Acute Myeloid Leukemia Diagnosed During Pregnancy: Facing Challenges. Systematic Review and Analysis Of 174 Reported Cases

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1421-1421
Author(s):  
Israel Henig ◽  
Liat Vidal ◽  
Oryan Henig ◽  
Noam Benyamini ◽  
Irit Avivi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Birth Weight ◽  
Pregnant Women ◽  
Gestational Age ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fetal Outcome ◽  
Available N ◽  
Live Baby ◽  
Acute Myeloid

Abstract Introduction Data on pregnancy-associated acute myeloid leukemia (PA-AML) are scanty, coming from case reports and very small retrospective case series. The aim of the current study was to analyze reported maternal and fetal clinical characteristics and treatment decisions and provide a comprehensive basis for the development of guidelines for the management of women with PA-AML. Methods A systematic search of articles on PA-AML diagnosed during pregnancy or immediately after delivery, published between January 1967 and June 2013 in journals indexed in PubMed, was performed. Search terms of “acute leukemia”, “acute myeloid leukemia” and “acute promyelocytic leukemia” (APL) were crossed with terms “pregnancy”, “gestation” and “partum”. Additional potentially relevant reports referenced in reviewed articles were evaluated. Data on women's age, gestational stage, AML subtype, therapy, timing of its application, achieving complete remission (CR), survival status and fetal outcome (malformations, survival, birth weight) were recorded. Results One hundred and seventy three PA-AML cases, reported in 88 papers, were analyzed. AML was reported in 120 cases (69%) and APL in 53 cases (31%). The French-American-British (FAB) AML categorization, available for 59 non-M3 AML cases, showed the distribution of AML subtypes similar to that reported in non-pregnant women (M1 - 3%, M2 - 12%, M4 - 30%, M5 - 27%, M6 - 5%, M7 - 1%). Median age at diagnosis was 28 years (range 15-45). Thirty seven women (22%) were diagnosed during 1st trimester, 85 (50%) in 2nd and 47 (28%) in 3rd trimester. The trimester was not reported in 4 cases. One hundred and twenty five women received chemotherapy during pregnancy: 18 in whom therapy was started in 1st trimester, 81- in 2nd and 26 - in 3rd trimester. In 46 patients, treatment was administered either after elective abortion (n = 26), or after delivery of a live baby (n =20). Data on therapy were unavailable in 2 cases. Delay in therapy beyond 1 week (range 2-20) from diagnosis (n = 21) did not affect the overall survival (OS) compared to that obtained in women treated promptly (median 11.5 vs 10.5 months, respectively; p=0.572). Among patients for whom remission data were available (n=151), 82 (73%) treated during pregnancy, and 27 (70%) treated after delivery, achieved CR. Within a median follow-up of 9 months (range 0-300), median OS for the entire cohort was 10.5 months (9 for AML vs 15.5 for APL; p=0.001). A multivariate analysis showed APL to be the only independent predictive factor for an improved OS (p=0.037), while maternal age and treatment delay had no statistically significant impact on OS (p= 0.83 and 0.889, respectively). Notably, the OS of women with PA-AML tended to improve over time (19 months for women treated over the last 30 years vs 8 months for those treated earlier; p = 0.09) (Figure 1); however, it is still less than the median OS of 3 years reported in age-matched non-pregnant women (http://seer.cancer.gov). One hundred and forty seven pregnancies were evaluable for the fetal outcome (excluding elective abortions); 117 (80%) pregnancies ended in delivery of a live baby. Six pregnancies where fetuses were exposed to chemotherapy during the 1st (n=1) or 2nd (n=5) trimester resulted in delivery of malformed newborns; 28 pregnancies ended in fetal death (5 stillbirths, 13 intrauterine fetal deaths, 4 post-delivery deaths, 5 unplanned abortions, 1 cause unavailable). Fetal outcome was unavailable for 2 babies. The median birth weight was 2.3 Kg for the 89 babies with reported weight (range 1.7-5 Kg). Among the 83 babies for whom data about birth weight and pregnancy week were available, 59% had a weight appropriate for the gestational age, 30% were small for gestational age and 11% were large for gestational age. In 89% of cases where information was available, the delivery was pre-term. No case of fetal leukemia was reported. Conclusions Based on our retrospective analysis, the outcome of women diagnosed with AML during pregnancy appears to be worse than that reported in age-matched non-pregnant women. The survival rate of the fetuses exposed to chemotherapy is encouraging. The incidence of malformations is low and the birth weight of most newborns is appropriate for the gestational age. Therapy delay could be considered in some of these patients, but large registry-based studies are warranted to establish treatment recommendations for the management of PA-AML. Disclosures: No relevant conflicts of interest to declare.

