ALBERT

Description: INTRODUCTION: Chronic lymphocytic leukemia (CLL)-like monoclonal B cell lymphocytosis (MBL) is considered a precursor of CLL. It is found in 5-10% of elderly healthy individuals and shows a progression rate to CLL requiring therapy of 1.1% per year. A balance between microenvironmental factors and intrinsic properties of the emerging B cell clone may be decisive for the transition from MBL to CLL, although biomarkers of progression remain unknown. The objective is to describe biological markers (B cell gene expression profiles and serum cytokine levels) that predict progression from MBL to CLL. METHODS: Gene expression profiles of clonal B cells from 14 MBL subjects (median age: 76 years, clonal B cells: 0.5-4.3 x109/L) were evaluated. With a median follow-up from analysis of 59 months (range: 10-77), 3 cases (21.4%) had progressed to CLL Binet stage A at last follow-up (clonal lymphocytosis 〉5x109/L, range: 6.2-7.9). Clonal B cells (CD19+CD5+) were isolated from peripheral blood by immunomagnetic methods (Miltenyi Biotec). Extracted RNA (RIN〉7) was hybridized to GeneChip Human Gene 2.0 ST arrays (Affymetrix). Gene expression profiles were compared between MBL cases that progressed to CLL (P-MBL, n=3) and non-progressive MBL cases (NP-MBL, n=11). Differential gene expression was evaluated employing linear models for microarrays in R, and genes with P1.5 or 5x109/L, range: 6.4-17.3). Clonal B cells and cytokine levels were compared between P-MBL (n=5) and NP-MBL (N=36). For cytokine levels, the optimal cut-off values to stratify MBL cases according to their progression risk were assessed using the maxstat R package, whereas for clonal B cells a cut-off value of 3.9 x109/L was considered according to the results obtained by Kostopoulos et al (Blood Cancer J, 2017). The effect of different covariates on progression-free survival was evaluated using log-rank test. Cox proportional hazards regression models were performed to assess their independent prognostic value. P

Description: Abstract 1382 The effectiveness of rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given R-FCM up to 6 cycles as induction therapy, achieving an overall response rate of 93% and 46% of CR with negative minimal residual disease (MRD) (Bosch et al. JCO, etc). Second, three months after concluding R-FCM, patients having achieved CR or PR receive rituximab maintenance (375 mg/m2) every three months for two years (up to 8 cycles). We present here the preliminary results of the second part of the study, namely the efficacy of rituximab maintenance. Evaluation of response was performed three months after the last cycle of maintenance and included bone marrow (BM) examination, MRD assessment in peripheral blood and BM by four-color flow cytometry. Patients in whom rituximab maintenance was prematurely interrupted due to toxicity were considered as failures. Fifty-six patients (median age 60 years, 70% female) responding to R-FCM were evaluable for response to rituximab maintenance. Median number of cycles of maintenance given was 8 (range, 3 to 8), 77% of patients completed the entire planned treatment, whereas 91% received 6 or more cycles. Treatment was delayed due to insufficient hematological recovery in 12 cycles (2.7%). Toxicity was mainly hematological, with neutropenia being observed in 31.8% of cycles (Grade 3&4 in 8.9%), thrombocytopenia in 3.4% and anemia in 3.9%. Hypogammaglobulinemia occurred in 38% of patients (low levels of IgA in 50%, IgG in 34%, and IgM in 60%). Eight patients, three of them with hypogammaglobulinemia, experienced grade 3&4 infectious episodes (4 pneumonia, 2 gastrointestinal, 1 myositis, and 1 cerebral abscess). Herpes virus (I/VZ) reactivation was observed in 8 patients. Two patients died due to multifocal leukoencephalopathy and hemophagocytic syndrome, respectively. After rituximab maintenance, 44.6% of patients were in CR MRD negative, 41% in CR, 3.6% in PR, and 10.7% failed to treatment. Failures were due to disease progression (two patients), development of severe neutropenia (two patients), and death (two patients). Among 28 patients that were in CR MRD (-) at the onset of the maintenance part, 19 held the MRD negative status at the end of maintenance, 5 (18%) turned negative into positive MRD (probability of conversion, 40% at 30 months), whereas 4 failed to treatment (2 neutropenia, 1 progression, 1 death). Moreover, 5 of 24 patients (22%) in CR MRD(+) after R-FCM became MRD negative after rituximab maintenance, 17 maintained the CR, one patient achieved a PR, and one patient progressed under maintenance (Table 1). In conclusion, rituximab maintenance after chemoimmunotherapy seems to prolong duration of response and, in some cases, improves the quality of response towards a CR with negative MRD. Maintenance with rituximab had the major benefit in patients in CR with positive MRD. The exact role and the best dosage and treatment schedule of rituximab as maintenance therapy in CLL should be now investigated in randomized clinical trials. Disclosures: Bosch: Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab is currently not approved as maintenance therapy for patients with chronic lymphocytic leukemia. Garcia-Marco:ROCHE: Consultancy, Honoraria, Research Funding.

