Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18-65 years: NILG ALL 10/07.

An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) and compared with a published control series. Following induction-consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17-67), 140/161 with Ph- ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.

Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML.

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.

Post-remissional and pre-transplant role of minimal residual disease detected by WT1 in acute myeloid leukemia: A retrospective cohort study.

In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) is still under investigation. The aim of the present retrospective study was to assess the role of Wilms tumor gene 1 (WT1) overexpression in a large monocentric cohort of AML patients. Among 255 enrolled patients, MRD was investigated in those in complete remission (CR) with an available WT1 at baseline (>250 copies) and at two further time-points: after induction (n=117) and prior allogeneic hematopoietic cell transplantation (allo-HCT), n=65. Baseline BM WT1 overexpression was not associated with response to induction (p=0.244). Median overall survival (OS) and disease-free survival (DFS) were significantly shorter in patients with >350 WT1 copies after induction compared to those with ≤350 (HR for mortality 2.13; 95% CI 1.14-3.97, p=0.018 and HR for relapse 2.81; 95% CI 1.14-6.93, p=0.025). Patients with WT1>150 copies pre allo-HCT had a significantly higher 2-year cumulative incidence of relapse (CIR) compared to those with WT1≤150 (HR 4.61; 95% CI 1.72-12.31, p=0.002). The prognostic role of WT1 overexpression resulted independent from other well-established risk factors. According to these results, WT1 overexpression might represent an additional MRD tool for risk stratification in patients classified nowadays in CR.

Role of Chemotherapy and Allografting in the Treatment of Acute Lymphoblastic Leukemia.

We report the clinical outcomes of 83 patients with acute lymphoblastic leukemia (median age, 46 years; range, 18-75 years) treated at our institution between 1999 and 2011. Treatment refers to clinical trials open for accrual at the time of diagnosis or to institutional guidelines. Upfront allografting was considered for younger high-risk patients. Seventy-eight of 83 (94%) patients achieved complete remission after induction, although 53% of them eventually relapsed. Forty of 70 patients younger than 61 years underwent allografting. The median follow-up was 7.4 years (range, 0.2-15.0 years). Overall, the 5-year overall survival (OS) and event-free survival (EFS) were 40% and 39%, respectively. In patients undergoing transplantation, OS and EFS at 5 years were both 53%, whereas in a nontransplantation setting, both OS and EFS were 35% at 5 years (P = .044 for both OS and EFS). By multivariate analysis, the independent predictors of OS and EFS were age and leukocytosis in the overall population and allografting in young patients.

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia.

Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).

Survival improvement of poor-prognosis AML/MDS patients by maintenance treatment with low-dose chemotherapy and differentiating agents.

We evaluated a maintenance, post-remission treatment with low-dose chemotherapy plus differentiating agents on poor-prognosis acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients ineligible to allografting. Patients had either age over 60 and/or secondary AML, therapy-related AML, previous relapse, high-risk MDS. Forty-five patients received the maintenance therapy based on two alternated schedules: (a) 6-thioguanine + 13-cis retinoic acid + dihydroxylated vitamin D3 and (b) low-dose cytarabine + 6-mercaptopurine + all-trans retinoic acid + dihydroxylated vitamin D3. We compared their outcome, at a median follow-up of 52 months, to that of a matched population of 49 patients who stopped treatments after consolidation. Maintenance group had a lower relapse incidence (70.3 vs. 86.4 % at 5 years p = 0.007) and a longer disease-free survival (median 21.2 vs. 8.7 months, p = 0.017). The relapse reduction improved overall survival: median 40.4 months (35.9 % at 5 years) for maintenance group vs. 15.8 (14.2 % at 5 years) for controls (p = 0.005). At multivariate Cox analysis, both cytogenetic and maintenance therapies resulted independent outcome predictors for overall survival. Maintenance treatment also reduced minimal residual disease (detected by WT1 and CBFß-MYH11) in five of eight evaluable patients. The present results suggest that our strategy of maintenance therapy might improve the outcome of poor-risk AML/MDS patients.

Allogeneic stem cell transplant for adults with myelodysplastic syndromes: relevance of pre-transplant disease status.

