Screening for Clonal Hematopoiesis for Mitigating the Risk of Hematopoietic Neoplasms after PRRT.

Abstract

Lu-DOTATATE, a peptide receptor-based radionuclide therapy (PRRT), is one of latest treatment options for patients with progressive gastro-entero-pancreatic neuroendocrine tumors (NETs) and leads to significantly better disease-free survival.1 Although rare, an ominous adverse effect seen with PRRT is development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, a global multicenter study done by Vigne et al using the World Health Organization pharmacovigilance database VigiBase including 1,674 cases, showed0.91 and0.31% incidence ofMDSandAML, respectively. These adverse events were associated with treatment discontinuation in all affected patients, andmore importantly approximatelyone-third of these cases eventually had fatal outcomes.2 Based on accumulated clinical data over the past decade and a half, incidence of PRRT-relatedmyeloid neoplasms (t-MN) has been reported in 0.2 to 5.4% of the patients.3–6 Long-term follow-up data from Erasmus Medical Centre, including 1,214 patients showed MDS incidence at 1.5% after a median followup of 28 months and acute leukemia at 0.7% after a median follow-up of 55 months after first therapy.7 The final results of theNETTER-1studygroupshowedt-MNriskat1.2%post5years of the last patient is randomized.8 A slightly higher percentage of patients experienced t-MN after PRRT in two other studies, both of which combined PRRT with prior or concomitant chemotherapy. Of note, a much higher rate of t-MN (20%) was reported by Brieau et al in a limited series of 20 nonresectable NETs treated with Lu-PPRT after heavy pretreatment with chemotherapy.9Another studydonebyGoncalves et al from the Peter MacCallum Cancer center including 521 patients over a 12-year period showed 4.8% incidence of t-MN.10 Twenty-five percent of these patients had receivedprior chemotherapywith carboplatin/etoposide and 88% received concomitant radiosensitizing chemotherapy such as 5FU or capecitabine. Themedian overall survival (OS) after diagnosis of t-MN was shown to be mere 13 months. Although the novel approach of PRRT with combined chemotherapy may potentially offer better tumor control, it may also slightly augment the risk of t-MN. The quest for identifying predictive biomarkers for post-tMN continues. Unlike nephrotoxicitywhich is considered dosedependent side effect of PRRT, occurrence of long-term hematological toxicity is difficult to predict based onmarrow dosimetryalone.11AstudydonebyBrieauetal showedtwoprognostic factors for the development of t-MN identified in this study: (1) early grade 3 to 4 hematological toxicity after PRRT and (2) higher number of chemotherapy cycles before PRRT. Similarly, post-PRRT thrombocytopenia was significantly related to the development of secondary MDS or AML in a previous study.5 Hence, close monitoring should be recommended in patients experiencing early hematological toxicity after PRRT. A novel strategy to mitigate the risk of t-MN appears to be pretreatment identification of clonal hematopoiesis (CH) in patients at risk for t-MN. The acquisition of somatic mutations detected in theblood leading to the clonal expansionofmutated hematopoietic cells is referred to as CH. CH is commonly detected in healthy individuals; however, it is also associated with risk of hematologic disease. CHmutations generally occur at low frequencies in genes implicated in myeloid neoplasms such as DNMT3A, TET2, ASXL1, and TP53. In a large study analyzing next-generation sequencing (NGS) data from approximately 8,810 patients, CHwas identified in approximately 25% of thenon-hematopoieticcancerpatientsatbaselineandshown to be associated with increasing age, prior chemotherapy, radiation therapy, and tobacco consumption.12 Recently published data by Singh et al points toward CH beingoneof thereasonsfor thedevelopmentof t-MNafterPRRT. Theyevaluatedpreandpost-PRRTbloodsamplesof 13patients