A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control

GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group: et al.Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ∼60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.Peer Reviewe

Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char- acteristics, prognostic factors, and out- come of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Espanol de Tratamientos en Hematologíc [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) ex- perienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 109/L and an abnor- mal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic pred- nisone prophylaxis (LPA99 trial) in con- trast to those receiving selective prophy- laxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Pa- tients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial

Infrared mergers and infrared quasi-stellar objects with galactic winds - II. NGC 5514 : two extranuclear starbursts with LINER properties and a supergiant bubble in the rupture phase

A study of the morphology, kinematics and ionization structure of the infrared (IR) merger NGC5514 is presented. This study is based mainly on INTEGRAL two-dimensional (2D) spectroscopy (obtained at the 4.2-m William Herschel Telescope, WHT), plus optical and near-IR images. Clear evidence of two extranuclear starbursts with young outflows (OFs) and low-ionization nuclear emission region (LINER) activity are reported. One of these OFs has generated a supergiant bubble and the other is associated with an extended complex of H II regions. In the galactic bubble it was found that: (i) the [S II], Hα, [NII], [O I] and [O III] emissionline maps show a bubble with a distorted ellipsoidal shape, with major and minor axes of ~ 6.5 kpc [13.6 arcsec; at position angle (PA) = 120◦ ± 10◦] and ~ 4.5 kpc (9.6 arcsec); (ii) these maps depict four main knots, a very strong one and three others more compact and located at the border; (iii) the centre of the bubble is located at ~ 4.1 kpc (8.5 arcsec) to the west of the main nucleus; (iv) the WHT spectra show, in this area, two strong components: blue and red emission-line systems, probably associated with emission from the near and far side of the external shell, for which the mean OF velocities were measured as VOF blue = (−320 ± 20) km s−1 and V OF red = (+265 ± 25) km s−1; (v) these two components depict LINER properties, probably associated with large-scale OF + shocks; (vi) at the east border, the kinematics of the ionized gas and the [S II] emission-line maps show an extended ejection of 4 kpc aligned with the PA of the major axis; (vii) three other ejections were found, two of them perpendicular to the extended one. Each ejection starts in one of the knots. These results suggest that the bubble is in the rupture phase. For the complex of giant H II regions it was found that: (i) the Hα, [N II] and [S II] emissionline maps show a compact strong emission area (peaking at ~ 810 pc ~ 1.7 arcsec, to the east of the second nucleus) and faint extended emission with an elongated shape, and major and minor axes of ~ 5.1 kpc (10.8 arcsec; at PA ~ 20◦) and ~ 2.9 kpc (6.0 arcsec); (ii) inside this complex, the spectra show H II region and transition LINER/H II characteristics; (iii) at the border of this extended HII area the spectra have outflow components and LINER properties. INTEGRAL 2D [N II], Hα, [S II] and [O III] velocity fields (VFs) are presented. These VF maps show results consistent with an expansion of the bubble, plus four ejections of ionized gas. The U, B, V, I, J, H and KS images show a pre-merger morphology, from which faint filaments of emission emerge, centred on the bubble. The ionization structure and the physical conditions were analysed using the following 2D emission-line ratio and width maps: [S II]/Hα, [NII]/Hα, [O I]/Hα, [O III]/Hβ and FWHM–[N II]. In the region of the bubble, 100 per cent of the [N II]/Hα and [S II]/Hα ratios show very high values (>0.8) consistent with LINER processes associated with high-velocity shocks. These new results support the previous proposition that extreme nuclear and ‘extranuclear’ starbursts with galactic winds + shocks play an important role in the evolution of IR mergers/quasi-stellar objects

High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma

et al. PETHEMA/GEM (Programa para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma) Cooperative Study Groups.The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.This work was supported by the Cooperative Research Thematic Network (RTICs; RD06/0020/0006, RD06/0020/0005, RD06/0020/0031, RD06/0020/0101, RD06/0020/1056, and G03/136), MM Jevitt, SL Firm, Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01 897), and Consejería de Sanidad, Junta de Castilla y León, Valladolid, Spain (557/A/10).Peer Reviewe

Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia

International audienceRituximab-induced B-cell depletion has been proven to be a useful therapy for autoimmune hemolytic anemia (AIHA). The aim of this retrospective study was to evaluate the effectiveness of rituximab in the treatment of 36 patients with AIHA refractory to several treatments. These patients had received a median of four (one to eight) previous treatments, and 13 patients had undergone splenectomy. Rituximab was administered by intravenous infusion at a dose of 375 mg/m once weekly for four doses in 29 patients, and 7 patients received one to six doses. Overall, 28 (77%) of 36 patients achieved response. Twenty-two patients (61%) reached a complete response (CR), and 6 patients (16%) obtained a partial response. All patients that reached CR (61%) were able to maintain the response during more than 6 months, with a median follow-up of 14 months (1–86 months). Sixteen patients maintained response for more than 1 year. The predictors of maintained response were achievement of CR and negative Coombs test result. Splenectomized patients showed a better response rate than those nonsplenectomized. Rituximab was well tolerated, and only one patient presented a transitory rash during infusion. Rituximab induced clinical responses in multitreated severe refractory both warm and cold AIHA patients with little toxicity, and consequently, this therapy should be considered as an early therapeutic option in this setting

Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age >60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score >1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL