Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

Sequential development of mutant clones in an imatinib resistant chronic myeloid leukaemia patient following sequential treatment with multiple tyrosine kinase inhibitors: an emerging problem?

With the increasing use of new tyrosine kinase inhibitors it has been suggested that the spectrum of kinase domain mutations may change and possible selection of new resistant clones may occur. We describe a Ph + chronic myeloid leukaemia (CML) patient with primary resistance to imatinib who received without success sequential therapy with multiple TKIs, and developed sequential emergence of kinase domain mutations after these treatments

New category of probable invasive pulmonary aspergillosis in haematological patients

AbstractThe European Organization for Research and Treatment of Cancer and the Mycosis Study Group (EORTC-MSG) radiological definitions of invasive pulmonary aspergillosis (IPA) may lack diagnostic sensitivity. We evaluated applying less restrictive radiological criteria, when supported by specific microbiological findings, to define IPA in acute myeloid leukaemia (AML), lymphoproliferative diseases (LD) and allogeneic stem cell transplant (allo-SCT) patients. Overall, 109 consecutive episodes of proven/probable IPA in 56 AML, 31 LD and 22 allo-SCT patients diagnosed from February 2006 through to January 2011 were considered. IPA was diagnosed with EORTC-MSG criteria (control group, 76 patients) or without prespecified radiological criteria (study group, 33 patients). The latter differed from the former by the inclusion of patients with pulmonary infiltrates not fulfilling the three EORTC-MSG IPA specific findings of dense, well-circumscribed lesions with or without halo sign, air crescent sign or cavity. All the analysed clinical and mycological characteristics, 3-month response to antifungal therapy and 1- and 3-month cumulative survival were comparable in the control and study groups in AML, LD and allo-SCT patients. Seventeen of 33 (51.5%) patients of the study group fulfilled EORTC-MSG radiological criteria at subsequent imaging performed a median of 15 days (range, 6-40 days) after documentation of the pulmonary infection. Our study seems to confirm the possibility of revising the EORTC-MSG criteria by extending the radiological suspicion of IPA to less specific chest computerized tomography scan findings when supported by microbiological evidence of Aspergillus infection in high-risk haematological patients

C092 | UPDATED EFFICACY AND SAFETY OF THE BRUTON TYROSINE KINASE DEGRADER BGB-16673 IN PATIENTS WITH RELAPSED/REFRACTORY WALDENSTRÖM MACROGLOBULINEMIA: ONGOING PHASE-1 CADANCE-101 STUDY RESULTS

BACKGROUND: BGB-16673 is a potential first-in-class protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway. Updated ph 1 results in WM from the ongoing, open-label, ph 1/2 CaDAnCe-101 (BGB-16673-101; NCT05006716) are presented. METHODS: Pts with ≥2 prior WM treatments (tx), including an anti-CD20 antibody and covalent BTK inhibitor (cBTKi; US/EU only), received BGB-16673 QD orally. Endpoints included safety and tolerability (CTCAE v5.0), maximum tolerated dose, recommended dose for expansion, and overall response rate (ORR; modified IWWM-6 criteria) beginning after 4 weeks of tx. RESULTS: As of 17Dec2024, 30 pts with WM were enrolled and treated (100mg-350mg). Median age was 72.5 y (range, 56-81). Median number of prior tx was 3 (range, 2-11), including cBTKis (100%), BCL2 inhibitors (23.3%), and noncovalent BTKis (ncBTKis; 13.3%). Mutations in BTK (37.9%, 11/29) and TP53 (51.7%, 15/29) were seen. Median follow-up was 8.1 months (m; range, 0.3-28.1). TEAEs in ≥20% of pts were neutropenia/neutrophil count decreased (43.3%), diarrhea (30.0%), contusion/bruising (26.7%), anemia (23.3%), pyrexia (20.0%), and thrombocytopenia (20.0%). The most common grade [gr] ≥3 TEAE was neutropenia/neutrophil count decreased (33.3%). No atrial fibrillation, febrile neutropenia, or major hemorrhage occurred. Gr 2 hypertension was seen in 1 pt. Five pts (16.7%) had a gr ≥3 infection. TEAEs led to discontinuation (d/c) in 1 and dose reduction in 2 pts. One pt died due to a TEAE; 1 died of progressive disease (PD). In 29 evaluable pts, overall, major, and very good partial response rates were 89.7%, 75.9%, and 31.0%, respectively. Median time to first response was 0.95 m (range, 0.9-3.9), and median time to major response was 1.9 m (range, 0.9-6.4); responses deepened over time. Twenty-two pts (73.3%) remain on tx with ongoing responses. Responses were seen at the lowest dose (100 mg, 10/10), in cBTKi- (26/29) and ncBTKi-treated pts (4/4), and in pts with prior BTKi d/c due to PD (21/23). Responses were independent of mutations in BTK (with [w], 11/11; without [wo], 14/17), MYD88 (w, 23/25; wo, 2/3), CXCR4 (w, 14/14; wo, 11/14), and TP53 (w, 15/15; wo, 10/13). Median PFS was not reached. CONCLUSIONS: In this ongoing study, the novel BTK degrader BGB-16673 is tolerable and continues to show substantial antitumor activity in pts with heavily pretreated, BTKi–exposed WM, including those with BTK, CXCR4, and TP53 mutations.

