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Despite the significant proportion of older patients with newly diagnosed multiple myeloma (MM), most clinical trials driving therapeutic decisions in routine practice include younger and presumably healthier patients than those in the real world. Furthermore, longitudinal studies suggest that elderly, transplant-ineligible patients with MM are not benefitting enough from new anti-MM agents. We retrospectively analyzed the profile of and treatment patterns and outcomes in 675 transplant-ineligible patients with MM who started frontline therapy in routine practice. The mean (SD) age was 75.6 (6.7) years; 152 (47.4%) had Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, and 73 (25.1%) had high cytogenetic risk. The most frequent frontline therapy was non-VMP bortezomib-based regimens (n=207; 30.7%), which were more frequent among patients with ECOG PS 0/1 and higher risk (e.g., international staging system (ISS) stage III, severely impaired glomerular filtrate rate (GFR), high lactate dehydrogenase (LDH), and high-risk cytogenetics); 185 patients (27.4%) started an attenuated (lite) VMP regimen, and 159 (23.6%) a VMP (VISTA) regimen. Median progression-free survival and overall survival (OS) were 15.3 months (95%CI 14.0-16.9) and 33.5 months (95%CI 29.1-37.2), respectively; 405 patients (78.2%) achieved partial response or better. Age, ECOG PS, ISS stage, serum LDH, GFR, cytogenetic risk, and treatment regimen significantly influenced OS. In this study, a remarkable proportion of transplant-ineligible patients with MM were older, frontline regimens were highly heterogeneous, and patients at higher risk often received less efficacious combinations. These findings suggest that clinicians have limited objective criteria for therapeutic decisions for this patient group.

Fludarabine-cyclophosphamide-rituximab (FCR) has been the gold standard front-line treatment for fit CLL patients until novel agent's introduction. Decision between either time-limited FCR or "endless" Bruton's tyrosine kinase inhibitor (BTKi) therapy may be difficult in fit IGHV-mutated-non-TP53 cases. We describe the outcomes after front-line FCR in 110 CLL patients from 5 centres in Catalonia, Spain, over a period of more than 10 years. ORR was 96.3% and CR 74.5%. Median second-treatment free survival (TFS1) was 6.2 years and median OS was 10.8 years. 50 (45.5%) patients required a subsequent therapy. Median third-treatment free survival was better for BTKi than for chemotherapy ± antiCD20 strategies (not reached vs 3.1 years, p = 0.003). Only 50 (45.5%) patients completed 6 cycles of FCR, and the main reason for discontinuation was cytopenia 29 (26.4%). 15 (13.6%) patients developed a second cancer, and 5 (4.5%) patients experienced a Richter's transformation (RT). At the end of follow-up, 50 (45.5%) patients remained in CR. Response rates, TFS1, OS, RT, and second cancers did not differ between patients treated with 6 vs 4 cycles of FCR. In conclusion, front-line FCR treatment leads to very long CR in almost half of patients, and BTKi yields excellent outcomes in relapsed patients.

PETHEMA/GEM Cooperative Group., Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species–mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.

BACKGROUND Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). METHODS This study analyzed via multiplex ligation–dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. RESULTS The cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)–positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). CONCLUSIONS Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015;121:3809–3817. © 2015 American Cancer Society.

BACKGROUND The karyotype is a predictor of outcomes in adults with acute lymphoblastic leukemia (ALL). The unfavorable prognostic significance of complex karyotype (CK) has been reported, whereas the prognostic relevance of monosomal karyotype (MK) has not been consistently evaluated. We aimed to assess the prognostic value of CK and MK in adults with ALL treated with risk-adapted protocols of the Spanish PETHEMA Group. METHODS The karyotypes of 881 adult ALL patients treated according to the protocols of the PETHEMA Group between 1993 and 2012 were centrally reviewed. CK and MK were assessed according to Moorman's criteria, and Breem's criteria, respectively. Specific analyses according to the risk groups and to the presence of t(9:22) were performed. RESULTS Of 364 evaluable patients 33 (9.2%) had CK, and 68 of 535 evaluable patients (12.8%) had MK. Complete remission rate, remission duration, and overall survival were not significantly different according to the presence of CK or MK in the whole series, according to the B or T lineage, in the high-risk group, or in patients with t(9;22), regardless of imatinib treatment, and in patients who received chemotherapy alone or chemotherapy followed by stem cell transplantation CONCLUSIONS Our study shows that CK and MK were not associated with a worse prognosis in adult patients with ALL treated with risk-adapted or subtype-oriented protocols. In patients with Ph+ ALL, MK did not have an impact on prognosis irrespective of imatinib treatment. Cancer. © 0000 American Cancer Society Cancer 2014;120:3958–3964. © 2014 American Cancer Society.

The karyotype is an important predictor of outcome in acute lymphoblastic leukemia (ALL). Rearrangements of the 11q23 region involving the KMT2A gene confer an unfavorable prognosis. Forty-six adult ALL patients from the PETHEMA Group treated with risk-adapted protocols, with t(v;11q23) were selected for this study. Complete response (CR) was attained in 38 patients; 25 remained in CR after consolidation. Twelve (48%) received allogeneic hematopoietic stem cell transplantation (HSCT) and 13 delayed intensification and maintenance. The 5-year CR duration probability was 37% (95% CI, 19%-55%). A trend for a longer CR duration was observed in patients undergoing HSCT vs. those receiving chemotherapy. The 5-year overall survival (OS) probability was 20% (95% CI, 5%-35%). The OS was better, albeit not significant, in patients with a MRD level< 0.1% after induction (39% [95% CI, 14%-64%] vs. 13% [95% CI, 0%-36%]). Specific treatment approaches are required to improve the outcome of patients with KMT2A-rearrangements.

Background: Despite significant improvements in the treatment of MM, the outcome of patients with HR cytogenetics remains poor despite similar complete remission (CR) rates as compared to SR cases. Relapses among patients in CR are attributed to the persistence of MRD, but knowledge about the impact of MRD in patients with SR and HR cytogenetics, treated with modern therapies and monitored with next-generation techniques, is limited. Similarly, there is virtually no data about in vivo mechanisms of resistance in SR and HR MM; however, since MRD represents those very few cells that are resistant to treatment, it could be hypothesized that profiling MRD cells may shed light into the mechanisms of resistance in both SR and HR patients. Aim: To determine the clinical impact of MRD in MM patients with SR vs HR cytogenetics, and to identify transcriptional mechanisms determining MRD resistance by investigating the transcriptome of MRD cells in both patient subgroups. Methods: This study was conducted in a series of 390 patients enrolled in the PETHEMA/GEM2012 trial (6 induction cycles with VRD followed by ASCT and 2 courses of consolidation with VRD). FISH was analyzed on CD138 purified PCs at diagnosis. MRD was predefined to be prospectively assessed following induction, transplant and consolidation, using next-generation flow (NGF) according to EuroFlow. In 40 patients [28 with SR and 12 with HR cytogenetics: i.e., t(4;14), t(14;16) and/or del(17p)], diagnostic and MRD tumor cells persisting after VRD-induction were isolated by FACS according to patient-specific aberrant phenotypes. Due to the small number of sorted MRD cells (median of 25,600) we used a 3' end RNAseq method optimized for generating libraries from low-input starting material (MARSeq). Differential expression analyses were performed with DESeq2 R package. Results: At the latest time-point in which MRD was assessed, MRD-positive rates progressively increased (p =.006) from SR patients (148/300, 49%) to cases with t(4;14) (24/42, 57%) and del(17p) (29/38, 76%). Furthermore, MRD levels were significantly superior in patients with del(17p) compared to SR FISH (0.02% vs 0.006%, p =.009), while MRD levels in patients with t(4;14) (0.004%) were similar to those in SR MM. Only 10 patients had a t(14;16) and 4 were MRD-positive. Among patients achieving MRD-negativity (.05). Conversely, 3-year PFS rates for MRD-positive patients decreased from those having SR FISH to those with t(4;14) and del(17p) (59%, 46% and 24%, respectively), with statistically significant differences between the first and the latest subgroups (p Since clearance of MRD notably lowered the risk of relapse and persistence of MRD significantly shortened the PFS in each cytogenetic group (p ≤.001), we investigated the unique features of MRD cells persisting after VRD-induction by comparing their transcriptome to that of patient-matched tumor cells at diagnosis (n=40). Accordingly, MRD cells showed 763 genes significantly deregulated (Padj Conclusions: This is one of the largest studies integrating patients' cytogenetics and MRD status. Our results, based on intensive treatment and MRD monitoring using NGF, unveil that achieving MRD-negativity may overcome the poor prognosis of HR cytogenetics. By contrast, persistent MRD significantly reduces PFS rates, particularly in patients with del(17p). Interestingly, MRD cells from SR and HR patients may have different transcriptional mechanisms leading to VRD resistance, and further understanding of these could provide knowledge on how to eradicate MRD in both patient subgroups. Disclosures Puig: Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Garcia-Sanz:Affimed: Research Funding. Martinez-Lopez:BMS: Research Funding; Pfizer: Research Funding; Vivia: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bladé:Janssen: Honoraria. San-Miguel:Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