The aim of the present study was to investigate the outcome of 94 adult patients with myelodysplasia (MDS) who received an allogeneic stem cell transplant between January 1995 and September 2010 in two Italian hematology centers. At the time of transplant, 53 patients (56%) had relapsed/refractory disease. The cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was 33% (95% confidence interval [CI] 21-45%) and 78% (95% CI 66-90%), respectively. The cumulative incidence of transplant-related mortality (TRM) at 100 days was 13% (95% CI 6-21%). The 2-year progression free survival (PFS) and overall survival (OS) were 41% (95% CI 31-51%) and 49% (95% CI 38-59%), respectively. On multivariate analysis, advanced disease stage at transplant was the major independent variable associated with an inferior 2-year PFS (HR 3.66, 95% CI 1.98-6.76) and OS (HR 3.68, 95% CI 1.95-6.93). Use of an alternative donor was an independent variable associated with TRM (HR 3.18, 95% CI 1.31-7.72). In conclusion, our data suggest that disease status at the time of transplant is the major predictor for improved PFS and OS, and treatments required to reach this goal may have value in leading to an improved outcome.

Epidemiology of bloodstream infections in patients with acute myeloid leukemia undergoing levofloxacin prophylaxis.

BACKGROUND: Infections are a common cause of morbidity and mortality in patients with acute myeloid leukemia (AML). The evidence for efficacy of antibiotic prophylaxis in reducing the mortality rates and the incidence of bacterial infections was also reported by a systematic review published by Cochrane in 2012. The objective of our study was to report the incidence and the etiology of bloodstream infections in patients with AML undergoing levofloxacin prophylaxis during neutropenic episodes. METHODS: This was a retrospective study of patients with diagnosis of AML during 2001-2007. RESULTS: A total of 81 patients were included in the study. Two hundred and ninetyone neutropenic episodes were studied, of which 181 were febrile. Bacteria isolated from blood cultures were mostly Gram-positives during the induction (80%) and Gram-negatives during the consolidation (72.4%) phases of chemotherapy. Resistance to ciprofloxacin was found in 78.9% of isolated E. coli and it was higher during consolidation and higher than the hospital rate. The production of extended spectrum betalactamases (ESBL) in E. coli strains was reported in 12.1%, below the reported hospital rate during the study period. CONCLUSIONS: Regular microbiology surveillance is needed to better understand the impact of levofloxacin prophylaxis in neutropenic patients. Our study shows that Gram-positive bacteria are predominant during the induction phase of chemotherapy and Gram-negatives during the consolidation. The rate of fluoroquinolone resistance in the latter setting, even higher than the hospital rate, may suggest to reconsider levofloxacin prophylaxis.

Core binding factor acute myeloid leukaemia and c-KIT mutations.

Core binding factor (CBF) acute myeloid leukaemia (AML) represents 5-8% of all AMLs and has a relatively favourable prognosis. However, activating c-KIT mutations are reported to be associated with higher risk of relapse and shorter survival. To verify the incidence and prognostic value of c-KIT mutations in CBF AML, we retrospectively analysed bone marrow samples of 23 consecutive adult patients with de novo CBF AML [14 inv(16) and 9 t(8;21)] treated at a single institution from 2000 to 2011. All patients received standard induction chemotherapy with cytarabine, idarubicin and etoposide; 13 underwent allogeneic stem cell transplantation. c-KIT mutations in exons 8, 9, 10, 11, 13, 14 and 17 were assessed by PCR amplification in combination with direct sequencing. c-KIT mutations (3 in exon 10 and 4 in exon 17) were detected in 7/23 (30.4%) patients, 3 with t(8;21) and 4 with inv(16). No difference in c-KIT mutation status was observed between cases with inv(16) or t(8;21) alone and cases with additional cytogenetic abnormalities. No association between gender, age, white blood cell and platelet count, peripheral blood and bone marrow blast cells at diagnosis, achievement of complete remission, cytogenetic risk groups and Wilms tumour gene 1 (WT1) levels was found. On the contrary, lactate dehydrogenase (LDH) values were higher in mutated than in non-mutated patients (p=0.01). Overall survival (OS) rates were longer in CBF compared to the other types of AML and disease-free survival (DFS) was longer in inv(16) than in t(8;21) AML. OS and DFS were similar in mutated and non-mutated CBF AML patients. Our results confirm a better prognosis for CBF AML than all other AML categories, and for inv(16) than t(8;21) AML. However, no prognostic value for c-KIT mutational status was found in our series. The association between LDH levels and c-KIT mutation would indicate a more active proliferation for mutated CBF AML.