Hyper-Recovery Of Platelet After Induction Therapy Is a Significant Predictor For Relapse In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1420-1420
Author(s):  
Etsuko Yamazaki ◽  
Megumi Itabashi ◽  
Ogusa Eriko ◽  
Ayumi Numata ◽  
Wataru Yamamoto ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Birth Weight ◽  
Pregnant Women ◽  
Induction Therapy ◽  
Gestational Age ◽  
Myeloid Leukemia ◽  
Fetal Outcome ◽  
Newly Diagnosed ◽  
Live Baby ◽  
Acute Myeloid

Abstract Introduction Although chemotherapy induces complete remission (CR) in the majority of patients with newly diagnosed acute myeloid leukemia (AML), disease will recur in most. The pretreatment cytogenetic and molecular genetic findings are the most important predictors of outcome. However, there are some reports that post treatment parameter value are valuable for prediction of disease recurrence. Here, we examine clinical findings to assess risk of relapse in AML. Patients & Methods We performed a retrospective study involving 303 adult patients newly diagnosed with AML excepted acute promyelocytic leukemia between 2001 and 2012 and received either daunorubicin or idarubicin in combination with cytarabine as induction therapy. 230 patients (75.9%) obtained CR. Data was analyzed for cumulative incidence of relapse (CIR) and disease-free survival (DFS) in these 230 patients. Results The study included 140 males and 90 females, with median age at diagnosis of 48 years (range, 15-77 years). Pretreatment cytogenetics was determined in 228 (99%): 57 (25%) were categorized as favorable (t(8;21) or inv(16)/t(16;16) with or without other abnormalities), 23 (10%) had abnormalities of chromosome 7 and/or complex karyotype defined as Results: One hundred and seventy three PA-AML cases, reported in 88 papers, were analyzed. AML was reported in 120 cases (69%) and APL in 53 cases (31%). The French-American-British (FAB) AML categorization, available for 59 non-M3 AML cases, showed the distribution of AML subtypes similar to that reported in non-pregnant women (M1 - 3%, M2 - 12%, M4 - 30%, M5 - 27%, M6 - 5%, M7 - 1%). Median age at diagnosis was 28 years (range 15-45). Thirty seven women (22%) were diagnosed during 1st trimester, 85 (50%) in 2nd and 47 (28%) in 3rd trimester. The trimester was not reported in 4 cases. One hundred and twenty five women received chemotherapy during pregnancy: 18 in whom therapy was started in 1st trimester, 81- in 2nd and 26 - in 3rd trimester. In 46 patients, treatment was administered either after elective abortion (n = 26), or after delivery of a live baby (n =20). Data on therapy were unavailable in 2 cases. Delay in therapy beyond 1 week (range 2-20) from diagnosis (n = 21) did not affect the overall survival (OS) compared to that obtained in women treated promptly (median 11.5 vs 10.5 months, respectively; p=0.572). Among patients for whom remission data were available (n=151), 82 (73%) treated during pregnancy, and 27 (70%) treated after delivery, achieved CR. Within a median follow-up of 9 months (range 0-300), median OS for the entire cohort was 10.5 months (9 for AML vs 15.5 for APL; p=0.001). A multivariate analysis showed APL to be the only independent predictive factor for an improved OS (p=0.037), while maternal age and treatment delay had no statistically significant impact on OS (p= 0.83 and 0.889, respectively). Notably, the OS of women with PA-AML tended to improve over time (19 months for women treated over the last 30 years vs 8 months for those treated earlier; p = 0.09) (Figure 1); however, it is still less than the median OS of 3 years reported in age-matched non-pregnant women (http://seer.cancer.gov). One hundred and forty seven pregnancies were evaluable for the fetal outcome (excluding elective abortions); 117 (80%) pregnancies ended in delivery of a live baby. Six pregnancies where fetuses were exposed to chemotherapy during the 1st (n=1) or 2nd (n=5) trimester resulted in delivery of malformed newborns; 28 pregnancies ended in fetal death (5 stillbirths, 13 intrauterine fetal deaths, 4 post-delivery deaths, 5 unplanned abortions, 1 cause unavailable). Fetal outcome was unavailable for 2 babies. The median birth weight was 2.3 Kg for the 89 babies with reported weight (range 1.7-5 Kg). Among the 83 babies for whom data about birth weight and pregnancy week were available, 59% had a weight appropriate for the gestational age, 30% were small for gestational age and 11% were large for gestational age. In 89% of cases where information was available, the delivery was pre-term. No case of fetal leukemia was reported. Conclusions Based on our retrospective analysis, the outcome of women diagnosed with AML during pregnancy appears to be worse than that reported in age-matched non-pregnant women. The survival rate of the fetuses exposed to chemotherapy is encouraging. The incidence of malformations is low and the birth weight of most newborns is appropriate for the gestational age. Therapy delay could be considered in some of these patients, but large registry-based studies are warranted to establish treatment recommendations for the management of PA-AML. Disclosures: No relevant conflicts of interest to declare.

