Prednisone induces immunophenotypic modulation of CD10 and CD34 in nonapoptotic B‐cell precursor acute lymphoblastic leukemia cells

Gaipa, Giuseppe; Basso, Giuseppe; Aliprandi, Sara; Migliavacca, Maddalena; Vallinoto, Cristina; Maglia, Oscar; Faini, Andrea; Veltroni, Marinella; Husak, Zvenyslava; Schumich, Angela; Ratei, Richard; Biondi, Andrea; Dworzak, Michael

doi:10.1002/cyto.b.20408

Cited by 56 publications

(57 citation statements)

References 14 publications

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“…Notably, CD34 expression was highly variable during follow-up and tended to reincrease in some patients already at day 33, a few days after start of tapering of GCs. This pattern of decrease and reincrease favorably matches with the schedule of GC containing chemotherapy as well as with the direction of the in vitro GC-induced expression alterations of these two antigens (11). It may therefore be regarded a transient, GC-induced phenomenon related to modulation of responsive genes and of the translational machinery, as discussed recently (19,20).…”

Section: Results and Discussion Evolution Of Antigen Expression Durinsupporting

confidence: 58%

“…The latter follow generic patterns, but occur with some interindividual variability (7). In this respect, we have recently shown that the amount of phenotypic shifts correlates positively with treatment sensitivity in ALL (11). Nevertheless, the good message for MRD studies is that phenotypic shifts of highly relevant antigens like CD10 and CD34 are only transitory and revert to initial aberrant patterns after stop of GC containing therapy in many patients (Fig.…”

Section: Drug-induced Phenotype Shifts In All Are Reversiblementioning

confidence: 99%

“…Antigen expression was quantified on the basis of mean fluorescence intensity (MFI) values as reported using the CELL Quest TM software (7,11). DAKO Fluorospheres TM (type IIIa beads) with assigned values of molecules of equivalent soluble fluorochrome were used for intracenter longitudinal monitoring of instrument performance stability (17).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Alternatively, it may just be related to drug-induced cell death, resulting in loss of membrane antigens or higher nonspecific staining (9,10). More recently, however, we showed that this type of modulation can be elicited also in vitro in viable (annexin V negative) leukemic cells by incubation with low concentrations of prednisone (11). In these experiments, lymphoblast viability was sustained by bone marrow (BM) stroma cells, which is essential for them (12,13).…”

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confidence: 99%

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Modulation of antigen expression in B‐cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug‐induced regulatory phenomenon. Results of the AIEOP‐BFM‐ALL‐FLOW‐MRD‐Study Group

Dworzak¹,

Gaipa

Schumich³

et al. 2010

Cytometry Part B Clinical

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Background: Changes of antigen expression on residual blast cells of acute lymphoblastic leukemia (ALL) occur during induction treatment. Many markers used for phenotyping and minimal residual disease (MRD) monitoring are affected. Glucocorticoid (GC)-induced expression modulation has been causally suspected, however, subclone selection may also cause the phenomenon.Methods: We investigated this by following the phenotypic evolution of leukemic cells with flow cytometry from diagnosis to four time points during and after GC containing chemotherapy in the 20 (of 360 consecutive) B-cell precursor patients with ALL who had persistent MRD throughout.Results: The early expression changes of CD10 and CD34 were reversible after stop of GC containing chemotherapy. Modulation of CD20 and CD45 occurred mostly during the GC phase, whereas CD11a also changed later on. Blast cells at diagnosis falling into gates designed according to ''shifted'' phenotypes from follow-up did not form clusters and were frequently less numerous than later on.Conclusions: Our data support the idea that drug-induced modulation rather than selection causes the phenomenon. The good message for MRD assessment is that modulation is transient in at least two (CD10 and CD34) of the five prominent antigens investigated and reverts to initial aberrant patterns after stop of GC therapy, whereas CD20 expression gains new aberrations exploitable for MRD detection.

