Citations

Abstract Intravascular lymphoma (IVL) is a rare extranodal non‐Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003–2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS‐IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non‐CNS‐IVL patients with abnormal FDG‐PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS‐IVL and 63.5% (35/55) had non‐CNS‐IVL. CNS‐IVL group consists of clinically isolated CNS involvement (CNS‐only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M‐IVL) (14.5%; 8/55). Non‐CNS‐IVL group consists of clinically isolated skin involvement (skin‐only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P‐IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B‐cell IVL. Rituximab + high‐dose methotrexate‐based regimen were used in 75% (12/16) of CNS‐IVL patients and RCHOP in 60% (17/28) of non‐CNS‐IVL patients. Estimated 5‐year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin‐only IVL was associated with excellent survival. Platelet count <150x10 9 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

Abstract Introduction: Individuals with cancer may be at higher risk of atrial fibrillation (AF). However, sufficient data are lacking in AF risk among breast cancer survivors, especially for the mid-to long-term risk of AF and the impact of cancer treatment on this association. We aimed to investigate the risk of incident AF in women diagnosed with breast cancer and evaluate the association by length of follow-up and breast cancer treatment. Methods: Using the Korean Health Insurance Service database, we studied 96,476 women who were diagnosed with breast cancer (aged≥20 years) without prior history of AF and breast cancer and underwent breast cancer surgery between January 2007 and December 2013. They were matched 1:3 to a cancer-free population (n=289,428) based on birth year and sex and were followed to the end of 2018. Using ICD-10 codes (I48.0 to I48.4, I.48.9), AF was defined when it was a discharge diagnosis or was verified more than twice in an outpatient clinic. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of AF associated with breast cancer relative to the cancer-free population, adjusting for age, income, and comorbidities including diabetes, hypertension and hyperlipidemia. Results: During a median follow-up of 6.8 years, AF developed in 2,105 women with breast cancer (3.2 per 1,000 person-years). Mean age at baseline among participants was 49.6 years. Having breast cancer was associated with increased risk of AF (HR, 2.04; 95% CI, 1.93-2.15). This association was stronger for women aged &lt;50 years (HR, 3.98; 95% CI, 3.59-4.40). When we repeated analyses with lag periods of two years to explore the possibility of reverse causation and mid-to long-term risk of AF (n=91,370), the association was largely attenuated but remained significant (HR, 1.18; 95% CI, 1.09-1.28 for total women and HR, 1.60; 95% CI, 1.38-1.86 for women aged &lt;50 years). However, no increased risk of AF was observed in women with breast cancer aged &gt;65 years. Compared with no use of anthracyclines and taxanes, respectively, ever use of anthracyclines and taxanes was associated with increased risk of AF after further adjusting for other cancer treatment modalities including use of trastuzumab, radiotherapy, and endocrine treatment (HR, 1.25; 95% CI, 1.12-1.40 and HR, 1.37; 95% CI, 1.23-1.53, respectively). This association persisted only among women with breast cancer ever treated with anthracyclines when analysis was limited to those with two year-lag periods (HR, 1.23; 95% CI, 1.04-1.45). Conclusions: In this large-scale nationwide cohort study in South Korea, women with breast cancer had an elevated risk of incident AF, especially for women with breast cancer younger than 50 years, regardless of the length of follow-up. Our findings also suggest that cardiotoxic side effects of cancer treatment such as use of anthracyclines might increase both short-term and mid-to long-term risk of AF among women with breast cancer. Citation Format: Yong-Moon ("Mark") Park, Wonyoung Jung, Yohwan Yeo, Sang Hyun Park, Ronda Henry-Tillman, Hong Seok Lee, Tasneem Z. Naqvi, Kyungdo Han, Dong Wook Shin. Risk of atrial fibrillation among women diagnosed with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3214.

