Cytogenetic, Molecular and Clinical Features Associated with Rare CBFB-MYH11 Fusion Transcripts in Patients (Pts) with Acute Myeloid Leukemia (AML) and inv(16)/t(16;16)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2514-2514
Author(s):  
Colin G Edwards ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Sebastian Schwind ◽  
Peter Paschka ◽  
...  
Keyword(s):  
De Novo ◽  
Fusion Transcript ◽  
Type A ◽  
High Dose ◽  
Type I ◽  
Consolidation Therapy ◽  
Kit Mutation ◽  
Fusion Transcripts ◽  
Cell Counts ◽  
The Impact

Abstract Abstract 2514 Approximately 8% of de novo AML pts have inv(16)(p13q22) or t(16;16)(p13;q22) [inv(16)] and this cytogenetic group is associated with high complete remission (CR) rates and a relatively favorable outcome after cytarabine/daunorubicin (ara-c/dnr)-based induction and high-dose ara-c (HiDAC) consolidation therapy. However, ∼40% of these pts still relapse. The molecular mechanisms that impact on the prognosis of inv(16) pts remain to be fully elucidated. We and others reported that presence of the mutated KIT (mutKIT) gene is associated with worse outcome, but other contributing factors may play a role. Molecularly, inv(16) results in disruption of the MYH11 gene at 16p13 and CBFB gene at 16q22, creating a CBFB-MYH11 fusion gene. Since the genomic breakpoints within CBFB and MYH11 are variable and the fusion transcripts depend on the exons fused, at least 11 different sized CBFB-MYH11 fusion transcript variants have been found. The frequency of each fusion varies, with ∼85% being type A and ∼5% each types D and E; types B, C, and F-K were reported in single cases (hereafter we refer to non-type A fusions as “rare”). To our knowledge, only one study (Schnittger et al. Leukemia 2007;21:725) has examined the biological and clinical significance of rare CBFB-MYH11 fusions in AML. Fusion type was not found to be prognostic, but the cohort included pts with therapy-related and secondary AML. Thus, further studies are warranted. Accordingly, we analyzed 149 de novo CBFB-MYH11 positive AML pts aged <60 years (y; median, 40 y; range 18–59) receiving ara-c/dnr-based induction and HiDAC consolidation therapy (Cancer and Leukemia Group B protocols 9621, 19808, 10503). Among 149 pts, 129 (87%) had type A fusion, 17 (11%) type E, 2 (1%) type D, and 1 (<1%) type I. Pts with rare fusions had lower white blood cell counts (P=.02; median, 18.9 v 27.5 ×109/L), less often skin infiltration (P=.04; 0% v 18%) and tended to have FAB subtype M4Eo less often than the type A fusion pts (P=.13; 67% v 85%). Eighteen rare and 100 type A fusion pts had at least 1.7 y follow-up and thus could be analyzed for outcome. No significant differences in CR rates (P=1.00; 94% v 92%), cumulative incidence of relapse (CIR; P=.16; 5 y rates, 30% v 47%) or overall survival (OS; P=.30; 5 y rates, 78% v 60%) were found between rare and type A fusion pts. However, a trend toward longer event-free survival (EFS) was observed for rare fusion pts compared with type A pts (P=.07; 5 y rates, 66% v 42%; Figure). In an analysis of secondary cytogenetic abnormalities (abns) we found trisomies 8, 13 and 21 were more frequent in rare fusion pts than in type A pts (P=.03; P=.07; P<.001, respectively). Of the rare fusion pts, 44% had at least one of +8, +13 or +21 compared to only 11% of the type A pts. No rare fusion transcript pt harbored +22, which was present in 24 (19%) pts with type A fusion (P=.05; Table]. Strikingly, no rare fusion pt had mutKIT compared with 29% of type A fusion pts (P=.01). Given that +22 has been associated with improved and mutKIT with worse outcome, we also assessed the impact of fusion transcript type by restricting our analysis first to pts with no +22, then to pts without mutKIT, and finally excluding both +22 and mutKIT. No significant differences in CR rates, CIR, OS or EFS were observed between the two groups. We conclude that the type of fusion transcript does not appear to affect significantly the prognosis of inv(16) pts, although a favorable trend for pts with the rare transcript exists. Type A and rare fusion pts differ with regard to distribution of accompanying genetic or cytogenetic alterations, such as KIT mutation or +22, which did not occur in any of the rare fusion pts. Further studies are required to elucidate if the rare fusion transcripts themselves created the necessary biologic conditions that exclude the concurrent presence of the genome aberrations.Table.Secondary abns in pts with rare v type A fusionsAbn type*Rare fusion (n=20†) No. pts (%)Type A fusion (n=129) No. pts (%)P‡None [sole inv(16)]8 (44)81 (63).20+220 (0)24 (19).05+85 (28)11 (9).03+215 (28)2 (2)<.001+132 (11)2 (2).07At least one +8 or +13 or +218 (44)14 (11).001del(7q)/add(7q)0 (0)7 (5).60Other2 (11)11 (9).66*Pts may have multiple secondary abns.†2 unknown.‡Fisher's exact test. Disclosures: No relevant conflicts of interest to declare.