The Use of Purine Analogues Does Not Aggravate Infectious Complications During Induction and Consolidation Therapy of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1011-1011
Author(s):  
Marek Seweryn ◽  
Jerzy Wojnar ◽  
Dariusz Kata ◽  
Slawomira Kyrcz-Krzemien
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Infectious Complications ◽  
Induction Treatment ◽  
High Dose ◽  
Consolidation Therapy ◽  
Purine Analogues ◽  
Acute Myeloid

Abstract Abstract 1011 Poster Board I-33 Background: Addition of purine analogues to standard induction therapy of acute myeloid leukemia (AML) had previously been demonstrated to increase complete remission rate. The aim of this study was to analyze whether the use of cladribine or fludarabine during induction and consolidation increases the risk of infectious complications. Material and methods: 118 AML patients, included in two consecutive randomized trials between 1999-2006 in a single centre were analyzed. Induction therapy consisted of daunorubicin + cytarabine (DA-7, n=53) alone or in combination with cladribine or fludarabine (DAC-7 + DAF-7, n=65 ). Consolidation included one course of high-dose AraC + mitoxantrone and one course of high-dose AraC +/- purine analogues. A median age was 45(17-58) years and 48(20-60) years for patients treated with and without purine analogues, respectively. Results: The frequency of neutropenic fever as well as microbiologically documented bacterial, fungal and viral infections during induction and consolidation did not differ between two compared groups - receiving or not purine analogues. Time to infection occurrence and infection duration were similar in both study groups. During induction and both consolidation treatments significant lower values of lymphocytosis were observed in the group of patients treated with purine analogues. There was a slight tendency to increased rate of mucositis for patients treated with purine analogues (60% vs. 44.3%, p=0.07) during induction treatment, while infections affecting skin and soft tissues were significant frequent for patients treated without purine analogues (43.3% vs. 18%, p=0.03) during second consolidation treatment (high dose AraC). The usage of intravenous anti-infectious medications (antibiotics, antifungal, antiviral) and periods of hospitalization did not differ between two groups in this study. Conclusions: We conclude that the use of purine analogues, either cladribine or fludarabine along with conventional induction and consolidation therapy does not aggreviate infectious complications in adults with AML. Disclosures: No relevant conflicts of interest to declare.

Acute Myeloid Leukemia with Mutated NPM1 Presenting with Life-Threatening, Either Arterial or Venous, Thromboembolism: a Report of 4 Cases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4135-4135
Author(s):  
Maria Paola Martelli ◽  
Lorenzo Brunetti ◽  
Luca De Carolis ◽  
Elisabetta Agliani ◽  
Laura Berchicci ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Venous Thromboembolism ◽  
Myeloid Leukemia ◽  
Thromboembolic Event ◽  
Conflicts Of Interest ◽  
The Other ◽  
Leukemic Cells ◽  
Acute Ischemia ◽  
Life Threatening ◽  
Acute Myeloid

