Chimeric antigen receptor (CAR) T-cell therapy is a novel and promising form of cellular immunotherapy using genetically engineered, tumour-specific autologous T cells. CD19-specific CAR T-cells have been shown to be very effective as a treatment for relapsed/refractory B-cell acute lymphoblastic leukaemia and aggressive B-cell non-Hodgkin’s lymphoma. ICANS (immune effector cell-associated neurotoxicity syndrome) is one of the most frequently occurring toxicities of CAR T-cell treatment. We describe two cases of patients with neurologic symptoms following CAR T-cell infusion who were suspected to have ICANS, but in fact had cerebral toxoplasmosis and venous sinus thrombosis respectively. The focus on CRS and ICANS after CAR T-cell infusion may lead to less vigilance to the ‘normal’ threats faced by intensively pretreated patients with lymphoma such as infections and thrombosis. Both cases underscore the importance of a broad and thorough examination of patients if they experience neurologic symptoms after CAR T-cell treatment.
12074 Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Recently concern has been raised that anthracyclines may also increase BC risk, based on studies in childhood cancer survivors with/without a history of chest RT. So far, the association between anthracyclines and BC risk has not been examined in cancer survivors treated at adolescent/adult ages. Now that RT dose and volumes are decreasing, the potential contribution of anthracyclines to BC risk is an important issue. Methods: We assessed BC risk in a cohort of 2314 female 5-year HL survivors, treated at ages 15-50 years and diagnosed between 1965 and 2008 in 20 Dutch hospitals. Treatment factors were time-dependently included in the analysis, focusing on the effect of anthracycline exposure on BC risk. Results: After a median follow-up of 18.8 years, 258 women developed invasive BC or ductal carcinoma in situ as a subsequent malignancy. The 30-year cumulative incidence was 15.0% (95% Confidence Interval (CI) 12.8-17.4%). Mantle field RT (or other RT involving both axillae) was associated with increased risk of BC (Hazard ratio (HR) 1.9; 95% CI 1.2-2.8) compared to no supradiaphragmatic RT or RT to the neck only (Table 1). Gonadotoxic treatment (>4.2 g/m 2 procarbazine or pelvic RT) significantly decreased this risk. In a multivariable analysis, anthracycline exposure was associated with increased BC risk (HR 1.8; 95% CI 1.3-2.5) in patients who received a cumulative dose of >200 mg/m 2 . Among patients exposed to gonadotoxic treatment, the HR of BC associated with >200mg/m 2 anthracyclines was 3.8 (95% CI 2.0-7.2), with a trend for higher risk with higher anthracycline dose (HR 1.58 per 100mg/m 2 anthracycline, p<0.001). Conclusions: Our results suggest an association of anthracyclines with BC risk in HL survivors. Also when accounting for the protective effect of gonadotoxic treatment on RT-associated BC risk, anthracyclines significantly contributed to a higher BC risk.[Table: see text]
Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target of CC-115. CC-115 treatment showed a dose-dependent increase of SMG1-mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC-115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC-115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM.
Background: Patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) generally have a poor prognosis. We have shown that brentuximab vedotin (BV) in combination with DHAP (dexamethasone, cytarabine, cisplatin) is highly effective with manageable toxicity. Here we present the long-term follow-up, and also thymus and activation regulated chemokine (TARC) and metabolic tumor volume (MTV) analyses. Methods: Patients were treated with 3 cycles of BV-DHAP followed by autologous stem-cell transplant (ASCT). Serum was collected at baseline, after each cycle, after ASCT and during follow-up. Soluble (s)TARC was measured by ELISA. Immunohistochemical (IHC) staining was done for TARC on the lymph node biopsy at baseline. Baseline 18 F-FDG-PET-CT scans were analyzed for MTV using a threshold of standard uptake value (SUV) ≥4.0. Prognostic value of biomarkers for time to progression (TTP) was assessed by log-rank survival analysis. Results: Sixty-five patients, of whom 46% had primary refractory disease, were included. Central pathology review confirmed cHL diagnosis in 58/65 patients. Patients with other histologies were excluded from biomarker analyses, but not from clinical evaluation per intention to treat. After a median follow-up of 39 months, the 3-year progression free survival (PFS) was 77% (95%CI: 70-88) and the overall survival (OS) was 95% (95%CI: 90-100). Of confirmed cHL patients (n = 58), seven patients (12%) had weak or no TARC IHC staining in the Hodgkin-Reed Sternberg (HRS) cells and showed lower serum sTARC levels compared to patients with positive TARC staining (median 608 vs 3701 pg/mL; p = 0.04). cHL patients with no/weak TARC staining had a lower 3-year TTP rate (57% vs 93%, respectively; p < 0.001). Based on levels in healthy controls, cHL patients with a baseline sTARC < 1000 pg/ml (n = 14) were excluded in the subsequent sTARC analyses. sTARC decreased significantly after 1 cycle of BV-DHAP (p < 0.001; Figure 1A), and patients with sTARC < 1000 pg/mL after 1 cycle of BV-DHAP had a 3-year TTP of 91% vs 55% for patients with sTARC ≥1000 pg/mL at that timepoint (p = 0.01; Figure 1B). Baseline MTV correlated with baseline sTARC (r = 0.53; p < 0.001). Interim PET evaluation after 3 cycles of BV-DHAP showed