Repetitive Cycles of High-Dose Cytarabine Benefit Patients With Acute Myeloid Leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461

2004 ◽  
Vol 22 (6) ◽  
pp. 1087-1094 ◽  
Author(s):  
John C. Byrd ◽  
Amy S. Ruppert ◽  
Krzysztof Mrózek ◽  
Andrew J. Carroll ◽  
Colin G. Edwards ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Statistical Significance ◽  
Multivariable Analysis ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
The Impact ◽  
To Receive ◽  
Acute Myeloid

Purpose To study the impact of repetitive (three to four courses) versus a single course of high-dose cytarabine (HDAC) consolidation therapy on outcome of patients with acute myeloid leukemia (AML) and inv(16)(p13q22) or t(16;16)(p13;q22). Patients and Methods We examined the cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) for 48 adults younger than 60 years with inv(16)/t(16;16) who had attained a complete remission on one of four consecutive clinical trials and were assigned to receive HDAC consolidation therapy. Twenty-eight patients were assigned to either three or four courses of HDAC, and 20 patients were assigned to one course of HDAC followed by alternative intensive consolidation therapy. Results Pretreatment features were similar for the two groups. The CIR was significantly decreased in patients assigned to receive three to four cycles of HDAC compared with patients assigned to one course (P = .03; 5-year CIR, 43% v 70%, respectively). The difference in RFS also approached statistical significance (P = .06). In a multivariable analysis that adjusted for potential confounding covariates, only treatment assignment (three to four cycles of HDAC) predicted for superior RFS (P = .02). The OS of both groups was similar (P = .93; 5-year OS, 75% for the three to four cycles of HDAC group v 70% for the one cycle of HDAC group), reflecting a high success rate with stem-cell transplantation salvage treatment administered among patients in both treatment groups. Conclusion We conclude that, in AML patients with inv(16)/t(16;16), repetitive HDAC therapy decreases the likelihood of relapse compared with consolidation regimens including less HDAC.

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Luznik Leo ◽  
Chen R. Allen ◽  
Kaup Michele ◽  
Bright C. Emilie ◽  
Bolanos-Meade Javier ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Gvhd ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
The Impact

Abstract Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

Efficacy of dose intensification in induction therapy for localized Ewing sarcoma: Italian Sarcoma Group (ISG) and Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) ISG/AIEOP EW-1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11501-11501
Author(s):  
Roberto Luksch ◽  
Giuseppe Maria Milano ◽  
Francesco Barretta ◽  
Alessandra Longhi ◽  
Emanuela Palmerini ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Ewing Sarcoma ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Poor Responders ◽  
High Dose ◽  
Type I ◽  
Tumour Site ◽  
Dose Intensification ◽  
The Impact

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume < 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p < 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with < 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.

