Citations

Abstract A 44-year-old man was referred for 2 months of erythematous ulcerative papules and plaques on the scalp, face and lower legs. The lesions started as painful ‘pimples’. He also reported fever and chills. He had a 5-year history of well-controlled HIV on antiretroviral therapy since diagnosis and a prior history of recurrent syphilis. Exam showed a large violaceous plaque on the right cheek with surrounding erythematous papules and an additional erythematous papule on the left ear. On the bilateral ankles and calves were four ulcers with necrotic centres and purple borders. The differential diagnoses included pyoderma gangrenosum and cutaneous lymphoma. A punch biopsy of the right zygomatic area showed dermatitis with a dense, diffuse plasma cell infiltrate suggestive of syphilis. The acid-fast bacteria (AFB), periodic acid–Schiff with diastase (PAS-D), and spirochete stains were all negative. Rapid plasma regain (RPR) was reactive at 1 : 4096. HIV was detected at < 30 copies per mL. Absolute CD4 T-cell count was 529 cells per μL. AFB and fungal cultures were negative, and bacterial culture showed rare Staphylococcus aureus. Although the spirochete stain was negative, it is only 70% sensitive and the positive RPR with histopathology supportive of syphilis in a patient who was positive for HIV confirmed the diagnosis of lues maligna. The patient received one dose of 2.4 million units of intramuscular penicillin G benzathine. He continued empiric doxycycline 200 mg daily, which had previously been initiated, and continued doxycycline postexposure prophylaxis after diagnosis. The patient reported healing with no new lesions 3 weeks after treatment. A new question brought on by this case is whether prior history of recurrent syphilis infection has a role in developing lues maligna. This patient in particular required syphilis treatment four times in the 3 years leading up to his presentation. Current literature describes a patient who was treated for secondary syphilis, then reinfected with malignant syphilis. However, further research is needed to elicit whether recurrent syphilis infections increase the chances of severe infection or malignant syphilis.

e23310 Background: Chimeric antigen receptor T-cell therapy (CAR T) is FDA-approved in pts with triple-class exposed (TCE) relapsed/refractory (RR) MM after four or more prior lines of therapy (LOTs). Real-world access to CAR T remains challenging due to manufacturing capacity, financial barriers, and pt fitness. Pts with certain pre-existing comorbidities (e.g., central nervous system disease, heart disease, secondary malignancies) are commonly excluded from clinical trials, including those investigating CAR T. The objective of this study was to identify the factors associated with the use of CAR T in pts with TCE RRMM to better understand the unmet need in this population. Methods: We conducted an observational cohort study using Medicare fee-for-service data; each pt in the CAR T intention-to-treat (ITT) population between 2021 and 2023 was matched to three non-CAR T pts, without replacement. Pts were eligible if they had an initial MM diagnosis, were continuously enrolled, were TCE, and did not receive treatment in a clinical trial. The index date was the ITT date. Baseline characteristics included age, sex, race/ethnicity, census region, three comorbidity indexes (Charlson, Elixhauser, CMS hierarchical condition categories [HCCs]), a claims-based frailty index (CFI), and dual enrollment in Medicare and Medicaid (as a proxy to social economic status [SES]). Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CIs) comparing the characteristics of CAR T vs non-CAR T pts. Results: Seventy-three ITT CAR T pts (nine underwent apheresis but did not receive CAR T) were matched to 219 non-CAR T pts by LOT and index year. Matched pts were treated with varied standard regimens (daratumumab-containing: 63%). Median prior LOTs were similar in the two cohorts (8; range 2–13). Median time from MM diagnosis to index date was 44.6 and 51.9 months for CAR T and non-CAR T pts, respectively. Compared with non-CAR T pts, pts in the CAR T population were younger (aged < 75 years: 59% CAR T vs 36% non-CAR T), less frail (mean CFI: 0.18 vs 0.20) and had higher SES (without dual enrollment in Medicare and Medicaid: 96% vs 81%), but were similar in terms of sex, region, and race/ethnicity. Variation in individual comorbidity prevalence was observed between CAR T and non-CAR T pts. In a multivariable regression analysis, factors strongly associated with lower odds of CAR T use included age ≥75 years (OR 0.29; 95% CI 0.16–0.53), comorbidities (lung/other severe cancers [OR 0.39; 95% CI 0.20–0.74] and chronic obstructive pulmonary disease [OR 0.32; 95% CI 0.10–0.99] defined by HCCs), and SES (OR 0.09; 95% CI 0.02–0.37). Conclusions: Older age, certain comorbidities, and lower SES are associated with lower odds of receiving CAR T in real-world pts with TCE RRMM, demonstrating an unmet need for more accessible and effective treatment options with acceptable safety profiles for these pts.

