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Letters to the Editor
diagnostic and relapse samples have been reported with a frequency of up to 70% in patients with BCP-ALL.12 Moreover, corticosteroid-mediated changes of antigen expression profile have been observed during remission induction.13 In our series, CD58 demonstrated outstand- ing stability: no cases of reduced expression of this anti- gen were noted. All remaining markers, usually useful for MFC-MRD detection, underwent either increased or decreased expression in substantial proportions of relaps- es and MRD-positive patients. Nevertheless, we were not able to point to any trend in immunological changes.
Frequent loss of CD19 expression under selective pres- sure of CD19-targeted therapy leads to weakness of the application of CD19 as the main gating antigen in search- es for neoplastic B-cell precursors. As suggested by Cherian et al., CD22 and CD24 could be added to aid in monitoring BCP-ALL if CD19-negativity develops.10 However, both of these markers could be negative on leukemic cells particularly when KMT2A gene rearrange- ment occurs (12% of cases in current study).14 We have found total positivity for these antigens in the majority but not in all patients who developed relapse after blina- tumomab treatment. Other antigens could also be used (Figure 3) for primary gating,4 although their application might be based on initially detected expression.
Our data show that not only CD19 could be downmod- ulated under the pressure of blinatumomab. Expression of almost all other markers that are useful for MFC-MRD monitoring in BCP-ALL could be changed between ALL diagnosis, MRD and relapse. This suggests that MFC- MRD monitoring after CD19 targeting should be based on a sophisticated approach with combinations of multi- ple markers and flexible gating strategies (Figure 3) in order to minimize the possibility of false negative results. In fact, more than a half of patients with disease progres- sion or reappearance preserved CD19 expression, thus it has no sense to exclude this conventional antigen from tumor-cell gating. However, if residual leukemia is not found among CD19-positive cells, other B-cell compart- ments should be studied with consideration of the blast immunophenotype detected before CD19 targeting (Figure 3).4,10,15 Moreover, taking into account possible myeloid switching under the selective pressure of blinatu- momab therapy, the distribution of cells according to CD45 expression and light scatter should also be investi- gated.
Thus, large and relatively individualized panels of anti- bodies with additional B-lineage and aberrant markers (myeloid antigens, NG2, etc.) should be applied to increase the effectiveness of MFC-MRD detection in BCP-ALL patients after CD19-directed treatment.
Ekaterina Mikhailova, Evgeny Gluhanyuk, Olga Illarionova, Elena Zerkalenkova, Svetlana Kashpor, Natalia Miakova, Yulia Diakonova, Yulia Olshanskaya, Larisa Shelikhova, Galina Novichkova, Michael Maschan, Alexey Maschan and Alexander Popov
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Correspondence:
ALEXANDER POPOV - uralcytometry@gmail.com
doi:10.3324/haematol.2019.241596
Received: October 28, 2019. Accepted: December 22, 2020. Pre-published: December 30, 2020.
Disclosures: no conflicts of interest to disclose.
Contributions: EM and AP designed the study, collected cytometric data and wrote the paper. EG, NM and YuD collected clinical data. OI and SK collected cytometric data. EZ and YuO collected cytogenetic and molecular genetic data and wrote the paper. LSh collected clinical data and wrote the paper. GN, MM and AM designed the study and wrote the paper. All authors revised the final version of the manuscript
Funding: the KMT2A rearrangement assessment study was supported by RFBR grant n. 17-29-06052 and Presidential grant n. MK-1645.2020.7 (n. 075-15-2020-338)
References
1.Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381-4389. Topp MS, Gokbuget N, Zugmaier G, et al. Phase II trial of the anti- CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B- precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134-4140.
2. 3.
4. 5.
6.
7.
8.
9. 10.
Mejstrikova E, Hrusak O, Borowitz MJ, et al. CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J. 2017;7(12):659.
Jabbour E, Short NJ, Jorgensen JL, et al. Differential impact of mini- mal residual disease negativity according to the salvage status in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Cancer. 2017;123(2):294-302.
Novikova I, Verzhbitskaya T, Movchan L, et al. Russian-Belarusian multicenter group standard guidelines for childhood acute lym- phoblastic leukemia flow cytometric diagnostics. Oncohematology. 2018;13(1):73-82.
Popov A, Belevtsev M, Boyakova E, et al. Standardization of flow cytometric minimal residual disease monitoring in children with B- cell precursor acute lymphoblastic leukemia. Russia–Belarus multi- center group experience. Oncohematology. 2016;11(4):64-73.
Kalina T, Flores-Montero J, Lecrevisse Q, et al. Quality assessment program for EuroFlow protocols: summary results of four-year (2010-2013) quality assurance rounds. Cytometry A. 2015;87(2):145- 156.
Karawajew L, Dworzak M, Ratei R, et al. Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia. Haematologica. 2015;100(7):935-944. Cherian S, Miller V, McCullouch V, et al. A novel flow cytometric assay for detection of residual disease in patients with B-lymphoblas- tic leukemia/lymphoma post anti-CD19 therapy. Cytometry B Clin Cytom. 2018;94(1):112-120.
11.Jabbour E, Dull J, Yilmaz M, et al. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatu- momab failure: no change in the level of CD19 expression. Am J Hematol. 2018;93(3):371-374.
12. Borowitz MJ, Pullen DJ, Winick N, et al. Comparison of diagnostic and relapse flow cytometry phenotypes in childhood acute lym- phoblastic leukemia: implications for residual disease detection: a report from the children's oncology group. Cytometry B Clin Cytom. 2005;68(1):18-24.
13. Dworzak MN, Gaipa G, Schumich A, et al. Modulation of antigen expression in B-cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: evidence for a drug-induced reg- ulatory phenomenon. Results of the AIEOP-BFM-ALL-FLOW-MRD- Study Group. Cytometry B Clin Cytom. 2010;78(3):147-153.
14. De Zen L, Bicciato S, te Kronnie G, Basso G. Computational analysis of flow-cytometry antigen expression profiles in childhood acute lymphoblastic leukemia: an MLL/AF4 identification. Leukemia. 2003;17(8):1557-1565.
15.Cherian S, Stetler-Stevenson M. Flow cytometric monitoring for residual disease in B lymphoblastic leukemia post T cell engaging targeted therapies. Curr Protoc Cytom. 2018;86(1):e44.
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