Abstract Abstract 4135 Acute myeloid leukemia (AML) expressing mutated NPM1 gene and cytoplasmic nucleophosmin (NPMc+ AML) [Falini B et al, NEJM 2005;352:254-266] is a new entity of WHO classification that shows distinctive biological and clinical features. AML with mutated NPM1 usually presents with a high white blood cell count; the bone marrow biopsy is usually markedly hypercellular and leukemic cells frequently show myelomonocytic or monocytic features, with dysplasia and involvement of two or more cell lineages in about 25% of cases. Lack, or low expression, of CD34 in over 90% of cases is the most distinctive immunophenotypic feature of NPM1-mutated AML and is independent of leukemic cell maturation. NPM1 gene mutation without concomitant FLT3-ITD identify a subgroup of AML patients with a favorable prognosis and has been associated with an approximately 50-60% probability of survival at 5 years in younger patients. Here we report 4 out of 41 (10%) patients, admitted at our Hospital in the last year, with new-diagnosed AML with mutated NPM1 presenting with life-threatening thromboembolic (either arterial or venous) events. The main characteristics of these patients are summarized in Table 1. The patients had neither personal nor family history concerning thromboembolism. Hyperleukocytosis was a common feature of the vast majority of NPM1-mutated AML patients at diagnosis. Immunophenotypic analysis did not show a peculiar phenotype in these patients. Table 1 Characteristics of patients with NPM1-mutated AML and thrombosis. Case report no Age Sex (M/F) FAB subtype WBC/mmc Type of thrombosis Site of thrombosis 1 41 F M1 14970 arterial Anterior interventricular branch of left coronary artery 2 56 M M4 93990 arterial external iliac and femoral (right limb) 3 63 M M2 113000 deep venous great saphenous veins (bilateral) 4 73 F M4 190000 deep venous iliac and femoral In two patients (cases 1 and 2), the arterial thromboembolic event (acute myocardial infarction and acute ischemia of right lower limb, respectively) presented about one month before diagnosis of leukemia. In the other 2 patients (cases 3 and 4), deep venous thromboembolism was concomitant with the diagnosis of leukemia. One patient (case 4), who could not initiate chemotherapy for severe concomitant renal failure, died few days after diagnosis. The other patients recovered from the acute event and upon diagnosis of leukemia were promptly treated with standard polychemotherapy which allowed to obtain complete hematological remission associated with complete resolution of the thromboembolic event. The clinical course after chemotherapeutic treatment of the patients outlines the importance and life saving role of early chemotherapy even under adverse circumstances. The pathogenesis of thromboembolic disease in hematological malignancies is complex and multifactorial: tumor cell-derived procoagulant, fibrinolytic or proteolytic factors and inflammatory cytokines affect clotting activation. Other important factors include infectious complications and hyperleukocytosis. However, large vessel thrombosis is a very rare clinical presentation. Our report of severe thromboembolic events at presentation in AML with mutated NPM1 suggests some still unidentified biological features of this leukemia which we are currently investigating. Disclosures: No relevant conflicts of interest to declare.

Mesenchimal Stroma Cells From Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia Show Distinct Cytogenetic and DNA-Mutation Data as Compared with Bone Marrow Leukemic Blasts.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4697-4697
Author(s):  
Olga Blau ◽  
Wolf-Karsten Hofmann ◽  
Claudia D Baldus ◽  
Gundula Thiel ◽  
Florian Nolte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Control Analysis ◽  
Npm1 Mutation ◽  
Dna Mutation ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Abstract 4697 Bone marrow mesenchymal stroma cells (BMSC) are key components of the hematopoietic microenvironment. BMSC from patients with acute myeloid leukemia (AML) and myelodisplasic syndrome (MDS) display functional and quantitative alterations. To gain insight into these questions, we carried out cytogenetic analyses, FISH, FLT3 and NPM1 mutation examinations of both hematopoietic (HC) and BMSC derived from 53 AML and 54 MDS patients and 35 healthy donors after in vitro culture expansion. Clonal chromosomal aberrations were detectable in BMSC of 12% of patients. Using FISH we have assume that cytogenetic markers in BMSC were always distinct as the aberrations in HC from the same individual. 17% and 12% of AML patients showed FLT3 and NPM1 mutations in HC, respectively. In BMSC, we could not detect mutations of NPM1 and FLT3, independent from the mutation status of HC. For control analysis, BMSC cultures from 35 healthy donors were prepared under the same conditions. BMSC from healthy donors did show normal diploid karyotypes and absence of specific DNA-mutations of NPM1 and FLT3. Our data indicate that BMSC from MDS and AML patients are not a part of malignant clone and characterized by genetic aberrations. Lack of aberrations as detected in HC and appearance of novel clonal rearrangements in BMSC may suggest enhanced genetic susceptibility and potential involvement of BMSC in the pathogenesis of MDS and AML. Disclosures: No relevant conflicts of interest to declare.