Abstract Introduction: Radiotherapy has long been examined in association with second malignancies, but the impact of radiotherapy for initial primary lung cancer (IPLC) on the risk of second primary lung cancer (SPLC) remains controversial. We evaluated associations between IPLC radiotherapy and the risks of SPLC and overall mortality among lung cancer survivors. Methods: We identified 689,785 patients diagnosed with IPLC in 1988-2013 from SEER. We applied cause-specific Cox (CSC) regression to evaluate association between IPLC radiotherapy and SPLC risk, adjusting for age at IPLC diagnosis, IPLC stage and histology, and prior history of cancer. To allow a latency period of exposure to IPLC radiotherapy on SPLC risk, we performed subgroup analyses restricted to patients who survived ≥5 and ≥10 years after IPLC diagnosis. Using Cox regression, we evaluated association between IPLC radiotherapy and overall mortality, adjusting for the same covariates used in the CSC analysis. Mediation analysis quantified the indirect effect of IPLC radiotherapy on overall mortality mediated through radiotherapy-driven SPLC diagnosis. Validation utilized data from 7,758 IPLC patients (496 SPLCs) at Mayo Clinic. Results: Of 689,785 IPLC patients, 18,818 (2.7%) developed SPLC in SEER. IPLC patients treated with radiotherapy had a reduced SPLC risk versus non-irradiated patients when evaluated at the time of initial diagnosis (cause-specific hazard ratio [csHR]=0.90, P&lt;1x10-6). However, the association between IPLC radiotherapy and SPLC risk was reversed when analyses were restricted to those who survived at least 5 years (csHR=1.08, P=0.01) and 10 years (csHR=1.16, P=0.009), thus long-term survivors treated with IPLC radiotherapy having a significantly increased risk of SPLC. Mayo Clinic data showed consistent results, with the effect of IPLC radiotherapy increasing from csHR of 2.41 (P&lt;1x10-6) to 3.38 (P=0.001) among 5-year and 10-year survivors, respectively. Similarly, compared to non-irradiated patients, those treated with IPLC radiotherapy showed a significantly increased risk of overall mortality among 10-year survivors (hazard ratio [HR]=1.46, P&lt;1x10-6 in SEER and HR=1.54, P=5.1X10-5 in Mayo Clinic). Mediation analysis showed that a substantial proportion of the total effect of IPLC radiotherapy on overall mortality—ranging from 32% to 59%—was due to radiotherapy-driven SPLC among 10-year survivors in SEER and Mayo Clinic. Conclusions: IPLC radiotherapy is associated with increased risks of SPLC and overall mortality, with its effects more pronounced among long-term survivors. Citation Format: Eunji Choi, Vicky T. Lam, Jacqueline A. Aredo, Ashok V. Kumar, Jason Wampfler, Julie T. Wu, David C. Christiani, Iona Cheng, Christopher I. Amos, Rayjean J. Hung, Leah M. Backhus, Joel W. Neal, Heather A. Wakelee, Ping Yang, Summer S. Han. Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3445.

Importance Although isotretinoin may rarely be associated with laboratory abnormalities such as hypertriglyceridemia, the optimal approach to laboratory monitoring is uncertain, and there is wide variation in clinical practice. Objective To establish a consensus for isotretinoin laboratory monitoring among a diverse, international cohort of clinical and research experts in acne. Design, Setting, and Participants Using a modified electronic Delphi process, 4 rounds of anonymous electronic surveys were administered from 2021 to 2022. For laboratory tests reaching consensus (≥70% agreement) for inclusion, questions regarding more time-specific monitoring throughout isotretinoin therapy were asked in subsequent rounds. The participants were international board-certified dermatologist acne experts who were selected on a voluntary basis based on involvement in acne-related professional organizations and research. Main Outcomes and Measures The primary outcome measured was whether participants could reach consensus on key isotretinoin laboratory monitoring parameters. Results The 22 participants from 5 continents had a mean (SD) time in practice of 23.7 (11.6) years and represented a variety of practice settings. Throughout the 4-round study, participation rates ranged from 90% to 100%. Consensus was achieved for the following: check alanine aminotransferase within a month prior to initiation (89.5%) and at peak dose (89.5%) but not monthly (76.2%) or after treatment completion (73.7%); check triglycerides within a month prior to initiation (89.5%) and at peak dose (78.9%) but not monthly (84.2%) or after treatment completion (73.7%); do not check complete blood cell count or basic metabolic panel parameters at any point during isotretinoin treatment (all >70%); do not check gamma-glutamyl transferase (78.9%), bilirubin (81.0%), albumin (72.7%), total protein (72.7%), low-density lipoprotein (73.7%), high-density lipoprotein (73.7%), or C-reactive protein (77.3%). Conclusions and Relevance This Delphi study identified a core set of laboratory tests that should be evaluated prior to and during treatment with isotretinoin. These results provide valuable data to guide clinical practice and clinical guideline development to optimize laboratory monitoring in patients treated with isotretinoin.