Background and objective: The prognosis of acute lymphoblastic leukemia (ALL) is poor in older adults and elderly patients, and subtype-oriented prospective trials are scarce in these patients. We present the results of three prospective parallel subtype-oriented protocols in fit patients older than 55 years. Patients and methods: In 2008, three prospective phase II trials in patients older than 55 years were activated: ALLOLD07 for Philadephia (Ph) chromosome-negative ALL, ALLOPHO7 for Ph-positive ALL, and BURKIMABO8 for mature B-ALL. Early death (ED), complete remission (CR), disease-free survival (DFS), overall survival (OS) and toxicity were analyzed. Results: 56, 53 and 21 patients from the ALLOLD07, ALLOPHO7 and BURKIMABO8 trials, respectively, were evaluable. CR was 74%, 87% and 70%, with an ED rate of 13%, 11% and 15%, respectively. The medians of DFS were 8 and 38 months for ALLOLD07 and ALLOPHO7 protocols, not being achieved in the BURKIMABO8 trial (p = 0.001), and the median OS was 12, 37 and 25 months, respectively (p = 0.030). Neutropenia, thrombocytopenia and infections were less frequent in the ALLOPHO7 trial vs. ALLOLD07 and BURKIMAB trials, and renal toxicity and mucositis were more frequent in the BURKIMABO8 trial vs. the ALLOLD07 and ALLOPHO7 trials. ECOG score and WBC count had prognostic significance for OS in ALLOPHO7 and BURKIMABO8 trials, whereas no prognostic factors were identified in ALLOLD07 protocol. Conclusion: Subtype-oriented treatment had an impact in the outcome of older adults with ALL. The poorest outcome was observed in Ph-negative non-Mature B-cell ALL patients, for whom improvements in therapy are clearly needed. (C) 2015 Elsevier Ltd. All rights reserved.

Acute lymphoblastic leukemia (ALL) following solid organ or hematologic malignancy (secondary ALL, s-ALL) is not well characterized. We analyzed the characteristics and outcome of patients with s-ALL and compared them with those of patients with de novo- ALL. Of 448 patients, 24 (5%) had previous neoplasia. Sixteen patients had received previous cytotoxic therapy (therapy-associated ALL, t-ALL), and eight had not (antecedent-malignancy ALL, am-ALL). Except for more advanced age in patients with s-ALL, no statistically significant differences were observed in WBC count, CNS involvement, immunophenotype or cytogenetics between the groups, nor in complete remission (t-ALL: 94%; am-ALL: 75%; de novo-ALL: 85%), 3-year remission duration (58%; 50%; 72%), overall survival (71%; 38%; 60%) or event-free survival (53%, 38%; 53%). Our study did not show poor clinical or cytogenetic features or inferior outcome in ALL patients with antecedent neoplastic disease, irrespective of the type of treatment received for the neoplasia.

Over a 3-year period, 145 patients ineligible for myeloablative conditioning underwent reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (SCT) from an HLA-identical sibling in a prospective study. The median age was 54 years, 88 patients were male and 61 patients were beyond the early-intermediate phase of their disease. The 100-day probability of developing grade II-IV acute graft-versus-host disease (GVHD) was 34%, and the 1-year probability of developing chronic extensive GVHD was 41%. The 1-year probabilities of transplant-related mortality (TRM), overall (OS) and progression-free survival were 20, 60 and 52%, respectively. Multivariate analyses found a better OS in: (i) patients60 years; and (ii) recipients of a first SCT; and a higher TRM in: (i) age60 years, (ii) recipients of a prior autologous SCT, and (iii) an ECOG performance status1. The 1-year TRM in patients with 0 or 1 and2 of the above-mentioned adverse prognostic factors were 17 vs 53%, respectively (P0.001). In summary, our study shows that elderly patients have a higher TRM following an RIC protocol. However, age by itself should not preclude these RIC transplants, since TRM appears to be unacceptably high only in the presence of additional adverse factors.

Development of high-grade non-Hodgkin's lymphoma is a possible complication of chronic lymphocytic leukaemia/small lymphocytic lymphoma, known as Richter's syndrome (RS). Treatment for RS includes systemic chemotherapy and, recently, allogeneic stem cell transplantation (SCT). We describe a patient with B-chronic lymphocytic leukaemia who developed RS 4 months after allogeneic SCT from an HLA-identical sibling. The RS presented with systemic symptoms, lymphadenopathy, pancytopenia and serum lactate dehydrogenase elevation. The patient was treated with immunosuppressive drug withdrawal and a donor lymphocyte infusion (DLI) of 1 x 10(7) CD3/kg, leading to the disappearance of all symptoms and the attainment of complete donor chimerism. After 18 months of the therapeutic DLI, the patient continues in complete remission.

Reduced-intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (SCT) have been shown to lead to engraftment of donor stem cells without the severe extra-haematological toxicities of traditional myeloablative transplants. Between December 1998 and December 2000, 76 patients underwent a RIC peripheral blood SCT in a prospective multicentre study. The median age was 53 years, and 57 patients were beyond the early phase of their disease. The conditioning regimens consisted of fludarabine (150 mg/m2) plus melphalan (140 mg/m2) or busulphan (10 mg/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A plus short-course methotrexate. The preparative regimens were well tolerated. All patients experienced severe pancytopenia, but haematological recovery was prompt in all but two cases (early deaths). The 100-d probability of developing grade II–IV acute GVHD was 32% (10% grade III–IV), and the 1-year probability of developing chronic extensive GVHD was 43%. Early complete donor chimaerism was observed in 52/68 patients, and 16 evaluable patients were in complete chimaerism 1 year post transplant. With a median follow-up of 283 d (355 in 48 survivors), the 1-year probability of transplant-related mortality was 20%, and the 1-year overall and progression-free survivals were 60% and 55% respectively. In conclusion, RIC regimens lead to low early toxicity after allografting, with stable donor haematopoietic engraftment, with an apparent low risk of acute GVHD. Chronic GVHD, however, develops in a significant proportion of patients.