TNF-α and Its Receptors in Patients with Acute Myeloid Leukemia Undergoing alloHSCT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4484-4484
Author(s):  
Slawomira Kyrcz-Krzemien ◽  
Monika Zielinska ◽  
Agnieszka Wieclawek ◽  
Tomasz Czerw ◽  
Aleksandra Holowiecka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Serum Levels ◽  
Haematopoietic Stem Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Tnf Α ◽  
Acute Myeloid

Abstract Abstract 4484 Introduction Several studies have demonstrated, that TNF α and its receptors (sTNFR) can be used as prognostic markers for major transplant related complications (TRC) after allogeneic haematopoietic stem cell transplantation (alloHSCT). Measurement of that inflammatory cytokine and sTNFR during pretransplant conditioning and early after transplantation may also reflect the conditioning-induced tissue damage. Patients and methods Our study included a group of 36 adult patients with acute myeloid leukemia (AML) in complete remission, who underwent alloHSCT following standard myeloablative conditioning according to Bu/Cy protocol (17 patients) or reduced-toxicity myeloablative conditioning with treosulfan-based regimens (19 patients). 21 patients received alloHSCT from a sibling and 15 from an unrelated donor. The expression of TNF-α, TNFRI and TNFRII were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMC) before the start of conditioning, on the day of transplantation and on day 30 after alloHSCT. We examined β-actin as well, which constitutes an endogenous amplification control and is a housekeeping gene. sTNFRI and sTNFRII serum levels were measured using an enzyme-linked immunosorbent assay (ELISA) at the same defined time points before and after alloHSCT. The Mann-Whitney U test was used to evaluate the significance of differences between the analyzed groups and the Shapiro-Wilk and Lilliefords tests to estimate data distribution. Results TNFRII mRNA was not detected in PBMC, but TNF-α and TNFRI mRNA as well as β-actin were discovered. The real time PCR showed significant decrease (p<0.004) in TNFRI expression on day 30 after transplantation in comparison to day 0. On day 30 expression of TNFRI was higher in patients treated with Treosulfan-based regimens than in patients treated with Bu/Cy (p=0.027). Plasma levels of sTNFRI and sTNFRII observed on day 0 and 30 were significantly elevated (p<0.05) compared with the levels prior to conditioning. Conclusion Our data indicate that sTNFRI and sTNFRII can be investigated as the markers reflecting the toxicity of the conditioning regimens in AML patients undergoing alloHSCT. The associations between TNF-α, TNFRI expression, serum levels of sTNFR and the clinical outcome after alloHSCT should be evaluated. Disclosures: No relevant conflicts of interest to declare.

MYB Overexpression Is Directly Involved in Acute Myeloid Leukemia Pathogenesis and Could Constitute a New Therapeutic Target for Patients with Aberrant Expression of This Gene.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2402-2402 ◽  
Author(s):  
Carmen Vicente ◽  
Ana Conchillo ◽  
Daphnie Pauwels ◽  
Iria Vazquez ◽  
Laura Garcia-Orti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Synergistic Effect ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Recurrent Event ◽  
Aberrant Expression ◽  
Acute Myeloid