Description: Imaging studies are not routinely performed to evaluate response to therapy in patients with CLL. To ascertain whether CT scans should be part of the maneuvers to assess response in patients with CLL we have investigated response duration according to CT results in 34 previously untreated patients (median age, 56 years; range, 38 to 65 years; males: 79%) uniformly treated with FCM (fludarabine 25 mg/m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/ m2 on days 1 to 3, and mitoxantrone 6 mg/m2 i.v. on day 1, given at a 4-week intervals up to six courses) as part of a phase II study. Out of 69 patients included in the study, 64% achieved CR as defined by the NCI-Working Group criteria. Of those, 30% had abdominal lymphadenopathy as assessed by CT scans. The median follow-up of the series was 30 months. As shown in the figure, response duration was significantly shorter (54% at 20 months) in CR patients with abnormal CT (CT+ CR) than in those with no detectable lymphadenopathy (CT- CR) (95% at 20 months). Interestingly, response duration in patients with CT+ CR was not different from that of patients in PR (54% vs. 42% at 20 months, respectively; p=NS). These results demonstrate that residual abdominal lymphadenopathy negatively influences response duration in patients with CLL in whom by all other criteria a CR has been obtained. Therefore, CT scans should be performed in patients having achieved CR by conventional, NCI-Working Group criteria, and patients with residual disease by CT should be considered in PR rather than in CR. Figure Figure

Description: 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.

Description: Abstract 4631 BACKGROUND The precursor of nucleotide biosynthesis acadesine or 5-aminoimidazole-4-carboxamide (AICA) riboside induces apoptosis in CLL cells, and other lymphoproliferative diseases such as splenic marginal zone lymphoma and mantle cell lymphoma. This effect is selective for B-cells, at least ex vivo, however there is no evidence of whether this cytotoxic effect depends on well known prognostic variables such as ZAP-70 expression or IgVH mutational status. AIM To analyse ex vivo the cytotoxic effect of acadesine on peripheral CLL cells and correlate it with prognostic variables. METHODS Cryopreserved cells from 62 CLL patients were incubated ex vivo with acadesine at 0.2, 0.5, and 1 mM for 24 hours. Viability was determined by flow cytometry using Annexin V-FITC and DAPI staining combined with CD19-PE and CD3-PerCP to differentiate cell viability of B- and T-cells. Cells were considered sensitive to the drug when the percentage of acadesine-induced apoptosis was equal to or higher than 15% with respect to the viability of control cells. The mutational status of IgVH genes was determined by RT-PCR amplification using a set of six VH family-specific primers (VH1 through VH6) along with primers complementary to the constant region (IgM and IgG). Products were directly sequenced from both strands using the Big Dye Terminator Cycle Sequencing Ready Reaction (version 3.1, Applied Biosystems). Sequencing analysis and alignments were performed with use of V-QUEST software and the online international immunogenetics information (IMGT) data library. Samples in which fewer than 2 percent of base pairs differed from those of the consensus sequence have been considered unmutated. ZAP-70 expression was quantified by flow cytometry (cut-off:20%) and cytogenetic alterations associated with CLL (trisomy 12, del13q, del 17p and del11q) were determined by FISH. RESULTS After 24h of ex vivo incubation, 0.2 mM acadesine induced a significant cytotoxic effect (〉 15%) in 31 out of 62 patients (50%). Higher concentrations, 0.5 mM and 1 mM, induced a significant effect in 91.4% (57 of 62 patients) and 98% (61 of 62 patients), respectively. The viabilities (mean ±SD) of the different culture conditions are shown in the table. The cytotoxic effect induced by acadesine was analyzed with respect to the IgVH mutational status and ZAP-70 expression. No significant differences were observed between cases with unmutated IgVH (n=20) and mutated IgVH(n=37), or between ZAP-70 positive (n=24) and ZAP-70 negative cases (n=34). Interestingly, 5 cases showing deletion of 17p were sensitive to treatment with acadesine, in agreement with previously published studies showing that acadesine-induced apoptosis is independent of p53. Only one case showing deletion 17p and VH3-21 usage was not sensitive to acadesine. CONCLUSIONS Acadesine induces apoptosis in B-cells from CLL regardless of ZAP-70 expression, IgVH mutational status and 17p status. Disclosures: Campàs: Advancell: Employment. de Frías:Advancell: Employment.

