Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4000-4000
Author(s):  
Miklos Udvardy ◽  
Attila Kiss ◽  
Bela Telek ◽  
Robert Szasz ◽  
Peter Batar ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Case Reports ◽  
Fatal Outcome ◽  
Normal Karyotype ◽  
Secondary Aml ◽  
Poor Risk ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2nd and 3rd line treatment, while many studies are suggesting excellent results in 1st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML: De novo AML, 2nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment) De novo AML 1st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment) De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3) Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5) RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM) Allogeneous stem cell transplantation could have been performed in 1st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then. The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.

Attenuated Dose of Idarubicin for the Elderly De Novo Acute Myeloid Leukemia with Normal Karyotype.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4608-4608
Author(s):  
June-Won Cheong ◽  
Yuri Kim ◽  
Sun Young Park ◽  
In Hae Park ◽  
Jin Seok Kim ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
De Novo ◽  
Normal Karyotype ◽  
The Elderly ◽  
Remission Induction ◽  
Conventional Dose ◽  
The Difference ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract The incidence of acute myeloid leukemia (AML) increases with age. Because of poor performance status, co-morbidity and treatment-related side effects, a conventional dose chemotherapy containing anthracyclins may be toxic to the majority of elderly patients. In contrast, the administration of suboptimal dose of myelosuppressive chemotherapy could lead to an unsuccessful clinical outcome including lower complete remission (CR) rate. To evaluate the effect of attenuated dose of idarubicin, compared to the standard dose, on the clinical outcome and chemotherapy-related complications, we analyze the consecutive 32 elderly de novo AML patients (range, 60 – 74 years) with normal karyotype. Eleven patients received one cycle of conventional-dose remission induction chemotherapy (idarubicin, 12 mg/m2/day on days 1–3 and cytarabine 100mg/m2/day on days 1–7) (Group 1) and 21 patients received attenuated-dose idarubicn (8 mg/m2/day on days 1–3) and cytarabine (100mg/m2/day on days 1–7) (Group 2). Six cases (54.5%) in Group 1 and 12 cases (57.1%) in Group 2 had CR. The difference of CR between the two groups was not significant (P = 0.59). The intervals from the chemotherapy-starting date to the date of CR documentation were not also different between two groups (median 31.5 days on Group 1 vs 27.0 days on Group 2) (P = 0.29). The median number of transfusion requirement during the induction therapy was not different in the red blood cells (10 units, each) and platelets (16.5 units in Group 1 vs 18.0 units in Group 2; P > 0.05). Thirty patients received the recombinant human granulocyte colony-stimulating factor (G-CSF) three days after termination of chemotherapy. The duration of G-CSF administration was not different between two groups (P = 0.86). However, the frequency of septicemia and septic shock after induction chemotherapy was statistically significantly higher in Group 1 (54.5% and 9.5%, respectively) compared to that in Group 2 (36.3% and 0.5%, respectively) (P < 0.01). We also observed a higher incidence of clinically-documented invasive fungal infection in Group 1 (45.5%) compared to Group 2 (15.0%), although the difference was not statistically significant (P = 0.095). The incidence of other regimen-related toxicities including renal dysfunction, hepatic dysfunction and heart failure was not different between two groups. Overall survival and disease-free survival also were not different between the groups. In conclusion, the attenuated dose of idarubicin can be recommended for the remission induction chemotherapy for the elderly de novo AML patients with normal karyotype since it is associated with lower incidence of sepsis and septic shock with comparable CR rate.

WT1 Levels At Diagnosis and POST-Induction Provide Prognostic Information in Adult De Novo AML. Results From the Spanish Cetlam Group.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2524-2524
Author(s):  
Josep F Nomdedeu ◽  
Montserrat Hoyos ◽  
Maite Carricondo ◽  
Elena Bussaglia ◽  
Camino Estivill ◽  
...  
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
High Dose ◽  
Prognostic Impact ◽  
Post Induction ◽  
Group 3 ◽  
Group 2 ◽  
De Novo Aml ◽  
Intermediate Dose ◽  
Group 1

Abstract Abstract 2524 WT1 monitoring is an almost universal target to follow de novo AML. Its exppression in myeloid malignancies is upregulated in parallel to the blast percentage. Recently, WT1 determination has been standardized as result of an European Leukemia Net initiative. Early reports have demonstrated that the best results are obtained when peripheral blood is used to establish clinical predictions. Pediatric studies in AML have shown that raised WT1 levels after induction associate with unfavourable outcome. Despite all the mentioned, WT1 quantitation has not yet gained widespread use, in part because some AML show normal WT1 levels at diagnosis. To investigate the prognostic impact of the normalized bone marrow WT1 levels at diagnosis and post-induction in a consecutive series of de novo AML patients enrolled in the CETLAM group trials. Available bone marrow samples at diagnosis (586 cases) and post induction (367 cases) were obtained in each participating center and sent to the CETLAM repository center at the Hospital de la Santa Creu i Sant Pau for complete immunophenotype and molecular analyses. One μg of RNA was reverse transcribed to cDNA in a total reaction volume of 20μl containing Cl2Mg 5mM, 10× Buffer, DTT 10mM, dNTP's 10mM each, random hexamers 15μM, RNAsin 20 units (Promega) and 200 units of MMLV enzyme. WT1 expression levels were determined by real-time quantitative polymerase chain reaction (RQ-PCR) in an ABI PRISM 7700® Genetic Analyzer (Applied Biosystems, Foster City, CA) using the primers and conditions described by the ELN group (Cilloni et al J. Clin. Oncol 2009;27:5195-201). For WT1 copy number titration, the IPSOGEN® (Marseille, France) plasmid was employed. Results were expressed as copies and four normal bone marrow samples were used as test controls. Patients were treated between 2004 and 2011 according to the CETLAM03 protocol. Adults up to 70 years of age received induction chemotherapy with idarubicin, intermediate-dose cytarabine and etoposide, followed by consolidation with mitoxantrone and intermediate-dose ara-C. Subsequently, patients with favourable cytogenetics at diagnosis received one cycle of high-dose cytarabine.G-CSF priming during induction and consolidation was used. Patients with favorable cytogenetics and high leukocyte counts at diagnosis were treated with autologous transplantation instead of high-dose cytarabine. Furthermore, patients with a normal karyotype but an adverse molecular profile (FLT3 mutations or MLL rearrangements) were allocated to the treatment for unfavorable cases; this included allogeneic transplantation from an HLA-identical donor. Overall survival (OS) was measured from the date of enrolment until the date of death. Leukemia-free survival (LFS) for patients who achieved a CR was calculated from the date of CR to relapse or death. OS and LFS were plotted by the Kaplan-Meier method; differences between curves were analyzed by the log-rank test. The probability of relapse was calculated using cumulative incidence estimates and taking into account the competing risk of death in remission. A WT1 cut-off value of 5065.2 copies at diagnosis was obtained. Two hundred and four samples had WT1 levels greater than this value, whereas 382 samples showed levels below this cut-off. These groups had statistically different OS 55±3 vs 33±5 p<0.001, LFS 52±3 vs 30±6 p:0.004 and CIR 34±3 vs 56±6 p<0.001. As regards the post-induction results, four groups were established: Group 0 (135 patients) with WT1 levels between 0 and 17.5 copies, Group 1 (107 patients) with WT1 values ranging from 17.6 to 76 copies, Group 2 (54 patients) with WT1 between 76.1 and 170.5 copies and Group 3 (71 patients) with WT1 levels after induction greater than>170.6 copies. These groups showed statistically significant differences(p<0.001) in terms of OS: Group 0 59±4 months, Group 1 50±5 months, Group 2 45±7 months and Group 3 23±6 months. LFS was also statiscally different: Group 0: 58±4, Group 1: 46±5, Group 2: 39±8 and Group 3:19±8 (all p<0.001). Lastlly, CIR was markedly different between the four groups: Group 0:25±4, Group 1: 44±5, Group 2: 46±8 and Group 3: 68±8(p<0.001) . WT1 quantitation at diagnosis and post-induction provide a simple and well standardized measurement of the prognostic risk of adult AML patiens. Larger series need to be analyzed to ascertain whether this determination could be incorporated to initial AML risk stratification. Disclosures: No relevant conflicts of interest to declare.

Treatment-Related AML Patients Previously Treated with Taxanes for Breast Cancer Have Similar Outcomes As De Novo AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3555-3555
Author(s):  
Lindsey E. Roeker ◽  
Alexandra Wolanskyj ◽  
Michelle Elliott ◽  
William Hogan ◽  
Mark Litzow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Regimen ◽  
Cytogenetic Analysis ◽  
De Novo ◽  
Favorable Effect ◽  
Chromosome 11 ◽  
History Of ◽  
Group 2 ◽  
De Novo Aml ◽  
Group 1

Abstract Abstract 3555 Background: Although treatment-related acute myeloid leukemia (tr-AML) has been identified as an independent marker of poor prognosis, it is important to determine how characteristics of the patient, primary malignancy, or treatment regimen affect the development and outcome of tr-AML. Taxane therapy has become essential in the management of breast cancer in light of its favorable effect on survival in short term studies. However, clinical trials fail to capture acute leukemias related to recently introduced agents since development of tr-AML occurs years after chemotherapy. Aim: To examine the effect of taxane therapy on clinical outcome of patients who were treated for breast cancer and subsequently developed tr-AML. Methods: This retrospective chart review considers patients diagnosed with AML at Mayo Clinic between 1990 and 2011. Patients were included if they had previously received chemotherapy for breast cancer, or if they had never received any chemotherapy. Demographic data, previous diagnosis and treatment regimen, CBC at diagnosis, pathology and cytogenetic information, therapy used, and response were collected for each patient. IRB approval was obtained. Comparison between two groups was done using t-test; survival estimates using Kaplan-Meier curves were constructed with software JMP 9. Results: A total of 88 adult females with AML were identified. Median age at AML diagnosis was 58 years (range 19–86). Median hemoglobin was 8.9 g/dL (4–14.5), white blood cell count (WBC) 9.7 x109/L (0.6–237), platelets 67 x109/L (1–361), peripheral blood (PB) blasts 13%, bone marrow blasts (BM) 44%, and BM cellularity 90%. Of the 88 patients, 23 (26%) had previously received treatment for breast cancer (tr-AML), the remainder had de novo AML. Taxanes were included in the initial treatment for breast cancer in 14 (61%, median age 57, group 1), compared to 9 (39%) patients with no history of taxane exposure (median age 58, group 2). Median hemoglobin was 9.7 g/dL, WBC 4.5×109/L, platelets 72×109/L, PB blasts 2%, BM blasts 40% in group 1, compared to 8.3, 7.1, 50, 28%, 47%, respectively, in group 2. Cytogenetic analysis of group 1 showed diploidy in 8%, complex karyotypes in 8%, and chromosome 11 abnormalities in 38%, compared to 50%, 0%, 33%, respectively, in group 2. In group 1, 14% had good risk cytogenetics, 57% had intermediate risk, and 29% had poor risk, compared to 17%, 83%, and 0%, respectively, in group 2. Cytogenetic analysis of de novo AML showed diploidy in 71%, complex karyotypes in 14%, and chromosome 11 abnormalities in 0%. Complete remission (CR) was achieved in 79% of group 1 and 83% of group 2 (p 0.8). Differences in survival of group 1 (375 days) and group 2 (222 days) did not reach statistical significance (p 0.12). Median survival was 584 days for patients with de novo AML, 375 days in group 1 (p 0.47), and 222 days in group 2 (p<0.001). Conclusion: In agreement with previous reports, we found that tr-AML is a poor prognostic factor overall (p 0.04). However, patients with a history of breast cancer who had been treated with taxanes as a part of their initial chemotherapy regimen demonstrated similar survival as patients with de novo AML (p 0.47). Tr-AML patients only did significantly worse than patients with de novo AML if they had never received taxanes as part of their breast cancer therapy (p<0.001). Disclosures: No relevant conflicts of interest to declare.

Correlation Between Bone Marrow Dysplasia and Genomic Profile in De Novo Acute Myeloid Leukemia (AML): A Study By the ALFA Group

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2568-2568
Author(s):  
Thomas Cluzeau ◽  
Orianne Wagner-Ballon ◽  
Thomas Boyer ◽  
Estelle Guerin ◽  
Emmanuel Benayoun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Cell Lines ◽  
Research Funding ◽  
De Novo ◽  
Normal Karyotype ◽  
The Other ◽  
Molecular Abnormalities ◽  
Other Hand ◽  
De Novo Aml

Abstract Introduction: AML with multilineage dysplasia (MLD) are included in the WHO subset of "AML with myelodysplasia-related changes" (AML-MRC), together with AML arising from previous MDS or AML with MDS-related cytogenetic abnormalities. In the WHO classification, MLD is defined by dysplasia in at least 50% of the cells in at least two bone marrow (BM) myeloid cell lines. On the other hand, some genetically defined AML subgroups are specifically associated with morphologic changes, but close correlations do not exist for most of these entities. We searched for correlations between BM dysplasia and molecular aberrations in de novo AML patients included in 2 ALFA clinical trials Methods: BM cytomorphology was retrospectively reassessed in 192 patients with de novo AML (excluding CBF-AML), aged 18 to 70 enrolled in ALFA-0702 (n=123) and ALFA-0701 (n=69) clinical trials in 5 centers. 4 distinct morphologists performed the analysis from BM smears. Dysmegakaryopoiesis (DM), dyserythropoiesis (DE) and dysgranulopoiesis (DG) were quantified (respectively on 30, 200 and 200 cells) using 22 criteria designed by GFHC, which allow better evaluation of cytoplasmic and nuclear dysplasia in all BM lineages. Dysplasia was also evaluated using WHO criteria. NPM1, FLT3, MLL, CEBPA, IDH1, IDH2, WT1, DNMT3A, RUNX1, TET2 and ASXL1 gene mutations and EVI1 gene overexpression were detected by standard methods, as previously published (Renneville et al. Oncotarget 2014). Results: In the 192 patients analyzed, the incidence of molecular abnormalities was: MLL-PTD 5% (8/155), NPM1 31% (52/170), FLT3-TKD 9% (15/171), FLT3-ITD 19% (34/171), CEBPA double mutated (CEBPA-dm)11% (17/152), EVI1 overexpression 11% (17/152), IDH1 R132 9% (14/146), IDH2 R140 6% (10/159), IDH2 R172 2% (2/92), RUNX1 8% (6/67), DNMT3A 26% (11/43), TET2 12% (5/43) and ASXL1 7% (4/62). DG, DE and DM was evaluable in 59%, 83% and 85% of the patients, respectively. WHO-MLD was identified in 43/192 (22%) patients, and was not significantly associated with any genetic marker, even in AML with normal karyotype (Table 1). On the other hand, when using GFHC criteria, we observed in NPM1 mutated patients a higher % of bi-tri or multi nucleated megakaryocytes (25% vs 10%, p=0.03), of cytoplasmic DG (74% vs 58%, p=0.03); and more dysplasia in other cell lines including eosinophils, basophils, mastocytes, monocytes (p=0.008). In CEBPA-dm patients, lower % of global DG (21% vs 54%, p=0.04) was seen. In EVI1 overexpressing patients, we found a higher % of global DM, of micromegacaryocytes and of hypolobulated megacaryocytes (80% vs 31%, p=0.01; 18% vs 2%, p=0.01 and 19% vs 6%, p=0.001 respectively). In DNMT3A mutated patients, we observed a lower % of bi-tri or multi nucleated megakaryocytes (2% vs 28%, p=0.01) and a higher % of nuclear and cytoplasmic DG (21% vs 2%, p=0.005 and 1.2% vs 0%, p=0.03, respectively). In TET2 mutated patients, we observed less defects in nuclear segmentation and a higher % of abnormal chromatin condensation in granulocytes (1% vs 9%, p=0.02 and 6% vs 0%, p=0.008, respectively). Conclusion: Presence of WHO-MLD was not significantly correlated with any genetic subgroup. The 22 BM dysplasia parameters designed by the GFHC were evaluable in a majority of patients, and allowed us to find some specific cytomorphologic features in de novo AML with NPM1, CEBPA-DM, DNMT3A, TET2 mutation, or EVI1 overexpression. Those findings suggest that the definition of MLD may be refined by using more in depth quantification of dysplasia, especially with GFCH parameters. This study will be expanded with the inclusion of whole exome sequencing data (ongoing). Table 1. Correlation between MLD, normal karyotype and molecular abnormalities % AML-MLD % AML-MLD in AML with normal karyotype MLL-PTD 37,5% 29% NPM1 25% 28% FLT3-TKD 27% 33% FLT3-ITD 27% 25% CEBPA-dm 0% 0% IDH1 R132 21% 18% IDH2 R140 10% 0% IDH2 R172 0% 0% RUNX1 40% 40% DNMT3A 0% 0% TET2 0% 0% ASXL1 25% 50% EVI1 24% 0% Disclosures Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

AML in Israel: Younger Age at Diagnosis Does Not Improve Prognosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4130-4130
Author(s):  
Neta Goldschmidt ◽  
Sarah Cohen ◽  
Deborah Rund
Keyword(s):  
Supportive Care ◽  
De Novo ◽  
Tertiary Care ◽  
Normal Karyotype ◽  
Good Prognosis ◽  
Age At Diagnosis ◽  
Secondary Aml ◽  
Younger Age ◽  
Age Of Diagnosis ◽  
De Novo Aml

Abstract Abstract 4130 Introduction AML is generally considered a disease of the elderly, with a mean age of diagnosis in the Western world is approximately 60 years of age or older. Important prognostic parameters include: age, karyotype and new molecular markers (NPM1 and FLT3). Treatment in a tertiary care facility also may improve survival. We elected to examine these parameters and the long term outcome of AML patients (pts) treated in our institution which is an academic tertiary care center, among the largest in Israel. Methods We reviewed clinical data on pts with AML (de novo and secondary) treated at Hadassah in the years 1992-2009. Karyotype was determined by conventional cytogenetics and FISH analysis or molecular analysis when appropriate. Good prognosis karyotype was considered to include t(8;21), t(15;17) and inv16. FLT3 ITD (internal tandem duplications) and NPM1 analysis was determined on all pts for whom DNA was available, using PCR and either acrylamide gel electrophoresis (FLT3) or melting point analysis (NPM1). Kaplan Meier analysis determined duration of survival. Statistical significance was determined using Log rank and Chi square test, with significance set at a level of p<0.01. Results 293 patients were included, of which 236 (80%) had de novo AML and 57 (19.5%) had secondary AML, either following an antecedent hematological disease (AHD) such as MDS (n= 32, 11%) or therapy related AML (t-AML) (n=25, 8.5%). Our standard protocol for AML includes 7+3 induction and high dose Ara-C consolidations. Bone marrow transplantation (BMT), either allogeneic or autologous, is performed in high risk cases depending on donor availability. The mean age at diagnosis of the 293 pts was relatively young (all pts= 47.7±18.3 yrs; de novo AML= 45.6±17.6 yrs; secondary AML= 56.2±18.6 yrs; t-AML= 48.6±16.6 yrs). Mean age at diagnosis for Arab pts was 44.2±16.7, as compared to Jewish pts (49.4±18.6). For de novo AML Arab pts, mean age at diagnosis was 43.3±16.4 as compared to de novo Jewish pts (46.9±18). The male to female ratio was 60/29 (2.06) for Arab pts and 99/102 (0.97) for Jewish pts, 53/25 (2.12) and 80/78 (1.02) for de novo Arab and Jewish pts respectively. In the de-novo AML group, 58 (24%) had a good prognosis karyotype. In the entire group of pts, 108 (37%) had normal karyotype and 62 (21%) had FLT3 ITD. Of the 108 normal karyotype pts, 34 (31%) were found to have FLT3 ITD, and 17 (16%) were found to harbor NPM1 mutations; of the NPM1 positive patients, 12 (70%) were FLT3 ITD negative. Treatment with intention to cure was administered to 218 (92%) of the de novo AML and 36 (63%) of the secondary AML pts. Other pts received best supportive care. Eighty six (29%) pts underwent allogeneic BMT and 12 (4%) underwent autologous BMT. The 5 year survival was 35% and the 10 year survival was 17% with no difference between Arabs and Jews. Good prognosis karyotype significantly improved survival as did younger age, and absence of FLT3 ITD. Conclusions We conclude that in our institution, the median age of diagnosis of AML is more than two decades younger than that reported in literature. The reason for this may be demographic or related to environmental exposures such as smoking. The preponderance of male Arab pts is most likely due referral bias. The young age of the Arab male pts may be due to occupational or environmental exposures, such as smoking. Our treatment protocols and supportive care are similar to those used in Western countries. Despite these factors, survival was not as good as might be expected according to age, karyotype and FLT3 ITD status. Further studies are needed to elucidate the etiology of these findings. Disclosures: No relevant conflicts of interest to declare.

Frequent Mutation of the Polycomb-Associated Gene ASXL1 In Acute Myeloid Leukemia Secondary to Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2940-2940 ◽  
Author(s):  
Marta Fernandez-Mercado ◽  
Andrea Pellagatti ◽  
Janet Perry ◽  
Cristina Fernandez-Santamaria ◽  
Maria J. Calasanz ◽  
...  
Keyword(s):  
Disease Progression ◽  
Mutation Rate ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Common Mutation ◽  
Secondary Aml ◽  
Frequent Event ◽  
De Novo Aml

Abstract Abstract 2940 Recent studies have identified mutations of the ASXL1 gene in MDS and CMML. Mammalian ASXL proteins are believed to play a role in chromatin remodelling. We have previously reported that ASXL1 mutations are frequent in patients with MDS, CMML and AML. We observed that the mutation rate was relatively high in late MDS and AML with a lower frequency across early MDS. We found that the mutation is common in the normal karyotype group (especially AML secondary to MDS), occurring in 40% of all cases. ASXL1 mutations (including the common mutation c.1934dupG;p.Gly646TrpfsX12) were present in myeloid cells, but not in T-cells, indicating that they were acquired in all seven cases examined. The majority of the mutations identified were heterozygous frameshift mutations caused by deletion or duplication of a nucleotide. Given the high frequency of ASXL1 mutations in advanced MDS and AML in our earlier study, we have now screened a larger group of 143 AML samples, comprising 111 de novo AML and 32 AML secondary to either MDS or CMML, for mutations in the ASXL1 gene. In primary AML samples we found only 6/111 patients with ASXL1 mutations (5%), whereas the frequency of mutations was significantly higher in AML secondary to MDS (10/25, 40%) or CMML (5/7, 71%), strongly suggesting an association with disease progression in MDS and CMML. In order to determine the frequency of ASXL1 mutations in de novo and secondary AML patients with a normal karyotype and to identify cooperating mutations, we screened 85 samples for ASXL1 (all coding exons), NPM1 (exon 12), FLT3 (ITD and D835Y), TET2 (all coding exons), IDH1 (R132), IDH2 (R140 and R172) and RUNX1 (exons 3–7) mutations (Table 1). FLT3 and NPM1 mutations were more common in de novo AML (FLT3 51% and NPM1 58%) than in sAML (FLT3 9% and NPM1 12%), consistent with the role of NPM1 mutations as a hallmark of cytogenetically normal de novo AML. TET2 was mutated in 13% of primary AML, and in 28% of sAML, with most TET2 mutations found in AML secondary to CMML (5/7, 71%), as expected according to previous reports on higher mutation frequency in CMML patients. Mutations in IDH1 and in IDH2 were evenly distributed in primary and secondary cases. Similarly, RUNX1 mutation rate showed no significant differences between primary and secondary AML cases. Interestingly, ASXL1 mutations were mutually exclusive with NPM1 mutations, suggesting that they could be markers of different subgroups with a distinct aetiology. In conclusion, we have shown that mutation of ASXL1 is a very frequent event in AML secondary to MDS and CMML, but is much less frequent in de novo AML. Our data support a role for ASXL1 mutations in disease progression in MDS and CMML. Table 1. Mutation rate for genes screened in AML samples Primary AML Secondary AML From MDS From CMML ASXL1 5/53ü(9.4%) 10/25ü(40%) 5/7ü(71.4%) NPM1 31/53ü(58.5%) 3/25ü(12%) 1/7ü(14.3%) FLT3 26/51ü(51%) 3/25ü(12%) 0/7 TET2 7/52ü(13.5%) 4/25ü(16%) 5/7ü(71.4%) IDH1 7/52ü(13%) 3/25ü(12%) 0/7 IDH2 7/52ü(13%) 2/25ü(8%) 1/7ü(14.3%) RUNX1 6/53ü(11.3%) 4/25ü(16%) 1/7ü(14.3%) Disclosures: No relevant conflicts of interest to declare.