Abstract Abstract 2402 Poster Board II-379 The MYB proto-oncogene encodes a nuclear transcription factor with an essential role in proliferation, lineage commitment, and differentiation of hematopoietic progenitor cells. Proper levels of MYB are known to be important during hematopoietic cell development, and the Myb gene is a frequent target of retroviral insertions in myeloid, B- and T-cell leukemias in the mouse. Overexpression of MYB in T-acute lymphoblastic leukemia (T-ALL) causes a differentiation block of the T cells, and it has been shown that NOTCH1 mutation and MYB duplication cooperate in the pathogenesis of T-ALL. Our aim was to study the role of MYB in the pathogenesis of acute myeloid leukemia (AML), and to investigate its potential as a target for therapy. We functionally characterized MYB in 15 AML cell lines. Twelve of the 15 cell lines tested had MYB overexpression. Knockdown of MYB by siRNA in these cell lines caused decreased cell viability and proliferation, and reduced the clonogenic capacity, that could be explained in some cell lines by changes on the stage of cell differentiation. These results show that MYB overexpression is involved in the pathogenesis of AML. Moreover, knockdown of MYB in combination with common AML treatments (Idarubicin, Cytarabine and Sorafenib) had a strong synergistic effect on proliferation and viability of cells, suggesting that MYB could be a new target for therapy in AML. These observations prompted us to quantify MYB expression in a cohort of 159 patients with AML at diagnosis. We detected MYB overexpression in 14.5% (23/159) patients, with a higher prevalence within the intermediate prognosis group (17/83, 20.5%), particularly in patients with normal karyotype (NK) (14/62, 22.6%). Interestingly, 33% of patients without FLT-3 ITD and NPM1 mutations had MYB overexpression. To study the prognosis impact of MYB overexpression in AML, we performed a survival analysis in a preliminary series of 100 AML patients at diagnosis. As expected, significant differences in OS according to age, complete remission and cytogenetic prognostic group were found (p<0.01). MYB overexpression had no significant impact in the OS; however, this genetic marker allowed distinguishing a group of patients with a worse outcome within the group that did not get complete remission after treatment. Recently it has been described that MYB duplication causes elevated MYB expression in T-ALL; we detected duplication of MYB in 2 of 13 AML cell lines and in 2 patients with MYB overexpression (2/23, 8.6%). In conclusion, these results show that aberrant expression of MYB is involved in the activation of pathways responsible for the increased proliferative and clonogenic capacity that is characteristic of AML, independently of other genetic aberrations. Moreover, we show that MYB overexpression is a recurrent event in AML, especially in the subgroup of patients with NK, and that MYB could cooperate with other mutations in the leukemic transformation, as described previously in T-ALL. The synergistic effect of combined treatments with MYB knockdown, suggest that MYB silencing could be a new target for therapy in patients with AML and MYB overexpression. Disclosures: No relevant conflicts of interest to declare.

Trisomy 8 in the Light of Recent Cytogenetic Classification Advances. A Study From the French Acute Myeloid Leukemia Intergroup.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2594-2594 ◽  
Author(s):  
Nicolas Boissel ◽  
Christine Terré ◽  
Pascale Cornillet-Lefebvre ◽  
Odile Maarek ◽  
Eric Lippert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Prognostic Impact ◽  
Trisomy 8 ◽  
Factors Associated ◽  
Acute Myeloid ◽  
Similar Incidence

