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Context In the present phase II clinical trial (NCT02692248), we investigated the efficacy and toxicity of the combination of ibrutinib with R-GEMOX-D in patients with non-germinal center B-cell like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Objective The main objective was to evaluate the overall response rate (ORR) after four cycles. Patients Histological diagnosis of non-GCB DLBCL (Hans algorithm) with relapsed or refractory disease and non-candidates for autologous stem cell transplantation. Design Induction treatment with six (in cases of complete remission [CR] after cycle 4) or eight (in cases of partial response [PR] or stable disease after cycle 4) cycles of R-GEMOX-D at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. Results Sixty-four patients (median age 67 [25–84] years) were included. Patients had received a median of two previous lines of treatment; 61% were refractory ( 10% of patients) were thrombocytopenia (51.6%), neutropenia (46.9%), anemia (21.9%), and diarrhea (15.6%). Conclusions The combination of ibrutinib with R-GEMOX-D is associated with high response rates, especially in non-refractory patients. The vast majority of refractory patients progress very early, so this regimen could be considered as a bridge to other consolidation therapies. Biological studies analyzing cell of origin by gene expression profiling, minimal residual disease, and mutational spectrum are in progress. Funding Janssen (NCT02692248)

This study was supported by the Instituto de Salud Carlos III (ISCIII) PMP15/00007; Ministerio de Economía y Competitividad (MINECO) SAF2015-64885-R; Generalitat de Catalunya AGAUR 2014-SGR-795; and Gilead Spain (GLD15/00288). ECa is an Academia Researcher of the 'Institució Catalana de Recerca i Estudis Avançats' (ICREA) of the Generalitat de Catalunya. FN is supported by a pre-doctoral fellowship of the MINECO (BES-2016-076372). We are indebted to the Genomics core facility of the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). We are grateful to N Villahoz and MC Muro for their excellent work in the coordination of the CLL Spanish Consortium, and also thank C Capdevila, S Guijarro, L Pla and M Sánchez for their excellent technical assistance. We are also very grateful to all patients with CLL who have participated in this study., Nadeu, F., Clot, G., Delgado, J., Martín-García, D., Baumann, T., Salaverria, I., Beà, S., Pinyol, M., Jares, P., Navarro, A., Suárez-Cisneros, H., Aymerich, M., Rozman, M., Villamor, N., Colomer, D., González, M., Alcoceba, M., Terol, M.J., Navarro, B., Colado, E., Payer, Á., Puente, X.S., López-Otín, C., López-Guillermo, A., Enjuanes, A., Campo, E.

There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Women's Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P=.002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P

Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34 hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged 60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34 HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34 HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM. © 2011 Macmillan Publishers Limited All rights reserved.

The association between cytomegalovirus (CMV) infection and the development of Guillain–Barre syndrome (GBS) in the setting of allogeneic hematopoietic stem cell transplantation (alloSCT) has been reported only occasionally. We describe here a 23-year-old patient diagnosed with acute myelogenous leukemia who underwent a partially HLA-mismatched alloSCT and soon after developed GBS along with a CMV infection. Serum autoantibodies to several ganglioside antigens were concomitantly detected. Despite therapy with ganciclovir and plasma exchanges, the patient's clinical condition rapidly deteriorated, and he died 3 weeks later with persisting CMV antigenemia. Although a coincidental association cannot be excluded, it could be speculated that a pathogenetic link exists between the 2 disorders. In this sense, molecular mimicry between viral antigens and neural host tissues could be postulated as the hypothetical mechanism underlying the triggering of the autoimmune disease in the present case.

In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was correlated with shorter treatment-free interval (TFI) compared to cases harboring only IgVH mutation (median, 55 months vs not reached; P=0.01), resembling the clinical course of unmutated IgVH cases (median TFI, 44 months). As expected, deletions of 17p13 (P53 locus) and 11q22 (ATM locus) were observed in cases with unmutated IgVH, except one patient who showed mutations of both IgVH and BCL-6. No other statistically significant differences were observed among the genetic subgroups. Our data indicate that BCL-6 mutations identify a subgroup of Binet stage A B-CLL patients with a high risk of progression despite the presence of mutated IgVH gene.