SF3B1 Mutations Are Detectable in 48.9% of Acute Myeloid Leukemia with Normal Karyotype (AML-NK) and ≥15% Ring Sideroblasts and Are Closely Related to FLT3-ITD and RUNX1 Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 406-406
Author(s):  
Sabine Jeromin ◽  
Ulrike Bacher ◽  
Katharina Bayer ◽  
Frank Dicker ◽  
Christiane Eder ◽  
...  
Keyword(s):  
De Novo ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Coding Region ◽  
Very High Frequency ◽  
Ring Sideroblasts ◽  
Equity Ownership ◽  
Group 5 ◽  
De Novo Aml ◽  
Group 1

Abstract Abstract 406 Introduction: Mutations in the spliceosome gene SF3B1 (splicing factor 3b, subunit 1; SF3B1 mut) are frequent in patients with myelodysplastic syndromes (MDS) and ring sideroblasts (RS). In contrast, in AML occurrence of SF3B1mut has been published to be comparatively low (2–5%). However, analysis of SF3B1 mut in AML with RS is lacking. We aimed to determine the frequency of SF3B1 mut in AML patients according to the percentage of RS and the association of SF3B1 mut with other genetic markers. Patients and Methods: 275 AML patients (115 f/160 m; median age: 71.2 years, range: 20.8 – 89.9 years) were analyzed for SF3B1 mut by Sanger sequencing of the coding region (exon 11 to 16). RS were detectable in 176/275 cases (RS in ≥15% of erythroid precursors: n=106; RS in 1–14%: n=70), 99 cases showed no RS. The cohort comprised 202 de novo AML (FAB: M0 n=27, M1 n=36, M2 n=55, M4 n=32, M5 n=1, M6 n=51), 65 s-AML and 8 t-AML patients. Data on other mutations were available as follows: FLT3-ITD n=242, FLT3-TKD n=173, MLL-PTD n=235, NPM1 n=230, RUNX1 n=199, CEBPA n=152, NRAS n=141, KRAS n=56, ASXL1 n=90, IDH1 n=78, IDH2 n=58, TP53 n=74, and DNMT3A n=52. Chromosome banding analysis (combined with FISH if needed) was performed in 262 cases. According to MRC criteria, favorable karyotypes were found in 6, intermediate in 169, and adverse in 87 cases. 120/262 (45.8%) cases had a normal karyotype (NK-AML). Results: Overall, in 44/275 (16.0%) patients SF3B1 mut were detected with a median mutation/wildtype ratio of 45% (range: 10 – 50%). The most frequent mutation was Lys700Glu (19/44, 43.2%) followed by Lys666Asn/Arg/Thr (15/44, 34.1%) and Arg625Cys/Leu (3/44, 6.8%) and other mutations found in single cases only. Patients without detectable RS had almost no SF3B1 mut in contrast to cases with RS (3/99, 3.0% vs 41/176, 23.3%, p<0.001). Of note, all three patients with SF3B1 mut without RS were s-AML. SF3B1 mut were significantly more frequent in AML with RS ≥15% as compared to RS 1–14% (33/106, 31.1% vs 8/70, 11.4% p=0.003). The frequency of SF3B1 mut was significantly increasing by higher RS categories: group 1, RS 0–14%: SF3B1 mut in 6.5%; group 2, RS 15–34%: 17.9%; group 3, RS 35–54%: 45.4%, group 4, RS 55–74%: 41.2%, group 5, RS 75–100%: 54.5% (group 1 vs 2: p=0.017; 2 vs 3: p=0.020; comparison of the frequency of SF3B1 mut for all groups: p<0.001). In line, SF3B1 mut had higher percentages of RS vs SF3B1 wt (mean: 37% vs 13%, p<0.001), higher age (mean: 72 vs 69 years, p=0.044) and higher platelet counts (mean: 108 vs 71 x109/L, p=0.014). SF3B1 mut was not detected in any of the analyzed t-AMLs. Within cases with RS ≥15% the frequency of SF3B1 mut was only slightly higher in s-AML vs de novo AML (12/34, 35.3% vs 21/69, 30.4%, p=0.657), and likewise was the percentage of RS (mean: 45% vs 37%, p=0.137). In de novo AML, SF3B1 mut occurred more often in FAB M2 and M4 (M2: 13/55, 23.6%; M4 10/32, 31.3%; M2 and M4 combined vs others 23/87, 26.4% vs 4/115, 3.5%, p<0.001). Frequency was lower in FAB M6 vs others (3/51, 5.9% vs 24/151, 15.9%, p=0.094) and M0 (1/27, 3.7% vs 26/175, 14.9%, p=0.138), whereas SF3B1 mut were mutually exclusive of FAB M1 (0/36, 0% vs 27/166, 16.3%, p=0.005). In intermediate MRC karyotypes frequency of SF3B1 mut was much higher vs all others (38/169, 22.5% vs 4/93, 4.3%, p<0.001). In detail, SF3B1 mut showed high occurrence in NK patients (NK vs aberrant: 28/120, 23.3% vs 14/142, 9.9%, p=0.004) and within this subgroup a very high frequency of 48.9% (23/47) in cases with RS ≥15%. In contrast, SF3B1 mut were nearly mutually exclusive of complex karyotype (complex vs all others: 1/57, 1.8% vs 41/205, 20.0%, p<0.001). Furthermore, SF3B1 mut were associated with FLT3-ITD (7/21, 33.3% vs 30/221, 13.6%, p=0.025) and RUNX1 mutations (19/65, 29.2% vs 12/134, 9.0%, p=0.001). Conclusions: So far, SF3B1 mut were considered to be mainly relevant for MDS. In this study, SF3B1 mut were found in 31.1% of AML with RS ≥15% and even more striking in 48.9% of AML-NK with RS ≥15%. SF3B1 mut were associated with higher age, AML FAB M2 and M4 subtypes, normal karyotype, FLT3-ITD and RUNX1 mutations. Our study adds both de novo and s-AML with RS ≥15% to the myeloid entities with frequent occurrence of SF3B1 mut and suggests analysis of a possible prognostic impact of SF3B1 mut in AML with increased RS. Disclosures: Jeromin: MLL Munich Leukemia Laboratory: Employment. Bacher:MLL Munich Leukemia Laboratory: Employment. Bayer:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

