[SFCE harmonization workshops: Neonatal acute myeloid leukemia]. / Orientation et prise en charge de la leucémie aiguë myéloïde néonatale : recommandations du comité leucémies de la SFCE.

Neonatal acute myeloid leukemias (AML) occurred within the first 28 days of life and constitute only a small proportion of all AL. They are distinguished from leukemias of older children by their clinical presentation, which frequently includes cutaneous localizations ("blueberry muffin rash syndrome") and a leukocytosis above 50 ×109/L. This proliferation may be transient, causing a transient leukemoid reaction in a background of constitutional trisomy 21 ("Transient Abnormal Myelopoieseis" or TAM) or Infantile Myeloproliferative Disease in the absence of constitutional trisomy 21 ("Infantile Myeloproliferative Disease" or IMD). In cases of true neonatal AML, the prognosis of patients is poor. Overall survival is around 35 % in the largest historical series. This poor prognosis is mainly due to the period of onset of this pathology making the use of chemotherapy more limited and involving many considerations, both ethical and therapeutic. The objective of this work is to review this rare pathology by addressing the clinical, biological, therapeutic and ethical particularities of patients with true neonatal AML or transient leukemoid reactions occurring in a constitutional trisomy 21 (true TAM) or somatic background (IMD).

Trastornos mieloproliferativos y leucemia en síndrome de Down. Presentación de dos casos clínicos en el período neonatal / Myeloproliferative disorders and leukemia related to Down syndrome. Report of two clinical cases in neonatal period

ElsíndromedeDownpredisponeatrastornosmieloproliferativos. Se estima que del 5 % al 30 % de los neonatos con esta condición desarrollarán mielopoyesis anormal transitoria. El tratamiento no está estandarizado; la exanguinotransfusión y la citarabina podrían ser efectivos. Se describen dos casos de pacientes con síndrome de Down, quienes durante el período neonatal presentaron leucemia mieloide aguda y mielopoyesis anormal transitoria, los tratamientos utilizados y sus desenlaces. Se considera que la sospecha y el diagnóstico temprano de esta entidad son factores determinantes en el pronóstico.

Down syndrome predisposes to haematological disorders. It is estimated that 5-30% of neonates with this condition will develop transient abnormal myelopoiesis. Treatment is not standardized; exchange transfusion and the use of cytarabine could be effective. We present two clinical cases of patients with Down syndrome, who during the neonatal period showed acute myeloid leukemia and transient abnormal myelopoiesis, the treatments used and their outcomes. Suspicion and early diagnosis of this entity are considered determining factors in prognosis.

[Myeloproliferative disorders and leukemia related to Down syndrome. Report of two clinical cases in neonatal period]. / Trastornos mieloproliferativos y leucemia en síndrome de Down. Presentación de dos casos clínicos en el período neonatal.

Down syndrome predisposes to haematological disorders. It is estimated that 5-30% of neonates with this condition will develop transient abnormal myelopoiesis. Treatment is not standardized; exchange transfusion and the use of cytarabine could be effective. We present two clinical cases of patients with Down syndrome, who during the neonatal period showed acute myeloid leukemia and transient abnormal myelopoiesis, the treatments used and their outcomes. Suspicion and early diagnosis of this entity are considered determining factors in prognosis.

El síndrome de Down predispone a trastornos mieloproliferativos. Se estima que del 5 % al 30 % de los neonatos con esta condición desarrollarán mielopoyesis anormal transitoria. El tratamiento no está estandarizado; la exanguinotransfusión y la citarabina podrían ser efectivos. Se describen dos casos de pacientes con síndrome de Down, quienes durante el período neonatal presentaron leucemia mieloide aguda y mielopoyesis anormal transitoria, los tratamientos utilizados y sus desenlaces. Se considera que la sospecha y el diagnóstico temprano de esta entidad son factores determinantes en el pronóstico.

Recommendations for Diagnosis and Treatment of Children with Transient Abnormal Myelopoiesis (TAM) and Myeloid Leukemia in Down Syndrome (ML-DS).

Children with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20-30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor - thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.

Leukemoid reaction causing arterial thrombus in a patient with lung adenocarcinoma.

