Castro, Januario E.

Background Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), is a rare subset of primary cutaneous lymphoma known for its aggressive behavior, poor prognosis, and limited treatment options, particularly in the relapsed or refractory setting. We report a case of a patient diagnosed with PCDLBCL-LT who achieved a clinically significant response and sustained remission for seven months with acalabrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK), before disease progression. Case presentation An 88-year-old woman presented with a rapidly enlarging ulcerated lesion on the left lower leg. Histopathological and immunohistochemical analyses confirmed the diagnosis of PCDLBCL-LT. She was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy, followed by external beam radiation therapy (RT). These interventions resulted in only a partial response, and the disease progressed within several months. The patient was receiving direct oral anticoagulant (DOAC) therapy for left lower limb deep vein thrombosis, and she also had a history of hypertension. Considering the increased risk of major bleeding associated with DOAC use and the elevated risk of cardiovascular adverse events previously reported with ibrutinib, an alternative BTK inhibitor was considered. Accordingly, she was initiated on acalabrutinib at a dose of 100 mg orally twice daily. The patient exhibited a rapid and robust clinical response, with complete resolution of cutaneous lesions and sustained remission lasting seven months. Ultimately, the disease progressed, and given her advanced age and overall poor performance status, she was transitioned to hospice care. She subsequently died 14 months after initiating acalabrutinib. Conclusion This report documents the first known case of successful treatment of relapsed/refractory PCDLBCL-LT with acalabrutinib. Despite advanced age and poor performance status, the patient experienced rapid symptom resolution and durable remission without treatment-related adverse events. These findings suggest that BTK inhibitors may represent a promising therapeutic approach for PCDLBCL-LT, either as monotherapy or in combination with anti-CD20 antibodies. Further investigation into novel targeted therapies is urgently needed for this rare and aggressive lymphoma subtype.

Abstract BackgroundAlterations in RNA splicing are associated with different malignancies including leukemia, lymphoma, and solid tumors. The RNA splicing modulators such as FD-895 and pladienolide B have been investigated in different malignancies to target/modulate spliceosome for therapeutic purpose. MethodsThe different cell lines were screened using RNA splicing modulator to test in vitro cytotoxicity as well as ability to modulate RNA splicing capability via induction of intron retention (using RT-PCR and qPCR) was assessed. The Cignal Finder Reporter Array was used to screen the HeLa cell line to know the pathway affected the most by the splice modulators. Further the candidates associated with the pathways were validated at protein levels using western blot assay and gene-gene interaction study were carried out using GeneMANIA.ResultsWe show that FD-895 and pladienolide B have more apoptotic activities than conventional chemotherapy in different solid tumors. We found FD-895 or pladienolide B modulate Wnt signaling pathways and mRNA splicing. We showed that FD-895 or pladienolide B significantly down regulates not only Wnt signaling pathway-associated transcripts (GSK3β and LRP5), but also both transcript and proteins including LEF1, CCND1, LRP6, and pLRP6. ConclusionThese results indicate FD-895 and pladienolide B inhibit Wnt signaling by impeding with phosphorylation of LRP6 and modulates mRNA splicing through induction of intron retention in cervical cancer cells.