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• W3037397249 abstract "The receptor tyrosine kinase-like orphan receptor-1 (ROR1) is an evolutionary conserved type I surface membrane protein that is expressed during embryogenesis.1-3 Like most adult cells, normal B cells do not express ROR1. On the contrary, chronic lymphocytic leukaemia (CLL) cells express high levels of ROR1.4, 5 These properties make ROR1 an attractive target for the treatment of CLL. Indeed, a humanized monoclonal antibody, cirmtuzumab, which targets ROR1 and inhibits ROR1-signaling in vitro has been developed.6 A phase I study of cirmtuzumab in patients with CLL has demonstrated that this antibody can also inhibit ROR1-signaling in vivo, suppressing leukaemia cell activation of r-GTPases and phosphorylation of HS1.7 Monitoring of minimal residual disease (MRD) plays an increasing role in the management of CLL, particularly with the new therapeutic combinations.8 In this study, we have evaluated the expression of ROR1 on CLL cells before and after different treatment strategies to define its accuracy and reliability as a marker for MRD detection. Two cohorts of patients have been studied. The first cohort was composed of 110 untreated patients, 62 males and 48 females, median age 68 years (range 26–94). The diagnosis of CLL was based on the presence in the peripheral blood (PB) of more than 5000 × 109/l clonal lymphocytes expressing a conventional CLL morphology and immunophenotype: CD5+, CD19+, CD20+, CD200+, CD23+, CD10− and the weak clonal expression of kappa or lambda light chains. Thirty-five patients required treatments, while 16 were classified as monoclonal B-cell lymphocytosis (MBL). The second cohort was represented by 119 patients treated with several GIMEMA protocols (CLL1114, 0911, 1215, 1518); 67 were males and 52 females, the median age was 72 years (range 28–90). Overall, 277 samples have been analysed for MRD, 214 from the PB and 63 from the bone marrow (BM), at different time points of treatment as per protocol requirements. We also investigated the expression of CD43, CD81 to evaluate MRD. ROR1 has been evaluated at diagnosis, prior to treatment and at all MRD time points. Fresh leukaemic cells from PB and BM were stained with a combination of monoclonal antibodies (mAbs) and analysed using the Canto II flow cytometry (Becton Dickinson (BD), San Jose, CA, USA). The acquisition was carried out by collecting at least 30 000 events per tube on diagnostic samples and 1 × 106 for MRD detection. Data were analysed using the PAINT-A-GATE software (BD). Cell surface expression was quantified as the mean fluorescence intensity (MFI) of values obtained with specific mAbs compared with values given by the isotype controls. Conjugated CD5, CD19, CD20, CD23, CD200, CD43, CD81, CD34 mAbs from BD, kappa and lambda chain mAbs from DAKO (Agilent, Santa Clara, CA, USA) and ROR1-PE from Beckman Coulter (Life Sciences, Indianapolis, IN, USA) have been utilized. In the first cohort of 110 CLL cases, the mean number of leukaemic cells was 44 200/μl (±62 611). In all cases, the ROR1 antigen was expressed on all leukaemic cells with a median MIF of 29·5 ± 17·0 (range 9–101) Fig 1A. A significant correlation was found between the MIF of ROR1 and the number of leukaemic cells. When the leukaemic cells were <20 000/μl, the mean MIF was 25·1 ± 12·0 (range 11–63), while when the leukaemic cells were >50 000/μl the mean MIF was 34·5 ± 11·2 (range 19–55) (P < 0·02). Furthermore, the 35 patients who required treatment showed a significantly higher mean ROR1 MIF on CLL cells compared to the ROR1 MIF levels detected in 14 MBL cases: 35·8 ± 16·8 (range 14–91) vs. 25·0 ± 10·3 (range 12–45) (P < 0·04). In the second cohort of 119 patients, characterized by a mean number of leukaemic cells of 51 900/μl (±46 009), ROR1 expression was detected on all the leukaemic cell population with a median MIF of 35·0 ± 16·6 (range 11–91). In 9% of cases, MRD proved negative (<10−4 cells) in the PB and BM after treatment Fig 2A,B. Treatment did not affect ROR1 positivity, in fact when MRD was detected Fig 1B, all leukaemic cells expressed ROR1 and no significant changes in ROR1 MIF were observed before and after treatment, independently from the clinical protocol. In addition, no significant differences both in the percentage of ROR1+ CLL cell and in ROR1 MFI were recorded after the different treatment. In 195/214 PB samples (91%) that resulted MRD+ the residual leukaemic cells always espressed ROR1 with a mean MIF of 28·4 ± 15·3 (range 9–110); in the 55/63 BM MRD+ samples analysed (87%), leukaemic cells expressed ROR1 with a mean MIF of 30·9 ± 14·2 (range 9–90), with no significant differences compared to PB cells (32·5 ± 14·7, range 10–75; P = 0·58). Haematogones in the BM expressed ROR1 with a mean MIF of 28 ± 8·48 (range 22–34) Fig 2B, while the residual mature normal B lymphocytes did not express the ROR1 antigen. Finally, in both cohorts of patients no significant differences were found in the percentage and MIF of ROR1 expression according to age (<65 years vs. ≥65 years: 30·5 ± 17·8 vs. 28·2 ± 16·5, P = 0·47) or sex (female vs. male: 30·7 ± 17·7 vs. 25·8 ± 15·7, P = 0·18). Our results further confirm that the ROR1 molecule is always expressed on the surface of CLL cells.5 Higher levels of ROR1 are associated with higher circulating leukaemic cells and with disease aggressiveness, i.e. at the time of treatment, confirming that the expression of ROR1 correlates with cell proliferation and disease progression.9-11 The expression and MFI of ROR1 are preserved on CLL cells also during and after several types of treatment: ibrutinib + rituximab (CLL1114), venetoclax + ibrutinib (CLL1518),fludarabine + cyclophosphamide + ofatumumab (CLL0911); ibrutinib + ofatumumab (CLL1215). It was in fact always detected on residual leukemic cells after all treatment combinations. This characteristic makes ROR1 an accurate and reliable candidate to investigate MRD in combination with other molecules expressed on the surface of CLL cells, such as CD5, CD19. ROR1 assessment could replace the evaluation of light chain expression, a tool highly reliable to recognize CLL cells but not widely utilized in MRD monitoring.12 The presence of ROR1 on haematogones13 does not represent a problem in the study of MRD in the BM, since CLL cells are always identified being CD5/CD19/CD20-positive. In agreement with other authors,10 the documented negativity of ROR1 in mature B lymphocytes further confirms that this receptor may represent an important player in MRD analysis in CLL. At a time when MRD is always more a primary endpoint in clinical protocols for CLL patients, the inclusion of ROR1 in the mAb panel may improve the accuracy of MRD monitoring. This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Special 5x1000 Program Metastases (21198), Milan (Italy) to RF. IS and MML were supported by ROMAIL ONLUS, MP was supported by GIMEMA ONLUS. DPMS and GA designed the research study, DPMS, IS, MML, MP, PN, NMG carried out the lab work, DPMS and GA analysed the data, GA and RF wrote the paper." @default.
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• W3037397249 date "2020-06-24" @default.
• W3037397249 modified "2023-10-14" @default.
• W3037397249 title "ROR1 is an accurate and reliable marker of minimal residual disease in chronic lymphocytic leukaemia" @default.
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• W3037397249 doi "https://doi.org/10.1111/bjh.16910" @default.
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