Page 203 - 2022_03-Haematologica-web

Letters to the Editor
Guideline for management of non-Down syndrome neonates with a myeloproliferative disease on behalf of the I-BFM AML Study Group and EWOG-MDS^
In neonates with myeloid hyperproliferation, apart from benign causes, Down syndrome (DS) related transient abnormal myelopoiesis (TAM), acute myeloid leukemia (AML) and juvenile myelomonocytic leukemia (JMML) are considered.1-3 Besides TAM, rarely, non-DS related tran- sient myeloproliferative diseases occur, making clinical decisions challenging.4 TAM, according to World Health Organization (WHO) classification, only applies to children with (mosaic) Down syndrome.5 In the past, different ter- minology has been used in non-DS patients, such as tran- sient myeloproliferative disease (TMD) and transient leukemia. Since distinction from TAM is important, and it is challenging to determine whether this disease will be transient, the consensus group introduced the novel term ‘infantile myeloproliferative disease’ (IMD), in order to dis- tinguish it from TAM. Both TAM and IMD can usually be managed with a ‘watch and wait’ strategy, while most full- blown AML or JMML cases require intensive treatment. We collected rare IMD cases from study groups collaborat- ing in the International Berlin-Frankfurt-Münster AML Study Group (I-BFM AML SG). In addition, we reviewed the literature for neonatal cases of malignant myeloid hyperproliferation without DS. Based on these data, we developed, together with I-BFM AML SG and the European Working Group of Myelodysplastic syndromes in Childhood (EWOG-MDS) members, by consensus, clinical recommendations for the diagnostic approach and current adequate classification of malignant myeloid hyperprolifer- ation in infancy. This is meant guiding clinicians in choos- ing the right strategy, i.e., whether to ‘watch and wait’ or start highly intensive treatment in individual cases.
We centrally collected detailed information from data- basesofI-BFMAMLSGcollaboratorstoidentifyclinical and genetic characteristics of additional, not yet reported, cases with IMD. Children younger than one year, diag- nosed between 1990 and 2020, were included. Ethical approval and informed consent were obtained by each study group individually. Registration and data forms involved clinical features, hematological data, morphology and immunology, treatment, outcome and follow-up data. Available written reports of cytogenetic findings were col- lected and centrally reviewed by Dr. A. Buijs (University Medical Center Utrecht) and Prof. Dr. S. Raimondi (St. Jude Children’s Hospital, Memphis). We identified 15 new cases of IMD with, in some cases, novel recurrent molecular aberrations (Table 1). No germline aberrations were identi- fied; however, standardized diagnostics did not always include germline testing. Thirteen patients had somatic tri- somy 21 (T21) with or without a GATA1 mutation, one patient had low mosaic somatic trisomy 8 and a SETD2 mutation and one patient was not tested for somatic aber- rations. Notably, among the 15 newly-added cases, in four patients, evaluation for GATA1 mutations was not per- formed.
potential germline mosaic T21 was not always performed. Congenital/infant leukemia accounts for <1% of all childhood leukemias.6 When the rare event occurs in which a neonate is suspected of myeloid leukemia, TAM or IMD, clinical decision making can be challenging. Here, represen- tatives of the I-BFM AML SG, together with JMML experts from the EWOG MDS, provide a clinically-applicable con- sensus of diagnostic logistics for children younger than six weeks. This is based on literature and newly-added cases from our international survey, which may support clinical decision-making in individual cases (Figure 1). During two meetings with leading members from both the I-BFM AML SG and EWOG MDS, relevant literature was discussed and expert experience shared. We reached consensus on diag-
nostic strategies of neonates with myeloproliferation.
The differential diagnosis of myeloproliferation in infants includes, apart from (congenital) infections and other stres- sors, JMML, AML, TAM and other types of IMD.4,6 More frequent benign underlying conditions should be seriously considered before diagnosing a neonate with leukemia and beginning intensive treatment (Figure 1). A medical history and physical examination are important to reveal initial clues regarding infectious causes, other factors inducing stress-hematopoiesis and genetic predisposition (presence of dysmorphic and congenital abnormalities). A physical examination will also reveal hepatosplenomegaly, fluid accumulation and/or skin infiltration. A total blood count and morphological assessment of the peripheral blood smear carried out by an experienced hematologist or mor- phologist in an expert laboratory are mandatory, and peripheral blood immunophenotyping is, as a minimum
measure, advised.4
If a malignant condition is conceivable, the most impor-
tant challenge is to discriminate a rare transient case, where a ‘watch and wait’ strategy may be justified, from an aggressive leukemia subtype that may require intensive treatment in a limited time span. First, a distinction between megakaryocytic and non-megakaryocytic leukemia is important, based on the morphology and immunophenotyping of the peripheral blood blasts. Megakaryocytic hyperproliferation (French-American- British - FAB - classification M7) can be recognized by mod- erately basophilic agranular cytoplasm with blebs on mor- phology, combined with expression of CD41, CD42 and/or CD61 on flow cytometry.5
In case of megakaryocytic hyperproliferation, germline T21 and GATA1 mutations may point towards TAM. TAM blasts can also present without megakaryocytic markers, FAB M0 (undifferentiated).7 In TAM, early onset and hepatosplenomegaly with monoclonal megakaryocytic hyperproliferation with T21 and a GATA1 mutation can be confirmed.8 The origin of TAM lies in the fetal liver which is why, in most cases, peripheral blood sampling is suffi- cient for a diagnosis and a bone marrow puncture is unnec- essary.1 Without life-threatening disease, a ‘watch and wait’ policy with close monitoring, including regular phys- ical examination and blood counts, is justified.8 Low-dose cytarabine treatment is advised in case of multiorgan fail- ure, high WBC >100 x 109/l, hepatopathy (high
Thesearchforavailableliteratureandcasereportsofbilirubin/transaminases, ascites), severe
non-DS transient leukemia was performed in the PubMed database. Publications indexed until 1 January 2021 were included. Search terms included TMD, TAM and transient leukemia, used separately and combined with non-Down, non-Down syndrome, and without Down syndrome. A cross-reference check was performed in key articles. We included 23 articles that described one or multiple patients that met our search criteria (Table 2). Unfortunately, in these cases too, routine testing of somatic GATA1 and
hepatosplenomegaly, hydrops fetalis, pleural or pericardial effusions, renal failure, or disseminated intravascular coag- ulation.8 This treatment does not prevent the development of ML-DS (myeloid leukemia related to Down syndrome), but substantially reduces mortality in symptomatic patients.9 After remission, follow-up is advised every three months until the age of four years, because of a 20% chance of ML-DS development during that life span.8 ML- DS requires more intensive treatment, however this treat-
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