A leukemoid reaction is typically defined as white blood cell (WBC) count >50×109/L, predominantly neutrophil precursors, that are not due to tumour involvement in the bone marrow and not derived from clones. Leukemoid reactions associated with malignancy, known as paraneoplastic leukemoid reactions, are less common and are most notably seen with non-small cell lung cancer. A 64-year-old woman presented with right leg painful ulceration. On examination, she had multiple venous stasis ulcers more severe on the right, with no palpable pulses in her lower extremities. Her WBC count was 124×109/L and platelets were 517×109/L. Arterial dopplers showed limb-threatening arterial insufficiency which prompted right femoral endarterectomy. Few months earlier she was diagnosed with metastatic lung adenocarcinoma to the bone and she had leukemoid reaction with WBC 43.920× 109/L with 90% neutrophils. Repeat imaging showed progression of her malignancy and she passed shortly after. Inflammation is a key element of carcinogenesis and cancer progression. Among the different tumours, lung cancer is a non-haematologic malignancy that is most closely associated with leucocytosis. Some studies have found that leucocytosis was significantly associated with metastasis and shorter survival irrespective of other factors such as age or sex. The mechanism remains unclear however elevated levels of granulocyte colony-stimulating factor (CSF), granulocyte macrophage-CSF and interleukin 6 have been linked to this phenomena. The degree of leucocytosis seen in our patient is suggestive of CSF production leading to a paraneoplastic leukemoid reaction.

Paraneoplastic leukemoid reaction in a localised squamous cell oesophageal cancer with paracrine G-CSF production.

A 51-year-old-man presented with symptoms and baseline investigations suggestive of an infective process. Most strikingly, there was a pronounced neutrophil predominant leucocytosis. Lack of a clinical and biochemical response to empirical antibiotic therapy, prompted imaging for a deep-seated infective process, incidentally uncovering a gastro-oesophageal junction tumour. Resection of the tumour was followed by rapid resolution of the leucocytosis. He remains in clinical remission since tumour resection and adjuvant chemotherapy. Cancer-associated leukemoid reactions in non-disseminated tumours are rare. The role of polymorphonuclear (PMN) leucocytes both in the peripheral blood and the tumour itself is discussed herein. There is increasing recognition of the importance of the non-cancer cellular components of the tumour microenvironment. Myeloid suppressor cells are a subset of PMN leucocytes which play a role in tumour progression.The role of these cells and granulocyte colony-stimulating factor is highlighted in this case.

Transient leukemia of Down syndrome.

Childhood leukemia is mostly a "developmental accident" during fetal hematopoiesis and may require multiple prenatal and postnatal "hits". The World Health Organization defines transient leukemia of Down syndrome (DS) as increased peripheral blood blasts in neonates with DS and classifies this type of leukemia as a separate entity. Although it was shown that DS predisposes children to myeloid leukemia, neither the nature of the predisposition nor the associated genetic lesions have been defined. Acute myeloid leukemia of DS is a unique disease characterized by a long pre-leukemic, myelodysplastic phase, unusual chromosomal findings and a high cure rate. In the present manuscript, we present a comprehensive review of the literature about clinical and biological findings of transient leukemia of DS (TL-DS) and link them with the genetic discoveries in the field. We address the manuscript to the pediatric generalist and especially to the next generation of pediatric hematologists.

Leukemoid Reaction in a Pediatric Patient With Diabetic Ketoacidosis.

Herein, we report a case of a 12-year-old girl who presented with diabetic ketoacidosis and a leukemoid reaction. Although this association has been described in a few adult patients, pediatric cases have not been reported. A leukemoid reaction is commonly defined as an elevation in the white blood cell count greater than 50,000/µL in response to severe illness or stress other than hematologic malignancy; it is considered to be mediated by various hormones, cytokines, and factors that are released in response to inciting triggers, such as acidosis. As highlighted in our report, distinguishing a benign leukemoid reaction from a hematologic malignancy and even tumor lysis syndrome, particularly in a setting of diabetic ketoacidosis, is crucial to ensuring safe and efficacious therapeutic interventions.

Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update.

Children with constitutional trisomy 21 (Down syndrome (DS)) have a unique predisposition to develop myeloid leukaemia of Down syndrome (ML-DS). This disorder is preceded by a transient neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM). TAM and ML-DS are caused by co-operation between trisomy 21, which itself perturbs fetal haematopoiesis and acquired mutations in the key haematopoietic transcription factor gene GATA1. These mutations are found in almost one third of DS neonates and are frequently clinically and haematologcially 'silent'. While the majority of cases of TAM undergo spontaneous remission, ∼10 % will progress to ML-DS by acquiring transforming mutations in additional oncogenes. Recent advances in the unique biological, cytogenetic and molecular characteristics of TAM and ML-DS are reviewed here.