The Influence of PET/Gallium (PET/Gal) Status and High-Dose Rituximab (HDR) in Patients with Aggressive, Large, B-Cell Lymphoma (LBCL) Receiving Autologous Stem Cell Transplants (ASCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3058-3058 ◽  
Author(s):  
Amin M. Alousi ◽  
Rima M. Saliba ◽  
Grace-Julia Okoroji ◽  
Chitra Hosing ◽  
Barry I. Samuels ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
De Novo ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Disease Status ◽  
High Dose ◽  
Free Survival ◽  
The Impact

Abstract Background: PET/Gal status has been reported to be an important predictor of outcome in patients with LBCL who receive an ASCT. Newer conditioning regimens which include high-dose rituximab (HDR) have been shown to improve results (Khouri, JCO, 2005). The impact of HDR on the outcome of patients based on PET/Gal status has not been determined. Methods: A retrospective review of patients with chemo-sensitive, LBCL who received an ASCT on a research protocol at MD Anderson between 1995 and 2005 was performed. Factors that were considered for outcome included: Age, IPI, # of prior chemotherapies, B2-microglobulin, disease status at transplant, HDR and PET/Gal status. In patients who received HDR, it was given with stem cell mobilization and then again on days +1 and +8 following transplant. Results: A total of 188 patients were identified. Median age was 49 years with 108 (57%) male patients. 147 patients (78%) had de novo LBCL and 41 (22%) had a LBCL of follicular origin (LBCL-F). 83 (39%) patients received HDR. At transplantation, 95 patients (50%) were in PR, 71 (38%) in CRU and 22 (12%) in CR. 142 (76%) patients were PET/Gal negative, 37 (20%) PET/Gal positive and 9 (4%) were unknown. Median follow-up was 47 months. On multivariate analysis, for patients with de novo LBCL, PET/Gal status and HDR were the only predictors for progression and progression free survival (PFS). Patients who were PET/Gal negative and those that received HDR had a hazard ratio (HR) of 0.3 (p<0.001) and 0.5 (p=0.02) for progression, respectively (see the table below for the cumulative incidence (CI) for progression and PFS at 54 months according to HDR and PET/Gal status for de novo LBCL undergoing ASCT). PET/Gal Status and HDR were also found to be predictive for patients with LBCL- F on univariate analysis, however due to the small numbers in this subset; multivariate analysis could not be performed. PFS at 54 months for patients with LBCL-F who were PET/Gal negative was 40% versus 17% in the PET/Gal positive group, (p=0.006). PFS for those LBCL-F patients who received HDR was 81% as compared to 23% for those who did not receive HDR, (p=0.007). Conclusions: The two most important predictors of outcome following ASCT are PET/Gal status and whether HDR was given with the transplant regimen. The addition of HDR to the transplant regimen decreases the risk for progression irrespective of PET/Gal status; however the improvement is more significant in patients with a negative PET/Gal scan. C.I. for progression and PFS at 54 months for de novo DLBCL PET/Gal Status HDR CI of Progression (%) Progression Free Survival Positive No 83 17 Positive Yes 54 45 Negative No 35 55 Negative Yes 22 75

Achievement a Negative 18-FDG/PET Status at the End of Procedure by Tailored Treatment According Pre-Transplantation Pet Status in Lymphomas Improve 5 Years-OS and EFS.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2193-2193
Author(s):  
Dominique Bordessoule ◽  
Benoit Marin ◽  
Stéphane Girault ◽  
Fredericka Bompart ◽  
Julie Abraham ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Fdg Pet ◽  
De Novo ◽  
Residual Disease ◽  
Prognostic Score ◽  
Conditioning Regimen ◽  
Metabolic Imaging ◽  
High Dose ◽  
The Impact

