The Clinical Characteristics, Genetic Alterations and Prognostic Significance of De Novo Acute Myeloid Leukemia (AML) with Hyperleukocytosis (HL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2860-2860
Author(s):  
Feng-Ming Tien ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Wen-Chien Chou ◽  
Chi-Cheng Li ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
Genetic Alterations ◽  
Intensive Chemotherapy ◽  
Survival Curves ◽  
Prognosis Factor ◽  
Mutation Status ◽  
The Poor ◽  
Kaplan Meier

Abstract Introduction Acute myeloid leukemia (AML) with hyperleukocytosis (HL), commonly defined as white blood cell (WBC) counts >100,000/uL, are intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the clinical characteristics, genetic alterations in this group of patients are limited, and the role of hematopoietic stem cell transplantation (HSCT) is controversial. Method A cohort of 755 de novo AML patients diagnosed from 1994 to 2011 who had cryopreserved cells for analysis were enrolled. The mutation status of 18 genes was determined by Sanger sequencing and/or next generation sequencing (NGS). We compared cytogenetics and relevant mutations in these genes between AML patients with and without HL, and exposed their prognostic implications. Results The median age was 54 (range 15-94). 101 (13.4%) patients had HL. HL was associated with younger age (median age 47 vs. 54, P=0.022), higher peripheral blast percentage (77.6% vs. 39%, P<0.0001), and higher lactate dehydrogenase levels (1921.5 U/L vs. 778 U/L, P<0.0001). HL was correlated with French-American-British (FAB) M1, M4 or M5 subtypes, but inversely with M2 or M3 subtypes. The HL patients had more frequently AML with intermediate-risk cytogenetics (85.4 vs. 63.6%, P< 0.0001), but less commonly good-risk (9.3 vs. 21.7%, P=0.004) or poor-risk cytogenetic AML (5.2 vs. 14.6%, P=0.01). Specifically, HL occurred less frequently in core-binding factor AML, or complex karyotype. The most common molecular event in the patients with HL was FLT3/ITD (38.9%), followed by NPM1 (28.7%), CEBPA (26%), NRAS (20.9%), and TET2 (19.4%) mutations. The HL patients had significantly higher incidences of NPM1 (28.7% vs. 18.2%, P=0.013), FLT3/ITD(38.9% vs. 19.1%, P<0.0001), CEBPA (26% vs. 11.1%, P<0.0001), and TET2 (19.4% vs. 9.9%, P=0.006) mutations. In contrast, HL was mutually exclusive with KRAS mutations. Survival analysis was performed on the 525 patients who received standard intensive chemotherapy; among whom 69 patients had HL. The HL patients had lower complete remission (CR) rates compared to those without (63.8% vs. 78.2%, P=0.009). Further, the HL patients had significantly poorer overall survival (OS) and disease-free survival (DFS) than those without (median 24 months vs. not reached (NR), P=0.042; 6.5 vs. 11.8 months, P=0.005, respectively, Figure 1). Older age, poor-risk cytogenetics, RUNX1, TP53 and WT1 mutations were other poor prognostic factors for OS (median, 18.1 months vs. NR, P<0.0001; 8.5 months vs. NR, P<0.0001; 18 months vs. NR, P=0.001; 5.9 months vs. NR, P<0.0001; 14.0 months vs. NR, P=0.006, respectively) and DFS (median, 7.7 vs. 15.2 months, P=0.005; 0 vs. 12,2 months, P<0.0001; 5.2 vs. 12 months, P=0.001; 0 vs. 11.8 months, P<0.0001; 6.5 vs. 12 months, P=0.001, respectively). NPM1+/FLT3-ITD-, and biallelic CEBPA mutations were favourable prognostic factors for both OS and DFS. In the multivariate Cox proportional hazards regression analysis, HL was still an independent poor prognosis factor for OS and DFS (RR, 1.67; 95% CI, 1.15-2.43, P=0.007 and RR, 1.58; 95% CI, 1.12-2.25, P=0.010, respectively). Intriguingly, among the HL patients, those with HSCT had longer OS than those without (58.2 vs 10.7 months, P=0.004, Figure 2). Among the 172 patients receiving allogeneic HSCT, the poor prognostic impact of HL on OS and DFS was lost (P=0.832 and P=0.678, respectively). HSCT could ameliorate the poor survival impact of HL. Conclusion The HL patients represented 13.4% of our AML cohort and showed distinct clinic features and genetic alterations compared to those without HL. HL was an independent poor prognosis factor irrespective of cytogenetics change or mutation status, and the HL patients may potentially benefit from HSCT. Figure 1 The Kaplan-Meier survival curves for OS (A) and DFS (B) stratified by hyperleukocytosis (HL) or not in the 525 AML patients who received standard intensive chemotherapy (A) (B) Figure 1. The Kaplan-Meier survival curves for OS (A) and DFS (B) stratified by hyperleukocytosis (HL) or not in the 525 AML patients who received standard intensive chemotherapy. / (A). / (B) Figure 2 The Kaplan-Meier survival curves for OS stratified by HSCT or not in the 69 HL patients who received standard intensive chemotherapy Figure 2. The Kaplan-Meier survival curves for OS stratified by HSCT or not in the 69 HL patients who received standard intensive chemotherapy Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Derivative chromosome 9 deletions in chronic myeloid leukemia: poor prognosis is not associated with loss of ABL-BCRexpression, elevated BCR-ABL levels, or karyotypic instability