Abstract Abstract 2594 Poster Board II-570 Background: Trisomy 8 (+8) is one of the most common cytogenetical abnormality observed in acute myeloid leukemia (AML). The prognostic impact of +8 as sole aberration remains unclear and +8 may be classified either within intermediate- or high-risk subgroups. Recently, the prognostic impact of cytogenetic in AML has been refined by the identification of: 1) favorable genotypes in cytogenetically normal (CN) AML defined by the presence of either NPM1 gene mutation (NPM1m) or CEBPA gene mutation (CEBPAm) and the absence of FLT3 duplication (FLT3/ITD); 2) highly unfavorable AML with monosomal karyotype (MK). The aim of this study was to precise the prognostic impact of: 1) additional +8 in various cytogenetic risk subgroups; and 2) +8 as sole aberration when compared to different CN-AML genotypes. Patients: A total of 2087 patients with AML (AML-M3 excluded) were treated in the LAM-2001, LAM-SA-2002, ALFA-9802 and ALFA-9801 studies from the French AML Intergroup. After central review, cytogenetic analysis was considered successful in 1796 patients. Abnormalities were categorized according to the French AML Intergroup classification. All analysis (complete remission, CR; overall survival, OS; probability of continuous complete remission, %CCR) were stratified on studies. Results: +8 was present in 171/1796 (9.5%) with a similar incidence among the different cytogenetic subgroups: 22/243 fav-risk (9.1%), 99/1121 int-risk (8.8%), and 50/432 unfav-risk (11.6%). The incidence of +8 was significantly higher in MK-AML versus non MK-AML (30/223, 13.5%, p=.04). In none of these subgroups (fav, int, unfav, and MK), the presence of +8 was associated with a significantly different outcome (CR, OS, %CCR). When compared to patients with CN-AML, the 78 patients with +8 as sole anomaly had a similar age, a lower WBC (median WBC: 5 G/L vs 11.5 G/L, p=.004), a similar incidence of FLT3/ITD (22.2% vs 23.7%, 6/27 vs 101/426, p=.99), and a lower incidence of NPM1m (23.8% vs 46.5%, 5/21 vs 187/402, p=.05). In patients with +8 as sole anomaly, prognostic factors associated with a shorter OS were age (p=.01), high WBC (p=.01), and presence of +8 in all analyzed metaphases which was found in 1/3 of patients (p=.05). In those patients, when compared to CN-AML in general, CR rate was similar (88% vs 87%, p=.99), but %CCR and OS were shorter without, however, reaching significance (5y-%CCR: 31.8% vs 45.7%, p=.18). When compared to CN-AML patients with favorable genotypes (NPM1m or CEBPAm w/o FLT3/ITD), patients with +8 as sole anomaly had now a lower CR rate (87% vs 93%, p=.13) and significantly shorter %CCR and OS (5y-%CCR: 37.4% vs 57.8%, p=.05; 5y-OS 35.6% vs 59.0%, p=.05). Conversely, the prognosis of patients with +8 as sole anomaly appeared similar to that of patients with CN-AML w/o favorable genotypes (5y-OS: 32.6%). Conclusion: We report here the largest cohort of patients with +8. Additional +8 is equally distributed among cytogenetic risk subgroups and does not impact prognosis in each of these subgroups. Patients with AML with +8 as sole anomaly have an outcome comparable to that of CN-AML without favorable genotypes, suggesting that these patients should be managed similarly. Disclosures: No relevant conflicts of interest to declare.

Selective and Titratable Effects On AML Genome Wide Methylation Patterning, Transcription and Clonogenicity Using Very Low Concentrations of 5-Aza-2'deoxycytidine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2385-2385
Author(s):  
Elisabeth Heuston ◽  
Jason E. Farrar ◽  
Timothy Triche ◽  
Jonathan Buckley ◽  
Poul Sorensen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Cellular Reprogramming ◽  
Transcription Profiles ◽  
Genome Wide ◽  
Low Concentrations ◽  
Xenograft Models ◽  
Methylation Patterns ◽  
Acute Myeloid

Abstract Abstract 2385 Poster Board II-362 5-Aza-2'deoxycytidine (5AzadC) has significantly contributed to the treatment of myelodysplatic syndromes (MDS) and acute myeloid leukemia (AML). But while the cytotoxic effects of 5AzadC have been well characterized, its influence on methylation-induced cellular reprogramming remains poorly understood. We have treated several AML cell lines at extremely low concentrations of 5AzadC (0 nM to 1.0 nM) over the course of three days, followed by the determination of genome wide methylation changes, alterations in transcription profiles as well as cell viability, proliferation, apoptosis and changes in clonogenicity. The results demonstrate titratable responses on both genomic methylation and transcriptional patterns as well as a selective effect on clonogenicity compared to cytotoxicity. An alternative chemotherapeutic cytosine analog, cytosine arabinofuranoside (AraC), does not show the same selective depletion of clonogenic cells, suggesting that 5AzadC's effects are likely due to altered epigenetic changes associated with cellular reprogramming rather than a direct cytotoxic effect. We are currently evaluating 5AzadC and AraC effects on this population using immunophenotyping methods as well as xenograft models of tumorigenicity. These findings describe a potential role for very low concentrations of 5AzadC in treating acute myeloid leukemia through a selective affect on genome wide methylation patterns leading to altered transcription that differentially effects the clonogenic, leukemic stem cell compartment. Disclosures: No relevant conflicts of interest to declare.