Background: High serum levels of soluble intercellular adhesion molecule-1(s-ICAM-1/s-CD54) have been associated with adverse clinical features and poor outcome in chronic lymphocytic leukemia, Hodgkin’s disease and non-Hodgkin’s lymphoma, but their value in the different subtypes of non-Hodgkin’s lymphoma has not been well addressed. Patients and methods: Our aim was to study the serum levels of s-ICAM-1 in diffuse large B-cell lymphoma (DLBCL) and to correlate them with clinical characteristics and outcome. We analyzed the serum levels of s-ICAM-1 in a series of 55 patients with DLBCL diagnosed in a single institution. s-ICAM-1 levels were quantified by an immunoenzymatic assay. Median age was 62 years (range 22–96); 29 (53%) were male. Twenty-eight (51%) presented with advanced clinical stage (III/IV), 32 (58%) had extranodal involvement, 28 (51%) had high serum lactate dehydrogenase (LDH) and 23 (43%) had high β2 -microglobulin levels. All patients received anthracycline-containing regimens. Correlation between clinical variables and s-ICAM-1 levels were tested with the Mann–Whitney U-test and survival was plotted by the Kaplan–Meier method, and curves compared with the log-rank test. Results: Serum levels of s-ICAM-1 were significantly increased in patients with DLBCL compared with normal controls (589 ± 487 versus 279 ± 65 ng/ml, respectively; P

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

The performance of a leukocyte reduction bedside filter with different types of RBC concentrates was analyzed. Three types of RBCs were prepared: buffycoat-depleted RBCs suspended in saline-adenine-glucose-mannitol (SAGM)-additive solution (BC-RBCs; n = 20), RBCs suspended in SAGM-additive solution without buffy coat removal (SAGM-RBCs; n = 20), and RBCs drawn in CPDA-I conservative solution and processed for component preparation by the platelet-rich plasma method (CPDA-RBCs; n = 20). The units were filtered within 8 h of collection. One filter was used for every 2 units. High numbers of residual WBCs were found even in the units filtered first. Filtration of CPDA-RBCs resulted in a higher residual WBC content than SAGM-RBCs or BC-RBCs (p = 0.0032 and p = 0.0002, respectively). The filter performance strikingly decreased when the WBC load per filter exceeded 4 x 10(9) or the platelet load was less than 100 x 10(9). We conclude that filter performance varies with the WBC and platelet content of the RBC concentrates. Under the experimental conditions assayed in this study CPDA-RBCs are the least appropriate ones to be used for bedside leukocyte reduction.

GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study groups: et al., The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05

Background: While many studies have attempted to compare different GVHD prophylaxis within the reduced intensity conditioning allogeneic stem cell transplant setting (RIC SCT), few studies have been performed comparing different conditioning regimens. Due to the lack of evidence on the best RIC, the selection of the conditioning regimen is mainly based on the experience from each institution. In this study, we compared the outcomes of patients undergoing RIC SCT in 2 different settings: the Spanish Group of Transplantation (GETH), where fludarabine + melphalan (FluMel) has been the standard RIC in patients with lymphoid malignancies and Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH), where fludarabine + busulphan (FluBu) is the standard RIC. Patients and methods: We analyzed the outcomes of 136 patients diagnosed with lymphoma undergoing RIC with either FluBu (n=61) or FluMel (n=75) in the GETH or at DFCI/BWH between 2007 and 2014. Patient characteristics are shown in table 1. The following variables were included into the multivariable analysis: type of conditioning, GVHD prophylaxis, type of donor, age, previous transplant, and disease risk index (DRI) based on diagnosis and disease status at transplant. Median follow-up was 36 months. Results: The cumulative incidence of grades 2-4 acute GVHD was 13% vs 36% among patients receiving FluBu vs FluMel, respectively (p=0.002). In multivariable analysis only the type of conditioning significantly influenced the risk of grades 2-4 aGVHD [HR with FluMel 7.35, (95% CI= 2.27-23.8), p=0.0008]. The cumulative risk of non-relapse mortality at 1 year was 3.3% vs 31% for FluBu vs FluMel, respectively (p