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4547-4553 ◽  
Author(s):  
Brian J. P. Huntly ◽  
Anthony J. Bench ◽  
Eric Delabesse ◽  
Alistair G. Reid ◽  
Juan Li ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Prognostic Indicator ◽  
Genetic Alterations ◽  
Chromosome 9 ◽  
Derivative Chromosome ◽  
The Poor

Deletions of the derivative chromosome 9 have recently been reported in chronic myeloid leukemia. These deletions are large, occur at the time of the Philadelphia (Ph) translocation, span the translocation breakpoint, and represent a powerful prognostic indicator. However, the molecular mechanisms responsible for the poor prognosis associated with deletions are obscure, and several possible models are investigated here. First, we demonstrate that all derivative chromosome 9 deletions detected by fluorescence in situ hybridization were associated with an absence ofABL-BCR expression. However, loss ofABL-BCR expression also occurred without an overt deletion, suggesting the existence of other mechanisms by whichABL-BCR transcription can be abolished. Furthermore, analysis of survival in 160 patients demonstrated that loss ofABL-BCR expression, in contrast to deletion status, was not an indicator of poor prognosis. Second, we addressed the possibility that concomitant small deletions of the Ph chromosome modulateBCR-ABL transcription. Real-time reverse-transcription polymerase chain reaction was used to demonstrate that derivative chromosome 9 deletions were not accompanied by altered levels of BCR-ABL transcripts. Third, deletions may represent a consequence of genetic instability within the target cell at the time of the Ph translocation, with the poor prognosis reflecting a predisposition to subsequent additional genetic alterations. However, patients with deletions do not exhibit an increased frequency of secondary cytogenetic changes following disease progression. Taken together, these data support a model in which deletions of the derivative chromosome 9 result in rapid disease progression as a result of the loss of one or more genes within the deleted region.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Poor Prognosis in MLL-Rearranged Solid Tumor Therapy Related-Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hanzhou Qi ◽  
Hua Jin ◽  
Qifa Liu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Solid Tumor ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
Tumor Therapy ◽  
The Poor ◽  
De Novo Aml ◽  
Solid Tumor Therapy ◽  
Acute Myeloid

BACKGROUND: MLL rearrangement is very common in solid tumor therapy-related acute myeloid leukemia (t-AML). This study investigated the prognosis of MLL t-AML. METHODS: Patients with solid tumor t-AML and MLL de novo AML were enrolled in this retrospective study. The patients were divided into 3 groups: non-MLL t-AML(n=41), MLL t-AML(n=18) and MLL de novo AML(n=98). RESULTS: Of the 157 patients enrolled, 150 patients underwent anti-leukemia therapy. The complete remission (CR) rate was 83.3%, 85.5% and 86.2%(P=0.251), respectively, in MLL t-AML, non-MLL t-AML and MLL AML groups. The 3-years overall survival (OS) was 37.5%, 21.5% and 20.4% (P=0.046). The 3-years leukemia-free survival (LFS) was 28.0%, 32.2% and 22.7% (P=0.031), and the incidence of relapse was 30.0%, 50.4% and 53.5% (P=0.382), respectively, in the three groups. Multivariate analysis revealed that MLL t-AML was a risk factor while allo-HSCT a protective factor for relapse, LFS, and OS (P=0.005, P&lt;0.001 and P&lt;0.001) (P&lt;0.001, P&lt;0.001 and P=0.002, respectively). The 3-years OS was 0%, 17.9% and 0%(P=0.038), LFS was 0%, 23.1% and 0%(P=0.017), and relapse was 100%, 53.1% and 74.4% (P=0.001), respectively among three groups in patients undergoing chemotherapy alone, while OS was 64.3%, 52.7% and 40.7% (P=0.713), LFS was 60.0%, 48.8% and 37.0% (P=0.934), and relapse was 25.0%, 47.4% and 47.5% (P=0.872), respectively, among these group in the patients undergoing allo-HSCT. Intriguingly, MLL t-AML was no longer risk factor for relapse and LFS (P=0.882 and P=0.484, respectively), while it became a favorable factor for OS (P=0.011) in the patients undergoing allo-HSCT CONCLUSIONS: MLL t-AML had poor prognosis compared with non-MLL t-AML and MLL de novo AML,, but allo-HSCT might overcome the poor prognosis of MLL t-AML. Disclosures Liu: Nanfang Hospital, Southern Medical University: Research Funding.