Abstract In patients (pts) with non Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) with poor prognosis factors, pre-transplantation (ASCT) 18-fluorodeoxyglucose (FDG)-positron-emission tomography (PET) status is important for evaluation of response and predicting the outcome. A positive pre-ASCT PET (+PET) indicated a high risk (HR) of relapse which was increased by a positive post-ASCT PET. For these patients additional therapy (salvage therapies prior ASCT, targeted radiotherapy, second transplant or new treatment approaches) will be required (Spaepen K 2001, Filmont JE 2003; Svoboda J 2006, Mounier, 2007). In a french regional network, we try to obtain a negative metabolic status with additive « targeted-therapy », before or after the ASCT, in the hope to improve the clinical outcome for these HR NHL/HD. Objective: The study assessed the impact of tailored therapy according to pre-transplantation FDG-PET status on pts outcome after high-dose chemotherapy and ASCT. Patients & Methods: We performed a retrospective analysis of pts included according three criteria: 1) histologically proven malignant lymphoma (NHL/HD) with a metabolic active disease in PET imaging 2) planned to receive an ASCT for HR factors according international recommendations (de novo initial aaIPI III/IV or not in CR after front line chemotherapy or in early and unfavorable relapse; 3) having a PET prospectively performed prior and after ASCT on a CDET replaced in 2005 by a PET/CT (Siemens). The metabolic imaging interpretation had been performed by 2 experienced nuclear physicans first blinded to clinical and CT scan then discussed in multidisciplinary team. + PET defined as any focal or diffuse area of increased activity in a location suspect for residual disease and -PET if any metabolic activity according revised Cheson criteria. Survival analysis were performed using Kaplan-Meier method for event free survival (EFS), overall survival (OS). Results: For 95 consecutive pts treated from 05/1999 to 12/2006 18 HD and 77 NHL, an ASCT has been planned either in initial HR prognostic score (n=39), primary refractory disease (n=31), or in relapse (n=25). First line therapy were mainly ABVD for HD and ACVBP/CHOP +/− Rituximab for NHL. A pre-ASCT -PET was obtained in 52 pts (55%) and 43 pts (45%) remained pre-ASCT +PET. Additional salvage chemotherapy (MINE or DHAP(+/−R) most frequently) obtained a - PET status from pre-ASCT +PET in 9/43 pts (21%) prior the ASCT. ASCT has been performed for all these HR pts with a conditioning regimen mainly BICNU-Etoposide-Aracytine-Melphalan (BEAM). After ASCT, 22/43 pre-ASCT +PET pts were converted in a post-ASCT -PET status. Residual disease of post-ASCT +PET pts was treated by targeted radiation (n=11) or by a second transplant (n=2). One pre-ASCT -PET converted to positive (1/52). At the end of procedure, we obtained a –PET status in 88 pts (92%), persistant + PET in 7 pts (7%) (3 PR/4 PD). With a median follow-up of 4.14 years (range 0.61–9.48) since diagnosis, 15/43pts (35%) pre-ASCT +PET and 14/52pts (26%) pre-HDT/ASCT -PET pts relapsed. Mortality was 23% (22/95pts range -PET : 11/52 (21%) and +/−PET 11/43 (25%) respectively and 4/7 (57%) resistant +/+PET). In –PET and in +/−PET median OS and EFS were not reached, 5yOS was 79% and 73% (p=0.7) and 5 y-EFS 62% and 54% respectively (p=0.2). In residual post-ASCT+PET, median OS was 4,5 months. Conclusion: PET-guided consolidative therapy prior or post ASCT in patients with HR lymphoma is routinely feasible and could obtain a negative status in 92% of pts at the end of procedure and reduce relapses with encouraging results in terms of OS and EFS with a 5-y median follow-up. Next step is now on-going: including pts in multicentric PETdesigned trials to confirm prospectively the crucial role of the metabolic imaging to determine which is the best tailoring therapy.

scholarly journals Frequency of p190 and p210 BCR-ABL Fusions Genes in Acute Lymphoblastic Leukemia in a Long Group of Adults and Childhood

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5273-5273 ◽  
Author(s):  
Rosa Maria Arana-Trejo ◽  
Gregorio Ignacio ◽  
Raquel Amador-Sánchez ◽  
Jorge Cruz-Rico ◽  
Maria-Paula Hernández ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Age Group ◽  
Fusion Genes ◽  
Rt Pcr ◽  
Pcr Multiplex ◽  
The Impact