Prenatal therapy in transient abnormal myelopoiesis: a systematic review.

OBJECTIVE: To systematically review current evidence regarding prenatal diagnosis and management of transient abnormal myelopoiesis (TAM) in fetuses with trisomy 21. A novel case of GATA1-positive TAM, in which following serial in utero blood transfusion clinical improvement and postnatal remission were observed, is included. SEARCH STRATEGY AND DATA COLLECTION: A systematic search of electronic databases (inception to October 2014) and reference lists, hand-searching of journals and expert contact. All confirmed cases of prenatal TAM were included for analysis. Data on study characteristics, design and quality were obtained. RESULTS: Of 73 potentially relevant citations identified, 22 studies were included, describing 39 fetuses. All studies included comprised single case or small cohort studies; overall quality was 'very low'. Fetal/neonatal outcome was poor; 12 stillbirths (30.8%), 4 neonatal deaths (10.2%) and 7 infant deaths (17.9%). In two cases, the pregnancy was terminated (5.1%). TAM was primarily detected in the third trimester (79.4%), and in 14 a retrospective diagnosis was made postpartum. Ultrasound features indicative of TAM included hepatomegaly±splenomegaly (79.5%), hydrops fetalis (30.8%), pericardial effusion (23.1%) and aberrant liquor volume (15.4%). When performed, liver function tests were abnormal in 91.6% of cases. CONCLUSIONS: Prenatal TAM presents a challenging diagnosis, and prognosis is poor, with consistently high mortality. A low threshold to measure haematological and biochemical markers is advised when clinical features typical of TAM are detected in the context of trisomy 21. Larger prospective studies are warranted to accurately ascertain the role of GATA1 analysis and potential value of prenatal therapy.

Exchange transfusion in patients with Down syndrome and severe transient leukemia.

BACKGROUND: Among neonates with Down syndrome (DS) and transient leukemia (TL), hyperleukocytosis (white blood cell [WBC] count >100 × 10(9) /L) is associated with increased blood viscosity, respiratory failure due to pulmonary hypertension, multiorgan failure, and increased risk of early death. There have been no previous studies focusing on the effects of exchange transfusion (ExT) on WBC count, respiratory status, and other parameters in TL patients with hyperleukocytosis. METHODS: An observational retrospective study was carried out at a single center of all five DS neonates with TL, GATA1 mutations, and hyperleukocytosis, born at a median gestational age of 34 weeks (range, 30-38 weeks) with birthweight 2556 g (range, 1756-3268 g) during a 24 month study period between September 2011 and August 2013. All five neonates underwent ExT at a median age of 2 days (range, 0-5 days) before initiation of other cytoreductive therapy with cytarabine, which was carried out in two patients. RESULTS: All patients required respiratory support before ExT. After ExT, respiration status improved in all five patients: WBC count (mean) decreased by 85% from 143 × 10(9) /L to 21 × 10(9) /L. None developed tumor lysis syndrome. Three survived and two died: one hydrops fetalis neonate born at gestational week 30 died at age 5 days, and another died eventually from acute gastroenteritis 40 days after leaving hospital at the age of 155 days with complete remission. Two of the three surviving neonates developed acute megakaryocytic leukemia at age 90 days and 222 days. CONCLUSION: ExT was very effective in improving hyperleukocytosis and may have had favorable effects on respiration.

Transient myeloproliferative disorder in neonates without Down syndrome: case report and review.

Transient myeloproliferative disorder (TMD) is a clonal proliferation of megakaryoblasts, typically occurring in newborns with Down syndrome. It is believed that TMD occurs in the presence of GATA1 mutation together with trisomy 21. However, a limited number of patients with TMD but without Down syndrome have been reported, all with a blast population with numeric or rarely structural chromosome 21 abnormalities. We present the first case of a newborn boy with a TMD without trisomy 21 and without any of the mentioned molecular or cytogenetic abnormalities. This case report suggests that unknown disease mechanisms may provoke or mimic TMD. This case report is followed by a concise review of the literature discussing the different entities and pathomechanisms of TMD and acute megakaryocytic leukaemia in patients with or without Down syndrome.