scholarly journals Umbilical cord blood transplantation can overcome the poor prognosis of KMT2A-MLLT3 acute myeloid leukemia and can lead to good GVHD-free/relapse-free survival

2021 ◽  
Author(s):  
Juan Tong ◽  
Lei Zhang ◽  
Huilan Liu ◽  
Xiucai Xu ◽  
Changcheng Zheng ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Chemotherapy Group ◽  
Blood Transplantation ◽  
The Poor ◽  
First Complete Remission

AbstractThis is a retrospective study comparing the effectiveness of umbilical cord blood transplantation (UCBT) and chemotherapy for patients in the first complete remission period for acute myeloid leukemia with KMT2A-MLLT3 rearrangements. A total of 22 patients were included, all of whom achieved first complete remission (CR1) through 1–2 rounds of induction chemotherapy, excluding patients with an early relapse. Twelve patients were treated with UCBT, and 10 patients were treated with chemotherapy after 2 to 4 courses of consolidation therapy. The 3-year overall survival (OS) of the UCBT group was 71.3% (95% CI, 34.4–89.8%), and that of the chemotherapy group was 10% (95% CI, 5.89–37.3%). The OS of the UCBT group was significantly higher than that of the chemotherapy group (P = 0.003). The disease-free survival (DFS) of the UCBT group was 60.8% (95% CI, 25.0–83.6%), which was significantly higher than the 10% (95% CI, 5.72–35.8%) of the chemotherapy group (P = 0.003). The relapse rate of the UCBT group was 23.6% (95% CI, 0–46.8%), and that of the chemotherapy group was 85.4% (95% CI, 35.8–98.4%), which was significantly higher than that of the UCBT group (P < 0.001). The non-relapse mortality (NRM) rate in the UCBT group was 19.8% (95% CI, 0–41.3%), and that in the chemotherapy group was 0.0%. The NRM rate in the UCBT group was higher than that in the chemotherapy group, but there was no significant difference between the two groups (P = 0.272). Two patients in the UCBT group relapsed, two died of acute and chronic GVHD, and one patient developed chronic GVHD 140 days after UCBT and is still alive, so the GVHD-free/relapse-free survival (GRFS) was 50% (95% CI, 17.2–76.1%). AML patients with KMT2A-MLLT3 rearrangements who receive chemotherapy as their consolidation therapy after CR1 have a very poor prognosis. UCBT can overcome the poor prognosis and significantly improve survival, and the GRFS for these patients is very good. We suggest that UCBT is a better choice than chemotherapy for KMT2A-MLLT3 patients.

Dedifferentiated chondrosarcoma: A report of the clinicopathologic features and outcomes of 16 cases treated at a single institution.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e23500-e23500
Author(s):  
Charles Gusho ◽  
Steven Gitelis ◽  
Alan T. Blank
Keyword(s):  
Poor Prognosis ◽  
Nonoperative Management ◽  
Clinicopathological Features ◽  
Clinicopathologic Features ◽  
Single Institution ◽  
Dedifferentiated Chondrosarcoma ◽  
Wide Margin ◽  
The Poor ◽  
Kaplan Meier ◽  
Period Data