T cell depletion of the graft increases graft failure and relapse rate in allogeneic PBSC transplantation. Delayed lymphocyte add-back after T cell-depleted transplants might prevent these complications. We present 22 consecutive allogeneic PBSC transplants from related histocompatible donors with positive selection of CD34+ cells. Recipients received prophylactic donor lymphocyte infusions (DLI) depending on their risk of relapse and of developing GVHD. Patients were considered at high risk of relapse with AML > first CR, ALL > second CR, and CML in accelerated or blastic phase. Patients were considered at high risk of developing GVHD if older than 35 years, or with a donor sensitized through previous pregnancy or blood transfusion. Patients at high risk of relapse and low risk of GVHD were scheduled to receive three DLI. Patients at low risk of relapse and high risk of GVHD did not receive DLI. The remaining patients were scheduled to receive two DLI. The DLI were administered on days +28 (2 × 105/kg), +60 (2 × 105/kg) and +90 (2 × 106/kg) after transplant. G-CSF mobilized peripheral stem cells from healthy donors were positively selected by an immunomagnetic method. The mean CD34+ cells and CD3+ cells infused were 4.4 × 106(range 1.9–10.6) and 0.085 × 105 (range 0.01–0.67). Cyclosporin A was given to prevent GVHD. All the patients engrafted. Twenty-two prophylactic DLI were performed in 12 patients: seven developed acute GVHD (one case grade III–IV) and none presented pancytopenia. At a mean follow-up of 585 days (range 89–1103), 14 patients were alive in CR, one patient was alive in relapse, four patients had died of relapse and three had died of transplant-related complication. Individually adjusted prophylactic DLI at the doses we used with an escalating schedule allowed an acceptable GVHD rate and a good engraftment of donor hematopoiesis. Bone Marrow Transplantation (2001) 28, 963–968.

The present study was undertaken to assess the feasibility, toxicity and antileukemic activity of sequential chemotherapy including mitoxantrone, etoposide, carboplatin and intermediate-dose cytarabine in adult patients with refractory and relapsed acute myelogenous (AML) or lymphoid (ALL) leukemia. Fifty-one patients with poor-risk AML and ALL received 64 courses of MECA therapy. The overall response in the entire group was 51% (43% complete remission). The stage of the disease (relapsed or primarily refractory) and the age of the patients did not strongly affect the response rate. MECA therapy was more effective in ALL than in AML, and in those patients who presented at salvage treatment with a bone marrow infiltration lower than 25% blasts. Hematological and extra-hematological toxicities were tolerable and there were 6 deaths related to the treatment (11%). The incidence of documented infectious episodes was 71%. MECA therapy is a safe treatment and has a high antileukemic activity in relapsed and primarily refractory AML or ALL.

Introduction In the last years genome wide profilings have identified recurrent Copy Number Alterations (CNA) in genes potentially involved in the pathogenesis of Acute Lymphoblastic Leukemia (ALL). These studies have identified deletions in B-cell development genes (IKZF1, EBF1, PAX5, TCF3, etc.), cell cycle regulation genes (CDKN2A/B, RB1, TP53, etc.), glucocorticoid resistance genes (BTG1, CREBBP) and growth factor receptors genes (CRLF2, CSF2RA, IL3RA) among others. Some of these CNA (i.e. IKZF1, CDKN2A, CRLF2) have been reported to have prognostic significance in several pediatric series but there are very few data regarding their impact in B-lineage adult ALL. Our aim was to analyze the frequency and prognostic significance of CNA in a series of 125 B-lineage adult ALL patients treated according to risk-adapted protocols from the Spanish PETHEMA Group. Methods Bone marrow or peripheral blood (with significant blast burden) samples from 125 B-lineage adult ALL patients enrolled in risk-adapted protocols from the PETHEMA Group were analyzed at diagnosis. MLPA assays (MRC-Holland) were performed for the following genes: IKZF1, IKZF2, IKZF3, EBF1, CDKN2A/B, PAX5, ETV6, BTG1, RB1, hsa-miR-31, X/Y PAR1 region genes (CRLF2, CSF2RA, IL3RA) and 14q32.33 region genes (IGH D, MTA1, KIAA0284). Fragment analysis was made by Genescan in an ABI-3130 sequencer (Applied Biosystems). Data normalization provided a value indicative of the presence or absence of CNA: 0-0.20 homozygous deletion, 0.21-0.70 heterozygous deletion, 0.71-1.30 normal, 1.31-1.70 heterozygous duplication and 1.71-2.20 homozygous duplication. Results The median age [range] was 40 [15-74] years, 71 (57%) males, median WBC count 12.11 x109/L [0.4-388]. Immunophenotype: pro-B 14 (11%), common 71 (58%), pre-B 26 (21%), mature-B 10 (8%), unavailable 2 (2%). Cytogenetics: normal 16 (13%), hyperdiploid 6 (5%), hypodiploid 2 (2%), t(9:22) 20 (16%), t(1;19) 8 (6%), 11q23/MLL 11 (9%), 8q24/C-MYC 7 (5%), complex 1 (1%), iAMP21 2 (2%), other translocations or deletions 31 (25%), no growth 20 (16%). CNA frequencies of the 125 patients are shown in the table. IKZF1 deletions were significantly associated with EBF1 deletions, high WBC count and Philadelphia (Ph) chromosome. In the IKZF1 deleted cohort whole gene deletions were as frequent as Ik6 isoforms (28% each). A high codeletion rate was detected in genes located in 9p (CDKN2A/B with PAX5, CDKN2A/B with hsa-miR-31 and PAX5 with hsa-miR-31). CDKN2A/B also showed concomitant deletions with ETV6 while PAX5 showed codeletions with BTG1. CDKN2A/B and PAX5 deleted patients had higher WBC counts than non-deleted individuals. Clinical follow-up data was available for 123 patients of the whole series and for the 105 patients of the Ph-negative cohort. Multivariate analysis showed that advanced age, BTG1 deletions and EBF1 deletions were negative prognostic factors for achieving Complete Remission (CR) and WBC count and IKZF1 deletions significantly reduced CR duration in both cohorts. Interestingly, there were significant differences in relapse rates between whole and partial gene IKZF1 deletions. IKZF1 haploinsufficient patients had a probability of CR duration at 3 years of 83% ± 30% vs. 6% ± 12% of partial gene deletion carriers. Advanced age and IKZF1 deletions were predictors for overall survival in the Ph-negative cohort and age>30 years, IKZF1 deletions and hsa-miR-31 deletions were associated with poor prognosis in the whole series. Conclusions In B-lineage adult ALL, deletions of IKZF1, EBF1, BTG1 or hsa-miR-31 are markers with prognostic significance in addition to age and WBC count. Patients with partial IKZF1 gene deletions have a significantly higher probability of relapse than those with whole gene loss. These genetic abnormalities could help to better define prognostic subgroups in adult patients with B-lineage ALL. Supported by the grants PI10/01417 and RD12-0036-0029 from Instituto Carlos III and a grant from the Spanish Society of Hematology and Hemotherapy (2012). Disclosures: No relevant conflicts of interest to declare.

Purpose Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation. Patients and Methods Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 × 10−4 at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level ≥ 5 × 10−4. Results Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (≥ 1 × 10−3 after induction and ≥ 5 × 10−4 after early consolidation) as the only prognostic factor for DFS and OS. Conclusion Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.

A 40-year-old male weighing 90 kilograms was diagnosed with acute myeloblastic leukaemia M5a which was resistant to chemotherapy. Neither a related nor an unrelated HLA-compatible bone marrow donor could be found. A unit of cord blood was found with an HLA compatibility of four out of six loci, and was infused after conditioning with cyclophosphamide, total body irradiation and antilymphocyte globulin. The infused cord blood had 0.98 x 10(7) nucleated cells per kilogram. On day 35 after infusion the patient was considered to have graft failure. A second unit of cord blood was found, and after 3 days of antilymphocyte globulin, it was infused (day 41). The course was complicated by severe hypoxia and bilateral interstitial pulmonary infiltrates, and the patient was treated with high doses of methylprednisolone. On day 58 the leukocyte count increased to 3 x 10(9)/l, and there was total chimerism of the first cord blood unit infused. Two weeks later leukocyte counts decreased progressively and the patient died of a disseminated fungal infection. We discuss the importance of the number of nucleated cells per kilogram of body weight infused, and the role of intensive immunosuppression in engraftment of cord blood transplantations in adults.

