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Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high‐risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome‐negative B‐cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD‐negative after induction therapy., Fundació Internacional Josep Carreras; Generalitat de Catalunya, Grant/Award Number: 2017 SGR 288 GRC; Instituto de Salud Carlos III; Ministerio de Salud Carlos III RTICC‐FEDER, Grant/Award Numbers: RD12/0036/0029, RD/0036/044; Obra Social “La Caixa”; Sociedad Española de Hematología y Hemoterapia; Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI14/01971, PI10/01417

The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.

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.

Background and aim Only 20-30% of elderly patients with acute lymphoblastic leukemia (ALL) are enrolled in clinical trials because of co-morbid disorders or poor performance status. We present the results of treatment of Philadelphia chromosome-negative (Ph-) ALL patients over 55 yr treated in the PETHEMA ALL-96 trial. Patients and methods From 1996 to 2006, 33 patients > or = 55 yr with Ph- ALL were included. Induction therapy was vincristine, daunorubicin, prednisone, asparaginase, and cyclophosphamide over 5 weeks. Central nervous system (CNS) prophylaxis involved triple intrathecal (IT) therapy, 14 doses over the first year. Consolidation-1 included mercaptopurine, methotrexate, teniposide and cytarabine, followed by one consolidation-2 cycle similar to the induction cycle. Maintenance consisted of mercaptopurine and methotrexate up to 2 yr in complete remission (CR) with monthly reinduction cycles (vincristine, prednisone and asparaginase) during the first year. Results Median (range) age was 65 yr (56-77). Phenotype (30 patients): early-pre-B 7, common/pre-B 18, T 5. Cytogenetics (28 patients): normal 12, complex 10, t(4;11) 2 and other 4. CR was achieved in 19/33 (57.6%) patients, early death occurred in 12 (36.4%) and 2 (6%) were resistant. Overall survival and disease-free survival probabilities (2 yr, 95% CI) were 39% (21%-57%) and 46% (22%-70%), respectively (median follow up of 24 months). Removal of asparaginase and cyclophosphamide from the induction decreased induction death (OR 0.119, CI 95% 0.022-0.637, P = 0.013) and increased survival (20% vs. 52%, P = 0.05). Conclusions The prognosis of elderly Ph- ALL patients is poor. In this study, less intensive induction decreased toxic death, allowing delivery of planned consolidation therapy and increased survival probability.