e23500 Background: Dedifferentiated chondrosarcoma (DCS) is a rare and aggressive malignancy with a poor prognosis. The purpose of this investigation was to assess the clinicopathological features and outcomes of DCS patients treated at a single institution. Methods: This study was a retrospective review over a consecutive twenty-year period. Data including treatment details and outcomes were recorded. Results: A total of 16 cases from 2000 to 2018 were reviewed. The median age was 62 years (IQR, 52-69 years) and the majority of DCS arose in the femur (50%, n = 8) and pelvis (25%, n = 4). Fourteen (88%) cases received limb salvage/wide margin resection (n = 13) or intralesional surgery (n = 1). For all DCS, the median estimated overall survival (OS) was 46 months (95% CI, 1-90 months) with both a five and ten-year survival probability of 32%. On Kaplan-Meier analysis there was no difference between operative versus nonoperative management (p = 0.747), surgery alone versus surgery/chemotherapy (p = 0.265), nor surgery alone versus surgery/chemotherapy/radiation (p = 0.698). Conclusions: Our findings confirm the poor prognosis of DCS patients, though with a five-year estimate of 32%, higher than previous literature. Together with existing literature, our data may enable future strategic recommendation of DCS patients.

scholarly journals Genetic Alterations and Their Clinical Implications in Older Patients with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4956-4956
Author(s):  
Cheng-Hong Tsai ◽  
Hsin-An Hou ◽  
Wen-Chien Chou ◽  
Chien-Chin Lin ◽  
Chien-Yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
The Elderly ◽  
Genetic Alterations ◽  
Patient Specific ◽  
Intensive Chemotherapy ◽  
P53 Mutations ◽  
Acute Myeloid

Abstract Introduction Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. Methods and Materials A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger (<60 years, n=315). Result Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival. Conclusion Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated. Disclosures Tang: Novartis: Consultancy, Honoraria.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

scholarly journals Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2873-2882 ◽  
Author(s):  
OI Olopade ◽  
M Thangavelu ◽  
RA Larson ◽  
R Mick ◽  
A Kowal-Vern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Favorable Prognosis ◽  
Multiple Abnormalities ◽  
French American British

Abstract We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

High expression of SLC38A1 predicts poor prognosis in patients with de novo acute myeloid leukemia

2019 ◽  
Vol 234 (11) ◽  
pp. 20322-20328 ◽  
Author(s):  
Yan Li ◽  
Haigang Shao ◽  
Zhenzhen Da ◽  
Jinlan Pan ◽  
Bin Fu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
High Expression ◽  
Acute Myeloid

scholarly journals In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3861-3868 ◽  
Author(s):  
E Klumper ◽  
R Pieters ◽  
AJ Veerman ◽  
DR Huismans ◽  
AH Loonen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
Acquired Drug Resistance ◽  
The Poor ◽  
Response To Chemotherapy

Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.

Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA)

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2717-2723 ◽  
Author(s):  
Claude Preudhomme ◽  
Christophe Sagot ◽  
Nicolas Boissel ◽  
Jean-Michel Cayuela ◽  
Isabelle Tigaud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Prognosis Factor ◽  
Cebpa Mutations ◽  
Factor C ◽  
French Association ◽  
Acute Myeloid

The transcription factor C/EBPα is crucial for differentiation of mature granulocytes. Recently, differentCEBPA gene mutations likely to induce differentiation arrest have been described in nearly 10% of patients with acute myeloid leukemia (AML). In the present study, we retrospectively analyzed the prognostic significance of CEBPA mutations in 135 AML patients (French-American-British [FAB]-M3 excluded). All patients were prospectively enrolled between 1990 and 1996 in a multicenter trial of the ALFA (Acute Leukemia French Association) Group (median age 45 years, median follow-up 5.7 years). Mutations were assessed using direct sequencing of the CEBPA gene. Twenty-two mutations were found in 15 (11%) of 135 patients tested. Twelve patients had at least one mutation located in the N-terminal part of the protein leading to the lack of expression of the full-length C/EBPα protein. CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P = .02). FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P = .54). Presence of CEBPA mutations was identified as an independent good prognosis factor for outcome even after adjustment on cytogenetics and FLT3 status (estimated 5-year overall survival 53% vs 25%, P = .04).FLT3-ITD appeared to act as a major bad prognosis factor in patients with CEBPA-mutated AML. We thus propose a risk classification that includes in the favorable subgroup all patients from the intermediate subgroup displaying CEBPA mutations when not associated with FLT3-ITD.

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