We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P = .008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.

Renal involvement is observed frequently in association with malignant gammopathies, mainly those related to light chain deposition [1]. Nevertheless, light chain deposition renal disease has also been described in non-malignant monoclonal gammopathy, namely in IgG or IgA plasma cell dyscrasia [2,3]. Renal involvement in IgM monoclonal disorders is traditionally described in patients with malignant disease (Waldenstrom’s macroglobulinaemia) that includes the deposition of monoclonal IgM and light chains on mesangium and glomerular capillary wall [4–6]. IgM monoclonal gammopathy without malignant criteria can be found in asymptomatic patients or associated with polyneuropathic disease, but renal involvement has rarely been described in this clinical setting [7,8]. We report the case of a patient with non-malignant IgM/k gammopathy, who developed nephrotic proteinuria and progressive renal failure in association with renal deposition of IgM and k light chains.

Patients with hematological malignancies who relapse after autologous stem cell transplantation (auto-SCT) generally have poor prognosis. Salvage treatment is often associated with severe toxicities. The aim of our study was to evaluate retrospectively the toxicity and outcome of rescue therapy in patients with acute leukemias, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD) and multiple myeloma (MM) relapsing after auto-SCT. Fifty-four of the 62 patients who relapsed received some form of salvage chemotherapy. Six (10%) patients were treated by second stem cell transplantation, which was allogeneic in 5 cases. Toxicity of the salvage therapy was significant. As a result of adverse effects, salvage therapy had to be discontinued or reduced in 14 patients (26%). The outcome of salvage was evaluated after 90 days. Of the treated patients, 14 (26%) entered into complete remission with another 5 (9%) reaching partial response. The disease was stabilized in 5 patients (9%) but 30 (56%) patients were in progression or dead. Overall survival of the patients was poor with the median survival of 8.7 months after relapse and the leading cause of death being progressive disease. In conclusion, the development of new, more efficient regimens is critical if disease-free survival is to be increased in patients who relapse after auto SCT.

Introduction:Renal impairment (RI) is a common complication in multiple myeloma (MM) with an incidence of 20-40%, due to the older age of the affected patients (pts) and the nature of the disease. Prognosis of pts with RI has improved in recent years (yrs), but remains closely associated with the recovery of renal function. There is little information on the renal response of relapsed refractory MM (RRMM) to new antimyeloma drugs within clinical practice, using standardized criteria such as glomerular filtration rate (GFR) estimated by the Cockroft-Gault (CG) and the Modification of Diet in Renal Disease (MDRD) formulas.The primary objective of the study is to describe the renal response in RRMM pts with moderate (CrCl 30–50 mL/min) or severe renal impairment (RI) (CrCl < 30 mL/min) after initiating treatment (Tx). Secondary objectives include response rate, overall survival (OS), safety, and health resource utilization. We present results from a pre-planned, interim analysis with a data cut-off of June 15, 2014. Methods:This is a large ongoing observational, prospective, multicenter study in RRMM pts with moderate or severe RI (based on the CG formula) receiving antimyeloma Tx. The overall planned sample size is 300 pts to be followed for up to 36 months (mos) after the end of Tx. Renal and MM responses are evaluated according to the International Myeloma Working Group criteria. Renal complete response (renalCR) is defined as a sustained (for at least 2 mos) increase of baseline estimated glomerular filtration rate (eGFR) to ≥ 60 mL/min; a partial renal response (renalPR) is defined as an increase from < 15 to 30–59 mL/min, and a minor renal response (renalMR) from < 15 to 15–29 mL/min or, from 15–29 to 30–59 mL/min. Results:A total of 150 pts were included in the interim analysis, mean ± SD age was 74 ± 9 yrs, 53% were male, and 53% had moderate and 47% had severe RI. At baseline, 57% of pts were in first relapse. At diagnosis, 45% of pts had ISS stage III, 29% had ISS stage II, 9% had ISS stage I, and 17% had no ISS stage available. Main antimyeloma therapies were: lenalidomide (LEN)-based (37%), bortezomib (BORT)-based (30%), BORT + LEN based (5%), chemotherapy-based (25%) and, thalidomide-based (3%). The median follow-up was 4 mos. To date 38% of pts have discontinued Tx, 13% due to adverse events (AEs), and 29% have died. The main causes of death were: disease progression (8.7%), infection (6.7%), respiratory failure (3.3%), kidney insufficiency (2%), fractures (2%). The mean baseline CG/MDRD was 39.7/42.2 (± 6.3/10.2) mL/min in the moderate RI subgroup and 20.2/19.8 (± 7.6/9.8) mL/min in pts with severe RI (correlation coefficient CG vs. MDRD: 0.93). Overall, 15.3% (n = 23; 95% confidence interval [CI] 9.5–21.1,) had a renal response according to the CG formula, i.e. renal function iimproved by at least 1 KDIGO stage; 4.7% had renalCR, 0.7% renalPR and 10% renalMR. According to the MDRD formula, the renal response was 21.3% (8.6% renalCR, 12.7% renalMR). Median time to best renal response was 1.5 (range 0.6–4.6) mos. The renal response based on CG/MDRD according to antimyeloma therapies was 10.9%/20% for LEN-based, 26.7%/31.1% for BORT-based, 0%/12.5%, for LEN + BORT-based, and 10.2%/15.4%, for chemotherapy-based therapies. 24 hour (hr) proteinuria measurement was available at baseline in 70 pts (median of 1.3 g/24 hr), 77.1% of whom had > 0.3g/24 hr. Of these, 4 (7.4%) achieved complete proteinuria response (< 0.3g/24 hr) and 4 (7.4%) achieved partial response (< 1g/24 hr) by the 4th follow-up visit. The overall myeloma response (≥ partial response) was 38.0% achieved after a median of 2.9 (1.3–5.2) mos. LEN-based myeloma response was 45.5%, BORT-based 48.9% and LEN + BORT-based 50.0%. These responses seemed to be higher than those obtained with chemotherapy-based therapies (17.6%). The median time to progression (TTP) was 4.5 mos (95% CI 4.2–7.3). TTP was 16.2 mos with LEN-based, 11.8 mos with BORT-based, not reached with LEN + BORT-based, and 8.3 mos with chemotherapy-based therapies. Overall, 52% of pts had an AE and 12% a serious related AE. Conclusions: The most commonly used Tx in clinical practice in RRMM pts with RI are LEN or BORT-based. The results of this interim analysis suggest that these Tx can improve RI in approximately 15% of cases, and are associated with a higher antimyeloma response than chemotherapy-based Tx. Disclosures Morales: Celgene: Consultancy. Ruiz Boza:Celgene : Employment, Other. Garcia:Celgene: Honoraria.

