Citations

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]

5025 Background: Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response. Methods: Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status. Results: Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment. Conclusions: Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.

2637 Background: Mutation-associated neoantigens (MANAs) constitute attractive antigens for the design of cancer vaccines. However, clinical implementation remains challenging because of the patient specific nature of MANAs, hereby requiring that a bespoke vaccine is designed for each subject. We developed a pipeline for the genomic characterization and the design of tailored vaccine using a modified vaccinia Ankara viral vector. Methods: Immunogenicity, safety and early clinical activity of personalized cancer vaccines are being assessed in two phase I trials, respectively in high grade serous OC and HPV-negative HNSCC. Patients (Pts) at high risk of relapse are enrolled in the study being in remission following surgical primary treatment. High risk is defined as stage IIIC or IVA for OC and stage III or IVA for HNSCC. A vaccine is manufactured for each patient. OC pts are treated at asymptomatic relapse based on radiological finding or elevation of CA-125 with the vaccine alone; HNSCC pts in complete remission after surgery and adjuvant therapy are randomized to receive the vaccine either at the end of locoregional treatment or in combination with standard of care at relapse. The vaccine was administered weekly for 6 weeks and a booster dose every three weeks over a year or until progression, whichever occurred first. Results: At the time of the data cut-off, a total of 8 pts were treated: 4 relapsing OC pts, 3 HNSCC pts in complete remission and 1 relapsing HNSCC pt. AE attributable to the vaccine were mainly grade 1 injection site reactions and fatigue. One OC pt displayed an objective response 6 weeks after initiation of vaccine and for 9 months with a normalization of CA-125 until death from an unrelated cause; 1 other OC pt remains on treatment with a stable radiological disease for 11 months. The 2 other OC progressed at the first evaluation on day 43. HNSCC pts treated in complete remission received respectively 20, 15 and 4 doses, and remain on treatment and disease free. One HNSCC patient received 9 doses of vaccine after relapse in conjunction with chemotherapy and anti-PD-1 therapy and remains on treatment with stable disease after 5 months. Immune monitoring demonstrates priming of a polyepitopic T cell response against class I and II antigens. Responses were observed regardless of HLA and without cross-reactivity to the germline protein. Adaptive response was associated with a shift of CD4 and CD8 T cells toward an effector phenotype and innate cellular immunity was activated with a strong maturation and activation of NK cells. Immune changes were stronger in pts with controlled disease versus progressors. Conclusions: Data demonstrate that TG4050 is safe, well tolerated and able to induce T cell responses whatever the HLA haplotype. Early signs of clinical activity were observed in OC pt. These data pave the way for further development and synergistic immunotherapeutic combinations. Clinical trial information: NCT04183166.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

VEXAS syndrome (vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X-linked, autoinflammatory manifestations and somatic) is an autoinflammatory condition caused by somatically acquired UBA1 mutations. Heiblig et al report on an international retrospective analysis of 30 patients with VEXAS syndrome treated with different Janus kinase (JAK) inhibitors, finding encouraging evidence supporting the use of the JAK1/2 inhibitor ruxolitinib with clinical remissions and reductions in steroid use seen in the majority of patients.

Abstract Despite much of the past 2 years being engulfed by the devastating consequences of the SAR‐CoV‐2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show‐cased at the 15th Post‐American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th‐10th December 2020 and 7th‐10th October 2021, respectively. The inaugural Post‐ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.