Erythroblastic synartesis is a rare cause of acquired dyserythropoiesis. Only 9 cases have been previously reported. We hereby report 3 cases of patients diagnosed with erythroblastic synartesis associated with monoclonal immunoglobulin and an overt malignant lymphoid disorder. A different B-cell clone may produce the monoclonal immunoglobulin, forming a biclonal disorder. In light of these data and literature review, treatment targeting the paraprotein seems to be efficient to control synartesis and correct anemia. In the case of monoclonal gammapathy associated with chronic lymphocytic leukemia, therapeutics should be adapted to control both chronic lymphocytic leukemia and monitored monoclonal immunoglobulin titer.

Purpose: Acute promyelocytic leukaemia (APL) therapy with all-trans retinoic acid and chemotherapy is associated with a high cure rate in clinical trials. As some patients are not enrolled in these trials due to early severe events, these results might be overestimated. To address this issue, we reviewed all APL patients referred to the Hospital Saint-Louis within the 2000-2010 period, with a special focus on inclusion in recruiting trials.Patients and methods: One hundred patients (including eight children) with newly diagnosed APL were admitted during this period, which covered two consecutive APL trials conducted by the French-Belgian-Swiss APL group.Results: The rate of patients not enrolled within recruiting trials was 29%. The main reason for non-inclusion was protocol ineligibility related to disease severity at diagnosis. Non-enrolled patients more frequently had white blood cell count (WBC) P 50 x 10(9)/L (31% versus 8%; p = .01), platelet count <40 x 10(9)/L (97% versus 65%; p = .001) and microgranular variant APL (38% versus 11%; p = .004) and were more frequently admitted in intensive care unit during induction (41% versus 24%; p = .094). Early mortality rate was higher in non-enrolled patients (21% versus 3%; p = .007), translating into a lower complete remission rate (79% versus 96%; p = .007) and lower event-free survival (65% versus 84% at 5 years; p = .05), while disease-free survival was similar in both non-enrolled and enrolled patient groups (81% versus 88% at 5 years; p = .68).Conclusion: Initial APL severity leads to a significant proportion of patients non-registered within clinical trials, which may underestimate the real early mortality, which remained nonetheless less than 10% in this study. (C) 2013 Elsevier Ltd. All rights reserved.