Abstract The Ph chromosome is a translocation (9;22)(q34;q11), that results in the constitutive activation of the BCR/ABL tyrosine kinase. The incidence of BCR/ABL in Acute Lymphoblastic Leukemia (ALL) increases with age, from less than 5% in younger children to 20-30% in older adults, with a peak incidence in patients aged 35-50 years. BCR/ABL1 has diverse breakpoints, in adult patients with Ph+ ALL the p190BCR/ABL transcript e1a2/e3a2 may be documented in 50-70%; p210BCR/ABL b2a2/b3a2 in 15-30% of patients and <1% having both breakpoint. Childhood patients with Ph+ ALL fusion genes present p190BCR/ABL transcipt e1a2/e3a2 in 90% and the remaining present other fusion transcrit or co-expression of both p190 and p210 BCR-ABL. OBJETIVE. The aim of this study was identify the occurrence of fusion genes to p190 and p210 BCR-ABL rearrangements in adult and childhood patients with ALL. METHODS. We include between 2008-2015 870 patients with ALL de novo from seven different hospitals from México, the 45% (394) were childood and the rest 55% (476) were adults. All patients were studied to RT-PCR multiplex and nested in RNA for fusion transcripts 190 and p210 BCR-ABL, at diagnosis, according to the international BIOMED-1 protocol. RESULTS. From 870 patients with ALL, the most frequent subtype FAB were L2 (87%) and second L1 (13%). The immunophenotype by B-ALL was to 80%, bilineal in 5% and the rest have not data. The overall incidence to BCR-ABL in both children and adults with ALL were to 17% [147/870]. The analysis by age group were; in 476 adults with ALL, their average age was 37 years old (range 17-84 years) and their incidence of BCR-ABL positive was 20% (95/476 cases). The distributions by type of fusion transcript were 83% p190 and 17% p210; we did not observe co-expression of transcripts to BCR-ABL. In children patients the average age was 9 years old (range 0.1-16 years), the incidence of BCR-ABL was 13.2% (52/394 cases). The distributions by type of fusion transcript to BCR-ABL were p190 78.8%; p210 13.4% and their co-expression by both isoforms 8%. CONCLUSION. The 20% frequency for BCR-ABL1 in adults with ALL is concordant with others reports published, with values from 17% to 37% with predominancy of p190 (83%). In our pediatric patients group with ALL, document a frequency of 13.2% by BCR-ABL1 positive; it is higher than other populations reporting 5-10%. The distributions of fusion transcript p190 and p210 coincides with previous prevalence estimates in other countries where p190 transcript was the most frequent. But the coexpression of both isoforms [p190/p210] were 8% it has not been reported in this age group with ALL. In conclusion, we recommend to identify the BCR-ABL transcript type in every patients with ALL at diagnosis, using a RT-PCR verified method for P190/p210 and followed the patient by mesure the impact clinical and will be adjust the treatment like o plus the cytogenetic studies. Disclosures No relevant conflicts of interest to declare.

Prognosis of AML with Unfavourable Cytogenetics Treated with Intensive Double Induction Chemotherapy: An Analysis of 342 Patients from the German AMLCG-2000 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2006-2006
Author(s):  
Klaus H. Metzeler ◽  
Christian Buske ◽  
Jan Braess ◽  
Karsten Spiekermann ◽  
Michaela Feuring-Buske ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Induction Therapy ◽  
De Novo ◽  
High Dose ◽  
Complex Karyotype ◽  
Younger Patients ◽  
Conventional Dose ◽  
De Novo Aml ◽  
Chemotherapy Patients ◽  
The Impact

