Outbreak in a haematology unit involving an unusual strain of glycopeptide-resistant Enterococcus faecium carrying both vanA and vanB genes.

OBJECTIVES: To report an outbreak due to an unusual strain of Enterococcus faecium containing both the vanA and vanB genes, in France, where the rate of glycopeptide-resistant enterococci (GRE) is below 1%. METHODS: Cases were patients infected or colonized with GRE on the haematology ward. Contact patients were screened by real-time PCR performed on rectal swabs. Clinical features were compared for GRE-positive and GRE-negative patients. GRE isolates were characterized by phenotypic and molecular methods including PFGE. Conjugation experiments were performed to identify van genetic support. RESULTS: After the index patient presented a bacteraemia with vanA/vanB E. faecium, 56 contact patients were screened, 7 of whom were found to be GRE positive: 6 additional cases with vanA/vanB E. faecium and 1 with GRE carrying vanA only. PFGE confirmed the clonal relationship of the seven vanA/vanB E. faecium strains, whereas the vanA isolate was distinct. Only the vanA gene could be transferred to enterococcal recipients by conjugation, and it was probably localized on a mobile genetic element. All isolates were resistant to vancomycin (MIC > 256 mg/L) and teicoplanin (MIC = 24-32 mg/L), but were susceptible to tigecycline (MIC = 0.09 mg/L), linezolid (MIC = 0.75 mg/L) and daptomycin (MIC = 1-2 mg/L). Significant differences (P < 0.001) between carriers and non-carriers of GRE were observed for the median duration of hospitalization (57 days versus 16.5 days) and of neutropenia (40 days versus 6 days), the median number of antibiotics used (5 versus 1.5) and the duration of glycopeptide treatment (14.5 days versus 0 days). CONCLUSIONS: vanA/vanB E. faecium strains, although rare, can emerge in the absence of previous outbreaks of vanA-GRE or vanB-GRE.

In vivo selection of a complex mutant TEM (CMT) from an inhibitor-resistant TEM (IRT) during ceftazidime therapy.

OBJECTIVES: A relapse from Escherichia coli bloodstream infection was observed in a patient with acute leukaemia treated with ceftazidime for 7 days for febrile neutropenia. Whereas the original E. coli isolate was resistant to ß-lactam/ß-lactamase inhibitor combinations (EC1), the relapse E. coli isolate showed a similar phenotype but with resistance extended to ceftazidime (EC2). We investigated the molecular mechanisms of ß-lactam resistance and sought if EC2 could have been selected in vivo from EC1. METHODS: EC1 and EC2 isolates were compared for antibiotic MICs, plasmid content, genotyping, ß-lactamase genes and their environment. Both isolates were conjugated with E. coli JW4111ΔampC and MICs determined for transconjugants. In addition, ceftazidime-resistant mutants were selected in vitro from EC1. RESULTS: EC1 and EC2 showed identical patterns for genotyping and resistance plasmids. PCR sequencing of blaTEM in EC1 showed the mutations M69L and N276D corresponding to TEM-35, also called inhibitor-resistant TEM (IRT)-4. In EC2, the TEM allele showed an additional mutation, R164S, known to confer resistance to ceftazidime. The combination of these three mutations was previously reported in TEM-158, described as the complex mutant TEM (CMT)-9, associated with resistance to ß-lactamase inhibitors and third-generation cephalosporins. In vitro selection of ceftazidime-resistant mutants from EC1 yielded six different CMT alleles, including TEM-158 containing the R164S mutation. CONCLUSIONS: This first known report of in vivo selection of CMT from IRT, reproduced in vitro, shows how the evolution of ß-lactamase enzymes is easily driven by antibiotic pressure, even during a short antibiotic therapy.

Dexamethasone in patients with acute lung injury from acute monocytic leukaemia.