Prognostic relevance of cytometric quantitative assessment in patients with myelodysplastic syndromes.

OBJECTIVES: Morphology and cytogenetics are currently used to define prognosis in myelodysplastic syndromes (MDS). However, these parameters have some limits. Flow cytometry has been recently included in the diagnostic panel for MDS, and its prognostic significance is under evaluation. METHODS: Marrow aspirates from 424 MDS patients were analyzed by flow cytometry to evaluate the impact of bone marrow cell immunophenotype on overall survival (OS) and leukemia-free survival (LFS). The immature compartment of myeloblasts was analyzed by the quantitative expression of CD34 (<3% vs. ≥3%), CD117, and CD11b(-) /CD66b(-) (<5% vs. ≥5%); myeloid maturation was analyzed by the expression of CD11b(+) /CD66b(++) (<15% vs. ≥15%) and CD11b(+) /CD66b(+) (<25% vs. ≥25%). RESULTS: In univariate analysis, the expression of immaturity markers (CD34(+) , CD117(+) , and CD11b(-) /CD66b(-) ) was associated with shorter LFS and OS (P < 0.0001); higher expression of differentiation markers (CD11b(+) /CD66b(++) and CD11b(+) /CD66b(+) ) was associated with longer LFS (P < 0.0001 and P = 0.0002, respectively) and OS (P < 0.0001). In multivariate analysis, expression of CD34(+) (P = 0.007), CD117(+) (P = 0.013), and CD11b(+) /CD66b(++) (P = 0.023) retained independent prognostic value for OS, while only the expression of CD34(+) was a prognostic factor for LFS (P = 0.0003). Two different risk groups were defined according to the presence of 0-1 or ≥2 of these factors with significant different LFS and OS (P < 0.0001). This score showed prognostic value in predicting survival even in subanalysis according to IPSS and WHO subgroups. CONCLUSIONS: Flow cytometric analysis in MDS may provide meaningful prognostic information. Blast percentage expressed as CD117(+) or CD34(+) cells and the quantitative assessment of myeloid maturation showed prognostic value for survival.

Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects.

Gain-of-function (GOF) mutations of Janus kinase 2 (JAK2) are frequently seen in myeloproliferative disorders (MPDs). Meanwhile, JAK3 activating substitutions have been found in a few megakaryocytic cell lines and in primary myeloid leukemia (AMKL). Here, we sought to discover novel leukemogenetic mutations in de novo acute myeloid leukemia of non-Down syndrome (N-DS) by DNA sequencing. A total of 191 normal Caucasian individuals were studied to define single nucleotide polymorphisms (SNPs) within the JH2 and JH6 domains. Although known activating substitutions were observed in rare cases of acute myeloid leukemia (AML) (V722I [2/134] or P132T [1/119]), all samples were wild-type (WT) for the oncogenic A572V (119/119). Interestingly, a novel homozygous mutation (P132A) was discovered in a patient with acute megakaryoblastic leukemia and in vivo studies demonstrated that its ectopic expression was oncogenic in a mouse xenotransplant model. This study defines a novel JAK3 mutation among patients with N-DS AML and demonstrates that normal individuals can also display germline JAK3 substitutions, previously proven to have oncogenic properties, in vitro and in vivo. The discovery of these substitutions in normal donors encourages future studies to define new risk factors among patients with MPDs.

AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance.

All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction-negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction-negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

Early CPAP prevents evolution of acute lung injury in patients with hematologic malignancy.

