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We performed a retrospective analysis on 421 adult patients who underwent unrelated cord blood transplantation (UCBT) for ALL. Median age was 32 years; 46% were in first CR (CR1), 32% in CR2 and 22% had advanced disease. Double UCBT was performed in 173 patients (41%). Myeloablative conditioning (MAC) was given to 314 patients (75%). Cumulative incidence (CI) of 60-day neutrophil recovery was 78%. CI of acute and chronic GVHD was 33 and 26%, respectively. Non-relapse mortality (NRM) at 2 years was 42%. Age⩾35 years (P<0.0001), advanced disease at UCBT (P<0.0001) and use of MAC (P<0.0001) were associated with increased NRM. Relapse incidence (RI) at 2 years was 28%; use of reduced intensity conditioning (RIC) (P=0.0002) was associated with increased RI. Two-year leukemia-free survival (LFS) was 39% for patients in CR1, 31% for CR2 and 8% for advanced disease. In multivariate analysis, factors associated with decreased LFS rate were: age ⩾35 years (P=0.034), use of MAC (P=0.032) and advanced disease (P<0.0001). These results show that UCBT is a valuable option to treat high-risk adult ALL when in remission. Strategies to decrease toxicity and relapse are needed to improve final outcomes.

We report outcomes after single (s) and double (d) umbilical cord blood transplantation (UCBT) after myeloablative conditioning (MAC) regimen for 239 patients transplanted for acute leukemia in first complete remission (CR1). All sUCBT patients received a total nucleated cell dose >2.5 × 10(7)/kg. Conditioning regimen for sUCBT was total body irradiation (TBI)12 Gy- or busulfan (BU)-based ± fludarabine (Flu) (n=68, group 1), thiotepa+BU+Flu (TBF) (n=88, group 2), and for dUCBT it was TBI12 Gy+cyclophosphamide ± Flu (n=83, group 3). dUCBT recipients were younger, received higher cell dose and less frequently antithymocyte globulin. In multivariate analysis, we found similar neutrophil recovery among the three groups; however, acute graft-versus-host disease II-IV was higher in dUCBT compared with others. Non-relapse mortality and relapse incidence were not statistically different among the three groups. Leukemia-free survival was 30% for sUCBT using TBI- or BU-based MAC compared with 48% for sUCBT TBF and 48% for dUCBT (P=0.02 and P=0.03, respectively), and it was not statistically different between sUCBT with TBF and dUCBT. In conclusion, use of sUCBT with adequate cell dose (>2.5 × 10(7)/kg) and a specific conditioning regimen in the MAC setting results in similar outcomes as dUCBT. The choice of TBF conditioning regimen for sUCBT may improve results, and whether this regimen may be effective in dUCBT should be further analyzed.

Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.

The role of autologous hematopoietic SCT (autoHSCT) in the treatment of high-risk (HR) adult ALL is controversial. In this study, we retrospectively analyzed the results of autoHSCT according to the status of minimal residual disease (MRD) at transplantation, as a joint analysis of the European Study Group for Adult ALL (EWALL). Data on 123 recipients of autoHSCT, aged 31 (16-59) years, with B-lineage (n=77) or T-lineage (n=46) ALL were included. In a cohort of Ph-negative ALL, the probability of leukemia-free survival at 5 years was higher for patients with MRD <0.1% compared with those with MRD > or = 0.1% (57 vs 17%, P=0.0002). The difference was significant for T-lineage ALL (62 vs 8%, P=0.001), and a tendency was observed for B-lineage ALL (54 vs 26%, P=0.17). In a multivariate analysis, adjusted for other potential prognostic factors, high MRD level remained the only independent factor associated with increased risk of failure (risk ratio, 2.8; P=0.0005). We conclude that MRD determines the outcome of autoHSCT in HR adult ALL. Our results suggest the need to reevaluate the role of this treatment option in prospective trials.