The use of steroids is not required in myeloid malignancies and remains controversial in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We sought to evaluate dexamethasone in patients with ALI/ARDS caused by acute monocytic leukaemia (AML FAB-M5) via either leukostasis or leukaemic infiltration. Dexamethasone (10 mg every 6 h until neutropenia) was added to chemotherapy and intensive care unit (ICU) management in 20 consecutive patients between 2005 and 2008, whose data were compared with those from 20 historical controls (1994-2002). ICU mortality was the primary criterion. We also compared respiratory deterioration rates, need for ventilation and nosocomial infections. 17 (85%) patients had hyperleukocytosis, 19 (95%) had leukaemic masses, and all 20 had severe pancytopenia. All patients presented with respiratory symptoms and pulmonary infiltrates prior to AML FAB-M5 diagnosis. Compared with historical controls, dexamethasone-treated patients had a significantly lower ICU mortality rate (20% versus 50%; p = 0.04) and a trend for less respiratory deterioration (50% versus 80%; p = 0.07). There were no significant increases in the rates of infections with dexamethasone. In conclusion, in patients with ALI/ARDS related to AML FAB-M5, adding dexamethasone to conventional chemotherapy seemed effective and safe. These results warrant a controlled trial of dexamethasone versus placebo in AML FAB-M5 patients with noninfectious pulmonary infiltrates.

Treatment of myelodysplastic syndromes with 5q deletion before the lenalidomide era; the GFM experience with EPO and thalidomide.

Anemia in MDS with 5q deletion was generally considered, until the advent of lenalidomide, unresponsive to available treatments. We analyzed erythroid response to erythropoetin (EPO) or darbepoetin (DAR) and thalidomide in MDS with 5q deletion treated by French centers (GFM) and in whom karyotype was successfully performed. Of 345 patients treated with EPO or DAR+/-G-CSF, 48 had 5q deletion. The response rate was 46% (31% major, 15% minor) according to International Working Group (IWG) 2000 criteria versus 64% in patients without 5q deletion (p=0.03). According to IWG 2006 criteria, the response rate in patients with 5q deletion was 39% versus 52% in patients without 5q deletion (p=0.10). Mean duration of response was 14 months versus 25 months (IWG 2000) and 13 months versus 27 months (IWG 2006) in 5q deletion and non-5q deletion patients (p=0.019 and 0.003, respectively). Of 120 MDS treated with thalidomide, all of whom had successful cytogenetic analysis, 37% of the 24 patients with 5q deletion responded (IWG 2000 criteria, 20% major, 17% minor) with a mean duration of 9.5 months, versus 32% (18% major, 14% minor) in MDS without 5q deletion and a mean response duration of 9 months (p=NS). Our results confirm that response rates to EPO or DAR and thalidomide are clearly inferior to those obtained with lenalidomide.

High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group.

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.

Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial.

Fifty-four percent of adults with acute lymphoblastic leukemia (ALL) who entered the LALA-94 trial experienced a first relapse. We examined the outcome of these 421 adult patients. One hundred and eighty-seven patients (44%) achieved a second complete remission (CR). The median disease-free survival (DFS) was 5.2 months with a 5-year DFS at 12%. Factors predicting a better outcome after relapse were any transplant performed in second CR (P<0.0001), a first CR duration >1 year (P=0.04) and platelet level >100 x 10(9)/l at relapse (P=0.04). Risk groups defined at diagnosis and treatment received in first CR did not influence the outcome after relapse. The best results were obtained in a subset of patients who were eligible for allogeneic stem cell transplantation (SCT). Geno-identical allogeneic SCT was performed in 55 patients, and 3 patients received donor lymphocyte infusions. Forty-four transplantations were performed from an unrelated donor (of which four were cord blood). We conclude that most adult patients with recurring ALL could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option.

Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group.

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.

TCRα rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome.