We compared the occurrence of severe infections following 71 reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplants (PBSCT) and 123 standard myeloablative PBSCT (MINI and STAND groups, respectively) from HLA-identical siblings. The probability of 1-year infection-related mortality (IRM) was 19% in the STAND group and 10% in the MINI group (log-rank, P = 0.3). On multivariate analysis the only significant variable associated with a higher risk of IRM was the development of moderate-to-severe GVHD (P = 0.005). The probability of developing CMV infection was 39% in the STAND group and 21% in the MINI group (P = 0.03) (43% and 21%, respectively, in seropositive donor/recipient pairs, P = 0.01), and the probability of developing CMV disease was 9.5% and 1%, respectively (P = 0.05) (11% and 1%, respectively, in seropositive donor/recipient pairs, P = 0.03). Multivariate analysis of CMV infection identified four variables associated with a higher risk: CMV positive serostatus (P = 0.05), STAND transplant group (P = 0.02), the development of moderate-to-severe GVHD (P < 0.001) and a dose of CD34(+) cells infused below 6 x 10(6)/kg (P = 0.01). Invasive fungal infections and pneumonias of unknown origin did not differ between groups, and neither did other severe non-CMV viral infections and bacterial infections. Our results suggest that RIC allogeneic PBSCT may decrease the risk of dying from an opportunistic infection and reduces the occurrence of CMV infection and disease. Overall, the development of GVHD (acute or chronic) is an important risk factor for these complications. Other infections continue to pose a significant threat to recipients of RIC allografts, stressing that prophylactic and supportive measures are an important aspect in their care.

The purpose was study the feasibility of ESHAP + G-CSF for peripheral blood hematopoietic progenitor cell (PBPC) mobilisation in resistant/relapsed Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Twenty-two consecutive patients with HD (8) and N-HL (14) received ESHAP chemotherapy and G-CSF (5 microg/Kg/d). When a minimum number of 10,000 peripheral blood CD34+ cells/mL was observed patients underwent leukapheresis until a CD34+ cell doseor = 2.5x10(6)/Kg was collected or the PBPC peak was lost. Blood cells kinetics and toxicity were analysed. Data concerning the day of first apheresis, number of procedures per patient, and cellular yield of the aphereses were recorded. Correlation between the CD34+ cell content in the apheresis product and the two diagnosis groups was attempted. Twelve patients (54%) developed short-lived severe neutropenia (0.5x10(9)/L). Thrombocytopenia (25x10(9)/L) had a median duration of 1 day. Fever appeared in 4 patients and CN Staph bacteriemia in 2 cases. Bleeding events did not supervene and no deaths occurred. Aphereses started at day +15 (median) and the median number of apheresis/patient was 2. Seventeen patients underwent 1 or 2 leukaphereses. Thirteen patients (59%) achieved the CD34+ cell target in the first apheresis. NHL patients obtained statistically significant better CD34+ cell collections than HD. Only 2 HD patients failed to mobilise, 1 previously treated with high-dose therapy and autologous bone marrow transplantation. ESHAP + G-CSF has been shown to be feasible for PBPC mobilisation in resistant/relapsed lymphoma. Toxicity was low and CD34+ cell yield high, especially in N-HL. This mobilisation regimen should be further explored in a larger patient population.

Background Older patients are increasingly prevalent in oncological practice. However, the evidence suggests that this group of patients is undertreated, mainly because of their advanced age, regardless of whether they are highly functional patients, do not present comorbidities, or could benefit from oncological therapies. The US National Comprehensive Cancer Network and the International Society of Geriatric Oncology have recommended that some form of geriatric assessment should be conducted to help Hematologists and Oncologists in order to identify current health problems and to guide interventions to reduce adverse outcomes and optimize the functional status Currently, the main tool for assessing older patients is a comprehensive geriatric assessment, although its complexity and duration may hinder its regular use in daily practice as a tool for clinical decision making. Several attempts have been made to assess comorbidities in the specific field of mielodysplasia, but mainly focused on organic damage rather than global assessment. Aim We are in the process of developing and validating a comprehensive health status assessment scale (Geriatric Assessment in Hematology, GAH Scale) with eight dimensions in patients ≥ 65 years with: Myelodysplastic syndromes (MDS), acute myeloblastic leukemia (AML) and multiple myeloma (MM). Methods After item-pool generation, stakeholder consultation and content validation, a brief scale of 8 dimensions with selected items has been created. Feasibility was confirmed in 83 patients. Afterwards, a multicenter, observational, prospective study has been carried out in 20 hospitals in Spain, enrolling 189 elderly naïve to treatment patients with newly diagnosed MDS, AML or MM. The scale validation process integrates the analysis of criterion and concept validity, internal consistency (Cronbach's alpha), test-retest reliability, as well as the evaluation of intraclass correlation coefficient (ICC) and factor analysis. After psychometric validation phase, further studies will be carried out in order to evaluate its clinical use for prognosis and clinical decision making. Results 189 patients fulfilling inclusion criteria have been enrolled in the study, 54% women. Median age at diagnosis was 73.3 ± 6.64 years. According to diagnosis, 103 patients (54.5%) had MDS or AML and 86 (45.5%) had MM. Regarding feasibility, mean time for filling in the questionnaire was 12.1 ± 4.5 min. 83.6% of patients answered 100% of questions of the scale. Mean percentage of unanswered questions per patient was 1%. Test-retest was completed by 112 patients. GAH Scale showed satisfactory test-retest reliability. ICC was statistically significant for each dimension, being greater than 0.65 for 6 of the 8 dimensions (p Internal consistency, content validity and factor analysis are being carried out and results will be presented in the forthcoming congress. Conclusion This new GAH Scale is a valid, reliable and consistent tool, simple enough to assess health status in older patients with haematological malignancies. Further studies will have to stablish if it may be a tool to improve decision making in such patients. Disclosures: Bonanad: Celgene: Consultancy. Gonzalez:Celgene: Consultancy. Durán:Celgene: Employment. Marcos:Celgene: Employment. López:Celgene: Employment. Cruz-Jentoft:Celgene: Research Funding.

Background and objective ALL in elderly patients is associated with poor prognosis and many patients are not included in therapeutic trials. Consequently, the results of subtype-oriented protocols in elderly ALL are poorly known. We present the results of three prospective parallel subtype-oriented protocols from the Spanish PETHEMA group in ALL patients older than 55 years. Patients and Methods In 2008 three prospective phase II trials for ALL patients older than 55 yr with the Charlson Comorbidity Index ≤3 were activated: ALLOld07 (Ph-negative patients, NCT01366898, n=54), ALLOPh07 (Ph-positive patients, NCT01376427, n=48) and BURKIMAB08 (mature B-ALL, NCT00388193, n=18). The ALL0ld07 protocol included moderate-dose induction chemotherapy without genotoxic drugs, followed by consolidation and maintenance therapy for 2 years (Gökbuget et al, ASH 2008), the ALL OPh07 included imatinib and dexamethasone for induction followed by maintenance therapy with mercaptopurine and methotrexate and imatinib for 2 years, followed by imatinib for one additional year (Ribera et al, Br J Haematol 2012; 159: 485-488), and the BURKIMAB08 protocol included specific therapy for Burkitt’s lymphoma/leukemia together with rituximab (Ribera et al, Cancer 2013; 119:1660-8). The main outcomes (early death [ED], complete remission [CR], remission duration [RD] and overall survival [OS]) and toxicity (CTCAE v4.0) were compared. Results 40, 45 and 16 patients from ALLOld07, ALLOPh07 and BURKIMAB08, respectively, were evaluable for this study. Patients with mature B-ALL were more frequently male, with poorer general status, higher frequency of bulky disease and higher LDH serum levels, whereas no significant differences were observed on comparison of ALLOld07 and ALLOPh07 patients. The comparison of the main outcomes of the three trials is shown in Table 1. By multivariate analyses for RD the protocol and WBC count were identified as prognostic factors (BURKIMAB08 was considered as reference category), with HR [95%CI] of 6.8 [0.9-52.1], p=0.064, when compared with ALL Old07 and 3.1 [0.4-24.8], p=0.278 when compared with ALL OPh07, global p value=0.042, and HR [95%CI]: 1.004 [1-1.009], p=0.058 for the WBC count, respectively. The ECOG score was the only variable influencing OS (HR [95%CI]: 0.4 [0.2;0.8], p=0.003). Hematological toxicity in induction and consolidation as well as infections were significantly less frequent in ALLOPh07 than in other two trials, whereas renal toxicity was more frequent in BURKIMAB08. Conclusion Risk-adapted therapy in elderly patients with ALL was feasible and produced significantly different results in terms of CR duration, being the best for mature B-ALL and the poorest for Ph-negative ALL. Supported by the grants PI10/01417 from FIS and RD12-0036-0029 from Instituto Carlos III Disclosures: No relevant conflicts of interest to declare.