Description: Introduction: Relapses after front-line therapy for Burkitt lymphoma/leukemia (BL) are unfrequent, and there is scarce information about the best rescue strategy for these patients. The objective of this study was to evaluate the incidence of relapse, salvage treatment and prognosis after relapse in patients with BL treated with two consecutive Spanish protocols. Patients and methods: Retrospective study of patients diagnosed with BL in 40 Spanish hospitals betwen January 1997 and October 2014 treated with first line chemotherapy according to protocols PETHEMA LAL-3/97 (specific chemotherapy without rituximab) and BURKIMAB (rituximab plus specific chemotherapy). The demographic, clinical and biological characteristics were collected at the time of diagnosis and at relapse, as well as the salvage treatment and outcomes. Results: 233 patients were diagnosed with Burkitt lymphoma (n=150) or leukemia (n=83) and received first-line therapy according to PETHEMA LAL-3/97 (n=53) and BURKIMAB (n=180) protocols. Baseline characteristics at diagnosis are described in Table 1. A total of 26 patients relapsed, 11 (28%) treated with PETHEMA LAL-3/97 protocol and 15 (10%) with BURKIMAB protocol (p=0.009). The cumulative incidence of relapse at 10 years was 27% (95% CI, 12%-42%) in PETHEMA LAL-3/97 protocol vs.16% (95% CI, 4%-28%) in BURKIMAB protocol (p= 0.013) (Figure 1). Time to relapse was shorter in PETHEMA LAL-3/97 protocol (median of 3.7 months) vs. BURKIMAB protocol (6.3 months), but it was not significant (p=0.506). No differences were observed in relapse incidence between Burkitt leukemia and Burkitt lymphoma in PETHEMA LAL-3/97 protocol (6/31 vs. 5/22, p=1) and BURKIMAB protocol (7/41 vs. 8/107, p=0.124). Out of 15 patients in whom rescue treatment strategy was evaluable, 12 received chemotherapy with high-dose methotrexate and/or cytarabine (4 of the them followed response, CR in 2, followed by SCT in the 2 patients achieving PR [autologous in one and allogeneic SCT in the other]), and the remaining 3 patients received DA-EPOCH-R (n=1, achieving CR), R-ICE (n=1, no response) and paliative care (n=1). At the time of the analysis, only 3 patients are alive. Median overall survival after relapse was 3 months (95% CI, 0.9-5.1) for PETHEMA LAL-3/97 relapsed group and 3.6 months (95% CI, 0.1-7.1) for BURKIMAB relapsed patients group. Conclusions: Patients with Burkitt leukemia/lymphoma treated with specific immunochemotherapy have lower probability of relapse compared with those treated with specific chemotherapy without rituximab. In our series, the most frequent regimens administered for the treatment of relapsed patients were based in high-dose methotrexate and/or cytarabine. The prognosis of relapsed Burkitt leukemia/lymphoma is poor, independently of the type of rescue therapy. Supported by grants RD12/0036/0029 (RTICC, FEDER), Instituto Carlos III, Spain. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can be translated to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial from the Spanish PETHEMA Group was to evaluate the response to a differentiated post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (assessed by 8-color, centrally-performed flow cytometry at the end of induction-week 5- and consolidation therapy-week 17-) in HR Ph-neg adult ALL patients. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60 yr, WBC count 〉30x109/L for B-cell precursor ALL or 〉100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD

