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Editorials
Among 91 of 119 cases with available data, three of the 91
(3.3%) were negative for minimal residual disease while 88
(96.7%) were positive with a median minimal residual dis-
ease 8 months after starting IR treatment of 18.7%±23.7
(range, 0.01%-94%). Interestingly, an overall higher MFI
modulation of all antigens analyzed, except for CD43, was
SI, MLM, PM and SR carried out the laboratory work. MSDP, FRM, SS, AC, GMR and IDG analyzed the data. NP, RF and AG wrote the paper.
Funding: this work was supported by funds from Associazione Italiana Ricerca sul Cancro (AIRC), Special 5x1000 Program Metastases (21198), Milan (Italy) to RF. SI and MLM were
supported by ROMAIL ONLUS, PM was supported by GIMEMA ONLUS.
References
1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32- 42.
2. Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lym- phocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28(11):2188-2196.
3. de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.
observed in cases with more profound reduction of the CLL
absolute cell count to values below 0.1x103/mL (n=25/91),
corresponding to a percentage of pathological cells within
the total leukocyte population of less than 1.5%, except for
two cases with values of 2.2% and 3.0% (mean
0.64%±0.80). These differences became statistically signifi-
cant for CD44 and CD49d downmodulation (CLL
<0.1x10 /mL vs. CLL ≥0.1x10 /mL: DMFI 5839±3800 vs. 3655±3226, P=0.025 and 1415±1146 vs. 648±626, P=0.009; respectively), as well as for CD184 upmodulation (CLL <0.1x103/mL vs. CLL ≥0.1x103/mL: DMFI 2111±1635 vs. 1291±1070, P=0.016) (Figure 3), suggesting a potential role for ibrutinib- mediated early modulation of CLL surface antigen expres- sion in predicting the degree of response to IR therapy.
Taken together, the present data demonstrate the pro- found immunophenotypic changes induced in vivo on pri- mary CLL cells by 14 days of IR therapy. Since most of the molecules involved mediate the interaction of leukemic B cells with the microenvironment, our results may help to elucidate the mobilization process of CLL cells observed during ibrutinib treatment and the relationship between antigen modulation and peripheral lymphocytosis in the context of treatment approaches combining ibrutinib with anti-CD20 antibodies. The ongoing extended follow-up will further clarify the influence of the early antigen modu- lation on long-term therapeutic efficacy in vivo, in order to better understand the biological basis of the effect of ibruti- nib over time and eventually to provide further specific antigen targets for CLL treatment.
Nadia Peragine,1 Maria Stefania De Propris,1
Stefania Intoppa,1 Maria Laura Milani,1 Paola Mariglia,1 Francesca Romana Mauro,1 Sara Raponi,1 Stefano Soddu,2 Antonio Cuneo,3 Gian Matteo Rigolin,3 Ilaria Del Giudice,1 Robin Foà1 and Anna Guarini4
1Hematology, Department of Translational and Precision Medicine, ‘Sapienza’ University, Rome; 2Italian Group for Adult Hematologic Diseases (GIMEMA) Foundation, Rome; 3Hematology, Department of Medical Sciences, University of Ferrara, Ferrara and 4Department of Molecular Medicine, ‘Sapienza’ University, Rome, Italy
Correspondence:
ROBIN FOA’ - rfoa@bce.uniroma1.it. doi:10.3324/haematol.2020.262071
Received: June 8, 2020.
Accepted: September 24, 2020.
Pre-published: October 5, 2020.
Disclosures: no conflicts of interest to disclose.
Contributions: NP, RF and AG designed the research study. MSDP,
33
4. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibruti- nib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15(10):1090-1099.
5. Beke Debreceni I, Szász R, Kónya Z, Erdődi F, Kiss F, Kappelmayer J. L- selectin expression is influenced by phosphatase activity in chronic lymphocytic leukemia. Cytometry B Clin Cytom. 2019;96(2):149-157.
6. Kriston C, Plander M, Márk Á, et al. In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment. Ann Hematol. 2018;97(11):2145-2152.
7. Chen S-S, Chang BY, Chang S, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia. 2016;30(4):833-843.
8. Shen Y, Best OG, Mulligan SP, Christopherson RI. Ibrutinib and idelal- isib block immunophenotypic changes associated with the adhesion and activation of CLL cells in the tumor microenvironment. Leuk Lymphoma. 2018;59(8):1927-1937.
9. Herman SE, Sun X, McAuley EM, et al. Modeling tumor–host interac- tions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia. 2013;27(12):2311-2321.
10. Rawstron AC, Böttcher S, Letestu R, et al. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual dis- ease monitoring in CLL. Leukemia. 2013;27(1):142-149.
11.Maffei R, Fiorcari S, Martinelli S, Potenza L, Luppi M, Marasca R. Targeting neoplastic B cells and harnessing microenvironment: the "double face" of ibrutinib and idelalisib. J Hematol Oncol. 2015;8:60.
12. Guarini A, Peragine N, Messina M, et al. Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib. Br J Haematol. 2019;184(3):392-396.
13. O'Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treat- ment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5- year experience. Blood. 2018;131(17):1910-1919.
14. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab in patients with chronic lymphocytic leukemia (CLL). Blood. 2019;133(10):1011-1019.
15. Thompson PA, Ferrajoli A, O'Brien S, Wierda WG, Keating MJ, Burger JA. Trisomy 12 is associated with an abbreviated redistribution lym- phocytosis during treatment with the BTK inhibitor ibrutinib in patients with chronic lymphocytic leukaemia. Br J Haematol. 2015;170(1):125-128.
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