Clinical and biological features of B-cell neoplasms with CDK6 translocations: an association with a subgroup of splenic marginal zone lymphomas displaying frequent CD5 expression, prolymphocytic cells, and TP53 abnormalities.

A translocation involving the cyclin-dependent kinase 6 (CDK6) gene [t(CDK6)] is a rare but recurrent abnormality in B-cell neoplasms. To further characterise this aberration, we studied 57 cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T-cell receptor alpha locus (TRA)/T-cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B-cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus-associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy-chain variable-region (IGHV) locus sequencing revealed that none harboured an IGHV1-02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features.

Platinum and high-dose cytarabine-based regimens are efficient in ultra high/high-risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study.

Ultra high-risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine-based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty-seven patients had R/R CLL (including 36 ultra high-risk CLL) and 28 had RS. Median age was 62 years (range, 18-79 years). Median number of previous therapies was 3 (range, 1-7), including fludarabine-based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression-free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥ 2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high-dose cytarabine-based regimens provide high response rates in high-risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non-transformed CLL.

The characteristics of coalbed water and coal in a coal seam situated in the Red River Basin, Vietnam.

An in-depth understanding of the hydrogeochemical characteristics of coal mines is helpful in establishing an effective and successful exploration program of coalbed methane (CBM). This study provides a comprehensive analysis of hydrogeological characteristics, characteristics of coalbed water, and characteristics of the coal sample from a coal seam located in the Red River Basin (RRB). These physicochemical characteristics along with the microbial composition of coalbed water were critically analyzed. A high concentration of chloride and sodium was found in the coalbed water, presumably due to the coal mine's stratigraphic association with marine or marine-transitional beds. A correlation between the occurrence of microbes and the chemical components in the coalbed water was established. The characteristics of the coal were systematically analyzed, including proximate, ultimate, and petrographic analyses. Based on the coal macerals, coal rank is classified as low-rank (sub-bituminous) with a vitrinite reflectance (Ro, max) of 0.36%, suggesting that this type of low-rank coal is favorable for biogenic methane generation. Pore structures and pore types were characterized using different methods, including low-temperature nitrogen adsorption/desorption (LTNA), mercury intrusion porosimetry (MIP), and scanning electron microscopy (SEM). Coal from the study area has microporous and macroporous features. Pore types of the coal were also characterized using SEM. The primary genetic pore types of the Red River coal include plant tissue holes and blowholes.

Voltammetric Determination of Amoxicillin Using a Reduced Graphite Oxide Nanosheet Electrode.

A reduced graphite oxide nanosheet electrode (RGOnS) was prepared as a sensor for amoxicillin (AMX) detection, an antibiotic commonly used in the livestock farm, by the square-wave adsorptive stripping voltammetry technique. Graphite oxide with nanosheet shape was produced from a graphite electrode by a chronoamperometry process at 5 V and then an electrochemical reduction process was carried out to form RGOnS with restored long-range conjugated networks and better conductivity. The electrodes were characterized by SEM, EDX, and FTIR spectroscopy. The RGOnS electrode prepared at an optimal reduction potential of -1 V for 120 s exhibits a larger electrochemical active surface area, and the obtained oxidation signal of AMX is approximately ten times higher than that of the pristine graphite electrode. The analytical conditions such as the pH of electrolyte and accumulation time were optimized. The calibration curve built under the optimal conditions provided a good linear relationship in the range of AMX concentration from 0.5-80 µM with the correlation coefficient of 0.9992. The limit of detection was calculated as 0.193 µM. Satisfactory results are obtained from the detection of the AMX in different samples using the prepared electrode.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

This retrospective study analyzed the impact of demographic and transplantation variables on outcomes of 1108 patients who have undergone allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning (RIC HSCT) for hematological malignancies and were reported to the Société Française de Greffe de Moelle et de Thérapie Cellulaire registry between November 1994 and December 2004. Only 442 patients (40%) were in complete remission (CR) at time of transplantation. Peripheral blood stem cells were used in the majority of patients (n = 878; 79%), 255 patients received fludarabine and low-dose total body irradiation, while 465 patients (42%) fludarabine and busulfan with rabbit anti-thymocyte globulins (ATG). The impact of demographic and transplant variables was studied on overall (OS) and event-free survival (EFS) in univariate and multivariate analysis. With a median follow-up of 21 months, 3-year probability of OS and EFS was 42% and 30%, respectively, and treatment-related mortality was 15% at 2 years. The multivariate analysis showed a significant negative impact on OS and EFS of the absence of CR status before transplantation; conditioning regimen, including >10 mg/kg ATG; and minor ABO incompatibility. In conclusion, this study highlights the major impact on RIC HSCT outcome of disease status before transplantation, ATG dose and ABO incompatibility.

Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France.

BACKGROUND: During August 2003, Europe sustained a severe heat wave that resulted in 14 800 heat-related deaths in France. Most of these excess deaths occurred in urban areas, where maximal temperatures broke all records. Heatstroke is the most severe form of heat-related illness. The clinical course of heatstroke in urban areas of temperate countries is poorly documented. METHODS: During the French heat wave (August 1-20, 2003), we conducted a prospective study in a university hospital located in Lyon, one of the largest metropolitan areas in France. We evaluated survival and functional outcome for 2 years and looked for factors influencing the prognosis. RESULTS: A total of 83 patients presented with heatstroke. The 28-day and 2-year mortality rates were 58% and 71%, respectively. Mortality was influenced as early as admission by the level of fever and the number of organ dysfunctions. Multivariate analysis revealed an independent contribution to mortality if patients came from an institution (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.05-3.71), used long-term antihypertensive medication (HR, 2.17; 95% CI, 1.17-4.05), or presented at admission with anuria (HR, 5.24; 95% CI, 2.29-12.03), coma (HR, 2.95; 95% CI, 1.26-6.91), or cardiovascular failure (HR, 2.43; 95% CI, 1.14-5.17). Most surviving patients exhibited a dramatic alteration of their functional status at 1 and 2 years. CONCLUSIONS: Heatstroke is associated with poor outcomes in temperate urban areas. This could be explained at least in part by our lack of experience. Western temperate countries need to be more prepared for future heat waves.

Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation.

We analyzed 27 CML patients treated with imatinib (IM) who developed a BCR-ABLT315I mutation. These patients had poor prognostic features: High or intermediate Sokal index (82%), and lack of CCyR under IM (59%). At T315I discovery, patients were in advanced phase (59%), with clonal evolution (84%). Median time since diagnosis was 39 months, and progression occurred 13 months after IM initiation, regardless of disease phase. Overall survival since IM initiation was 42.5 months for chronic, and 17.5 months for advanced phases, and all patients progressed. This mutation seems related to or (partially?) responsible for progression and poor survival.

Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia.

To identify prognostic factors alternative or additional to drug-resistance and apoptosis proteins, we studied the impact of the expression of heat-shock proteins (HSPs) in 98 newly diagnosed acute myeloid leukemia (AML). HSP27 was expressed by 39%, HSP60 by 26%, HSP70 by 58%, HSP90 by 41%, and HSP110 by 30% of cases. HSP expressions were correlated with that of differentiation antigens (CD34, CD14, CD15, CD33) and that of drug-resistance (MRP, MRK) and apoptosis (Bcl-2) proteins. HSP90 and HSP110 were correlated with FAB subtype and karyotypic grouping. Complete remission (CR) was obtained in 68 cases (69%). Median disease-free survival (DFS) of the 68 remitters was 18.1 months with a 3-year DFS rate of 41%. CR rates were higher in patients with lower expression of HSPs. Overall survival (OS) was significantly longer in patients with lower expression of HSPs. Cytogenetics, CD34 positive expression, MRK positive expression, and HSP110 positive expression remained as pejorative prognostic factors for OS in the multivariate analysis. When considering patients with intermediate risk cytogenetics, HSP110 and MRP positive expressions and CD33 negative expression were of poor outcome, while HSP27 and HSP60 positive expressions appeared of pejorative prognostic value in patients with unfavorable karyotypes.

Salvage therapy in refractory acute myeloid leukemia: prediction of outcome based on analysis of prognostic factors.