Is L5/S1 interbody fusion necessary in long-segment surgery for adult degenerative scoliosis? A systematic review and meta-analysis

2021 ◽  
pp. 1-8
Keyword(s):  
Systematic Review ◽  
Interbody Fusion ◽  
Case Reports ◽  
Adult Spinal Deformity ◽  
Meta Analysis ◽  
Lumbar Interbody Fusion ◽  
Lumbosacral Junction ◽  
Pelvic Fixation ◽  
Group 2 ◽  
Group 1

OBJECTIVE There is no consensus regarding the best surgical strategy at the lumbosacral junction (LSJ) in long constructs for adult spinal deformity (ASD). The use of interbody fusion (IF) has been advocated to increase fusion rates, with additional pelvic fixation (PF) typically recommended. The actual benefit of IF even when extending to the pelvis, however, has not been vigorously analyzed. The goal of this work was to better understand the role of IF, specifically with respect to arthrodesis, when extending long constructs to the ilium. METHODS A systematic review of the PubMed and Cochrane databases was performed to identify the relevant studies in English, addressing the management of LSJ in long constructs (defined as ≥ 5 levels) in ASD. The search terms used were as follows: “Lumbosacral Junction,” “Long Constructs,” “Long Fusion to the Sacrum,” “Sacropelvic Fixation,” “Interbody Fusion,” and “Iliac Screw.” The authors excluded technical notes, case reports, literature reviews, and cadaveric studies; pediatric populations; pathologies different from ASD; studies not using conventional techniques; and studies focused only on alignment of different levels. RESULTS The PRISMA protocol was used. The authors found 12 retrospective clinical studies with a total of 1216 patients who were sorted into 3 different categories: group 1, using PF or not (n = 6); group 2, using PF with or without IF (n = 5); and group 3, from 1 study comparing anterior lumbar interbody fusion versus transforaminal lumbar interbody fusion. Five studies in group 1 and 4 in group 2 had pseudarthrosis rate as primary outcome and were selected for a quantitative analysis. Forest plots were used to display the risk ratio, and funnel plots were used to look at the risk of publication bias. The summary risk ratios were 0.36 (0.23–0.57, p < 0.001) and 1.03 (0.54–1.96, p = 0.94) for the PF and IF, respectively; there is a protective effect of overall pseudarthrosis for using PF in long constructs for ASD surgeries, but not for using IF. CONCLUSIONS The long-held contention that L5/S1 IF is always advantageous in long-construct deformity surgery is not supported by the current literature. Based on the findings from this systematic review and meta-analysis, PF with or without additional L5/S1 interbody grafting demonstrates similar overall construct pseudarthrosis rates. The added risk and costs associated with IF, therefore, should be more closely considered on a case-by-case basis.

scholarly journals Impact of stroke-associated pneumonia on the outcome of acute ischemic stroke in internal carotid artery system

2020 ◽  
Vol 4 (9) ◽  
pp. 539-543
Author(s):  
D.T. Chipova ◽  
◽  
L.V. Santikova ◽  
A.Ch. Zhemukhov ◽  
◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Carotid Artery ◽  
Internal Carotid Artery ◽  
Acute Ischemic Stroke ◽  
Barthel Index ◽  
Inflammatory Markers ◽  
Internal Carotid ◽  
Fatal Outcome ◽  
Group 2 ◽  
Group 1