Background: Patients with primary refractory Hodgkin’s disease (PR-HD) have a dismal prognosis when treated with conventional salvage chemotherapy. We analyzed time to treatment failure (TTF), overall survival (OS) and clinical variables influencing the outcome in patients undergoing autologous stem cell transplantation (ASCT) for PR-HD and reported to the Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea (GEL/TAMO). Patients and methods: Sixty-two patients, 41 males and 21 females with a median age of 27 years (range 13–55) were analyzed. Forty-two patients (68%) had advanced stage at diagnosis, 47 (76%) presented with B symptoms and 29 (47%) with a bulky mediastinal mass. Seventy-five percent of the patients had received more than one line of therapy before ASCT. Thirty-three patients received bone marrow as a source of hematopoietic progenitors, and 29 peripheral blood. Six patients were conditioned with high-dose chemotherapy plus total-body irradiation and 56 received chemotherapy-based protocols. Results: One-year transplantation-related mortality was 14% [95% confidence interval (CI) 6% to 23%]. Response rate at 3 months after ASCT was 52% [complete remission in 21 patients (34%), partial remission in 11 patients (18%)]. Actuarial 5-year TTF and OS were 15% (95% CI 5% to 24%) and 26% (95% CI 13% to 39%), respectively. The presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF [relative risk (RR) 1.75, 95% CI 0.92–3.35, P = 0.08]. The presence of B symptoms at diagnosis (RR 2.08, 95% CI 0.90–4.79, P = 0.08), MOPP-like regimens as first-line therapy (RR 3.84, 95% CI 1.69–9.09, P = 0.001), bulky disease at ASCT (RR 2.79, 95% CI 0.29–6.03, P = 0.009) and two or more lines of therapy before ASCT (RR 2.24, 95% CI 0.95–5.27, P = 0.06) adversely influenced OS. Conclusions: In our experience, although overall results of ASCT in PR-HD patients are poor, one-quarter of the patients remain alive at 5 years. Despite this, other therapeutic strategies should be investigated in this group of patients to improve the outcome.

Objective. To analyze the results of a multicenter prospective randomized protocol, PETHEMA ALL-93, for high-risk acute lymphoblastic leukemia (HRALL).

To analyse the initial and evolutive characteristics of the patients with low-grade lymphoma and long survival (or = 12 years).The initial data (clinical, laboratory, histologic type, stage) and the clinical course (response to therapy, response duration) of 52 patients with low-grade lymphoma diagnosed before 1980 were analysed. The statistical study was carried out by means of the chi-square test with Yates' correction and Student's t; the actuarial survival was estimated, and the duration of remission was assessed by the Kaplan and Meier method. Curves were compared by the log rank method.The 12-year survival as a whole was 32% (CI: 95%: 18.5%-45.5%). Of the 52 patients, 13 (25%) survived over 12 years. Nine were men and 4 women, with median age of 41 years (range: 22-68 years). Three cases had lymphocytic lymphoma and 10 had follicular lymphoma; 2 were in stage I-II and 11 in stage III-IV. Those patients who would become long-survivors had at diagnosis lesser frequency of spread lymph-node regional involvement (or = 3 sites): 46% vs 81.8%, p = 0.04, as well as lesser percentage of bone-marrow involvement (38.4% vs 78.1%, p = 0.023). They were also better responders to treatment (CR+PR = 100% vs 71%, p = 0.013) and with longer duration (actuarial median duration of response 8 years vs 1.5 years, p = 0.005).According to the present analysis, low-grade lymphoma patients who have at diagnosis low tumoral involvement (not too extensive lymph-node involvement, disease-free bone-marrow) and show good response to treatment have a better prognosis and may hope for a longer survival.