Abstract Abstract 1083 Aim: Since combining differentiating agents and chemotherapy, acute promyelocytic leukemia (APL) is associated with a high cure rate. One remaining issue is the significant rates of early death and relapse observed in patients with high count APL (initial white blood cell count [WBC] ≥ 10.109/L). Early death rate might be underestimated in clinical trials, due to an unknown proportion of patients not registered because of initial severity. For this reason, we reviewed individual histories of all patients with APL referred to our institution during the last 10 years (09/2000-06/2010), with a special focus on admission in intensive care unit (ICU) and inclusion or non-inclusion in recruiting APL trials (European group APL-2000 and APL-2006), as well as long-term follow-up. Patients: A total of 100 patients with newly-diagnosed previously untreated APL, including 8 children, were admitted during this time period. Diagnosis was based on morphology and subsequently confirmed by the presence of the t(15;17) translocation and/or PML/RARA fusion transcript. Results: The rate of patients not enrolled within recruiting trials was 29% (n= 29). This rate was higher in children (n= 5/8, 62.5%) than in adults (n= 24/92, 26%) and remained stable during the two protocol periods (n=17/62, 27% for APL-2000; n= 12/38, 32% for APL-2006). Reasons for non-enrollment were inability to give informed consent in 10 patients (mechanical ventilation or neurological deficiency), physician's decision in 5 patients (2 very high leucocytosis, 1 severe infection, 2 severe liver dysfunction), and concomitant disease in 4 patients (2 HIV patients, 2 other cancers), refusal in 5 patients (including 1 Jehovah witness who eventually survived), and various administrative reasons in 5 patients. Non-enrolled patients had similar sex ratio (F/M=15/14 vs 35/36; p=.99), median age (40.5 [range, 4–79] vs 46 years [4-81]; p=.97), and frequency of additional chromosomal abnormalities (24% vs 28%; p=.80) than enrolled patients. Conversely, they had a higher rate of WBC ≥ 10.109/L (n=15/29 vs 22/71; p=.07) or ≥ 50.109/L (n=8/29 vs 5/71; p=.01), a lower rate of platelet count < 40.109/L (28/29 vs 46/71; p=.001), and a higher frequency of microgranular M3-variant subtype (11/29 vs 8/71; p=.004) and BCR3 PML-RARA isoform (14/25 vs 24/70; p=.09). Among the 29 non-enrolled patients, 24 nevertheless received the whole planned standard induction therapy, 2 received arsenic trioxide-based induction, and 3 early died before or the day after chemotherapy initiation. Ninety-nine patients were evaluable for response to induction (1 patient ongoing). Due to a higher early death rate (21% vs 3%; p=.007), the complete remission (CR) rate was lower in non-enrolled patients (79% vs 97%; p=.007). At 5 years, event-free survival (EFS) was estimated at 62% (95%CI, 37–79) vs 84% (95%CI, 72–91) (p=.02) and overall survival (OS) at 63% (95%CI, 36–81) vs 85% (95%CI, 72–93) (p=.03) in the non-enrolled and enrolled group, respectively. Once CR had been reached, non-enrolled patients displayed, however, a good post-CR outcome with 5-year remission duration at 78% and OS from CR at 80%. Of note, only one patient from this cohort died in first CR from a second neoplasia. Twenty-six patients (26%) were admitted in ICU for or during induction (13, 8, and 4 of them requiring mechanical ventilation, amine therapy, and dialysis, respectively). Chemotherapy was initiated in ICU in 19 of them. The rate of trial enrollment was 54% (n= 14/26) in ICU patients compared to 77 % (n= 57/74) in non-ICU patients (p=.04). Again, CR rate (p<.001), EFS (p=.004), and OS (p=.002) were significantly lower in ICU patients, but remission duration and OS from CR were very satisfactory in these patients despite their admission in ICU for or during induction (91% and 90% at 5 years, respectively). Conclusion: Even if this study only reports the experience of a large single center with potential patient selection, the observation that initial APL severity and/or need for ICU are associated with a lower trial enrollment rate suggests that early mortality might be underestimated in multicenter APL trials. Interestingly, patients who survive after early intensive care, including mechanical ventilation, may nevertheless receive an optimal induction and post-remission therapy and display the expected good outcome associated with APL. Disclosures: No relevant conflicts of interest to declare.

In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.

We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin alpha, epoetin beta, or darbepoetin alpha (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as "nonresponders" or "responders" according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.

Prognosis of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma has improved since the introduction of highly active antiretroviral therapy. Burkitt lymphomas (BLs) still have poor outcome in patients with bone marrow (BM) or central nervous system (CNS) involvement when treated with standard-dose chemotherapy. We have prospectively evaluated the LMB86 regimen in 63 human immunodeficiency virus (HIV)-infected patients with stage IV (BM and/or CNS involvement) BL consecutively recruited between November 1992 and January 2006. At BL diagnosis, the median CD4 cell count was 239 x 10(6)/L (range, 16-1188 x 10(6)/L). BM and CNS involvement were present in 55 (80%) and 48 (76%) patients, respectively. Forty-four patients (70%) achieved complete response. Seven treatment-related deaths occurred and all patients experienced severe BM toxicity. With a median follow-up of 66 months (range, 6-165 months), 11 patients relapsed. The estimate 2-year overall survival and disease-free survival were 47.1% (95% CI, 34-59.1) and 67.8% (95% CI, 51-80), respectively. We identified 2 poor prognosis factors: low CD4 count and ECOG more than 2. Patients with 0 or 1 factor had good outcome (2-year survival: 60%) contrasting with patients with 2 factors (2-year survival: 12%). We conclude that LMB86 regimen is highly effective in advanced HIV-related BL and should be proposed for patients with CD4 count higher than 200 x 10(6)/L or ECOG of 2 or less.

Background: MDS with del 5q are characterized by profound anemia, which until the recent introduction of lenalidomide (N Engl J Med 2005; 352: 549–57, J Clin Oncol 2005; 16S:5), was considered generally unresponsive to available treatments. In order to reevaluate the outcome of those patients in the pre-lenalidomide era, we analyzed response of anemia in MDS with del 5q treated with EPO ± G-CSF and thalidomide in previous GFM trials.