a a complete metabolic response (CMR) in 47 patients and a partial response (PR) in 5 patients. Patients with a CMR had a 3-year TTP of 93% vs 40% for patients with a PR (p < 0.001). EA – previously submitted to EHA 2021. The research was funded by: The study drug (BV) was provided for the study and the study was funded by Takeda. Takeda did not have any influence on the analysis of the data or the interpretation of the results. Keywords: Diagnostic and Prognostic Biomarkers, PET-CT, Hodgkin lymphoma Conflicts of interests pertinent to the abstract J. Driessen Educational grants: Takeda (ASH conference 2019) M. J. Kersten Honoraria: Millennium/Takeda Research funding: Millennium/Takeda J. M. Zijlstra Consultant or advisory role: Millennium/Takeda Educational grants: Takeda (ASH 2019) P. J. Lugtenburg Consultant or advisory role: Millennium/Takeda Research funding: Millennium/Takeda M. Hutchings Consultant or advisory role: Millennium/Takeda Research funding: Millennium/Takeda P. Brice Honoraria: Millennium/Takeda Research funding: Millennium/Takeda T. Gastinne Honoraria: Millennium/Takeda D. de Jong Consultant or advisory role: Millennium/Takeda A. Hagenbeek Consultant or advisory role: Millennium/Takeda Honoraria: Millennium/Takeda Research funding: Millennium/Takeda A. Diepstra Consultant or advisory role: Millennium/Takeda Research funding: Millennium/Takeda
Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare peripheral T-cell lymphoma (PTCL) that develops in the fluid of the seroma cavity or the pericapsular fibrotic tissue surrounding a breast implant. The first case of BIA-ALCL was reported in 1997. According to the Food and Drug Administration (FDA), 733 unique cases of BIA-ALCL have been reported worldwide as of 2020. Involvement of locoregional lymph nodes or other organs outside of the breast occurs infrequently. The management of patients with limited stage disease BIA-ALCL is primarily surgical, but the optimal treatment of patients with advanced stage disease is largely unknown. Aims: The aim of our study was to describe the incidence, treatment and survival of all reported BIA-ALCL cases in the Netherlands. Methods: All patients diagnosed with BIA-ALCL since 1997 were identified in in the Netherlands Cancer Registry (NCR) with survival follow-up through February 1st, 2021. Baseline characteristics, a history of cancer, time between breast cancer (due to possible breast reconstruction with an implant following cancer surgery) and BIA-ALCL, treatment modality, best response to treatment and survival outcomes were collected. Overall survival (OS) was defined as the time from BIA-ALCL diagnosis to all-cause-death. Results: Between 1997 and 2020, a total of 42 patients have been diagnosed with BIA-ALCL in the Netherlands. The incidence was constant with 1 to 2 patients per 2 years until 2017. From 2018 onwards, the number of patients increased fourfold and 24 patients have been diagnosed with BIA-ALCL since then. The median age of patients was 51 years (range 28-87 years). The majority of patients were diagnosed with stage I disease (76%; n=32). Stage II was seen in 17% (n=7) and stage III/IV in 7% (n=3) of patients. Of the 3 patients with advanced stage disease, one patient had leptomeningeal involvement, one had involvement of the manubrium sterni and one had liver involvement. Fourteen patients (31%) had a prior diagnosis of breast cancer. The median time between the breast cancer diagnosis and BIA-ALCL was 13,3 years (range 6,7-31,8). Treatment for all BIA-ALCL patients consisted of surgery (55%, n=23), chemotherapy (14%, n=6); chemotherapy and radiotherapy (7%, n=3); chemotherapy and autologous stem cell transplant (7%, n=3), surgery and chemotherapy (5%, n=2), surgery, chemotherapy and radiotherapy (2%, n=1) or radiotherapy (2%, n=1). For 3 patients (7%), the treatment was watchful waiting. Treatment modality according to disease stage is presented in Table 1. Of the 15 patients who received chemotherapy, 10 patients received CHOP with number of cycles varying between 3 and 8, 1 patient received 4 cycles of CHOP followed by 4 cycles of CEOP, 1 patient received 6 cycles of CHOEP, 1 patient received 3 cycles of CHOEP followed by 3 cycles of CEOP, and for 2 patients the exact regimen was unknown. Overall, with a median follow-up of 2,9 years (range 0,3-24,2), three patients had died and the 3-years OS was 98%. Image:Summary/Conclusion: In the Netherlands, 42 cases of BIA-ALCL have been reported since 1997, with 24% of the patients diagnosed with stage II-IV. Although the incidence of breast cancer, and thereby the number of breast reconstructions, is on the rise, it is likely that the rapid increase in the number of BIA-ALCL cases since 2018 is due to increased awareness of this disease. The treatment of BIA-ALCL has been heterogeneous and there is an urgent need for uniformity, making evaluation of different strategies possible. Nevertheless, the prognosis is excellent with a 3-year OS of 98%.
<div>AbstractPurpose:<p>Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7.</p>Patients and Methods:<p>Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs).</p>Results:<p>Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive <i>P</i> < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive <i>P</i> < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive <i>P</i> < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years.</p>Conclusions:<p>Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.</p></div>
IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.