Acute myeloid leukemia (AML) non-responsive to initial chemotherapy is generally of poor prognosis. High-dose cytarabine (HD-AraC) has been proposed as salvage therapy in combination with amsacrine. The aim of the current study was first to assess the toxicity and the efficacy of such a combination therapy, and secondly to determine prognostic factors allowing to predict whom patients could benefit of such a treatment. Out of 91, 45 patients referred to our institution have been treated by HD-AraC (3 g/m(2)/12h from day 1 to 4) combined with amsacrine (90 mg/m(2) per day from day 5 to 7) as a salvage regimen. Forty-five of the 91 patients (49%, 95% confidence interval (CI): 39-60%) achieved complete remission (CR). Thirty-five patients were refractory to the salvage therapy and 11 patients died from toxicity during aplasia. Median disease-free survival (DFS) was 11.5 months (95% CI: 6-16 months). After CR achievement, 26 patients received consolidation therapy according to the protocol in which they were included. Nineteen patients with an HLA-identical sibling donor underwent allogeneic bone marrow transplantation. At time of analysis, 27 of the 45 patients (60%) who achieved CR have relapsed. Median overall survival (OS) was 7.5 months (95% CI: 6-15 months). There was 12 long survivors (13%). In univariate analysis, initial karyotype was the main prognostic factor as well as in terms of CR achievement (P=0.002) than in terms of DFS (P=0.01) or OS (P=0.009). CR achievement was negatively influenced by higher WHO performance status index (P=0.006), higher LDH level (P=0.02), and higher CD34 expression by leukemic cells (P=0.03) at diagnosis, and presence of circulating blasts (P=0.001), platelet count <80 x 10(9)/l (P=0.0001), and polymorphonuclear (PMN) percentage <30% (P=0.01) at time of starting salvage therapy. DFS was negatively influenced by secondary AML (P=0.01), weight loss > or =5% (P=0.03), and higher white blood cell (WBC) count (P=0.03) at time of diagnosis. Age over 60 years (P=0.002), prior history of toxic exposure (P=0.01), higher CD34 expression (P=0.02), weight loss > or =5% (P=0.006), and WHO performance status index > or =2 (P=0.01) at diagnosis, and platelet count <80 x 10(9)/l (P=0.02) at time of salvage therapy were the main prognostic factors associated with shorter OS. In multivariate analysis, karyotype grouping at diagnosis (P=0.006) and blood count before salvage therapy (P=0.001) were of prognostic value for CR achievement. Karyotype remained of prognostic value for DFS and OS (P=0.007 and <0.0001, respectively).We conclude that HD-AraC combined with amsacrine was as a useful salvage regimen in AML non-responding to a first intensive course of chemotherapy. Using objective parameters of proven significance (karyotypic grouping and blood count before salvage), we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. Patients with favorable risk cytogenetics and those with intermediate risk cytogenetics and favorable blood count (PMN > or =30%, no circulating blasts, and platelet count > or =80 x 10(9)/l) before salvage therapy had a similar outcome than those achieving CR after only one course of chemotherapy. All other patients displayed a poor outcome. This suggests their orientation at an earlier time to alternate therapeutic programs based on investigational drugs.

Bone marrow biopsy in adult acute lymphoblastic leukemia: morphological characteristics and contribution to the study of prognostic factors.