Leukemoid reaction associated with pediatric nasopharyngeal carcinoma: An unusual presentation.

Nasopharyngeal carcinoma is a tumor originating from the surface epithelial cells of nasopharynx. It is rare in children and adolescents. Most common physical finding is a neck mass. Most children with nasopharyngeal carcinoma present with advanced stage disease. The presentation with hematological abnormalities in patients without systemic metastasis is extremely rare. We reported a 14-year-old boy presenting with a mass at the right side of the pharynx and leukemoid reaction. To our knowledge, this is the first report of leukemoid reaction associated with pediatric nasopharyngeal carcinoma in English literature.

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.

Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

Leukemoid reaction in malignant bone tumor patients - a retrospective, single-institution study.

BACKGROUND: To the Authors' knowledge, the literature regarding leukemoid reaction in patients with malignant bone tumor is sparse, and most of patients with leukemoid reaction have poor prognosis. AIM: To study the leukemoid reaction in malignant bone tumor patients. MATERIALS AND METHODS: A total of 105 consecutive malignant bone tumor patients with a white blood cell count > 50,000/microL were retrospectively identified over a 4-years period (2007-2010). Those patients without a secondary cause of their leukocytosis were defined as having a paraneoplastic leukemoid reaction. RESULTS: Three etiologies of the leukocytosis were found in those 105 patients: the major one was paraneoplastic leukemoid reaction which accounted for 56%; the second one was hematopoietic growth factors defect accounting for 30%; 14% patients were caused by infection and Tumor bone marrow involvement. The patients diagnosed with a paraneoplastic leukemoid reaction typically had neutrophil predominance (94.8%) and radiographic evidence of metastatic diseases (78%). They were clinically stable, but had a poor prognosis. 95% either died or were discharged to hospice within 12 weeks of their initial extreme leukocyte count. Both of the 2 (2%) patients who survived over 12 weeks received effective antineoplastic therapy. CONCLUSIONS: Patients with typical paraneoplastic leukemoid reaction were clinically stable despite having large tumor burdens. However, clinical outcomes were poor unless receiving an effective antineoplastic treatment.

Cutaneous pustular leukemoid reactions in trisomy 21.

We report two neonates with Down syndrome and postnatal leukemoid reactions who developed acute widespread pustular eruptions. The white blood cell (WBC) counts on the first day of life were markedly elevated, with blasts seen on examination of the peripheral blood smear. The skin eruptions progressed and became pustular. Viral and bacterial cultures were negative. Skin examination revealed pustules on an erythematous base on the cheeks, shoulders, trunk, and proximal extremities. Skin biopsy specimens showed an intraepidermal pustule with an inflammatory infiltrate including neutrophils, eosinophils, and mononuclear cells. The mononuclear cells had atypical, immature-appearing nuclei. In patient 1, these cells were strongly myeloperoxidase positive on immunohistochemistry, indicating myeloid lineage. In patient 2, these cells were CD3-positive T cells. Patient 1 received a 5-day infusion of continuous cytarabine (ara-C) secondary to high WBC counts and symptomatic hyperviscosity. During therapy, the high WBC count and the pustules resolved. The lesions of patient 2 improved with topical mometasone furoate and resolved as her WBC count decreased. Recently, similar cases have been reported. Transient myeloproliferative disorders, or leukemoid reactions, should always be considered when newborns with Down syndrome or trisomy 21 mosaicism develop a pustular eruption.

Leukemoid response in ethylene glycol intoxication.

A 33-y-old male developed severe acidosis, renal failure, and profound neutrophilia after ingesting ethylene glycol. Workup for his neutrophilia excluded infectious and malignant causes. An elevated leukocyte alkaline phosphatase (LAP) level confirmed a leukemoid response, and the neutrophila resolved. Although several leukemoid reactions have been published due to therapeutic agents these reports are often incomplete or inaccurate; this is the first case of leukemoid response to a toxin. Leukemoid response is distinguishable from leukemia by the absence of clonally derived cells, although this is not easily apparent in extreme neutrophilia. Elevated LAP is useful in identifying leukemoid reaction from leukemia in cases of extreme neutrophila. If a patient develops extreme neutrophila in association with drug or toxin exposure, a leukemoid reaction should be considered and an LAP obtained.