Description: INTRODUCTION: CXCL9, CXCL10 and CXCL11 (CXCL9-10-11) are closely related cytokines that specifically bind to their receptor CXCR3. They act inducing chemotaxis, proliferation and/or cytotoxicity of CD4+ Th1 and cytotoxic T cells, which express CXCR3. Although the CXCL9-10-11/CXCR3 axis promotes immune activation, their pro- or anti-tumor effects in chronic lymphocytic leukemia (CLL) remain controversial. The aims of this study are: 1. To investigate serum levels of CXCL9-10-11 and the protein expression of their receptor CXCR3, as well as Th1 and cytotoxic gene expression signatures and protein expression of the cytotoxic molecules granzyme B and perforin in peripheral blood (PB) CD4+ T cells of controls, CLL-like monoclonal B-cell lymphocytosis (MBL) and CLL Binet stage A patients. 2. To assess the correlations between all previous parameters. 3. To evaluate Th1, cytotoxic and PD1+ T cell populations during disease progression. METHODS: Samples from 52 MBL subjects, 61 untreated CLL patients (Binet stage A/B [CLL-A/CLL-B]: 53/8) and 31 age-matched controls were employed. Serum levels (pg/mL) of CXCL9-10-11 were measured in 24 controls, 41 MBL and 44 CLL-A patients using Human CXCL9/MIG Quantikine ELISA Kit (R&D Systems) and U-PLEX Platform (Meso Scale Discovery). In addition, cryopreserved PB mononuclear cells from 8 controls, 11 MBL, 10 CLL-A and 8 CLL-B were studied by flow cytometry. Anti-CD3, anti-CD4, anti-granzyme B, anti-perforin, anti-CXCR3 and anti-PD1 antibodies, FVS510 and Fixation/Permeabilization Kit were used for cell staining (BD Biosciences). Protein expression of CXCR3, granzyme B, perforin and PD1 (measured as percentage of positive cells in PB CD4+ T cells) was assessed using FACSCanto II cytometer (BD Biosciences). In addition, purified CD4+ cells from PB (purity≥90%) were isolated by immunomagnetic methods (Miltenyi Biotec) to analyze gene expression in 9 controls, 13 MBL and 14 CLL-A patients. Extracted RNA (RIN〉7) was hybridized to GeneChip Human Gene 2.0 ST arrays (Affymetrix). Differential gene expression was evaluated with linear models in R, and genes with P-value1.5 were considered differentially expressed. Linear regression and Pearson correlations were calculated to evaluate the relationship between the different components of the CXCL9-10-11/CXCR3 axis (Figure 1). P-values0.8 for 6/7 genes). Significant positive correlations were also observed between CXCR3 protein expression and cytotoxic genes as well as granzyme B protein (Table 2). Protein expression of CXCR3 and cytotoxic molecules were similarly increased in the different stages of the disease. However, CLL-B patients displayed an increased percentage of CD4+ T cells expressing PD1 (around 7% in MBL and CLL-A versus 16% in CLL-B), although significance was not achieved (Table 1). CONCLUSIONS: 1. The increased levels of the different components of the CXCL9-10-11/CXCR3 axis in MBL and CLL-A, together with the strong correlations observed, point to an important activation of this molecular pathway in the first stages of the disease. 2. Correlations between CXCR3 and Th1/cytotoxic genes/proteins suggest that the increased Th1/cytotoxic features of CD4+ T cells in MBL and CLL-A are triggered by CXCL9-10-11/CXCR3 stimulation, and might be considered as a potential target for CLL immunotherapy. 3. The lower percentage of PD1+ CD4+ T cells in MBL/CLL-A may allow efficient effector Th1/cytotoxic responses at these stages of the disease. ACKNOWLEDGEMENTS. PI11/01621, PI15/00437, 2017/SGR437, Fundació La Caixa, Fundación Española de Hematología y Hemoterapia (FEHH). Disclosures Gimeno: Abbvie: Speakers Bureau; JANSSEN: Consultancy, Speakers Bureau. Rai:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Pharmacyctics: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Bosch:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of patients with CLL. Based upon the excellent results obtained with our chemotherapy-only regimen fludarabine, cyclophosphamide and mitoxantrone (FCM) (Bosch et al. Clin Cancer Res, 2008) we have build up a new chemoimunotherapy combination, R-FCM (rituximab plus FCM). In November 2005 we initiated a multicentric