Abstract Background: The prognosis of patients with acute myeloid leukemia (AML) has improved in recent years, partly due to the use of intensive double induction chemotherapy. Patients with adverse cytogenetic risk factors, especially those with a complex aberrant karyotype, however, still have a grave prognosis. Previous results from the German AMLCG study group have shown that younger patients with a complex karyotype may profit from double induction therapy containing one course of high dose AraC. It is unclear whether further intensification of induction chemotherapy may prolong survival. Methods: We investigated the outcomes of patients with unfavourable cytogenetics treated with either high-dose AraC and mitoxantrone (HAM) followed by thioguanine, conventional-dose AraC and daunorubicin (TAD) or with two courses of HAM in the prospectively randomized AMLCG-2000 trial. We included patients with unbalanced chromosomal aberrations (−5, −7, del(5q) or del(7q), or abnormalities involving 3q) and patients with a complex aberrant karyotype. Results: A total of 392 patients with unfavourable cytogenetics were analysed. Of those, 261 had de novo AML, 51 had secondary AML following a myelodysplastic syndrome (sAML) and 30 had therapy-related AML (tAML). The rate of complete remissions (CR) was significantly higher in patients with de novo AML compared with secondary or therapy-related AML (39 % vs. 20% vs. 23%, P=0.01). The overall survival (OS), however, was significantly shortened only in patients with tAML but not in those with sAML (median OS, 43 d (tAML) vs. 248 d (sAML) vs. 213 d (de novo AML), P=0.027). 233 patients had a complex aberrant karyotype. Although their CR rate was similar to patients with other unfavourable cytogenetics, OS was significantly worse (median, 169 vs. 327 days, P<0.001). Among patients with a complex karyotype, those with 5 or more cytogenetic abnormalities had a significantly shorter event-free survival (EFS) than those with only 3 or 4 aberrations, but OS was similar. 171 patients were randomly assigned to HAM-HAM induction therapy and 171 received TAD-HA. Both groups were well matched with respect to baseline characteristics. The CR rate was 32% in both arms, and there were no significant differences in EFS or OS. When the impact of the induction regimen was analyzed for younger patients (≤ 60 years) with a complex karyotype (N=90), HAM-HAM induced a CR rate of 48%, compared to 34% with TAD-HAM (n.s.) and significantly prolonged the EFS (median, 85 vs. 61 days; P=0.037). So far, this advantage in the EFS did not translate into an improved OS. Conclusion: Among patients with AML and unfavourable cytognetics, subgroups with different risks for relapse and death can be identified. Therapy-related AML with adverse cytogenetic features had a particularly bad prognosis in this trial. For the total cohort, double induction with HAM-HAM does not result in significantly improved outcomes. However, younger patients with a complex karyotype may profit from treatment with two courses of high-dose AraC.

Impact of Post-Remission Treatments in Patients Aged 65–70 Years with De Novo AML: A Comparison of Two Concomitant Randomized ALFA Trials with Overlapping Age Inclusion Criteria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 557-557
Author(s):  
Raphael Itzykson ◽  
Claude Gardin ◽  
Cécile Pautas ◽  
Xavier Thomas ◽  
Pascal Turlure ◽  
...  
Keyword(s):  
Risk Factor ◽  
De Novo ◽  
Univariate Analysis ◽  
Significant Risk ◽  
High Dose ◽  
Inclusion Criteria ◽  
Aged Patients ◽  
Ambulatory Treatment ◽  
De Novo Aml ◽  
The Impact