BACKGROUND:Sweet syndrome is an acute neutrophilic dermatosis that occurs with malignant diseases, mainly myeloid hemopathies, in about 20% of cases. When associated with myelodysplasia, Sweet syndrome may be clinically atypical. It can be histologically unusual. Concomitant infiltration of mature neutrophils and immature myeloid cells has been reported, and its significance is still debated. In few patients, lymphocytic infiltrates are the presenting feature of Sweet syndrome with myelodysplasia.OBSERVATIONS:We present 9 male adult patients with chronic Sweet syndrome, all with recurrent eruptions of erythematous and annular plaques that were associated with relapsing polychondritis in 4 of the 9 patients. Results from sequential biopsies showed that infiltrates were initially composed of lymphocytes and that neutrophilic dermal infiltration typical of Sweet syndrome occurred 24 to 96 months later, except in 2 cases. Moreover, atypical mononuclear cells were present on all initial biopsy specimens and strongly reacted to CD68 and myeloperoxidase, indicating a myeloid origin. Myelodysplastic syndrome occurred in all 9 patients, concomitantly with the neutrophilic infiltrate in 4 cases.CONCLUSIONS:Lymphocytic infiltrates with a clinical aspect of Sweet syndrome might represent the initial stage of a cutaneous dysgranulopoiesis syndrome and should lead to the research of atypical myeloid cells in skin infiltrate, blood, and bone marrow for the early detection of an associated myelodysplastic syndrome.

Two patients with Ph-positive chronic myelocytic leukemia in erythroblastic transformation and rearrangement of the short arm of chromosome 18 are reported. Fluorescence in situ hybridization studies showed that the 18p rearrangement resulted from translocation of the main part of chromosome 22 long arm to 18p, including BCR-ABL1 fusion. The 18p abnormality resulted, thus, in loss of 18p and duplication of BCR-ABL1 in both patients. The possible relation to the erythroblastic type of blastic phase is briefly discussed. In addition an apparently intact germline ABL1 gene was duplicated and inserted into chromosome 6 at band p21 in one of these patients.

A translocation (10;11)(p12;q14) was observed in two children, one with acute eosinophilic leukemia and the other with acute T-cell lymphoblastic leukemia. The presence of CALM-AF10 fusion was ascertained by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Fluorescence in situ hybridization (FISH) analysis showed that AF10 gene splitting was associated with partial inversion of chromosome 11 in the first patient. In addition, FISH analysis also determined the orientation of the CALM gene, 5′ telomere to 3′ centromere on 11q.

Pulmonary complications of leukemias are usually due to infections, hemorrhage, radio- or radio-chemotherapy (1). They are rarely linked to leukemic localization in the lung (2). In fact, if pulmonary leukemic infiltrates are commonly found at autopsies, they are rarely clinically diagnosed (3). We describe here a case of acute monoblastic leukemia with a lesion localized to the lung.

Primary blasts of a t(11;17)(q23;q21) acute promyelocytic leukaemia (APL) patient were analysed with respect to retinoic acid (RA) and arsenic trioxide (As 2 O 3 ) sensitivity as well as PLZF/RARα status. Although RA induced partial monocytic differentiation ex vivo , but not in vivo , As203 failed to induce apoptosis in culture, contrasting with t(15;17) APL and arguing against the clinical use of As203 in t(11;17)(q23;q21) APL. Prior to cell culture, PLZF/RARα was found to exactly co-localize with PML onto PML nuclear bodies. However upon cell culture, it quickly shifted towards microspeckles, its localization found in transfection experiments. Arsenic trioxide, known to induce aggregation of PML nuclear bodies, left the microspeckled PLZF/RARα localization completely unaffected. RA treatment led to PLZF/RARα degradation. However, this complete PLZF/RARα degradation was not accompanied by differentiation or apoptosis, which could suggest a contribution of the reciprocal RARα/PLZF fusion product in leukaemogenesis or the existence of irreversible changes induced by the chimera.

Chromosomal translocations involving the human 12p13 band frequently affect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against different parts of TEL and against the AML1 proteins, we undertook Western blot and immunofluorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to affect the 5′ untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT–PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.