Abstract Objective To compare the artificial intelligence‐enabled electrocardiogram (AI‐ECG) atrial fibrillation (AF) prediction model output in patients with migraine with aura (MwA) and migraine without aura (MwoA). Background MwA is associated with an approximately twofold risk of ischemic stroke. Longitudinal cohort studies showed that patients with MwA have a higher incidence of developing AF compared to those with MwoA. The Mayo Clinic Cardiology team developed an AI‐ECG algorithm that calculates the probability of concurrent paroxysmal or impending AF in ECGs with normal sinus rhythm (NSR). Methods Adult patients with an MwA or MwoA diagnosis and at least one NSR ECG within the past 20 years at Mayo Clinic were identified. Patients with an ECG‐confirmed diagnosis of AF were excluded. For each patient, the ECG with the highest AF prediction model output was used as the index ECG. Comparisons between MwA and MwoA were conducted in the overall group (including men and women of all ages), women only, and men only in each age range (18 to <35, 35 to <55, 55 to <75, ≥75 years), and adjusted for age, sex, and six common vascular comorbidities that increase risk for AF. Results The final analysis of our cross‐sectional study included 40,002 patients (17,840 with MwA, 22,162 with MwoA). The mean (SD) age at the index ECG was 48.2 (16.0) years for MwA and 45.9 (15.0) years for MwoA ( p < 0.001). The AF prediction model output was significantly higher in the MwA group compared to MwoA (mean [SD] 7.3% [15.0%] vs. 5.6% [12.4%], mean difference [95% CI] 1.7% [1.5%, 2.0%], p < 0.001). After adjusting for vascular comorbidities, the difference between MwA and MwoA remained significant in the overall group (least square means of difference [95% CI] 0.7% [0.4%, 0.9%], p < 0.001), 18 to <35 (0.4% [0.1%, 0.7%], p = 0.022), and 35 to <55 (0.5% [0.2%, 0.8%], p < 0.001), women of all ages (0.6% [0.3%, 0.8%], p < 0.001), men of all ages (1.0% [0.4%, 1.6%], p = 0.002), women 35 to <55 (0.6% [0.3%, 0.9%], p < 0.001), and men 18 to <35 (1.2% [0.3%, 2.1%], p = 0.008). Conclusions Utilizing a novel AI‐ECG algorithm on a large group of patients, we demonstrated that patients with MwA have a significantly higher AF prediction model output, implying a higher probability of concurrent paroxysmal or impending AF, compared to MwoA in both women and men. Our results suggest that MwA is an independent risk factor for AF, especially in patients <55 years old, and that AF‐mediated cardioembolism may play a role in the migraine–stroke association for some patients.

e19532 Background: The traditional approach to the treatment of early-stage classical Hodgkin lymphoma (cHL) has been combined modality therapy (CMT) with both chemotherapy and radiotherapy (RT). CMT has shown improved disease control, but RT can lead to long-term adverse effects, including secondary malignancies and cardiac toxicity. Multiple clinical trials have assessed treatment de-escalation strategies to chemotherapy-alone regimens, but results are conflicting. We aimed to assess the real-world implications of these trials by comparing patient outcomes based upon treatment with CMT or chemotherapy-alone. Furthermore, we proposed to assess differences in treatment outcomes stratified by disease bulk, favorable/unfavorable disease, and PET2 response. Methods: We conducted a retrospective, multi-center cohort study of consecutive adult patients with early-stage (stage IA-IIB) cHL treated between January 2010-December 2020. Baseline characteristics, treatment modality, and outcomes were abstracted by chart review. Available PET2 scans (n=110) were independently reviewed by a blinded nuclear radiologist. Deauville score (DS) ≥4 was characterized as positive (+), and DS≤3 negative (-). All analysis was conducted using intention-to-treat principles based upon the initial treatment plan (CMT or chemotherapy-alone). Results: In 125 patients [58% male, median age 34 (range, 18-78)] with early-stage cHL, CMT was intended in 63 (50%) patients, with chemotherapy-alone in 62 (50%). Bulky disease was observed in 43 (34%), unfavorable disease in 81 (65%), and 15 (14%) were found to be PET2+. With median follow-up of 59.8 months (95%CI, 48.6 to 71.0), 5 (4%) deaths occurred, and 17 (14%) patients had relapsed/refractory disease. No significant differences in overall survival (OS) were seen based upon treatment intention. However, there was substantially reduced progression-free survival (PFS) (Table) with chemotherapy-alone in the whole cohort, and also in those with bulky, unfavorable, and PET2+ disease. No significant PFS differences were seen based upon treatment intention for patients with non-bulky, favorable, or PET2- disease. Conclusions: Based on our real-world experience, CMT appears particularly beneficial for patients with bulky disease, unfavorable prognostic factors, and PET2+ disease. However, while recent trials showed a benefit of CMT in non-bulky, favorable and PET2- patients, chemotherapy-alone may be comparable for these patients in actual clinical practice.[Table: see text]