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

Background and Objectives: To evaluate the impact of early and delayed consolidation chemotherapy on the outcome of children with acute lymphoblastic leukemia (ALL) stratified according to risk groups., Design and Methods: From 1989 to 1994, 195 children (< or = 15 years old) diagnosed as having ALL (ALL-L3 excluded) in 15 Spanish hospitals entered the prospective, randomized PETHEMA ALL-89 trial. Patients were stratified into low-risk (LR), intermediate-risk (IR) and high-risk (HR) groups according to their initial features and the rate of response to induction therapy. LR-ALL patients were randomized to receive or not early consolidation chemotherapy (C-1). After receiving C-1, IR patients were randomized to receive or not delayed consolidation chemotherapy (C-2). HR patients received C-1 and C-2 chemotherapy. Standard maintenance chemotherapy was administered to all patients for 2 years. High doses of intravenous methotrexate and 12 triple intrathecal doses were given as prophylaxis against central nervous system (CNS) disease., Results: The mean (and standard deviation) age was 6 (4) years and 120 patients were males. Fourteen patients had early pre-B-ALL, 149 common or pre-B-ALL, and 32 T-ALL. Complete remission (CR) was attained in 189 patients (97%), 11 of whom (6%) had a slow response. Risk group stratification after CR was: LR 89, IR 50 and HR 56 patients (including a subset of 26 patients at very high risk). Ten-year event-free survival (EFS) and overall survival (OS) probabilities for the whole series were 58% (95% CI: 52-64%) and 69% (61-77), respectively, with a median follow-up of 8.7 years. Dividing the patients according to risk group, the 10-year EFS and OS probabilities in the LR group were 71% (63-79) and 86% (80-92), respectively; in the IR group 69% (57-81) and 76% (64-88), respectively, and in the HR group 30% (18-42) and 44% (32-57), respectively. For LR patients receiving C-1, EFS and OS were 79% (57-92) and 90% (82-98), respectively, versus 62% (48-76) and 66% (51-81) in patients not receiving C-1 (p= 0.06). For IR patients, EFS and OS were significantly improved in those receiving early and delayed consolidation (EFS 87% (74-88) vs. 52% (41-70), and OS 92% (87-97) vs. 61% (51-71)(p=0.036). Prognostic factors for EFS identified in multivariable analyses were: age >10 years in the LR group (OR 3.5, 95% CI 1.3-9.5, p=0.01), and treatment with C-2 in IR patients (OR 5.0, 95% CI 1.4-17.8, p=0.01). The CNS relapse rate was 4% for all the series (including the HR subset). Tolerance to treatment was good., Interpretation and Conclusions: In this study, early consolidation seemed to improve the prognosis of children with LR-ALL, but differences in EFS were not significant. Delayed consolidation had a favorable influence on the outcome of IR-ALL. CNS preventive treatment without cranial irradiation was effective in all the groups of ALL patients.

Background and Objective: Intensive induction and post-remission therapies have improved the prognosis in adult acute lymphoblastic leukemia (ALL). However, different from children, the impact of late intensification therapy in the overall results of treatment has not been consistently evaluated. The objective of this study was to analyze the results of a multicenter prospective protocol, PETHEMA ALL-89, in which, after intensive induction and consolidation therapy, randomization to receive delayed intensification treatment was performed., Design and Methods: One hundred and eight adults (age > or = 15 years) diagnosed with ALL (ALL L3 excluded) in 22 Spanish hospitals from 1989 to 1994 were treated with a five-drug induction therapy, followed by four cycles of early post-remission treatment during four months, and maintenance therapy for two years. Patients in remission at the end of the first year were randomized to receive one six-week cycle of late intensification therapy. Uni- and multivariate analyses of early response to treatment, complete remission (CR), leukemia-free survival (LFS) and overall survival (OS) were performed., Results: The median (range) age of the series was 28 (15-74) years and leukocyte count 26 x 10(9)/L (1-600). ALL L1/L2 was present in 38/70 patients, early pre-B in 13, common in 53, pre-B in 12 and T in 30 cases. The CR rate was 86%, and refractory disease 9%. Median LFS was 34 months, with a 5-yr probability of 41% (95% CI, 29-53), whereas median OS was 51 months and 5-year probability 47% (34-59%). There were no differences in either LFS and OS between patients who did or did not receive delayed intensification therapy. Prognostic factors for CR attainment were advanced age and slow response to therapy. These two features were, in addition to high leukocyte counts, the parameters with negative influence in both LFS and OS., Interpretation and Conclusions: The results of PETHEMA ALL-89 are similar to those referred in other chemotherapy-based protocols in adult ALL. Delayed intensification has not improved the length of remission and survival. Efforts to improve the prognosis of adult ALL patients must be mainly focused in early intensification treatment.

Invasive tracheobronchial aspergillosis is an uncommon form of Aspergillus lung infection observed in immunocompromised patients. A 43-year-old patient diagnosed with acute lymphoblastic leukemia presented prolonged fever and hemoptysis during remission induction chemotherapy. The bronchoscopic examination showed pale mucosa with multiple raised white-colored nodules of 3 to 5 millimeters in diameter in all the bronchi. Hyphae of Aspergillus sp were observed in the biopsy of one of the nodules and in the examination of the bronchoalveolar lavage. Despite amphotericin B therapy, the patient developed bilateral necrotizing pneumonia and multiple abscesses in the brain and in the thyroid gland, and died. From a review of the literature in the Medline database, four similar cases (two in AIDS patients, one in lymphoma and the remaining case in an acute myeloid leukemia patient) have been reported.