49 Background: Most cell lines derived from primary effusion lymphomas (PEL) are both HHV-8+ and EBV+. A new cell line (ISI-1) which is only HHV-8+ was established from the lymphomatous pleural effusion of a HIV-infected patient. Cell line characteristics: The morphology and phenotype of the original lymphomatous cells as well as of the cells in culture were characteristic of PEL: large/anaplastic cells, CD2−, CD3−, CD19−, CD20−, CD38+, CD71+, CD45+, CD30+, MHC class I +, class II −. A clonal rearrangement of IgH gene was demonstrated by Southern blot analysis. The cytogenetic study revealed multiple chromosome abnormalities. Presence of HHV-8 and absence of EBV DNA sequences were demonstrated using PCR and Southern blot analysis. These characteristics have remained stable after 20 months. Cytokines production: The cell line was maintained in RPMI-1640 and FCS (15%) and the spontaneous cytokines production was evaluated in the culture supernatant using ELISA assays. Large amounts of IL10 (26218 pg/ml [106 cells]) and low concentrations of IL6 (49 pg/ml [106 cells]) were detected. Intracytoplasmic IL10 production and the expression of the IL10 receptor were demonstrated using flow cytometry. Animal model: 5×106 cells were infused intra peritoneously in 6 NOD/SCID mice. All mice developed lymphomatous ascitis between day 27 and 96. Nodal and splenic involvement were present in 3/3. New cell lines (ISI-11, ISI-12) could be established from the ascitis and spleen of two mice and exhibited the same phenotype and clonal IgH gene rearrangement than ISI-1. At day 14 ex vivo, ISI-11 produces IL10 (3179 pg/ml [106 cells]) and no detectable IL6. Conclusion: A new HHV-8+ EBV - B cell line (ISI-1) produces large amounts of IL10 and induces tumors in NOD/SCID mice.

An unambiguous case of Sezary syndrome associated with the presence of unusual retroviral infection markers is described. The blood smear showed 15% typical Sezary cells but also tare atypical lymphocytes with convoluted nuclei, evocative of characteristic adult T-cell leukemia (ATL) flower cells. However, the patient did not present any clinical or biological manifestations of ATL, and human T-cell leukemia virus type 1 (HTLVI)serology was consistently negative. After being cultured for 4 months, peripheral blood mononuclear cells (PBMC) produced typical type C retrovirus-like particles with budding forms strongly ressembling HTLV-1 virions. The producer cells did not express HTLV-l-specific antigens detectable by indirect immunofluorescence (IIF). Southern blotting of uncultured PBMC DNA, submitted to digestion with the restriction enzymes Pstl and Sad, and hybridized with a full genomic HTLV-I probe, showed the presence of specific homologous sequences, absent in all of the healthy donor control PBMC DNAs. These HTLV-l-like sequences presented a restriction enzyme pattern distinct from that of the HTLV-1 prototype genome and of other HTLV-1 proviruses studied up to now. Polymerase chain reaction (PCR) with highly conserved HTLV-1 derived pol and env primers was consistently negative with the patient's DNA. All these results taken together suggest that our patient carries a retroviral agent partially homologous to, but probably different from HTLV-1. The possibility is discussed that this type of retroviral agent might be associated with a subtype of cutaneous T-cell lymphoma (CTCL) represented by a typical Sezary syndrome with a very low percentage of ATL-like flower cells in the blood smear.

Approximately 67% of peripheral blood lymphocytes in a case of nonmycosis fungoides-type cutaneous T-cell lymphoma, exhibited Sézary-like changes. Immunotyping showed a helper phenotype with an abnormally faint expression of the T3 membrane antigen, while quantitative electron microscopic study was suggestive of neoplasia. However, T-cell receptor gene study did not show any DNA rearrangement in Ficoll-separated blood lymphocytes, whereas clonal T-cell proliferation was simultaneously evidenced in cutaneous (non-Sézary-like) tumor cells. It is concluded that reactive nonneoplastic Sézary-like cells may be present not only in various benign conditions, as previously known, but also in T-cell lymphomas. This study provides further evidence for the nonspecificity of Sézary-like changes, and stresses the utility of T-cell receptor gene rearrangement study for diagnostic and prognostic procedures during the course of T-cell lymphoproliferative disorders.