Study protocol of LANTana: a phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, UK.

INTRODUCTION: Suitability for peptide receptor radionuclide therapy (PRRT) for neuroendocrine neoplasia (NENs) depends on presence of somatostatin receptor-2 (SSTR2) determined by [68Ga]Ga-DOTA-peptide-positron emission tomography (PET). Some patients have low or no uptake on [68Ga]Ga-DOTA-peptide-PET, precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. Demethylating agents increase uptake on PET imaging in vivo such that tumours previously negative on PET become positive, correlating with a dose dependent increase in tumorous SSTR2 expression. LANTana will determine whether treatment with the demethylating agent, ASTX727, results in re-expression of SSTR2 using [68Ga]Ga-DOTA-peptide-PET to image epigenetic modification of the SSTR2 locus, allowing subsequent PRRT. METHODS AND ANALYSIS: 27 participants with a histological diagnosis of NEN (Ki67<55%) with no or low uptake on baseline [68Ga]Ga-DOTA-TATE-PET/CT will be recruited. Patients will receive 5 days of ASTX727 (fixed dose 35 mg decitabine+100 mg cedazuridine). [68Ga]Ga-DOTA-peptide-PET/CT will be repeated day 8±2; where there is significant uptake greater than liver in most lesions, PRRT will be administered. Primary objective is to determine re-expression of SSTR2 on PET imaging. Tolerability, progression-free survival, overall response and quality of life will be assessed. Methylation in peripheral blood mononuclear cells and tumorous methylation will be evaluated. ETHICS AND DISSEMINATION: LANTana has ethical approval from Leeds West Research Ethics Committee (REC Reference: 21/YH/0247).Sponsored by Imperial College London and funded by Advanced Accelerator Applications pharmaceuticals. Results will be presented at conferences and submitted to peer-reviewed journals for publication and will be available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBERS: EUDRACT number: 2020-003800-15, NCT05178693.

Daratumumab, bortezomib and dexamethasone at first relapse for patients with multiple myeloma: A real-world multicentre UK retrospective analysis.

Daratumumab, bortezomib and dexamethasone (DVd) is approved for patients with relapsed multiple myeloma following the CASTOR phase 3 clinical trial. This retrospective multicentre analysis assesses the overall response rate (ORR) and progression-free survival (PFS) in routine clinical practice for patients at first relapse treated with DVd incorporating weekly bortezomib. Data were collected from 296 sequential patients treated across 15 UK centres. After a median follow-up of 21 months, the ORR was 82% (26% partial response, 56% very good partial response or better) and the median PFS was 16 months [95% confidence interval (CI) 12-20 months]. Results were similar regardless of prior lenalidomide exposure. The median time to next treatment was 20 months (95% CI 15-25 months) and the estimated overall survival at two years was 74%. Patients with high-risk features (by cytogenetics, International Staging System or extramedullary disease) and those treated within 18 months of initiation of progression-free treatment, or within 12 months of autologous stem cell transplant, had significantly inferior outcomes. The grade 2 and 3 peripheral neuropathy rate was 7%. DVd with weekly bortezomib was effective in a heterogenous real-world population at first relapse with a low rate of peripheral neuropathy. However, high-risk patients had inferior outcomes and should be considered for alternative treatments.

Nodular Lymphocyte Predominant Hodgkin Lymphoma With Aberrant Immunophenotype or Variant Histopathology: Insights From Case Series of Three Patients.

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) with variant histopathology or aberrant immunophenotype is exceedingly rare and there is paucity of data with regards to its clinical characteristics and course. CASE REPORT: Herein, we present three cases of NLPHL with aberrant immunophenotype or variant histopathological picture, which displayed distinct clinical and imaging findings. These case reports involved a patient with CD30 and CD20 positivity without Reed-Sternberg cells present, a NLPHL patient with aggressive, persistent disease activity with progressive transformation to germinal centres, and a patient with combined morphology of NLPHL and classical Hodgkin's lymphoma. CONCLUSION: Aberrant immunophenotype/variant NLPHL might represent a distinct form of NLPHL, sharing characteristics with classical Hodgkin, non-Hodgkin lymphomas or benign, progressive transformation of germinal centre lymphadenopathy.

Ixazomib, lenalidomide, and dexamethasone is effective and well tolerated in multiply relapsed (≥2nd relapse) refractory myeloma: a multicenter real world UK experience.

There are limited real world data on ixazomib, lenalidomide, and dexamethasone (IRd) in multiply relapsed myeloma. We analyzed outcomes of 116 patients who received IRd predominantly at second and subsequent relapse including those refractory to proteasome inhibitors (PIs). With a median follow up 16.3 months, the overall response rate was 66.9%; median progression-free survival (PFS) was 17.7 months with median overall survival (OS) not reached (NR). PFS and OS were significantly shorter in advanced disease (PFS; 12.6 vs. 21.2 months (p = .01), OS; 15.9 months vs. NR (p = .01) for ISS3 vs. ISS 1&2, respectively). PFS and OS were significantly shorter in clinical high risk (CHR) compared to standard risk (SR) patients (PFS; 9.3 months vs. NR (p = .001), OS; 11.5 months vs. NR (p < .001), respectively). There was a trend toward shorter PFS in PI-refractory patients 13.7 vs. 19.6 months for non-PI refractory (p = .2). The triplet combination was generally well tolerated.