The aim of the present study was to analyze the main clinical and evolutive characteristics of a series of 10 patients diagnosed with sepsis by Candida tropicalis over a 5-year period in a Hematology Unit. The mean age of the 10 patients was 23 years (range 13-66 years) with 6 males and 4 females. Eight patients had acute leukemia, 1 non-Hodgkin's lymphoma and another patient had severe bone marrow aplasia. All the patients presented intense granulocytopenia (0.5 x 10(9)/L), had intravenous catheters and were receiving wide spectrum antibiotics as treatment for bacterial infection. The diagnosis of the fungal infection was based on the growth of C. tropicalis in blood cultures together with the evidence of tissue involvement by the fungus. Fever (38 degrees C) was the initial symptom of the infection in all the patients, being accompanied by myalgia in 5 cases, pleuritic pain in 2 and septic shock in 1. Violaceous erthymatomous pustules disseminated over the trunk and limbs, the histologic study of which demonstrated the presence of C. tropicalis were observed in 9 patients. Septic metastasis were found in the liver (2 cases), serosae (2 cases), the psoas muscle and the brain (1 case), respectively. Eight patients underwent treatment with amphotericin B which was complemented with 5-fluorocytosin in 6, with death occurring in the remaining 2 patients prior to the start of treatment. Three patients died with active fungal infection (2 by cerebral hemorrhage and 1 by septic shock). In 2 patients the infection evolved to chronic systemic candidiasis and in the remaining 5 patients infection was resolved with hemoperipheral values returning to normal. Sepsis by Candida tropicalis is a severe complication in patients with granulocytopenia, being mainly characterized by fever, cutaneous papulae and, to a lesser extent, muscle pain. Amphotericin B alone, or in combination with 5-fluorocytosin constitute a treatment of choice in this infection, which nonetheless is associated with an undisdainful mortality.

The efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in graft failure after bone marrow transplantation (BMT) has been evaluated in 25 patients. rhGM-CSF was administered intravenously at a dose of 5 or 10 micrograms/kg. Fourteen patients (seven allogeneic BMT [allo-BMT], seven autologous BMT [ABMT]) were treated for primary bone marrow failure (no granulocyte recovery after BMT), and 11 cases (all allo-BMT) received rhGM-CSF for secondary bone marrow failure (absolute neutrophil count lower than 0.5 x 10(9)/L after a previously sustained granulocyte recovery). Two allo-BMT and three ABMT patients with primary bone marrow failure achieved a granulocyte response to rhGM-CSF. In contrast, nine patients with primary graft failure did not respond to rhGM-CSF (four ABMT, three HLA-identical T-depleted BMT, one minor mismatch BMT, one unrelated BMT). Ten of 11 allo-BMT patients treated for secondary bone marrow failure attained an ANC higher than 0.5 x 10(9)/L, but most became severely neutropenic again at a median time of 4 weeks. The possible cause triggering graft failure (graft-vs.-host disease [GVHD], cytomegalovirus [CMV] infection) remained unsolved in most of these cases. Actuarial probability of survival of the entire series was 16 +/- 9% at 15 months. The severity of graft failure and the presence of other concomitant complications in most of our patients may justify these poor results. In conclusion, rhGM-CSF had less efficacy in patients with primary bone marrow failure than in those with secondary bone marrow failure. In the latter setting, measures addressed to correct the initial cause of graft failure are mandatory.

Transient appearance of anti-erythrocyte autoantibodies was demonstrated in two women in the first stages of Rh alloimmunization. Any mimicking antibodies, or concurrent autoimmune haemolytic anaemia could be reasonably discarded in both patients. These facts are discussed on the basis of polyclonal activation followed by clonal selection driven by the antigen, as a mechanism of the humoral immune response. Investigation of such cases seems of great interest in subjects with recent alloimmunization in order to assess the incidence of this phenomenon and the antigen systems involved.