Bone marrow (BM) sections were examined in 128 untreated adult patients with newly diagnosed acute lymphoblastic leukemia (ALL), seen in our institution over a 19-year period. BM biopsy was performed in order to assess the incidence, degree and prognostic significance of histological data of the disease. BM features studied were reticular fibrosis, total cellularity, residual hematopoiesis, mitotic activity, and blastic infiltration. T-cell lineage ALL were diagnosed in 23% of the cases, while B-cell lineage ALL represented 70% of the cases. There were 7% of non-T-non-B-cell lineage ALL. The percentage of BM leukemic cells was related to cellularity (P=0.02), while it was related to the disappearance of normal cell lines (P<0.0001). BM cellularity was related to the percentage of circulating leukemic cells at diagnosis (P=0.006). Residual hematopoiesis was related to a higher initial granulocyte count (P=0.04) and lower percentage of circulating blasts (P=0.04). The degree of fibrosis was inversely related to that of BM cellularity (P=0.04). All patients, but four, received standard ALL induction chemotherapy according to different successive protocols. In this whole cohort of patients, complete remission (CR) rate was 78%. Median disease-free survival (DFS) and median overall survival (OS) were 13.7 months and 20.2 months, respectively. In univariate analysis, CR rate was positively affected by mitotic activity (P=0.01) and residual hematopoiesis (P=0.008). OS was positively influenced by a higher leukemic cell mitotic activity (P=0.03) and the persistence of more than two residual normal cell lines in BM (P=0.04). Patients presenting with both of those characteristics had better outcome than patients who did not, as well as, in terms of CR (P=0.03), or DFS (P=0.002), or OS (P=0.003). T-cell lineage ALL and L3 ALL did not significantly influence those results. Our findings did not confirm that among marrow features, reticular fibrosis has any prognostic value. A multivariate analysis of both clinical and histological data was performed to test their prognostic relevance. In a model including age, immunophenotype, Philadelphia chromosome status, mitotic index, and level of normal residual hematopoiesis, the only significant predictor of CR achievement were the persistence of normal residual hematopoietic cell lines (P=0.01) and the mitotic activity of leukemic cells (P=0.002). Philadelphia chromosome status (P=0.03) and age (P<0.0001) were of prognostic value, respectively for DFS and OS. We conclude that some characteristics of BM biopsy afford not only descriptive but also prognostic information for predicting the outcome. The persistence of normal residual hematopoiesis and intense leukemic cells mitotic activity were both factors of favorable outcome, while BM fibrosis did not display any prognostic value.

[Treatment of acute myeloid leukemias in the adult in relapse]. / Traitement des leucémies aiguës myéloïdes de l'adulte en rechute.

Main chemotherapy regimens used to treat adult patients with acute myeloid leukemia (AML) in first or further relapse were reviewed. In retrospective study, second complete remission rates ranged from 30% to 64%, while they ranged from 8% to 89% in prospective trials. The second complete remission rates were closely associated with age and duration of first complete remission. Combination therapies resulted in higher complete remission rates but were associated with higher toxicity. Median duration of second complete remission was < 14 months and overall median survival was < 12 months. The probability of 3-year survival ranged from 8% to 29%. The inhomogeneity of these studies, the differences in dosages and schedules, and the frequent absence of randomisation make it difficult to select the best salvage therapy. No reinduction regimen has so far clearly proven superior. Only stem cell transplantation provided durable remissions for the majority of AML patients after a first relapse. Considering the poor outcomes of patients with AML in first relapse, improved therapies need to be developed. A number of novel agents that include several differentiation agents, enzyme inhibitors, and monoclonal antibodies have been studied to provide improved outcomes for patients with AML who have relapsed. This is the same for acute promyelocytic leukaemia (APL). Arsenic trioxide has shown great promise for the induction, consolidation, and maintenance of complete remission in relapsed patients with APL. Within this context autologous and allogeneic bone marrow transplantations are also considered in second or subsequent relapse. Molecular monitoring for the PML-RARalpha fusion protein permits prompt intervention for early molecular relapse ultimately improving chances of prolonged remission.

[Current therapeutic strategies in acute lymphoblastic leukemia in the adult]. / Stratégies thérapeutiques actuelles dans les leucémies aiguës lymphoblastiques de l'adulte.

This comprehensive overview on the most recent developments in treatments of adult acute lymphoblastic leukemia (ALL) discuss the controversies in the management of adult ALL in relation with its different phases of therapy, give an overview of current chemotherapy and stem cell transplantation approaches. Treatment strategies in adult ALL have resulted in the achievement of complete remission rates of about 80%, and long-term disease survival in about 30% of patients. However, the disease appears very heterogeneous and therapeutic strategies are now applied to adults according to groups of ALL with different prognoses. Features of poor outcome (older age, hyperleukocytosis, non-T-cell immunophenotype, Philadelphia chromosome-positive karyotype, longer time to achieve complete remission) were found in about 75% of adult ALL. This review of the literature summarized then data regarding prognostic factors involved in the determination of risk-adapted strategies. New treatment options, needed to be developed to further improve on the therapeutic perspectives for adult patients with ALL, and therapeutic schedules of main cooperative groups are also reviewed.

