EBMT NEWSLETTER | July 2015 | Volume 47 - Issue 2

Important dates
Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT).
Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, Blaise D, Ciceri F, Corbacioglu S, Dalle JH, Duarte RF, Fukuda T, Huynh A, Masszi T, Michallet M, Nagler A, NiChonghaile M, Pagluica T, Peters C, Petersen FB, Richardson PG, Ruutu T, Savani BN, Wallhult E, Yakoub-Agha I, Carreras E.
Bone Marrow Transplant. 2015 Jun;50(6):781-9. doi: 10.1038/bmt.2015.52. Epub 2015 Mar 23.
Sinusoidal obstruction syndrome or veno-occlusive disease (SOS/VOD) is a potentially life-threatening complication of hematopoietic SCT (HSCT). This review aims to highlight, on behalf of the European Society for Blood and Marrow Transplantation, the current knowledge on SOS/VOD pathophysiology, risk factors, diagnosis and treatments. Our perspectives on SOS/VOD are (i) to accurately identify its risk factors; (ii) to define new criteria for its diagnosis; (iii) to search for SOS/VOD biomarkers and (iv) to propose prospective studies evaluating SOS/VOD prevention and treatment in adults and children. 
The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.
Bode SF, Ammann S, Al-Herz W, Bataneant M, Dvorak CC, Gehring S, Gennery A, Gilmour KC, Gonzalez-Granado LI, Groß-Wieltsch U, Ifversen M, Lingman-Framme J, Matthes-Martin S, Mesters R, Meyts I, van Montfrans JM, Pachlopnik Schmid J, Pai SY, Soler-Palacin P, Schuermann U, Schuster V, Seidel MG, Speckmann C, Stepensky P, Sykora KW, Tesi B, Vraetz T, Waruiru C, Bryceson YT, Moshous D, Lehmberg K, Jordan MB, Ehl S; Inborn Errors Working Party of the EBMT.
Haematologica. 2015 Jul;100(7):978-88. doi: 10.3324/haematol.2014.121608. Epub 2015 May 28.
Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells. 

High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplantation for High-Risk Primary Breast Cancer.
Pedrazzoli P, Martino M, Delfanti S, Generali D, Rosti G, Bregni M, Lanza F; European Group for Blood and Marrow Transplantation (EBMT), Solid Tumor Working Party.
J Natl Cancer Inst Monogr. 2015 May;2015(51):70-5. doi: 10.1093/jncimonographs/lgv010
The efficacy of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation for breast cancer (BC) has been an area of intense controversy among the medical oncology community. Over the last decade, due to the presentation of negative results from early randomized studies, this approach has not longer been considered an option by the vast majority of medical oncologists. We critically revised the published literature regarding HDC in the setting of high-risk BC, including a recent meta-analysis using individual patient data from 15 randomized studies. A significant benefit by HDC in recurrence-free survival has been clearly documented in unselected patient populations. In HER2-negative population, particularly in the triple-negative disease, a positive effect of intensified therapy in overall survival is biologically plausible and supported by clinical evidence. Over the years HDC with support of adequate number of stem cells has become a safe treatment modality. The administration of higher doses of chemotherapy with stem cell support may still represent a therapeutic option (and not a recommendation) in selected BC patients.

Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year-old: A study from the Acute Leukemia Working Party (ALWP) of the European group of Blood and Marrow Transplantation (EBMT).
Poiré X, Labopin M, Cornelissen JJ, Volin L, Richard Espiga C, Veelken JH, Milpied N, Cahn JY, Yacoub-Agha I, van Imhoff GW, Michallet M, Michaux L, Nagler A, Mohty M.
Am J Hematol. 2015 May 25. doi: 10.1002/ajh.24069. [Epub ahead of print]
Acute myeloid leukemia with monosomal karyotype (MK AML) carries a very poor prognosis, even after allogeneic stem cell transplantation (SCT). However, SCT remains the only curative option in this high-risk population. Because myeloablative conditioning regimen (MAC) is associated with less relapse, we hypothesized that more intensive conditioning regimen might be beneficial for MK AML patients. We reviewed 303 patients over age 45 diagnosed with either de novo or secondary MK AML, One hundred and five patients received a MAC and 198 a reduced-intensity conditioning (RIC). The median age at SCT was 57 year-old, significantly lower in the MAC (53 year-old) than in the RIC group (59 year-old). The median follow-up was 42 months (range 3-156 months). The 3-year overall survival (OS), leukemia-free survival (LFS) and relapse rate (RR) were not significantly different between both groups with overall values of 34%, 29% and 51%, respectively. On the contrary, the 3-year non-relapse mortality (NRM) was significantly higher in MAC recipients (28%) compared to RIC patients (16%, p=0.004). The incidence of grade II to IV acute graft-versus-host disease (GvHD) was significantly higher after a MAC (30.5%) than after a RIC (19.3%, p=0.02). That of chronic GvHD was comparable between both groups (35%) and did not impact on LFS. Interestingly, within our MK AML cohort, hypodiploidy was significantly associated with worse outcomes. Due to reduced toxicity and comparable OS, LFS and RR, RIC appears as a good transplant option in the very high-risk population, including older patients, diagnosed with MK AML.
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