phase II clinical trial that includes R-FCM as initial treatment followed by a maintenance therapy phase consisting of rituximab (375 mg/m2 every there months for 2 years). We report here the final results of the initial phase of this study, namely R-FCM treatment. From November 2005 to November 2007, 72 patients under the age of 70 with active CLL according the NCI and IWCLL criteria (Cheson et al. Blood, 1996; Hallek et al. Blood, 2008) were treated. Patients received rituximab 500 mg/m2 on day 1 (375 mg/ m2 in the first cycle), fludarabine 25 mg/ m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/ m2 on days 1 to 3, and mitoxantrone 6 mg/ m2 i.v. on day 1, given at 4-week intervals up to six cycles. Treatment outcome was correlated with clinical and biological parameters. Minimal residual disease (MRD) was evaluated by four-color flow cytometry (Rawstron et al. Leukemia, 2007). Median cycles of R-FCM administered were 5 (range, 3–6), with 91% of patients completing all planed treatment. Response was evaluated three months after finishing therapy. Altogether, the overall response, MRD-negative CR, MRD-positive CR, and PR rates were 93%, 46%, 36%, and 10%, respectively. Variables correlated with a lower CR rate were del(17p) (25% CR) and increased β2-M serum levels (72% CR). No differences in response were observed according to the age of the patients. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Treatment-related mortality was 1%. With a median follow up of 24 months no cases of secondary MDS/AML have been observed.. Although based in two different phase II studies that preclude a completely valid statistical comparison, the CR rate obtained with R-FCM (82%, of which 46% MRD-negative CRs) favorably compares with that achieved with FCM (CR 64%, MRD-negative CRs 38%). In summary the 82% CR rate obtained with R-FCM is among the highest ever reported for any form of therapy for CLL. Both high β2-M serum levels and del(17p) predicted lower CR rate. Treatment toxicity was acceptable and manageable. Based on these results, R-FCM warrants further investigation, particularly in randomized clinical trials.

Description: Different from acute myeloblastic leukemia, the prognostic significance of complex karyotype (CK) is not well known in adults with ALL. A recent study showed that CK (≥5 chromosomal abnormalities) confer an increased risk of treatment failure and poor survival (Moorman, 2007). The aim of study was to analyze the possible prognostic influence of CK in Ph- adult (≥15yr) ALL patients treated with risk-adapted protocols from the Spanish PETHEMA Group. The cytogenetic studies were reviewed following the ISCN criteria (2005). CK was defined as the finding of 3 or more structural chromosomal abnormalities. Patients were included in three different trials: ALL-96 for standard-risk (SR) ALL, and ALL-93 or ALL-AR03 for high-risk (HR) ALL. Patients with Burkitt’s ALL were not included in these trials. Patients included: 237. SR: n=44, 25 males, WBC count 12x109/L (SD: 14), 5 patients with CK (11.4%), 39 non-complex karyotype and normal karyotype (non- CK) (88.6%). HR: n= 193, 107 males, WBC count 58x109/L (SD: 77), 25 patients with CK (13%), 168 non- CK (87%). Complete remision (CR), disease free survival (DFS) and overall survival (OS) according to karyotype group and trial are showed in Table: When CK was defined as the finding of ≥ 5 structural chromosomal abnormalities (n=11, SR=3, HR=8), DFS and OS were also significantly shortened in patients with SR ALL and CK (p=0.007 and p=0.001, respectively), but not in patients with HR ALL. Complex karyotype (defined as ≥ 3 or ≥5 structural chromosomal abnormalities) did not have any prognostic relevance in adults with high-risk Ph- ALL, whereas a significant short survival observed in standard-risk patients with complex karyotype.