To analyse the frequency and the main clinico-haematologic characteristics of the patients with Ph'-positive chronic myelogenous leukaemia (CML) with long survival.Of a series of 100 patients with CML diagnosed in the chronic phase and treated in the conventional way at the "Farreras Valentí" School of Haematology between 1969 and 1982, and followed-up for at least 10 years, those surviving more that 8-10 years since the diagnosis were considered eligible for this study. Their clinico-haematological characteristics at diagnosis were compared to those of the remaining patients by means of the Student's t and Mann-Whitney's U tests, plus chi square with the Yates correction. The actuarial survival in the series was assessed according to the Kaplan and Meier method. The Sokal prognostic index was calculated in the longest survivors.The median survival of the series was 45 months (range: 4-171). Ninety-one patients died, 2 are alive in chronic phase and in 7 others the follow-up has been lost in the chronic phase. Eight patients survived more than 10 years and 14 more than eight years. Of these, six were men and eight women, 10 were under 50 years of age, one-half lacked splenomegaly at diagnosis and only 2 had Ph' chromosome mosaicism. According to the Sokal prognostic index, six of these patients were in the low-risk group, four were of intermediate risk, and four others were in the high-risk group. None of them had aplasia due to busulphan during the follow-up. When comparing the initial features of the patients surviving 8-10 years with those of the remainders, only the presence of a lower percentage of blast-cells (p = 0.03) and a lower number of blasts in peripheral blood (p = 0.01) in the former achieved statistically significant difference.These findings confirm the difficulty in identifying the CML patients with expected long survival at diagnosis. High numbers of cases must be analysed in order to attain definite conclusions in this regard.

A 52 year old male presenting chronic myeloid leukemia (CML) Philadelphia chromosome positive (Ph) four years after the diagnosis of a non Hodgkin's lymphoma is described. The patient had received high total doses of alkylating drugs (cyclophosphamide and chlorambucil) as part of chemotherapy treatment for a diffuse mixed lymphoma. At four years of diagnosis of the lymphoma the appearance of hepatosplenomegaly, leukocytosis with myeloma and basophilia and thrombocytosis were observed. These alterations augmented progressively until a cytogenetic study of the bone marrow two years late established the diagnosis of CML upon demonstrating the presence of the Ph chromosome with no other karyotypic anomalies being observed. The explorations carried out at that time confirmed that the lymphoma continued to be in remission. The CML initially responded to treatment with busulphan. However, following a year and a half the disease evolved to a phase of acceleration and the patient died a few weeks later due to pneumonia with no signs indicative of lymphoma activity having been detected since the diagnosis of the CML.

Cytogenetic response induced by interferon alpha in the myeloproliferative disorder with eosinophilia, T cell lymphoma and the chromosomal translocation t(8;13)(p11;q12)

Rituximab in combination with CHOP-like chemotherapy has demonstrated to improve the results in young and elderly patients with DLBCL compared to chemotherapy alone. Re-treatment with rituximab is feasible in patients with indolent lymphoma, but there is few data on the effect of rituximab in combination with chemotherapy in the re-treatment of relapsed patients with DLBCL who have respond previously to rituximab + chemotherapy. In order to investigate the effect of rituximab in this setting, we have performed a multicenter retrospective study in 50 patients with DLBCL re-treated with rituximab in combination with chemotherapy. We have included in this study 46 patients (31 males, 15 females), median age 60 (range, 20 to 81 years), who achieved CR with the previous rituximab-containing regimen. At initial diagnosis, 32 patients had Ann-Arbor stage III or IV and 20 patients had IPI 3 or 4. The median interval between courses was 14.7 months. The most frequent regimens administered as up-front therapy in combination with rituximab were CHOP-like regimens (30 patients) and the commonest chemotherapy regimens used as salvage therapy were R-ESHAP (20 patients), R-ICE (7 patients), rituximab in combination with gemcitabine-based regimens (4 patients) and TTR (3 patients). The overall response rate in the assessable population was 81% (46% CR, 35% PR). In 25 assessable patients who have received rituximab in combination with chemotherapy as second-line therapy, the overall response rate was 92% (56% CR, 36% PR). The overall response rate was slightly lower in those patients re-treated with rituximab as third-line therapy (78% with 33% CR and 45% PR). The follow-up is too shorter (median 6 months) to assess the impact of re-treatment on duration of remission. The adverse events were not different to those usually observed with these regimens. In conclusion, the re-treatment with rituximab in relapsed patients with DLBCL who had respond previously to rituximab in combination with chemotherapy seems not to compromise the results in terms of response. Logically, larger prospective studies are necessary to confirm these encouraging results.