PURPOSE: Although chemotherapy and transplantation improve outcome of patients with hematological malignancy, complications of these therapies are responsible for a 20-50% mortality rate that increases when respiratory symptoms evolve into acute lung injury (ALI). The aim of this study is to determine the effectiveness of early continuous positive airway pressure (CPAP) delivered in the ward to prevent occurrence of ALI requiring intensive care unit (ICU) admission for mechanical ventilation. METHODS: Patients with hematological malignancy presenting in the hematological ward with early changes in respiratory variables were randomized to receive oxygen (N = 20) or oxygen plus CPAP (N = 20). Primary outcome variables were need of mechanical ventilation requiring ICU admission, and intubation rate among those patients who required ICU admission. RESULTS: At randomization, arterial-to-inspiratory O(2) ratio in control and CPAP group was 282 ± 41 and 256 ± 52, respectively. Patients who received CPAP had less need of ICU admission for mechanical ventilation (4 versus 16 patients; P = 0.0002). CPAP reduced the relative risk for developing need of ventilatory support to 0.25 (95% confidence interval: 0.10-0.62). Among patients admitted to ICU, intubation rate was lower in the CPAP than in the control group (2 versus 14 patients; P = 0.0001). CPAP reduced the relative risk for intubation to 0.46 (95% confidence interval: 0.27-0.78). CONCLUSIONS: This study suggests that early use of CPAP on the hematological ward in patients with early changes in respiratory variables prevents evolution to acute lung injury requiring mechanical ventilation and ICU admission.

Combined antifungal therapy, iron chelation and surgical resection as treatment of hepatic zygomycosis in a patient with haematological malignancy.

We describe the case of a 19-year-old boy with acute leukaemia who developed primary hepatic zygomycosis. The patient presented with febrile neutropenia and severe abdominal tenderness. Despite the administration of antibiotics and liposomal Amphotericin-B (L-AmB), the CT scan demonstrated an increase in the size of liver lesions. A wide surgical resection was carried out and liver specimens demonstrated a branching, filamentous fungus that was identified as Rhizomucor pusillus by both phenotypic and molecular methods. The patient was treated with L-AmB combined with posaconazole, and deferasirox was subsequently added given the potential synergistic effect of this iron chelator in combination with L-AmB. Three months after surgical intervention, an allogeneic stem-cell transplantation was successfully carried out. The present case confirms that an early surgical management combined with antifungal agents is crucial to optimise the outcome of patients with zygomycosis and the use of deferasirox is a promising alternative.

Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10.

PURPOSE: To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor. RESULTS: The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well. The [corrected] 5-year overall survival rates were 31%, 34%, and 34%, [corrected] respectively. CONCLUSION: In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy.

M4 acute myeloid leukemia: the role of eosinophilia and cytogenetics in treatment response and survival. The GIMEMA experience.

BACKGROUND: Myelomonocytic acute myeloid leukemia (M4-AML) is frequently associated with the cytogenetic marker inv(16) and/or the presence of eosinophilia. The aim of this study was to analyze the incidence and prognostic role of these factors in a large series of patients. DESIGN AND METHODS: Adult patients with acute myeloid leukemia consecutively enrolled in the GIMEMA trials AML10 and LAM99p were retrospectively analyzed. RESULTS: Among 1686 patients, 400 cases of M4-AML were identified; of these, 78% had neither eosinophilia nor inv(16), 6% had eosinophilia only, 8% had inv(16) only and 8% had both. Univariate analysis showed that both eosinophilia and inv(16) were correlated with a higher probability of complete remission, lower resistance to chemotherapy and increased overall survival. Multivariate analysis showed that the simultaneous presence of the two factors significantly increased the probabilities of both complete remission and overall survival. The presence of only one of the two factors also increased the probabilities of complete remission and overall survival, but not to a statistically significant extent. The relapse-free survival of the responding patients was not influenced by the two factors. CONCLUSIONS: In a large series of patients with M4-AML we confirmed the favorable role of inv(16), but the weight of this factor among the whole M4 population was of limited relevance. Eosinophilia, which affects a small proportion of cases, also emerged as a favorable prognostic factor. Based on the results of this large case population, overall and relapse-free survival rates of patients with M4-AML are not significantly better than those of patients with non-M4 AML, while the concomitant presence of both inv(16) and eosinophilia was associated with a significantly improved prognosis.

Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.

Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.

Prognostic value of quantitative analysis of WT1 gene transcripts in adult acute lymphoblastic leukemia.

We quantified Wilm's tumor gene (WT1) using a real time quantitative polymerase chain reaction in 20 adult patients with acute lymphoblastic leukemia at presentation. A WT1 level greater than 906 (median value for the whole series) was a significant predictor of a poor disease-free and overall survival in uni- and multivariate analyses.

A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol.

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.