Background Bortezomib-based combinations, including alkylating agents (VMP or CyBorD) or immunomodulatory drugs (VTD or RVD) have been established as regimens widely used in newly diagnosed MM patients. Bendamustine is a bifunctional alkylating agent effective in relapsed and/or refractory MM patients, and approved in Europe in combination with prednisone for elderly newly diagnosed MM. Since bendamustine may be more efficient than other alkylators, an attractive possibility would be to explore it in combination with bortezomib and prednisone (BVP) in newly diagnosed MM patients both transplant and non transplant candidates. Patients and Methods 60 newly diagnosed MM patients were included in the trial. The first cycle consisted on bendamustine at 90 mg/m2 given IV on days 1 and 4, in combination with bortezomib at 1,3 mg/m2 given IV on days 1, 4, 8, 11, 22, 25, 29 and 32 and prednisone at 60 mg/m2 given PO on days 1 to 4. In the following cycles, bendamustine was given on days 1 and 8, and bortezomib on days 1, 8, 15 and 22 (weekly schedule), and prednisone as it was previously described. Patients younger than 65 years proceeded to peripheral blood stem cell collection (PBSC) using growth factors alone after 4 cycles; HDT-ASCT was performed after 6 cycles. Patients older than 65 years received up to nine 28-day cycles. Results Between May 2011 and July 2012 enrollment was completed (60 pts). Median age was 61 years (range 38-82; 18 pts ≥65), 67% had ISS stage II/III, and 67% had unfavorable cytogenetics: t(4;14), t(14;16), del 17p or 1q gains by FISH. After a median of 6 cycles (2-9), 75% of patients achieved at least PR, including 16% of sCR, 9% CR and 28% of VGPR. Although the differences were not statistically significant, there was a trend to higher CR rate in the group of patients Forty patients proceeded to stem cell collection after a median of 4 cycles of BVP. Upon using G-CSF alone, 14 pts (35%) failed to collect a minimun of 2 x 106 CD34+ cells/Kg. An ammendment was done and plerixafor was recomended for poor mobilizers (peripheral CD34 cell count inferior to 10/μL on day 4); all patients but 2 achieved, with G-CSF plus plerixafor, the minimum of CD34+ cells required to proceed to ASCT. These 2 patients successfully collected CD34+ cells using chemotherapy plus G-CSF and plerixafor. Of the 31 patients who received HDT-ASCT, sCR and CR rate before transplant was 18% and 13%, respectively, upgrading up to 39% of sCR and 13% CR after transplant. 7 pts (22%) achieved immunophenotypic CR. After a median f/u of 12 months (5-25), 8 pts have progressed, resulting in a 15-m TTP of 85%. Concerning OS, 89% of patients remained alive at 15 months. None of patients achieving sCR and CR have progressed and all of them are alive at 15 months. Regarding cytogenetic abnormalities, although there were not significant differences, one patient progressed in standard risk group and five in the high risk subgroup resulting in a 15 m-TTP of 93% vs 85%. No significant differences have been observed in terms of 15 m-OS between standard and high risk cytogenetic subgroup (100% vs 92%, respectively). As far as toxicity is concerned, hematologic toxicities included: G3/4 anemia (11%), neutropenia (23%), and thrombocytopenia (14%). The most common G3/4 non-hematologic toxicities were: asthenia (10%), infections (9%), and peripheral neuropathy (4%). Conclusions In patients candidates to HDT-ASCT, response rates obtained before and after transplant are comparable to other three drug bortezomib-based combinations, such as VTD or CyBorD. However, growth factors alone for stem cell collection after four BVP cycles as induction resulted in a 35% of poor mobilizers who were rescued with plerixafor. In the elderly population, although the number of patients included was small, BVP seems not superior to VMP in response rates. Disclosures: Mateos: Janssen, Mundipharma: Honoraria. Off Label Use: bendamustine plus bortezomib and prednisone is not an approved combination for first line of therapy. Oriol:Celgene: Consultancy. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. Alegre:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bladé:Janssen, Mundipharma: Honoraria. San Miguel:Janssen, Mundipharma: Membership on an entity’s Board of Directors or advisory committees.

Abstract 2582 Background and objectives. Concurrent imatinib and chemotherapy followed by allogeneic stem cell transplantation (SCT) is the most used treatment for young patients with Ph+ALL. However, the amount of chemotherapy before SCT is not well established. The Spanish PETHEMA Group conducted two consecutive protocols (CSTIBES02 -Haematologica 2010; 95: 87–95- and ALL Ph08) differing in the imatinib dose (400 mg/d vs. 600 mg/d) and the amount of chemotherapy (two consolidation cycles vs. one consolidation cycle) before SCT. The short –term outcomes are herein compared. Patients and methods. CSTIBES02 trial included 30 patients with a median age of 44 yr and ALL Ph08 includes 26 patients (median age 37 yr). The main clinical and biological features of the two series of patients are comparable. The initial induction chemotherapy schedule included VCR, DNR and PDN at the same doses in the two protocols, but in the CSTIBES02 mitoxantrone and ARA-C were administered on day 15 if >5% blast cells were present in bone marrow smear, whereas no change in the chemotherapy schedule was prescribed in the ALL Ph08 trial according to the percentage of blast cells on day 15. The first consolidation cycle included HD MTX, ID ARA-C, MP and teniposide in both protocols. Patients in CR were then submitted to SCT in ALL Ph08 study, whereas those included in CSTIBES02 received a second consolidation cycle before SCT. Imatinib was administered concurrently with chemotherapy from diagnosis (400 mg/d in CSTIBES02 trial and 600 mg/d in ALL Ph08 study). Results. The main short-term outcomes are compared in the table Conclusion. Despite non-significant improvement has been observed in ALL Ph08 protocol regarding CR attainment, molecular response after induction and consolidation, 2-yr EFS has been improved after the increase of imatinib dose and the decrease of amount of chemotherapy. Both decrease in relapse before SCT and TRM observed in the ALL Ph08 protocol are responsible for the better EFS. Supported in part by grants RD06/0020/1056 from RTICC and P-EF-11 from FJC Disclosures: No relevant conflicts of interest to declare.

Abstract 322 Introduction: Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance ( Patients and methods: HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25×109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level Results: On June 2009, 235 HR ALL pts were evaluable [mean (SD) age 37(14) yr, 129 males, 155 precursor B-ALL, 80 T-ALL, WBC count 64(96) ×109/L]. Induction death: 20(8%), resistance: 11 (5%), CR: 202 (87%). Slow cytologic response on d14 was observed in 137/186 (74%) pts, MRD Conclusions: These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR after consolidation the results of therapy are not hampered by avoiding allogeneic SCT. MRD is the main prognostic factor for CR, DFS and OS. Supported by grants P-EF/07 from FIJC and RD 06/0020/10556 from RETICS, and PI051490 from FIS, Instituto Carlos III. Disclosures: No relevant conflicts of interest to declare.