Magnetic resonance imaging (MRI) can facilitate accurate organ delineation and optimal dose distributions in high-dose-rate (HDR) MRI-Assisted Radiosurgery (MARS). Its use for this purpose has been limited by the lack of positive-contrast MRI markers that can clearly delineate the lumen of the HDR applicator and precisely show the path of the HDR source on T1- and T2-weighted MRI sequences. We investigated a novel MRI positive-contrast HDR brachytherapy or interventional radiotherapy line marker, C4:S, consisting of C4 (visible on T1-weighted images) complexed with saline. Longitudinal relaxation time (T1) and transverse relaxation time (T2) for C4:S were measured on a 1.5 T MRI scanner. High-density polyethylene (HDPE) tubing filled with C4:S as an HDR brachytherapy line marker was tested for visibility on T1- and T2-weighted MRI sequences in a tissue-equivalent female ultrasound training pelvis phantom. Relaxivity measurements indicated that C4:S solution had good T1-weighted contrast (relative to oil [fat] signal intensity) and good T2-weighted contrast (relative to water signal intensity) at both room temperature (relaxivity ratio > 1; r2/r1 = 1.43) and body temperature (relaxivity ratio > 1; r2/r1 = 1.38). These measurements were verified by the positive visualization of the C4:S (C4/saline 50:50) HDPE tube HDR brachytherapy line marker on both T1- and T2-weighted MRI sequences. Orientation did not affect the relaxivity of the C4:S contrast solution. C4:S encapsulated in HDPE tubing can be visualized as a positive line marker on both T1- and T2-weighted MRI sequences. MRI-guided HDR planning may be possible with these novel line markers for HDR MARS for several types of cancer.

Abstract Lung adenocarcinoma (LUAD), the most prevalent subtype of lung cancer, can arise from two different cell populations: alveolar type 2 (AT2) cells and bronchiolar club cells. By utilizing genomic data from the cancer genome atlas program, human LUAD cell lines, and the well-characterized LSL-KrasG12D/Trp53-/- (KP) mouse model, we demonstrated that tumors arising from club cells are much more aggressive and follow a different trajectory of tumorigenesis when compared to those arising from AT2 cells. Intriguingly, our data strongly suggest that expression and signaling activity of protein kinase C iota (PKCι) can profoundly affect the cell of origin and oncogenic signaling pathways employed by resultant tumors. Specifically, KP-mediated transformation of club cells appears to be dependent on PKCι-ELF3-NOTCH3 and PKCι-YAP1 signaling axes, while AT2 cell malignancy is dependent on the PKCι-independent WNT signaling. In addition, club-cell-origin tumors exhibit an enrichment of cancer stem cells and increased infiltration of immunosuppressive myeloid cells in comparison to AT2-cell-origin tumors. This results in accelerated progression and increased likelihood of metastasis by LUAD tumors that originate from club cells. Taken together, our results indicate that PKCι expression and signaling activity can profoundly influence the cells of origin, tumor trajectories, and therapeutic vulnerabilities of LUAD tumors. Citation Format: Duy T. Nguyen, Ning Yin, Capella R. Weems, Lee Jamieson, Kayleah Meneses, Yi Liu, Nicole R. Murray, Alan P. Fields. A lineage-specific role of oncogenic protein kinase Cι in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4299.

Background: A pivotal clinical trial comparing the efficacy and safety of ibrutinib with zanubrutinib in patients with Waldenström macroglobulinemia (WM) did not achieve its primary endpoint of complete response or very good partial response. In addition, median progression-free survival was not reached in either treatment arm. In the absence of treatment effectiveness differentiation based on clinical trial evidence, we conducted a real-world study to assess patient characteristics, treatment patterns, and all-cause healthcare resource utilization (HRU) in patients with WM who received ibrutinib or zanubrutinib as first-line (1L) therapy. Methods: In this retrospective cohort study, we used the ConcertAI Database to collect claims data of patients with WM aged ≥18 years who initiated single-agent ibrutinib (420 mg/day) or zanubrutinib (320 mg/day) as 1L therapy on or after 9/1/2021 (index date). A 6-month washout period of guideline-recommended WM antineoplastic agents was required to confirm 1L status. Patients were excluded if they were receiving ibrutinib and zanubrutinib concurrently, died within 30 days of the index date, had a record of hematopoietic stem cell transplant, had a record of other ibrutinib indications in the 6 months before index, or were participating in a clinical trial. Baseline demographics and clinical characteristics, therapy duration (number of days between the first and last day of the medication supply), and HRU (all-cause and WM-specific) per-patient-per-month (PPPM) were assessed. Results: The study included 51 patients (ibrutinib, n=30; zanubrutinib, n=21). In both cohorts, most participants were male (ibrutinib, n=20 [67%]; zanubrutinib, n=16 [76%]), and the mean age at baseline was 73 years and 75 years, respectively. At baseline, the median Charlson Comorbidity Index was 0, and the WM-related and ibrutinib/zanubrutinib-related clinical events were similar between the two cohorts. While the zanubrutinib cohort had a higher prevalence of infections (33% vs 3%) and musculoskeletal pain (24% vs 7%) at baseline, the ibrutinib cohort had a higher prevalence of hypertension (20% vs 14%). The baseline prevalence of anemia was similar in both cohorts (ibrutinib, 27%; zanubrutinib, 29%). Mean follow-up was 6.9 months (ibrutinib) and 6.3 months (zanubrutinib). The mean ± SD duration of therapy was 152 ± 112 days (ibrutinib) and 113 ± 99 days (zanubrutinib; p=0.195). The ibrutinib cohort had a significantly lower all-cause HRU PPPM (4.53 ± 3.96 vs 8.53 ± 6.66, p=0.020) and lower WM-specific HRU PPPM (0.11 ± 0.26 vs 0.54 ± 1.14, p=0.104). Conclusions: In this real-world analysis, patients with WM treated with 1L ibrutinib had a numerically longer duration of therapy and lower all-cause and WM-specific HRU PPPM, compared to those treated with 1L zanubrutinib. Due to a small sample size and short follow-up, these findings should be interpreted cautiously.