Abstract Background: The outcome of older patients with AML treated with intensive chemotherapy remains poor. No standard of treatment for post-remission therapy been demonstrated in these patients, and repeated high-dose cytarabine (AraC) post-remission courses have only been shown of benefit in patients aged of 50 years or less. Objective: To compare the overall outcome and the impact of post-remission strategies in patients with newly-diagnosed AML aged 65 to 70 years and enrolled during the same period (12/1999 to 10/2006) in two concomitant randomized ALFA trials with overlapping age inclusion criteria. The ALFA-9803 study (Gardin et al, Blood, 2007) was designed for elderly patients (65y+ with de novo or post-MDS AML) while the ALFA-9801 trial was designed for middle-aged patients (50–70y with de novo AML) (Pautas et al. ASH 2007 #162). All other inclusion criteria were similar among the two trials. Patients and Treatments: Analysis was restricted to the 211 patients aged 65–70y with de novo AML. A frontline randomization between idarubicin (IDA) and daunorubicin (DNR) was included in the two trials, with a total IDA/DNR dose of 36/180 mg and 36–48/240 mg during induction, for the 9803 and 9801 trial respectively. After induction, both trials essentially differed by the post-remission chemotherapy, which comprised two intermediate-dose cytarabine (IDAC) cycles in the 9801 trial and a second randomization between one repeated 3+7 like cycle and six 1+5 anthracycline-based ambulatory consolidations in the 9803 trial. Only two patients received a stem cell transplantation in first CR (1 allogeneic, 1 autologous). In both studies, the initial randomization between IDA and DNR had no impact on OS. Nevertheless, all analyses were stratified on IDA/DNR randomization arm. Results: Seventy-six patients were treated in the 9801 trial and 135 in the 9803 trial. Median age was 67 years and M/F sex ratio was 110/101. Median WBC was 7.4 G/L. Cytogenetic risk was favorable in 9 (4%), intermediate in 118 (56%) and unfavorable in 54 (26%) patients, respectively. Ninety-five and 116 patients were randomized to receive DNR and IDA, respectively. Aside from median age (67 vs 68 years in 9801 and 9803, respectively; P&lt;.001), patient characteristics were similar between the two protocol subgroups, in terms of inclusion date, sex, PS, FAB, cytogenetics, and WBC. The overall CR rate was 62%. In univariate analysis, there was a trend for a higher CR rate in the younger 9801 trial (70 vs 57%; p=.17). As expected, cytogenetics was identified as the sole significant risk factor for CR achievement (89% in favorable, 68% in intermediate, and 44% in unfavorable-risk; p=0.03). Median follow-up, OS, RFS, and EFS were 35, 14, 12 and 6.5 months, respectively. In univariate analysis, the trial did not influence OS (3-year OS, 20 vs 17% in the 9801 and 9803 trial, respectively; p=.71), RFS or EFS. Again, the only identified risk factor for OS and EFS was high-risk cytogenetics. After CR achievement, 44 9801-patients (58%) received the planned IDAC consolidation, while 30 (22%) and 33 (24%) 9803-patients received the planned 3+7 like or ambulatory consolidation, respectively. In these patients, no significant differences in CR duration (median CR duration: 12.4, 14.8 and 11.9 months with IDAC, 3+7 like, and ambulatory consolidation, respectively; p=0.57) was observed among these three different post-remission strategies. In multivariate analysis, only unfavorable cytogenetics affected OS (HR=1.8 [95% CI 1.3–2.6], p=10-3) and EFS (HR=2.0 [1.4–2.8], p&lt;10-4), with a trend for adverse RFS (HR=1.6 [.99–2.7], p=.055). Conclusion: In patients aged 65–70 years with de novo AML, more intensive post-remission therapy containing IDAC does not appear to significantly improve EFS, RFS, or OS, as compared to less intensive consolidation or even repeated anthracyclin-based ambulatory treatment. The poor early outcome of those with unfavorable cytogenetics justifies the evaluation of new global therapeutic approaches in this patient subset.

No Benefit of Combining Additional Compounds with Standard High Dose Cytarabine Consolidation: Results of the Prospective Randomized AML2003 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 255-255 ◽  
Author(s):  
Stefani Parmentier ◽  
Martin Bornhäuser ◽  
Christian Thiede ◽  
Christoph Röllig ◽  
Michael Kramer ◽  
...  
Keyword(s):  
Complete Remission ◽  
Induction Therapy ◽  
High Dose ◽  
Unrelated Donor ◽  
Consolidation Therapy ◽  
Event Free Survival ◽  
Long Term Outcome ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
The Impact