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Section: Results and Discussion Evolution Of Antigen Expression Durinsupporting

confidence: 58%

Section: Drug-induced Phenotype Shifts In All Are Reversiblementioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

mentioning

confidence: 99%

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Modulation of antigen expression in B‐cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug‐induced regulatory phenomenon. Results of the AIEOP‐BFM‐ALL‐FLOW‐MRD‐Study Group

Dworzak¹,

Gaipa

Schumich³

et al. 2010

Cytometry Part B Clinical

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“…In addition, improved characterization of the normal and leukemic cells will also facilitate the recognition of ALL cells despite the occurrence of immunophenotypic shifts, which frequently are apparent during the early phases of therapy. [38][39][40][41][42] Indeed, our current data show that 6-color FCM resulted in a higher concordance with molecular MRD data than 4-color FCM. Whereas using 4-color FCM 6% of samples were found to be positive by FCM only, this percentage dropped to almost 0% (0.2%) using 6-color FCM.…”

Section: -17supporting

confidence: 51%

Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia

et al. 2012

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Most current treatment protocols for acute lymphoblastic leukemia (ALL) include minimal residual disease (MRD) diagnostics, generally based on PCR analysis of rearranged antigen receptor genes. Although flow cytometry (FCM) can be used for MRD detection as well, discordant FCM and PCR results are obtained in 5-20% of samples. We evaluated whether 6-color FCM, including additional markers and new marker combinations, improved the results. Bone marrow samples were obtained from 363 ALL patients at day 15, 33 and 78 and MRD was analyzed using 6-color (218 patients) or 4-color (145 patients) FCM in parallel to routine PCR-based MRD diagnostics. Compared with 4-color FCM, 6-color FCM significantly improved the concordance with PCR-based MRD data (88% versus 96%); particularly the specificity of the MRD analysis improved. However, PCR remained more sensitive at levels o0.01%. MRD-based risk groups were similar between 6-color FCM and PCR in 68% of patients, most discrepancies being medium risk by PCR and standard risk by FCM. Alternative interpretation of the PCR data, aimed at prevention of false-positive MRD results, changed the risk group to standard risk in half (52%) of these discordant cases. In conclusion, 6-color FCM significantly improves MRD analysis in ALL but remains less sensitive than PCR-based MRD-diagnostics.

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Advances in measurable residual disease monitoring for adult acute lymphoblastic leukemia

Meleveedu

Litzow

2019

Adv Cell Gene Ther

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Adult acute lymphoblastic leukemia management has traditionally relied upon pretreatment conventional risk factors for treatment decisions. Despite using intensive multiagent chemotherapy followed by a prolonged maintenance or allogeneic stem cell transplantation, these patients remain at a high risk of relapse. Improved techniques for detection of measurable residual disease (MRD) have tremendously changed the posttreatment disease burden assessment and evolved as a powerful predictor of relapse and survival superseding historical prognostic factors. Moreover, MRD measurement has become an integral part of risk stratification, prognosis assessment, intensification or de‐escalation of treatment, monitoring of disease burden, and an endpoint in clinical trials. With existing approaches like allogeneic hematopoietic stem cell transplantation and emergence of novel agents (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor [CAR] T cells) that are highly effective in eradicating residual disease, understanding the role of MRD in treatment decisions is getting more and more important and complex. This review will highlight the advances that have been achieved in MRD monitoring over the years and the practical applications in different time points of treatment to provide a framework for rational management decisions by practicing hematologists and oncologists.

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Prednisone induces immunophenotypic modulation of CD10 and CD34 in nonapoptotic B‐cell precursor acute lymphoblastic leukemia cells

Abstract: Conclusions: The prednisone-induced immunophenotypic modulation can be reproduced in vitro and this phenomenon may reflect sensitivity to chemotherapy. q

Cited by 56 publications

References 14 publications

Modulation of antigen expression in B‐cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug‐induced regulatory phenomenon. Results of the AIEOP‐BFM‐ALL‐FLOW‐MRD‐Study Group

Modulation of antigen expression in B‐cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug‐induced regulatory phenomenon. Results of the AIEOP‐BFM‐ALL‐FLOW‐MRD‐Study Group

Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia

Advances in measurable residual disease monitoring for adult acute lymphoblastic leukemia

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