Background: The aim of this study was to analyze the influence of age on the clinical and biological features as well as the results of treatment in 41 adult patients with acute lymphoblastic leukemia (ALL)., Patients and Methods: The patients diagnosed with ALL from January 1989 to October 1995 in a single center were studied. Two groups of patients were analyzed based on age. The main clinical, hematologic and biochemical parameters, morphologic subtype and immunologic phenotype and the results of the cytogenetic study were analyzed. Likewise, the attainment of complete remission (CR), its duration and overall survival (OS) were also studied. Comparison of the cited variables and the results of treatment among the two groups of patients was performed., Results: Group I was made of 19 (11 males, 8 females) patients > or = 50 years of age (mean age 65 +/- 9 years). Group II included 22 patients (11 males and 11 females) with a mean age of 28 +/- 11 years. Significant differences were only observed between the two groups in regard to the proportion of peripheral blood blasts (p < 0.02), serum LDH values (p = 0.05) and the performance status at the time of diagnosis ( p < 0.00007). In the patients in group 1 cytogenetic alterations were more frequent (10/16 vs 4/20, p < 0.02), being mainly pseudodiploid. Complete remission was achieved in 7/16 patients in group I and in 17/22 in group II (p < 0.02). The median duration of CR was 34 and 18 months, respectively. The median OS was 7 months in group 1 and 15 months in group II with an estimated survival at 5 years of 0% in group I and 38% in group II (p < 0.05)., Conclusions: Patients with acute lymphoblastic leukemia over the age of 50 years have a worse general status and more cytogenetic alterations (particularly structural) than younger adult patients, presenting a lower probability of achieving complete remission and a shorter survival.

We have analysed the immunological characteristics of blasts from 89 acute lymphoblastic leukaemia (ALL) cases (62 adults and 27 children), by using a panel of antilymphoid and myeloid associated monoclonal antibodies (McAb) and the APAAP method, which detects membrane and cytoplasmic expression of antigens. The McAb CD19 was the marker most consistently expressed in B lineage ALL, being positive in 100% of cases, compared to CD24 and CD22 expressed in 82% and 79%, respectively. Similarly, for the T lymphoid lineage, the McAb CD3 was the most reliable and specific marker, being expressed in all T-ALL cases including those with an early thymic phenotype (CD7+, TdT+). Lymphoblasts from eight adults (12.9%) and three children (11.1%) expressed one to four myeloid associated antigens recognized by CD13, CD14, CD33 and anti-myeloperoxidase. There were no substantial clinical and morphological differences between the two ALL groups with or without myeloid associated markers. However, the presence of myeloid associated markers in adult ALL was associated with a significantly lower complete remission (CR) rate (P = 0.05) and with a shorter survival (P = 0.001); this variable was independent of advanced age and high WBC. It is concluded that immunophenotypic analysis in ALL should include myeloid markers for its probable prognostic implications.

The preliminary results of the LAL-86 protocol applied to 43 patients diagnosed of acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL) between May 1986 and April 1989 are reported. Induction treatment consisted of one or two courses of vincristine, daunorubicin, prednisone, cytosine arabinoside and 6-thioguanine combination therapy. This phase was followed by consolidation treatment, in which VM-26, cyclophosphamide, BCNU and L-asparaginase were added to the former agents. Central nervous system prophylaxis was done with intrathecal methotrexate. Patients under 45 years of age with HLA identical sibs were subjected to allogeneic bone marrow transplantation (BMT) in the first complete remission (CR); when no HLA-identical sibs were available patients were randomised into autologous BMT or maintenance therapy. The remaining patients received maintenance chemotherapy. CR was achieved in 34 ALL patients (79%), 5 were refractory to treatment and 4 died during remission induction. Allogeneic BMT was carried out in 6 cases, autologous BMT in 3, and the remainders received chemotherapy. When performing this review, 7 patients had relapsed and the actuarial probability of 2-year duration of CR was 70%. Sixteen patients have died with a two-year disease-free survival probability of 60%. The preliminary results of the LAL-86 protocol are encouraging, but greater number of patients is needed, as well as a longer follow-up, to assess the effect of chemotherapy and compare these findings to the results of autologous or allogeneic BMT in the first RC.

Sepsis due to Candida parapsilosis with involvement of the joints and the lungs, respectively, is reported in two patients with acute leukemia. The first patient had ankle arthritis 72 days after an allogenic bone marrow transplant for acute lymphoblastic leukemia. The second patient had pneumonia with cavitation during pancytopenia after chemotherapy for acute monocytic leukemia. In both cases, C. parapsilosis sepsis responded to therapy with amphotericin B, associated with miconazole in the first patient and with 5-fluorocytosine in the second one. The rarity of septic foci during C. parapsilosis fungemia and the good outcome of both patients are emphasized. This good result was probably due to early antifungal therapy and the relatively rapid recovery of granulocytopenia.