T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an 'early-cortical' thymic maturation arrest characterized by expression of cytoplasmic TCRß but no surface T-cell receptor (TCR) and frequent ectopic expression of the TLX1/3 NK-like homeotic proteins (NKL). We designed a TCRα VJC PCR to identify clonal TCRα rearrangements in 32% of 127 T-ALLs, including 0/52 immature/TCRγδ lineage cases and 41/75 (55%) TCRαß lineage cases. Amongst the latter, TCRα rearrangements were not identified in 30/54 (56%) of IMß/pre-αß early-cortical T-ALLs, of which the majority (21/30) expressed TLX1/3. We reasoned that the remaining T-ALLs might express other NKL proteins, so compared transcript levels of 46 NKL in T-ALL and normal thymic subpopulations. Ectopic overexpression of 10 NKL genes, of which six are unreported in T-ALL (NKX2-3, BARHL1, BARX2, EMX2, LBX2 and MSX2), was detectable in 17/104 (16%) T-ALLs. Virtually all NKL overexpressing T-ALLs were TCRα unrearranged and ectopic NKL transcript expression strongly repressed Eα activity, suggesting that ectopic NKL expression is the major determinant in early-cortical thymic T-ALL maturation arrest. This immunogenetic T-ALL subtype, defined by TCRß VDJ but no TCRα VJ rearrangement, is associated with a favorable outcome in GRAALL-treated adult T-ALLs.

Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias.

Strong expression of at least one of the three D-type cyclins is common in human cancers. While the cyclin D1 and D3 genes (CCND1 and CCND3) are recurrently involved in genomic rearrangements, especially in B-cell lymphoid neoplasias, no clear involvement of the cyclin D2 gene (CCND2) has been reported to date. Here, we identified chromosomal translocations targeting the CCND2 locus at 12p13, and the T-cell receptor beta (TCRB) or the TCRA/D loci in T-cell acute lymphoblastic leukemias (T-ALLs). Expression analysis demonstrated dramatic cyclin D2 overexpression in the translocated cases (n=3) compared to other T-ALLs (total, n=89). In order to evaluate dysregulation in T-ALL with respect to normal T-cell differentiation, we analyzed CCND2 expression in normal purified human thymic subpopulations. CCND2 levels were downregulated through progression from the early stages of human T-cell differentiation, further suggesting that the massive and sustained expression in the CCND2-rearranged T-ALL cases was oncogenic. Association with other oncogene expression (TAL1, HOXAs, or TLX3/HOX11L2), NOTCH1 activating mutations, and/or CDKN2A/p16/ARF deletion, showed that cyclin D2 dysregulation could contribute to multi-event oncogenesis in various T-ALL groups. This report is the first clear evidence of a direct involvement of cyclin D2 in human cancer due to recurrent somatic genetic alterations.

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL.

Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor alpha (RARalpha) and the retinoic X receptor (RXR). In contrast to differentiation-therapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered.

Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML).

In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFalpha/beta genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P=0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P=0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (P<0.0001 and P=0.0002) owing to an excess of early events. c-Kit mutations were associated with a shorter EFS and RFS (P=0.002 and P=0.003) in t(8;21) but not inv(16) patients. As previously observed, Ras mutations did not affect prognosis. Screening for RTK mutations may help to identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or RTK inhibitors.

High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia.

Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials.

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15-50-year-old patients without sibling donors in both LALA-85/87 trials and 15-55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case-control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARalpha isoform (P= 0.0003) and high WBC counts (> or = 10,000/ mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P= 0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (> or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established.

Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study.

Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph+ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53-87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11-52%) in controls (P=0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival (OS) is 66% at 1 year vs 43% in the control group (P=0.005). The 1-year relapse-free survival is 58 vs 11% (P=0.0003). The use of imatinib in elderly patients with Ph+ ALL is very likely to improve outcome, including OS.

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia.

The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.

Copy-number analysis identified new prognostic marker in acute myeloid leukemia.

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.

Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group.

PURPOSE: To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission. PATIENTS AND METHODS: Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT. RESULTS: Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively. CONCLUSION: These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.