Epigenetic Inactivation of DBC1 in Acute Myeloid Leukaemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4429-4429
Author(s):  
Chen Zhao ◽  
Aili Dai ◽  
Ling Chen ◽  
Xiaoping Sun ◽  
Xin Han ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Acute Myeloid

Abstract Abstract 4429 DNA hypermethylation has important implications in the tumorigenesis and prognosis in acute myeloid leukemia (AML). To identify relevant methylated genes in AML, we have compared several expression and methylation profilings. With expression analysis, we identified that TRPC6, DBC1, DCC and SOX9 have decreased expression levels in the most analyzed AML cell lines. Among these candidates, DBC1 (deleted bladder cancer 1), a putative tumor suppressor, drew our attention because it is frequently methylated not only in hematological malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and acute lymphoblastic leukemia, but also in epithelial cancers. DBC1 may play an important role in the regulation of cell growth and programmed cell death. But the mechanisms of transcriptional control and function role in the hematological malignancies, especially on acute myeloid leukemia, are not well known. In this study, we analyzed the DBC1 expression pattern in 9 AML cell lines with RT-PCR analysis. DBC1 mRNA expression was observed in normal bone-marrow but diminished expression in all of 9 AML cell lines. DBC1 methylation was frequently observed in AML cells (9 of 9, 100%) and inversely correlated with DBC1 mRNA expression in a COBRA analysis (Combined Bisulfite Restriction Analysis). We also detected a frequent methylation of DBC1 in primary AML patient samples (9 of 9, 100%). These findings indicate that DBC1 is frequently silenced by hypermethylation in AML. We are in the process of investigation the functional role of DBC1 in the pathogenesis. In addition, diagnostic and prognostic values of DBC1 in AML are being pursued.* Chen Zhao and Aili Dai contributed equally to the presented work. Disclosures: No relevant conflicts of interest to declare.

Micafungin Versus Voriconazole for Empirical Antifungal Therapy In Febrile Neutropenic Patients with Acute Myeloid Leukemia: A Randomized, Controlled Trial.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1062-1062
Author(s):  
Tatsuo Oyake ◽  
Shugo Kowata ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antifungal Therapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fungal Infections ◽  
Controlled Trial ◽  
End Point ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients ◽  
Acute Myeloid

Abstract Abstract 1062 Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality among neutropenic patients after chemotherapy. The risk for these infections is related to the intensity and duration of neutropenia, and varies from 2% to 40%. Mortality rates associated with documented IFIs are considerable, reportedly ranging from 30% to 60%. Empirical antifungal therapy is the standard care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Several antifungal agents including voriconazole (VRCZ) or liposomal amphotericin B (L-AMB) have been studied as empirical therapy for febrile neutropenia (FN). However, limited data are available concerning the efficacy of micafungin (MCFG) in FN patients with acute myeloid leukemia (AML). Methods: We conducted a randomized, cooperative group, open-label trial comparing MCFG (150 mg once daily) with VRCZ (6 mg/kg twice on day 1 followed by 4 mg/kg twice daily) as first-line empirical antifungal treatment for 95 hospitalized FN patients with AML during induction or consolidation chemotherapy (MCFG, 49; VRCZ, 46). The efficacy end point was a favorable overall response, as determined by a five-component end point according to the criteria of Walsh et al (N Engl J Med 2004; 351: 1391). Results: At the time of enrolment, there were no significant differences in the demographics or baseline characteristics between the two groups. The mean treatment duration for MCFG and VRCZ was 10 and 9 days, respectively. The efficacy rates of MCFG and VRCZ were not significantly different (37.8% vs. 32.4%). The rates of breakthrough fungal infections (proven, probable and possible IFIs), successful treatment of baseline fungal infections, survival 7 days after end of therapy, and resolution of fever during neutropenia were similar in the two groups. However, premature discontinuation of therapy occurred less often in the MCFG group than in the VRCZ group (32.4% vs. 55.9%, P=0.0457*). In safety evaluation, there were fewer adverse events in the MCFG group than in the VRCZ group (27.0% vs. 64.7%, P=0.0013*). *: Chi square test Conclusions: MCFG was as effective as VRCZ, and better tolerated than VRCZ as empirical antifungal therapy in FN patients with AML. Disclosures: No relevant conflicts of interest to declare.

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