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Abstract Study Objectives Sleep is an important dimension in the care of chronic obstructive pulmonary disease (COPD), but its relevance to exacerbations is unclear. We wanted to assess whether sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) is associated with an increased risk of COPD exacerbations and does this differ by socio-environmental exposures. Methods We included 1647 current and former smokers with spirometrically confirmed COPD from the SPIROMICS cohort. We assessed incidence rate ratios for exacerbation using zero-inflated negative binomial regression adjusting for demographics, medical comorbidities, and multiple metrics of disease severity, including respiratory medications, airflow obstruction, and symptom burden. Our final model adjusted for socio-environmental exposures using the Area Deprivation Index, a composite measure of contemporary neighborhood quality, and Adversity–Opportunity Index, a composite measure of individual-level historic and current socioeconomic indicators. We used a pre-determined threshold of 20% missingness to undertake multiple imputation by chained equations. As sensitivity analyses, we repeated models in those with complete data and after controlling for prior exacerbations. As an exploratory analysis, we considered an interaction between socio-environmental condition and sleep quality. Results After adjustment for all co-variates, increasing PSQI scores (range 0–21) were associated with a 5% increased risk for exacerbation per point (p = .001) in the imputed dataset. Sensitivity analyses using complete cases and after controlling for prior exacerbation history were similar. Exploratory analysis suggested less effect among those who lived in poor-quality neighborhoods (p-for-interaction = .035). Conclusions Poor sleep quality may contribute to future exacerbations among patients with COPD. This represents one target for improving disease control. Clinical Trial Registration Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). ClinicalTrials.gov Identifier# NCT01969344. Registry URL: https://clinicaltrials.gov/ct2/show/.

Abstract Multiple clinical trials have assessed de-escalation strategies from combined modality therapy (CMT) to chemotherapy-alone for the treatment of early-stage classical Hodgkin lymphoma (cHL), confirming similar outcomes. The application of these data to the real-world is limited, however. We conducted a retrospective, multicenter cohort study comparing CMT vs chemotherapy-alone in patients with early-stage cHL (stage IA-IIB) treated between January 2010 and December 2020. Positron emission tomography (PET) scans after chemotherapy cycle 2 (PET2) were independently reviewed by a nuclear radiologist (Deauville score ≥4, positive; ≤3, negative). Patient outcomes were compared by using an intention-to-treat analysis. Among 125 patients (CMT, n = 63; chemotherapy-alone, n = 62) with a median follow-up of 59.8 months (95% CI, 48.6-71.0), no differences in overall survival were observed (5-year overall survival, CMT 98.0% vs chemotherapy-alone 95.1%; log-rank test, P = .38). However, there was reduced progression-free survival (PFS) with chemotherapy-alone among all patients (2-year PFS, CMT 95.1% vs chemotherapy-alone 75.3%; log-rank test, P = .005) and in those with bulky (n = 43; log-rank test, P &lt; .001), unfavorable (n = 81; log-rank test, P = .002), or PET2-positive (n = 15; log-rank test, P = .02) disease. No significant differences in PFS were seen for patients with non-bulky (log-rank test, P = .35), favorable (log-rank test, P = .62), or PET2-negative (log-rank test, P = .19) disease. Based on our real-world experience, CMT seems beneficial for patients with early-stage cHL, especially those with PET2-positive and unfavorable disease. Chemotherapy-alone regimens can lead to comparable outcomes for patients with favorable, non-bulky, or PET2-negative disease. We conclude that although results seen in clinical trials are replicated in certain patient subgroups, other subgroups not fitting trial criteria do poorly when radiotherapy is excluded.