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Chronic lymphocytic leukaemia (CLL) is invariably accompanied by some degree of immune failure, and CLL patients have a high rate of second primary malignancy (SPM) compared to the general population. We comprehensively documented the incidence of all forms of SPM including skin cancer (SC), solid organ malignancy (SOM), second haematological malignancy (SHM) and separately Richter's syndrome (RS) across all therapy eras. Among the 517 CLL/small lymphocytic lymphoma (SLL) patients, the overall incidence of SPMs with competing risks was SC 31.07%, SOM 25.99%, SHM 5.19% and RS 7.55%. Of the 216 treated patients, 106 (49.1%) had at least one form of SPM, and 63 of 106 (29.2% of treated patients) developed an SPM 1.5 years (median) after treatment for their CLL. Melanoma accounted for 30.3% of SC. Squamous cell carcinoma (SCC), including eight metastatic SCCs, was 1.8 times more than basal cell carcinoma (BCC), a reversal of the typical BCC:SCC ratio. The most common SOMs were prostate (6.4%) and breast (4.5%). SHM included seven acute myeloid leukaemia (AML) and five myelodysplasia (MDS) of which eight (four AML, four MDS) were therapy-related. Any SPM occurred in 32.1% of 53 Monoclonal B-lymphocytosis (MBL) patients. Age-adjusted standardised rates of SPM (per 100,000) for CLL, MBL and the general Australian population were 2648, 1855 and 486.9, respectively. SPMs are a major health burden with 44.9% of CLL patients with having at least one SPM, and apart from SC, associated with significantly reduced overall survival. Dramatic improvements in CLL treatment and survival have occurred with immunochemotherapy and targeted therapies, but mitigating SPM burden will be important to sustain further progress., Competing Interests: The authors have no conflict of interest to declare., (© 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Despite advances in therapy, a significant proportion of patients with chronic lymphocytic leukemia (CLL) relapse with drug resistant disease. Novel treatment approaches are required, particularly for high risk disease. The imipridones represent a new class of cancer therapy that has been investigated in pre-clinical and clinical trials against a range of different cancers. We investigated the effects of the imipridone, ONC-212, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment and a TP53 ko CLL cell line (OSU-CLL- TP53 ko). ONC-212 induced dose-dependent apoptosis, cell cycle arrest and reduced the migration of CLL cells in vitro, including cells from patients with TP53 lesions and OSU-CLL- TP53 ko cells. The effects of ONC-212 were associated with protein changes consistent with activation of the mitochondrial protease, CIpP, and the integrated stress response. We also observed inhibition of pathways downstream of the B-cell receptor (BCR) (AKT and MAPK-ERK1/2) and a pro-apoptotic shift in the balance of proteins of the BCL2 family of proteins (BCL2, MCL1, BCLxL, BAX and NOXA). In conclusion, the study suggests ONC-212 may represent an effective treatment for high risk CLL disease by inhibiting multiple facets of the BCR signaling pathway and the pro-survival effects of the BCL2-family proteins., Competing Interests: Edwin J. Iwanowicz and Henk Lang have financial interests in Madera Therapeutics, LLC.  In addition, Donald S. Karanewsky is a consultant for Madera Therapeutics, LLC., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)