Aim: to study the stroke-associated pneumonia (SAP) effect on the outcome of ischemic stroke (IS) in the internal carotid artery system. Patients and Methods: 87 patients with IS underwent the follow-up study, of which 75 had no inflammatory bronchopulmonary complications (group 1), and 12 had pneumonia manifestation (group 2). The study was performed on days 1, 5, and 9 after IS, and 6 months and 12 months after discharge from the hospital. Neurological deficit severity (NIHSS, Barthel index) and inflammatory markers (peripheral blood leukocyte composition, C-reactive protein (CRP), ESR) were studied. Results: it was found that the presence of SAP was associated with increased mortality during the acute IS period (4 (33.1%) patients died in group 1 and 10 (13.3%) — in group 2, p<0.05), greater severity of neurological deficits (63.3±5.3 and 71.5±4.0 points on the NIHSS scale, respectively, p<0.05) and incapacitation (Barthel index — 63.3±5.3 and 71.5±4.0 points, respectively, p<0.05) at the end of the inpatient treatment period. In group 2, signs of an inflammatory response were detected on day 5, and the values of the white blood cell shift index, ESR and CRP significantly (p<0.05) differed from the initial values. During examination at 6 months and 12 months, there were no significant differences in these indicators between the groups. An association was established between the probability of SAP occurrence and the presence of swallowing disorders (r=0.672; p<0.05), the age of patients (r=0.572; p<0.05) and the presence of diabetes mellitus (r=0.522; p<0.05). The studied laboratory inflammatory markers allow us to timely assume the occurrence of pulmonary pathology. Conclusion: timely diagnosis and prevention of SAP can reduce the risk of fatal outcome, facilitate rehabilitation measures, and improve early IS outcomes. KEYWORDS: ischemic stroke, cardioembolic stroke, atherothrombotic stroke, complications, acute period, inflammatory markers, strokeassociated pneumonia, long-term outcomes. FOR CITATION: Chipova D.T., Santikova L.V., Zhemukhov A.Ch. Impact of stroke-associated pneumonia on the outcome of acute ischemic stroke in internal carotid artery system. Russian Medical Inquiry. 2020;4(9):539–543. DOI: 10.32364/2587-6821-2020-4-9-539-543.

Abstract 9411: Urine Aquaporin-2 Level is a Novel Marker for the Better Prognosis After Long-Term Tolvaptan Treatment in Patients With Advanced Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Teruhiko Imamura ◽  
Koichiro Kinugawa ◽  
Takeo Fujino ◽  
Toshiro Inaba ◽  
Hisataka Maki ◽  
...  
Keyword(s):  
Heart Failure ◽  
De Novo ◽  
Collecting Duct ◽  
Initial Response ◽  
Aquaporin 2 ◽  
Long Term Treatment ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Introduction: Preserved function of collecting duct is essential for the response to tolvaptan (TLV), and urinary level of aquaporin 2 (U-AQP2) can be a marker for vasopressin-dependent activity of collecting duct. Hypothesis: Higher levels of U-AQP2 in proportion to plasma levels of vasopressin (P-AVP) may be associated with better initial responses to TLV and eventually result in the improved prognosis after long-term treatment of TLV. Methods: Consecutive 60 in-hospital patients with stage D heart failure (HF) who received TLV on a de novo basis were enrolled during 2011-2013. We also selected 60 HF patients by propensity score matching who were hospitalized during the same period but never treated with TLV. Events were defined as death and/or HF re-hospitalization. Results: TLV (3.75-15 mg/day) was continuously administered except death or ventricular assist device implantation occurred. There were 41 patients (group 1) who had increases in UV over the first 24 h after TLV initiation, and all of them had U-AQP2/P-AVP ≥0.5 х103 with higher U-AQP2 levels (5.42 ± 3.54 ng/mL) before TLV treatment. On the other hand, UV rather decreased even after TLV initiation in 19 patients over the first 24 h (group 2). Those in the group 2 universally had U-AQP2/P-AVP <0.5 х103, extremely low U-AQP2 levels (0.76 ± 0.59 ng/mL, p<0.001 vs. group 1), and similar P-AVP with the group 1 at baseline. The 41 and 19 patients without TLV treatment (group 3 and 4) were respectively matched to the group 1 and 2 by propensity scores. Interestingly, every patient in the group 3 had U-AQP2/P-AVP ≥0.5 х103, and vice versa in the group 4. Among the four groups, congestion-related symptoms were only improved in the group 1 after 1 month of enrollment. The patients in the group 1 had significantly better event-free survival over 2-year by TLV treatment compared with the group 3 (76% vs. 43%, p<0.014). In contrast, the patients in the group 2 and 4 had very poor prognoses regardless of TLV treatment (7% vs. 11%, p=0.823). Conclusions: U-AQP2/P-AVP is a novel predictor for the initial response to TLV in HF patients. Patients with higher U-AQP2/P-AVP may enjoy a better prognosis by long-term TLV treatment probably due to efficient resolution of congestion.

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