Abstract Abstract 255 Introduction: Standard treatment of acute myeloid leukemia (AML) comprises one or two cycles of chemotherapy to induce complete remission (CR) followed by postremission treatment in order to prevent relapse of the disease (consolidation therapy). In 2003, we initiated a prospective multicenter randomized trial to investigate the impact of different consolidation strategies on long-term outcome in AML patients ≤ 60 years. Consolidation options comprised upfront allogeneic stem cell transplantation (allo SCT) in aplasia after induction therapy, autologous SCT, and three cycles of standard high-dose-cytarabine-based consolidation. For patients receiving high-dose cytarabine, the main study aim was to evaluate the benefit of adding additional mitoxantrone and amsacrine to cytarabine consolidation. Design: From 2003 to 2009, 1182 patients (median age, 48 years; range 16–60 years) with untreated AML were randomly assigned at diagnosis to different consolidation strategies after classical 7+3 induction. According to the risk-adapted treatment strategy of the trial, cytogenetically or molecular intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-identical-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. IR and AR patients with no available donor should receive autologous SCT. All favorable risk patients and patients with no available donor were scheduled for high-dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine alone while the other half received high dose cytarabine with the addition of amsacrine and mitoxantrone. Standard chemotherapy consisted of three cycles with high dose cytarabine (2 × 3 g/m2, day 1,3,5) whereas combined consolidation contained two cycles of MAC (cytarabine 2 × 1g/m2, day 1–6, mitoxantrone 10 mg/m2, day 4–6) plus one cycle of MAMAC (cytarabine 2 × 1 g/m2, day 1–5, amsacrine 100 mg/m2, day 1–5). In order to evaluate the effect of the two cytarabine based consolidation strategies, we determined overall survival (OS) and event free survival (EFS) using the method of Kaplan Meyer. Survival distributions were compared using the log rank test. Results: 1182 patients were randomized for further intervention (Arm A+B: n=582, 49.3%; Arm C+D: n=600, 50.7 %). Median follow-up was 41.4 months (95%-CI 39.3–43.6). A total number of 375 patients received allogeneic (n=322) or autologous SCT (n=53) and 807 patients were consolidated with cytarabine. Of these patients, 407 were randomized for cytarabine alone and 400were randomized to receive cytarabine plus mitoxantrone and amsacrine (MAC/MAC/MAMAC). Complete remission rate (CR) after second induction therapy was 59.1% (n=698). Between the four arms, there were no significant differences of the CR rates. Five-year OS of patients receiving high dose cytarabine alone was 47.1% (95%-CI 42.0–52.2%), for patients receiving MAC/MAMAC as consolidation therapy it was 46.8% (95%-CI 42.3–51.3%; p = 0.610). Three-year event free survival (EFS) was also not significant with 30.5% (95%-CI 26.6–34.4%) for patients receiving high dose cytarabine alone and 35.6% (95%-CI 31.7–39.5%; p = 0.059) for patients receiving MAC/MAMAC. Conclusions: According to our data, the addition of mitoxantrone and amsacrine to high dose cytarabine consolidation confers no benefit for treatment outcome in younger AML patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals De Novo Endotoxin-Induced Production of Antibodies against the Bile Salt Export Pump Associated with Bacterial Infection following Major Hepatectomy

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Kun-Ming Chan ◽  
Chih-Hsien Cheng ◽  
Tsung-Han Wu ◽  
Chen-Fang Lee ◽  
Ting-Jung Wu ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Bile Salt ◽  
Liver Tissue ◽  
De Novo ◽  
Major Hepatectomy ◽  
Liver Volume ◽  
Severe Infection ◽  
High Dose ◽  
Bile Salt Export Pump ◽  
The Impact

Background. Clinically severe infection-related inflammation after major liver resection may cause hyperbilirubinemia. This study aims to clarify the impact of bacterial infection and endotoxins on the hepatobiliary transporter system and to explore possible mechanisms of endotoxin-related postoperative hyperbilirubinemia.Method. Mice that underwent major hepatectomy with removal of at least 70% of liver volume were exposed to lipopolysaccharide (LPS) at different dosages. Subsequently, hepatobiliary transporter compounds related to bile salt excretion were further investigated.Results. The expression of genes related to hepatobiliary transporter compounds was not significantly different in the liver tissue of mice after major hepatectomy and LPS exposure. However, bile salt export pump (BSEP) protein expression within the liver tissue of mice treated with LPS after major hepatectomy was relatively weaker and was even further reduced in the high-dose LPS group. The formation of antibodies against the BSEP in response to endotoxin exposure was also detected.Conclusion. This study illustrates a possible mechanism whereby the dysfunction of hepatobiliary transporter systems caused by endotoxin-induced autoantibodies may be involved in the development of postoperative jaundice associated with bacterial infection after major hepatectomy.

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