Background As therapeutic advances have increased life expectancy for patients (pts) with relapsed/refractory (RR) multiple myeloma (MM), second primary malignancies (SPMs) have become an increasingly important safety consideration. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation, and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased risk of SPM. Pts who are triple-class exposed (TCE), defined as prior exposure to an IMiD, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb), represent an increasingly large subgroup of RRMM pts. The objective of this study was to describe the incidence and characteristics of SPMs in Medicare-insured pts with TCE RRMM initiating a new line of therapy (LOT). Methods Adult pts with an incident diagnosis (Dx) of MM (≥2 outpatient Dx 30-365 days apart OR ≥1 inpatient Dx AND 6 months of continuous eligibility prior to initial Dx) during the study period (Nov 14, 2006-Dec 31, 2020) who were TCE (≥1 claim each for an IMiD, a PI, and an anti-CD38 mAb) were selected from the Center for Medicare and Medicaid Services Chronic Conditions Data Warehouse (TCE pts were assumed to have RRMM based on exposure). The first LOT after TCE was defined as the index LOT and the associated date of initiation was defined as the index date. Pts with SPMs prior to the index date were excluded. SPMs were identified based on having ≥2 outpatient Dx of SPM (of the same cancer type) 30-365 days apart OR ≥1 inpatient Dx of SPM. Dx of SPM included Dx of invasive malignancies or myelodysplastic syndromes (MDS), excluding MM, Waldenström macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a Dx of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each pt. Cumulative incidence of SPM (with death as a competing risk) was also calculated. For pts who experienced SPM, overall survival (OS) and measures of healthcare resource utilization (HRU) and costs (in 2021 USD, on a per patient per month [PPPM] basis) were calculated. Results A total of 3,088 TCE RRMM pts were identified, of whom 989 had no evidence of SPM prior to the index date (Table). These 989 pts had a mean age of 75.2 years, a mean of 2.9 prior LOTs and a mean of 3.1 years since MM Dx. Over a median follow-up of 7.1 months, 166 pts (19.3 per 100 PY) experienced an SPM, including 93 (10.8 per 100 PY) with a solid tumor and 73 (8.5 per 100 PY) with a hematologic malignancy. The latter included 27 (3.1 per 100 PY) with acute myeloid leukemia (AML) and 18 (2.1 per 100 PY) with MDS. The cumulative incidence of SPM (95% confidence interval [CI]) at 12, 24, and 36 months was 15.2% (12.8-17.9%), 19.7% (16.8-22.8%), and 23.8% (20.2-27.6%), respectively (Figure). Median (95% CI) OS from SPM Dx was 7.9 months (5.4-10.9). Kaplan-Meier estimated probability of survival (95% CI) at 12, 24, and 36 months following SPM Dx was 40.3% (31.6-48.9%), 27.6% (18.6-37.4%), and 9.5% (2.1-23.8%), respectively. Mean (95% CI) total costs after SPM were $22,514 ($19,105-$26,404) PPPM. Conclusions The incidence of SPM in Medicare-insured TCE RRMM pts is high. Many SPMs in these pts, such as AML, are life-threatening and may interfere with or prevent MM treatment. Pts with SPMs have poor survival and high HRU and costs. With increasing OS for RRMM pts due to therapeutic advancements, there is a need for effective treatments that are not associated with increased risk of SPMs.