For more than 25 years, melphalan and prednisone has remained as the gold standard treatment for elderly multiple myeloma (MM) patients. Bortezomib has shown significant activity with manageable toxicity in refractory/relapse MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan. Aim: To define the appropriate dose of bortezomib in combination with MP and to analyse the efficacy of V-MP in untreated MM patients ≥ 65 years old. Methods: This is a dose escalation study with two sequential dose levels (Ph 1) and expansion of the cohort at the MTD by 60 patients to further refine estimates of efficacy (Ph 2). In the first cohort, bortezomib (1mg/m2) was administered as a iv bolus to 6 consecutive patients on days 1,4,8,11,22,25,29 and 32 followed by a 10 day rest period in combination with oral melphalan, 9 mg/m2, and prednisone, 60mg/m2, once daily on days 1 to 4. In the 2nd cohort, bortezomib was administered at 1.3mg/m2. MTD was defined as that dose level below which 2/6 patients had a DLT. Patients: 12 patients have been enrolled to date - 6 in cohort 1 and 6 in cohort 2. Results: Toxicity has been manageable. The first cohort at 1 mg/m2 has completed at least two 6-week treatment cycles. There was no DLT in the first cycle. The 2nd cohort has enrolled 6-patients at a dose of 1.3 mg/m2 but none has completed the first cycle yet. In the first cohort, there was one patient with grade 3 neutropenia (ANC = 0,668) observed at Cycle 1 Day 25. During the second cycle, there were no patients with grade 4 therapy-related toxicity and only one grade 3 adverse event (neutropenia) was observed. The most common grade1 or 2 toxicities were nausea, vomiting, rash, constipation, diarrhea, fever, herpes zoster infection, anorexia, neutropenia, anemia and thrombocytopenia. Ocular neuropathic pain (grade 2) developed de novo in 1 patient during the first cycle; one dose of bortezomib was held and the adverse event resolved with analgesic treatment in 4 days. Treatment was continued at a dose of 0,5 mg/m2 at D11 and D22. After this date, bortezomib at 1.0 mg/m2 was restarted. The second cohort is in the first 6-week cycle at present, so observations are limited. One serious adverse event (pulmonary embolism and probably septic shock with death) was observed in this cohort in a patient at day +11. He had normal WBC. Two grade 3 adverse events (leucopenia and neutropenia) were observed in one patient. Other grade 1 or 2 toxicities are similar to those observed in the first cohort. Regarding response, after two cycles of treatment, in the first cohort, 3 out of the 6 patients have experienced >50% reduction in M-protein (two with > 75% reduction) and the others three have experienced either a minor response (1) or stable disease (2). In the second cohort, response data are not available at this time. Conclusion:The combination of V-MP is well tolerated at standard doses of MP with bortezomib 1 mg/m2 with no DLTs in 6-patients. Bortezomib (1.3 mg/m2) is being explored in the second 6-patient cohort in order to define the MTD. So far, no patient has developed DLT. Rapid M-protein responses have been seen. Results will be updated and presented for the 2nd cohort.