Bilevel positive airway pressure ventilation: factors influencing carbon dioxide rebreathing.

PURPOSE: Use of bilevel positive airway pressure (BLPAP) ventilators for noninvasive ventilation (NIV) is an established treatment for both acute and chronic ventilatory failure. Although BLPAP ventilator circuits are simpler than those of conventional ventilators, one drawback to their use is that they allow variable amounts of rebreathing to occur. The aim of this work is to measure the amount of CO(2) reinsufflated in relation to the BLPAP ventilator circuit in patients, and to determine predictive factors for rebreathing. METHODS: Eighteen adult patients were ventilated on pressure support, either by intubation or with mask ventilation, during a weaning period. The mean inspiratory fraction of CO(2) (tidal FiCO(2)) reinsufflated from the circuit between the intentional leak and the ventilator was measured for each breath. The influence of end-tidal CO(2) concentration (ETCO(2)), respiratory rate (RR), percentage of inspiratory time (T (i)/T (TOT)), application of expiratory positive airway pressure (EPAP), and inspiratory tidal volume on magnitude of tidal FiCO(2), as well as the influence of intubation versus NIV, were studied by univariate comparisons and logistic regression analysis. RESULTS: In a total of 11,107 cycles, tidal FiCO(2) was 0.072 +/- 0.173%. Of fractions measured, 8,976 (81%) were under 0.10% and 2,131 (19%) were over 0.10%, with mean values of 0.026 +/- 0.027% and 0.239 +/- 0.326%, respectively. ETCO(2), EPAP, NIV versus intubation, and RR had significant predictive value for tidal FiCO(2) >0.10%. CONCLUSIONS: BLPAP ventilators present a specific rebreathing risk to patients. However, that risk remains modest, even in intubated patients, provided that EPAP is applied.

Hemodynamic responses to acute and gradual renal artery stenosis in pigs.

BACKGROUND: Reduction of renal blood flow (RBF) due to a renal artery stenosis (RAS) can lead to renal ischemia and atrophy. However in pigs, there are no data describing the relationship between the degree of RAS, the reduction of RBF, and the increase of systemic plasma renin activity (PRA). Therefore, we conducted a study in order to measure the effect of acute and gradual RAS on RBF, mean arterial pressure (MAP), and systemic PRA in pigs. METHODS: RAS was induced experimentally in six pigs using an occluder placed around the renal artery downstream of an ultrasound flow probe. The vascular occluder was inflated gradually to reduce RBF. At each inflation step, percentage of RAS was measured by digital subtraction angiography (DSA) with simultaneous measurements of RBF, MAP, and PRA. Data were normalized to baseline values obtained before RAS induction. Piecewise regression analysis was performed between percentage of RAS and relative RBF, MAP, and PRA, respectively. RESULTS: In all pigs, the relationship between the degree of RAS and RBF was similar. RBF decreased over a threshold of 42% of RAS, with a rapid drop in RBF when RAS reached 70%. PRA increased dramatically over a threshold of 58% of RAS (+1,300% before occlusion). MAP increased slightly (+15% before occlusion) without identifiable threshold. CONCLUSIONS: This study emphasizes that the relation between the degree of RAS and RBF and systemic PRA is not linear and that a high degree of RAS must be reached before the occurrence of significant hemodynamic and humoral effects.

A single dose pegfilgrastim for supporting neutrophil recovery in patients treated for high-risk acute myeloid leukemia by the EMA 2000 schedule.

Dose intensity has been demonstrated to be one determinant for treatment efficacy in younger adults with high-risk (relapsed and refractory) acute myelogenous leukemia. Between 2000 and 2006, 56 patients entered the EMA 2000 study and received timed sequential reinduction chemotherapy. From 2004, chemotherapy was also followed by one subcutaneous dose of pegfilgrastim. Thirty-six patients reached a complete remission, while nine obtained a partial remission. Median time to granulocyte and platelet recovery was 34 and 38 days respectively. The major non-hematologic toxicities were severe infections but despite this 23 remitters could proceed to their post-remission treatment, although 13 did not because of severe toxicity or early relapse. The median overall survival was 9.3 months. The EMA 2000 regimen is a highly effective treatment with a response rate of 64% and a low early death rate. The period of critical neutropenia was relatively short in both phases and the supportive use of pegfilgrastim, although showing a trend toward reduced neutropenic period, did not appear to reduce the risk of infection in this group and may not be a critical requirement for reducing the risk of treatment-related toxicity.