C056 | UPDATED EFFICACY/SAFETY OF THE BRUTON TYROSINE KINASE DEGRADER BGB-16673 IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA: RESULTS FROM THE ONGOING PHASE (PH) 1 CADANCE-101 STUDY

BACKGROUND: BGB-16673, a potential first-in-class protein degrader, blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway. Updated ph 1 results in R/R CLL/SLL from open-label CaDAnCe-101 (BGB-16673-101; NCT05006716) are reported. METHODS: Patients (pts) with ≥2 prior treatments (txs; including a covalent BTK inhibitor [cBTKi] in US/EU/Australia) received BGB-16673 QD orally. Endpoints included safety, maximum tolerated dose, recommended dose for expansion, and ORR (modified iwCLL 2018 criteria; 2014 Lugano criteria in SLL). RESULTS: As of 17Dec2024, 66 pts were enrolled and treated (50 mg-500mg). Median age was 70 y (range, 47-91); 65.2% (43/66) had del(17p) and/or TP53 mutation; 79.6% (39/49) had unmutated IGHV. Pts had a median of 4 prior txs (range, 2-10), including cBTKis (n=61; 92.4%), BCL2 inhibitors (BCL2is; n=54; 81.8%), and noncovalent BTKis (ncBTKis; n=14; 21.2%). Median follow-up was 13.1 months (m; range, 0.3-29.9). TEAEs in ≥30% were fatigue (36.4%; grade [gr] ≥3, 1.5%) and contusion/bruising (30.3%; no gr ≥3). Most common gr ≥3 TEAE was neutropenia/neutrophil count decreased (21.2%). Atrial fibrillation (gr 1 in the context of bacterial pneumonia) and febrile neutropenia (in the context of COVID-19 pneumonia and norovirus diarrhea) occurred in 1 pt (1.5%) each. Hypertension (gr 3, n=2) and major hemorrhage (gr 1, n=1; gr 3, n=1) occurred in 2 pts (3.0%) each. TEAEs led to dose reductions in 6 pts (9.1%) and 4 deaths. In evaluable pts, ORR (partial response with lymphocytosis [PR-L] or better) was 80.3% (53/66; 2 complete response [CR]/CR with incomplete marrow recovery [CRi; 3.0%]). ORR at 200mg was 93.8% (15/16; 1 CR). Median time to first response was 2.8 m (range, 2.0-10.9); 33 pts (50.0%) remained on tx for ≥12 m; 38 had ongoing responses. Of 19 pts with initial PR-L, 10 improved to PR and 1 to CR; of 15 pts with stable disease, 1 improved to PR-L, 5 to PR, and 1 to CRi. Responses occurred in pts with prior cBTKi (49/61; 80.3%) or ncBTKi (10/14; 71.4%); double- (cBTKi and BCL2i; 36/41; 87.8%) and triple-exposure (cBTKi, BCL2i, ncBTKi; 9/12; 75.0%); del(17p) and/or TP53 mutation (33/43; 76.7%); with (17/24; 70.8%) and without (33/39; 84.6%) BTK mutations, and at the lowest dose (50 mg, 1/1). Median PFS was not reached. CONCLUSIONS: Novel BTK degrader BGB-16673 is tolerable, with robust and deepening responses in pts with heavily pretreated R/R CLL/SLL, including pts with prior BTKis and BTKi mutations.

P114 | FACTORS INFLUENCING THE REGIMEN CHOICE FOR FIRST-LINE THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA: THE FIRST-CLL STUDY

Treatment options for patients with chronic lymphocytic leukemia (CLL) have significantly increased over the years, and different first-line chemo-free regimens are now available. Selecting the optimal treatment requires careful consideration of multiple factors, including biological risk, side effect profiles, concomitant medications, patient fitness and individual preferences. In the absence of mature head-to-head comparisons, this decision-making process remains complex. The FIRST-CLL study describes the allocation of first-line treatments for CLL in a real-world Italian cohort and explores the relative weight of several parameters – such as clinical-biological characteristics, logistical factors and patient preference - in the regimen selection. We collected data from 133 consecutive patients who started treatment from February 2024 to February 2025 in 9 Italian centers. For each case, the treating physician was asked to score from 1 to 5 the importance of different variables in the treatment choice. Among enrolled patients, 56 (42%) received a Bruton tyrosine kinase inhibitor (BTKi), 46 (35%) ibrutinib plus venetoclax (IV) and 31 (23%) venetoclax plus obinutuzumab (VO). IV was the most prescribed regimen in patients 80 years old (84%). VO, mainly prescribed to older patients with reliable caregiver support, was avoided when caregiver availability was limited, in which case BTKi was favored. Among patients with TP53 disruption, 73% received zanubrutinib. In patients with a history of cardiac arrhythmias, the regimen not including a BTKi (VO) was favored in 50% of cases. Interestingly, a history of heart failure or a recent major bleeding did not preclude BTKi use, although the number of patients is limited. Among BTKi-treated patients, acalabrutinib was preferred in those on antiplatelet therapy. Figure 1 depicts the impact of each analyzed parameter on treatment selection, according to treating physicians. Prognostic features, routes of administration, therapy duration, patient’s preference, age and comorbidities resulted key factors, while tumor lysis syndrome risk and lymph node size did not significantly affect physicians’ choices. With the limit of subjective judgment of individual physicians, our real-world findings highlight how a range of clinical and logistical factors influence therapeutic decisions in the current Italian scenario for first-line CLL treatment