Abstract 4108 Introduction ALL/LL is a heterogenous disease with various subtypes that differ markedly in their cellular and molecular characteristics. Chemotherapy regimens, response to therapy and risk of relapse also vary among different disease subtypes. Here we report the experience in our center in the management of this heterogeneous group of haematological malignancies. Objectives The objectives of the study are: - To determine the event free survival (EFS) in patients diagnosed with different subtypes of ALL/LL, including those who received an allogeneic stem cell transplantation. - To determine the overall survival (OS) for the patients diagnosed of ALL/LL and for those who received an allogeneic stem cell transplantation. Patients and Methods: Forty-two patients have been diagnosed of ALL/LL in our hospital from February'02 to April'09. 24 male (57%) and 18 female (43%), median age of 42,5 years (18-74), including sixteen cases of B-ALL (38%); 13 Ph+ ALL (31%); 6 T-ALL (14%) and 7 LL (17%). B and T-ALL were treated with the same chemotherapy regimen (Pethema: Spanish group for the treatment of haematological malignancies). Ph+ ALL were treated with chemotherapy and the addition of Imatinib (Pethema regimen) and Lymphoblastic Lymphomas (LL) were treated with HyperCVAD regimen. Elderly patients or those with significant comorbidities were treated with “adapted risk” chemotherapy regimens. Allogeneic stem cell transplantation, related or unrelated, was indicated in first complete remission (CR) for all cases of Ph+ ALL, and cases of B or T ALL who do not achieved CR with negative Minimal Residual Disease (MRD), or in second CR for cases with LL. Results Thirty-three patients (78%) achieved CR at the end of the first induction phase. Two patients (5%) died in this phase and 5 patients (14% of the evaluable patients) relapsed at any moment of the treatment scheduled for them. Fourteen patients (33%) received an allogeneic transplantation: 7 (50%) from an unrelated donor. Nine of this 14 patients (64%) were transplanted in 1st CR. At the moment of the study, 21 patients (50%) are alive. The EFS for the patients included in the study is 41% with a median follow-up of 10,47 months (1,1-78,1). The EFS for the different subtypes are: 57% for B-ALL; 23% for Ph+ ALL; 44% for T-ALL and 57% for LL. The EFS for the transplanted patients is 34% and for the non transplanted patients group is 49% The OS is 43% with a median follow up of 11,57 months (1,11-78,1). The OS for the transplanted patients is 40% and for the rest of the patients is 48% Conclusions Pethema chemotherapy regimens for B, T and Ph + ALL, achieve a good percentage of CR, according to other similar regimens of chemotherapy reported. However, toxicity and relapses are still elevated. The research of a related or unrelated HLA-identical donor must be done from the diagnosis, specially in those forms of recognized bad prognosis. Disclosures: No relevant conflicts of interest to declare.

Although autologous transplant is the election in poor prognosis patients with Non Hodgkin agressive histologies, some patients relapse, for others collection of progenitor cells is not possible and in some categories as Mantle Cell Lymphoma results after autologous transplant are dismal. From 1999, three prospective multicenter trials with non-myeloablative allogeneic transplant in hematological malignancies have been performed in Spain. Up to now, 36 patients have been registered in these trials. From them,28 (58%)had aDBLCL,1 (3%) a transformed MZL,1 (3%) a BL and 14 (37%) a MCL. The conditioning regimen consisted of fludarabine 30 mg /m2 intravenously (IV) on days −8 to −4 followed by melphalan 70–140 mg/m2 IV on days −3 and−2. The last 25 patients enrolled in the latest trial received rituximab 375mg/ m2;on days −8, −1,+8 and +15 as part of conditioning; filgrastim stimulated peripheral blood stem cells were infused on day 0. GVHD prophylaxis consisted of cyclosporine A (CsA) from day −7 plus short-course methotrexate (MTX) (10mg/m2, days +1, +3, +6), followed by folinic acid rescue. Median age was 51 years (range 27–68);at transplant 5 (13%) of the patients were in CR1, 4 (11%) in a later CR and 29 (76%) had active disease 18 (47%) had sensitive disease and 11 (29%) resistant disease. Days to reach more than 500x 109 granulocytes and more than 20000x109 platelets were +14 (range 10–93) and +12(range 8–18). At a median time of 25 days (range 19–97), 19 patients (50%) developed acute GVHD (13 patients (34%) grade II–IV). At a median time of 107 days(80–267), 68% out of 19 patients at risk developed cGVH being extensive in 11 (39%)Disease was evaluated at day +100 and at that moment 23 patients(65%) were in CR (including 4 / 8 patients transplanted on PGR), 4% in PR and 23% have died due to NRM(Non relapse mortality). With a median follow up of 31 months (range: 6–67 months), 19 patients (50%) are alive, 17 disease free and 19(50%) have died, 10(26%) due to NRM and 8 (21%) due to progression with a proyected NRM at 1 year of 22%. OS and EFS at 5 years of of 43 and 36% respectively. None of the variables analysed influenced on NRM. Regarding efficacy of transplant in different histologies, OS and DFS for MCL were 71% and for BDLCL, 31% and 20% respectively. In this preliminary analysis results in MCL are quite good however for patients with DLBCL should be improved. severe toxicity is still present and to date it should be performed only in the setting of well designed clinical trials.

In the present study we have evaluated the outcome of reduced intensity conditioning allogeneic transplant (RIC) in 31 patients with symptomatic B-CLL. 74% of the patients were older than 50 years, and 70% had previously received purine analogues, with 38% of them relapsing or progressing after treatment. At transplant, 83% had active disease. Data from VH homology, FISH analysis, CD38 expression and ZAP 70 expression was available in 21, 27,12 and 2 patients, respectively. 21 out of 31 were conditioned with melphalan plus fludarabine according to our GETH 99–051 protocol; the other patients received other fludarabine-containing regimens. All patients engrafted. Early complete donor chimerism (CDC) (days +28) in Bone Marrow (BM) was observed in 67% of patients; all except two relapsing patients remained CDC after day +180. With a median follow up of 36 months (1–63), 9 patients have died, two of them due to disease progression and seven (22%) due to TRM. In the univariate analysis age older than 55 years, aGVHD and more than two lines of previous chemotherapy significantly influenced TRM (p 23 patients are evaluable for response: CR ( no CD19/CD5/CD23 + cells in BM) was 90% in transplanted patients with active or progressive disease −21 cases−. In 68% of patients, the response was time related to the development of GVHD; with the two latest responses observed at days +240 and +360. Regarding biological characteristics, 12 of the analyzed patients showed unmutated IgVH. The CR rate, EFS and OS of these patients did not differ from that of mutated IgVH patients . In this series 11 patients showed poor prognosis cytogenetics abnormalities (11q- in 7 and 17 p- in 4) and 5 of them had also unmutated IgVH. This group of patients showed a similar outcome to that of patients with normal cytogenetics. CD38 overexpression was detected in 7 out of 10 patients and only one has relapsed. Two patients died due to progression, one was unmutated with normal FISH and the other was 17 p- and CD38+; eight patients had at least two of the above mentioned abnormalities, including 3 with 17p-, and 7 of them, remained in CR between 20 and 63 months. According to this data, a GVL effect associated with GVHD appears to exist in CLL patients receiving RIC allograft Our data demonstrates the efficacy of RIC related allogeneic transplantation in patients with B-CLL and adverse prognostic features. Moreover, our data suggests that CLL could be cured with RIC allograft, avoiding the high TRM of myeloablative regimens.