Central nervous system involvement in adult acute lymphoblastic leukemia.

Central nervous system (CNS) involvement is identified at the time of diagnosis in less than 10% of adult acute lymphoblastic leukemia (ALL). These patients can attain long-term disease-free survival. CNS disease at presentation does not appear to be an independent poor prognostic factor. Because of the difficulty in treating CNS leukemia, innovative treatments and alternative delivery techniques are needed. The outcome in such patients is a reflection of an aggressive systemic and CNS-directed therapy. However, CNS toxicity represents the dose-limiting side effect of treatment. With effective CNS prophylaxis including intrathecal chemotherapy, high-dose systemic administration of certain agents and cranial irradiation, most adults with ALL without CNS disease at diagnosis may remain free of CNS leukemia. Leukemic relapse remains a major therapeutic problem and CNS involvement at the time of relapse occurs in 1-15% of cases. Adult ALL with CNS recurrence remains of poor prognosis and is generally associated with a systemic relapse.

[Adult acute lymphoblastic leukemia with central nervous system involvement: an overview]. / Leucémies aiguës lymphoblastiques de l'adulte avec envahissement du système nerveux central : mise au point.

At the time of diagnosis, central nervous system (CNS) involvement is identified in less than 10% of adult acute lymphoblastic leukemia (ALL). Long-term disease-free survival can be achieved in these patients. CNS disease at presentation does not appear to be an independent poor prognostic factor. In CNS leukemia, innovative treatments and alternative delivery techniques are, however, warranted. Outcome in such patients is a reflection of an aggressive systemic and CNS-directed therapy. However, CNS toxicity represents the dose-limiting side effect of treatment. With effective CNS prophylaxis including intrathecal chemotherapy, high-dose systemic administration of certain agents and cranial irradiation, most adults with ALL without CNS disease at diagnosis may remain free of CNS leukemia. CNS involvement at the time of relapse occurs in 1 to 15% of cases. Leukemic relapse remains a major therapeutic challenge. Adult ALL with CNS recurrence remains of poor prognosis and is generally associated with a systemic and medullary relapse.

Proportion of long-term event-free survivors and lifetime of adult patients not cured after a standard acute lymphoblastic leukemia therapeutic program: adult acute lymphoblastic leukemia-94 trial.

BACKGROUND: In adult acute lymphoblastic leukemia, treatment results generally are expressed in terms of overall survival or disease-free survival at 3 years. In this investigation, the authors attempted to express the results in terms of the proportion of long-term disease-free survivors and in terms of lifetime in patients who developed recurrent disease or died. METHODS: Univariate and multivariate analyses were used to assess the influence of different covariates on the 2 result criteria in 922 participants in the Adult Acute Lymphoblastic Leukemia-94 multicenter trial. RESULTS: The proportion of long-term survivors was 21.5% (95% confidence interval [95% CI], 18.1-25.4%) and was higher in women than in men. The proportion decreased with increasing age, white blood cell count, and lactate dehydrogenase level. The lowest proportion was observed in patients ages 44 years to 55 years (11.4%; 95% CI, 7-17.9%) and in patients with the t(9;22) BCR-ABL karyotype (13.4%; 95% CI, 8.8-19.8%), and the highest proportion was observed in patients with the t(4;11) MLL-AF4 karyotype (31.3%; 95% CI, 18.2-48.3%). The mean expected lifetime of patients who were not cured was 11.4 months (95% CI, 9.1-14.1 months). It was longer in men than in women and was shorter with increasing age, performance status, hemoglobin level, and white blood cell count. CONCLUSIONS: The results of this study highlighted and specified the importance of some classic prognostic factors in patients with acute lymphoblastic leukemia.

Secondary or concomitant neoplasms among adults diagnosed with acute lymphoblastic leukemia and treated according to the LALA-87 and LALA-94 trials.

BACKGROUND: Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL. METHODS: The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years. RESULTS: By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months. CONCLUSIONS: The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk.