Pattern associated leukemia immunophenotypes and measurable disease detection in acute myeloid leukemia or myelodysplastic syndrome with mutated NPM1

Abstract

Background: The presence of measurable residual disease after therapy is a significant risk factor of relapse in patients with acute myeloid leukemia (AML). By detecting cells with leukemia-associated immunophenotype (LAIP), multiparameter flow cytometry (MFC) can detect residual leukemia at a level significantly lower than that detected by morphology. However, changes in LAIPs during or after therapy may pose a challenge to MRD testing. AML with mutated NPM1 represents the largest subtype of AML sharing a common leukemogenic mechanism and similar LAIPs. Here, we identified a common pattern of LAIPs in myeloid blasts with mutated NPM1, and studied its stability and limit of detection after therapy.Methods: We summarized aberrancies of leukemic blasts with mutated NPM1 at diagnosis in 61 patients and paired relapse in 25 patients. In addition, we examined the detection of leukemic blasts in 590 specimens collected from 152 patients in complete remission after induction for AML/MDS-EB with mutated NPM1.Results: Our findings demonstrate myeloid blasts with mutated NPM1 have a characteristic pattern of LAIPs that is present in nearly all cases of AML/MDS-EB with mutated NPM1 at initial diagnosis and relapse, regardless of morphologic variations, FLT3 ITD status, or karyotype abnormality. The myeloid blasts with mutated NPM1 can be detected at an approximate level of 0.1% of total leukocytes in morphologic remission with high specificity validated by clinical outcome.Conclusion: The characteristic pattern of LAIPs of myeloid blasts with mutated NPM1 is common and stable, and allows sensitive and specific detection of AML or MDS with mutated NPM1 after therapy.

Leukemia‐associated immunophenotypes subdivided in “categories of specificity” improve the sensitivity of minimal residual disease in predicting relapse in acute myeloid leukemia

“…Cautions on the atypical expression of CD56 on maturing myeloid cells or monocytes were already described by Wells et al () who justified the expression of CD56 in these compartments as an early or intense granulopoiesis following a marrow insult. Moreover, CD33‐based LAIPs typically described the monoblastic/monocytic acute leukemia by immunophenotyping and these data defined the impossibility of monitoring the MRD in this subgroup of AML.To date, the global frequency of LAIPs reported at diagnosis on the literature ranged from 80 to 100% for AML (Zhou et al, ), while at least two LAIPs were considered useful in monitoring MRD (Al‐Mawali et al, ; Buccisano et al, ; San Miguel et al, ; Terwijn et al, ; Venditti et al, ; Walter et al, ). However, no further explanations have been provided on specific combinations of LAIPs as well as no studies have addressed on the role of number and typology of LAIPs on the sensitivity of MRD.…”

“…Some LAIPs are indeed more specific than others. In previous studies, (Al‐Mawali et al, ; Buccisano et al, ; Cui et al, ; Feller et al, ; Olaru et al, ; Rossi et al, ; Rossi et al, ; San Miguel et al, ; Terwijn et al, ; Venditti et al, ; Voskova et al, ; Walter et al, ; Zhou et al, ) LAIPs have been related to coexpressions of antigenic surface markers, including CD33+/CD56+ or CD117+/CD15+ combinations. In spite of that, subsequent works have described these LAIPs as not specific for MRD monitoring (Rossi et al, ; Wells et al, ).…”

From the Editor: Thank you! Remembrances and Issue Highlights

“…Continuing with the theme of AML is the contribution from Zhou et al (21), who demonstrate that myeloid blasts associated with mutated NPM1 have a distinct leukemic associated immunophenotype (LAIP) present in most cases of AML and selected cases of myelodysplastic syndrome. Myeloid blasts with mutated NPM1 were primarily characterized by their reduced side-scatter, increased CD33 and CD123, moderate CD45 and CD117, decreased or absent CD34 and CD13 and absence of CD15 and CD64.…”

MRD Tailored Therapy in AML: What We Have Learned So Far

“…In the ELN 2018 MRD guidelines, an integrated LAIP-based DfN approach was recommended. Several studies have been using this LAIP-based DfN approach where LAIPs at diagnosis were assessed, but also DfN patterns at follow up were analyzed ( 16 , 18 , 19 ). The dominant LAIPs at diagnosis, LAIPs that arise due to clonal evolution, and the immunophenotypic shifts after therapy are taken into account with this approach.…”