALK (32 y; P<0.0001) and showed relative overexpression of 49 genes, including multiple activators of small GTPases such as CGNL1 (FC, 5.6; Padj=2.4×10-6), SRGAP1, ALS2, DOCK1, and NCKAP1. ALK expression was similar in cases with NPM1::ALK and X::ALK and there was no significant difference in OS. Non-ALK TK fusions were seen in 17/273 ALK− cases (6%), including TYK2 (N=9); JAK2 (N=6); and ROS1 (N=2). All were Type I ALCLs (P<0.0001). ALK− cases with non-ALK TK fusions overexpressed 38 genes compared to ALK− cases without TK fusions, including cytokines involved in the IL17 signaling pathway such as CXCL6 (FC, 12.5; Padj=4.2×10-3), CXCL1, and CSF3. We then assessed the relationship between ALK− cases with non-ALK TK fusions and ALK+ cases by separately comparing each subset to ALK− cases without TK fusions. FC values for ALK− cases with non-ALK TK fusions were significantly correlated with FC values for ALK+ ALCLs over the set of expressed genes (R=0.54; P<0.0001). At a median follow-up of 32 months, 0/4 systemic ALCL patients with non-ALK TK fusions had died, while 30% of those with ALK− ALCL without TK fusions had died, but this was not statistically significant (P=0.26). The other 13 ALK− cases with non-ALK TK fusions were either localized ALCLs or did not have outcome data available. Of 20 TP63 fusions, 17 (85%) were TBL1XR1::TP63 and 3 were X::TP63. As previously reported, TP63 fusions were associated with poor OS (median OS, 10 months; not reached for other ALK− ALCLs; P=0.007). Four ALCLs had a novel NCL::UBTF fusion involving genes encoding the nucleolar proteins nucleolin and nucleolar (upstream binding) transcription factor-1. Four cases each had PARG::BMS1 and TNK1::GPS2 (the latter seen only in Type I ALCLs). Conclusions: This large consortium-based analysis of coding fusions further elucidates the molecular distinction between Type I and Type II ALCLs. Both ALK and non-ALK TK fusions were seen exclusively in Type I ALCLs, which we have shown previously are enriched for JAK-STAT3 pathway genes and correlate strongly with pSTAT3Y705 positivity by immunohistochemistry. These fusions were not identified in Type II ALCLs, which previous data suggest are associated with epigenetic alterations. ALK+ ALCLs with NPM1::ALK and X::ALK showed differences in gene expression, suggesting biological differences. Furthermore, ALCLs with non-ALK TK fusions shared gene expression features with ALK+ ALCL. Clinical fusion detection could enhance molecular classification of Type I and Type II ALCLs and may guide precision therapy.