Pierre Fenaux

Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that occurs in elderly patients. One of the main diagnostic criteria is the accumulation of heterogeneous monocytes in the peripheral blood. We further explored this cellular heterogeneity and observed that part of the leukemic clone in the peripheral blood was made of immature dysplastic granulocytes with a CD14(-)/CD24(+) phenotype. The proteome profile of these cells is dramatically distinct from that of CD14(+)/CD24(-) monocytes from CMML patients or healthy donors. More specifically, CD14(-)/CD24(+) CMML cells synthesize and secrete large amounts of alpha-defensin 1-3 (HNP1-3). Recombinant HNPs inhibit macrophage colony-stimulating factor (M-CSF)-driven differentiation of human peripheral blood monocytes into macrophages. Using transwell, antibody-mediated depletion, suramin inhibition of purinergic receptors, and competitive experiments with uridine diphosphate (UDP)/uridine triphosphate (UTP), we demonstrate that HNP1-3 secreted by CD14(-)/CD24(+) cells inhibit M-CSF-induced differentiation of CD14(+)/CD24(-) cells at least in part through P2Y6, a receptor involved in macrophage differentiation. Altogether, these observations suggest that a population of immature dysplastic granulocytes contributes to the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the differentiation capabilities of monocytes.

Burkitt's Acute Lymphocytic Leukemia (L3ALL) in Adults

Burkitts acute lymphocytic leukemia is a rare type of adult ALL, probably difficult to distinguish from disseminated Burkitts lymphoma involving the bone marrow. This tumor is highly proliferative and tends to involve the CNS at diagnosis or early during the disease course. It shows rapid chemosensitivity, initially leading to the risk of severe acute tumor lysis syndrome. Principles of its treatment, by comparison with the other types of ALL, include: 1. A low-dose chemotherapy prephase to prevent acute tumor lysis syndrome. 2. Multiagent chemotherapy using high-dose cyclophosphamide, an anthracycline, high-dose MTX, high-dose ara-C, and probably VP16. A short and intensive treatment (6 to 8 months) without maintenance is indicated. 3. Early intensive CNS treatment, with multiple triple intrathecal injections, high-dose MTX, and high-dose ara-C, and possibly cranial irradiation. Autologous or allogeneic stem cell transplantation do not seem to be useful in first CR. Using such approaches, recent results suggest that about two thirds of L3ALL in adults can be cured, more than in any other type of adult ALL.

Segmental coecal cytomegalovirus colitis during fludarabine, cytarabine and mitoxantrone induction chemotherapy for myelodysplastic syndrome

We report the case of a 59-year-old woman treated for a refractory anemia with excess blasts (RAEB) who developed cytomegalovirus (CMV) colitis during induction therapy combining fludarabine, cytarabine and mitoxantrone. CMV infection occurred rarely during cytarabine and anthracyclin based induction therapy for acute myelogenous leukemia or RAEB. CMV infection is usually observed in immunocompromised patients but some cases have been recently observed in patients after autologous stem-cell transplantation with or without CD34+ stem-cell selection. We discuss this case and issues arising from it in relation to the use of combination of high-dose cytarabine and fludarabine.

Predicting the outcome of patients with higher-risk myelodysplastic syndrome treated with hypomethylating agents

Correspondence: Pierre Fenaux, MD, PhD, Service d ’ h e matologie clinique, H o pital Avicenne, Assistance-Publique des H o pitaux de Paris, Universit e Paris 13, INSERM U848, 125 route de Stalingrad, 93009 Bobigny, France. Tel: x02 (33)148957051. E-mail: Pierre.fenaux@avc.aphp.fr Th is commentary accompanies an article to be published in Leukemia & Lymphoma . Please refer to the table of contents of the print issue in which this commentary appears. COMMENTARY

Diagnostic et prise en charge des manifestations auto-immunes et/ou inflammatoires associées aux syndromes myélodysplasiques primitifs (à l’exclusion de la leucémie myélomonocytaire chronique)

Les syndromes myelodysplasiques (SMD) sont un ensemble de maladies neoplasiques des cellules souches medullaires caracterisees par une hematopoiese inefficace responsable de cytopenies sanguines et par un risque eleve de progression vers une leucemie aigue myeloide (LAM). Dans certains cas, des manifestations cliniques peuvent s’associer aux SMD, d’origine infectieuse ou medicamenteuse, mais egalement d’origine dysimmunitaire, auto-immune ou inflammatoire, ayant un lien physiopathologique [...]

Sequential Chemotherapy with Mitoxantrone, Etoposide and Cytarabine for Previously Treated Acute Myeloid Leukemia: EMA 86 Regimen

EMA 86 regimen, associating mitoxantrone, 12 mg/m2/day on days 1–3, etoposide, 200 mg/m2/day as a continuous infusion on days 8–10 and cytarabine, 500 mg/m2/day as a continuous infusion on days 1–3 and 8–10, was administered to 133 patients. 70 patients had refractory AML and 63 had late first relapse. 60% achieved complete remission (CR), including 44% of refractory patients and 76% late first relapse patients (p = 0.0002). 11% died from therapy-related toxicity. Median survival is 7 months, with 11% survival at 5 years. Median disease-free survival (DFS) is 8 months, with 20% DFS at 5 years.