Myeloablative transplant has been investigated in poor prognosis indolent lymphoma; although recurrence rate is low it is associated with high mortality; the use of non-myeloablative conditioning regimens could reduce TRM maintaining the GVH effect. Up to February 2004, 40 patients with indolent NHL(87% Folicular lymphoma(FL) 5% a lymphocytic well differenciate lymphoma (WDLL) 5% Waldenström Macroglobulinemia(WM) and 3% a Marginal Lymphoma(MZL) have been registered in two prospective multicenter trials;Conditioning regimen consisted of Fludarabine 150 mg and Melphalan 70–140 mg. GVHD prophylaxis consisted of CSA plus short-course MTX. All patients received filgrastim-stimulated peripheral blood stem cells from a HLA related identical donor.Median age at transplant was 50 years (34–67) and 15(40%) had received a previous autologous transplant. At transplant, 5 patients (13%) were in CR1 (after several lines of chemotherapy), 9 (22%) in >CR1, 16 (40%) in PR, 1(2%) had stable disease (after 3 chemotherapy lines) and 9(23%) progressive disease. All patients engrafted. Acute GVHD developed in 22 patients (55%) (18 patients grade II–IV). Chronic GVHD developed in 22 out of 27 patients at risk (81%), being extensive in 13; Disease was evaluated at day +100 and at that moment 22 patients(58%) were in CR, 3 (8%) in PR, two (5%) had stable disease and 11 patients (27%) have died. With a median follow up of 30 months (range: 10–56 months), 24 patients (60%) are alive disease free, 16 (39%) have died, 14 of them (35%) due to transplant toxicity and 2 patients (5%) due to progression. Overall Survival (OS) and Event Free Survival (EFS) are 60 and 58 % respectively. Analysing variables which influence on OS and EFS, patients ≥55 years have a OS significantly shorter than patients < 55 years old (22% vs 66%; p:0,01). Moreover, patients who develop chronic GVHD have an OS and EFS significantly better than those which do not develop it (OS: 89,7 vs 57%; p=0,02 (HR: 9,3-IC95% (2,08–41,5); EFS: 89 vs 42%; p=0,002 (HR: 11,08-IC95% (2,49–49,28)). In conclusion, our results demonstrates the efficacy of non-myeloablative transplant in indolent NHL with a very low relapse rate, indicating the important role of chronic GVHD in the control of the disease; however, mortality rate is still high, mainly in patients ≥55 years

Sustained complete remissions (CR) have been reached with allogeneic transplant in patients with poor prognosis B-CLL; however, mortality rates are high (20–50%); in order to reduced TRM, NM conditioning are widely used in haematological malignancies; however it is not clear if the use of NM regimens can maintain the efficacy reducing the toxicity. IN this report we performed a retrospective comparison between 30 patients (group A) who have received myeloablative conditioning consisted of TBI plus Cy in 23 pts (74%), TBI, Cy plus VP-16 in 6 pts (19%) and BuCy in 1 patient and 31 patients (Group B) who have received a NM transplant. Conditioning regimens in Group B included: Fludarabine plus Melphalan, 20 pts (64%), Fludarabine, Busulphan and ATG, 5 pts (16%), Fludarabine, TBI and ATG, 4 pts (13%) and Fludarabine plus TBI, 1 patient. All patients received peripheral blood stem cells from a HLA related identical donor. T-cell depletion was performed in 14 patients of the group A. Median age at transplant was significantly higher in the group B patients (53 versus 45, respectively) (p With a median follow-up of 71 and 36 months for groups A and B respectively,Overall Survival and Event Free Survival are similar for both groups (53% versus 64% and 60% versus 68%, respectively). Although patients in the NM transplant group were older toxicity was similar in both groups; moreover a similar efficacy has been observed suggesting the clear role of graft versus tumour effect in B-CLL probably more important that the type ofconditining. Table 1 GROUP A Myeloablative Group B Non-myeloablative p Number of previuous chemotherapy lines 2 (1-6) 2 (1-8) NS Acute GVHD 15/30 (48%) 20/31 (64%) NS Grade II-IV 11/30 (35%) 12 /31(38%) NS Chronic GVHD 12/26pts at risk (46%) 18/27 pts at risk (66%) NS Extense 8 pts (30%) 9 pts (33%) NS TRM 7/30 (23%) 7/31 (22%) NS

Background and aim: Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance and MRD levels (assessed by cytofluorometry at the end of induction and consolidation therapy) in HR Ph- adult ALL patients. Patients and methods: HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25x109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy (≥10% blasts in bone marrow assessed on d14) intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level Results: On June 2008,192 patients were evaluable (mean (SD) age 37(10) yr, 105 males, 119 precursor B-ALL, 73 T-ALL, WBC count 65(99) x109/L). Induction death: 17(9%), resistance: 12 (6%), CR: 163 (85%). MRD Conclusions: These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR the results of therapy are not hampered by avoiding allogeneic SCT. Supported by grants P-EF/07 from FIJC and RD 06/0020/1014 from Instituto Carlos III

Background: MRD is an established biomarker to evaluate treatment efficacy, define patients at risk based on persistent MRD, and eventually, act as surrogate for prolonged survival based on sensitive MRD-negative definitions. Accordingly, the IMWG has developed criteria for MRD-negativity defined by next-generation sequencing, NGF or PET/CT, and has recommended their inclusion in clinical trials. Notwithstanding, most flow cytometry results have been obtained using less sensitive methods and in fact, there is no data about the impact of NGF-based MRD assessment in clinical trials. Aim: To define the feasibility, sensitivity and clinical impact of NGF-based MRD assessment in the phase III PETHEMA/GEM2012 trial. Methods: A total of 458 patients were enrolled into the PETHEMA/GEM2012 trial. MRD was predefined to be prospectively assessed at three time-points: after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), after HDT/ASCT, and after two courses of consolidation with VRD. MRD monitoring was performed blinded for clinical outcomes in four PETHEMA/GEM laboratory cores, and data was centralized for MRD analyses. MRD assessment was performed following EuroFlow SOPs in a total of 1,134 bone marrow (BM) samples from 419 patients. The 39 cases without MRD assessment had suboptimal response to induction and were thus considered as MRD+ for intention-to-treat analyses. Noteworthy, in 14 BM samples with undetectable MRD, B-cell precursors, erythroblasts and mast cells represented Results: Overall, 225/458 (49%) patients had undetectable MRD at the latest time-point in which MRD was assessed and were thus classified as MRD-. Conversely, 233/458 (51%) cases remained MRD+: 28% with ≥10-4 MRD, 12% with 10-5 MRD, and 11% with 10-6 MRD. Detailed analyses of MRD kinetics in 320 patients with available MRD results at all three time-points, showed that the percentage of MRD- patients increased from 35% into 54% and 58% after induction, HDT/ASCT and consolidation, respectively. Furthermore, a restricted analysis among MRD+ patients showed that whereas after induction only 8% of them had MRD levels as low as 10-6, subsequent intensification with HDT/ASCT and consolidation could reduce MRD levels down to 10-6 in 32% of MRD+ cases. Progression-free survival (PFS) rates at 3-years were of 92%, 70%, 54% and 44% for patients being MRD-negative, MRD+ 10-6, 10-5 and ≥10-4, respectively (P Conclusions: This is the largest study of MRD monitoring in MM based on the total number of samples analyzed (n=1,134). Our results show that NGF-based MRD assessment is feasible in large multicenter clinical trials, is highly-sensitive, and allows the identification of hemodiluted BM samples inadequate for MRD assessment. Risk of relapse among MRD-negative patients was remarkably reduced (3%), and was particularly related to the reappearance of extramedullary plasmacytomas, which urges the need for combined cellular and imaging MRD monitoring in these patients; by contrast, even MRD levels as low as 10-5 and 10-6 conferred significantly inferior PFS. Overall, this study defines MRD-negativity as the most relevant clinical endpoint for both standard- and high-risk transplant-eligible MM patients. Figure Figure. Disclosures Paiva: Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Merck: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; EngMab: Research Funding. Oriol: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Celgene: Speakers Bureau. de la Rubia: Janssen: Other: Honoraria; Amgen: Other: Honoraria; Celgene: Other: Honoraria. Rosinol: Celgene: Honoraria; Janssen: Honoraria. Mateos: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. San Miguel: Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.