Chromosome Instability in Acute Myeloid Leukemia Is Associated to increased spontaneous breakage and Copy Number Variations (CNVs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4240-4240
Author(s):  
Ariela Freya Fundia ◽  
Irene Beatriz Larripa ◽  
Susana Hayde Acevedo
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Copy Number Variations ◽  
Fragile Sites ◽  
Bone Marrow Cultures ◽  
Acute Myeloid ◽  
Marrow Cultures

Abstract Abstract 4240 Acute Myeloid Leukemia (AML) is a genetically pleiomorphic disease characterized by multiple genetic lesions including structural and numerical chromosome aberrations, gene mutations and changes in gene expression. The underlying mechanism behind the acquisition of these genetic abnormalities is not known, but it is likely that are facilitated by factors that increase chromosomal and genetic instability. The aim of this work was to explore chromosomal instability (CIN) in de novo AML patients by evaluating chromosome fragility and acquired DNA copy number variations (CNVs). Leukemic karyotypes were scored on bone marrow cultures (24-48 hs, without mitogens) from 24 AML patients using conventional cytogenetic and FISH. Spontaneous and FUdR -induced chromosomal fragility was studied on PHA-stimulated lymphocytes cultures (72 hs) from 10 patients and 10 healthy individuals, with and without FUdR (10mg/ml). One hundred metaphases were analyzed blind using conventional cytogenetic with sequential GTG banding. CNVs were scored on bone marrow cultures from 14 AML patients using fluorescence in situ hybridization (FISH) with two probes targeting specific regions on chromosomes 5q31 (LSI EGR/D5S721:D5S23) and 7q31 (LSI D7S522/CEP7), loci reported to be critical hotspots involved in AML. The cut-off value for FISH scoring was calculated after analyzing 250 cells from each of 10 normal bone marrow samples. The cutoff for allelic losses was equal to 0.8% for either 5q or 7q probe. Nine out of 24 AML cases presented normal karyotypes in bone marrow samples while the following abnormalities: t(3;8), t(3;11), t(4;11), t(15;17), t(9;22) and inv(16) were detected in the remaining patients. Significantly increased frequencies of spontaneous chromosome breakage, scored on untreated cultures, were detected in patients (0.22±0.03) respect to controls (0.07±0.03) (p<0.05), showing a random pattern of distribution. No differences were observed between patients and controls with FUdR treatment. Statistical analysis with Ch2 test considering data of FUdR breakpoint distribution over all individuals, identified 21 common fragile sites (c-fra) in AML cases (p<0.005). The most common sites were located at 1p32, 1p22, 1q21, 3p14, 3q27, 4q31, 5q31, 6p21 and 9q13. A high inter-individual variation in the pattern of expression was observed. Using FISH, we obtained the DNA copy numbers at 5q and 7q in all AML samples. Only losses of DNA were found with both probes. The 5q signal count in patients with normal karyotypes was on average 6.4% (range 0.5-30%), while it was 24.9% (range 0.8-90%) for patients with abnormal cytogenetic. The 7q signal count was on average 3.9% (range 0.5-10.3%) and 20.6% (range 2-63%) for cases with normal and abnormal karyotypes, respectively. Particularly, we showed that 12/14 (85.7%) AML cases, either with normal or abnormal karyotypes, exhibited copy number losses at both regions, showing different values between each patient. These findings showed that leukemic patients exhibit a CIN phenotype, providing an unstable background and facilitating the acquisition of additional genetic changes, such as CNVs, which could play an important role in disease progression. Disclosures: No relevant conflicts of interest to declare.

Origin of stroma cells in long-term bone marrow cultures from patients with acute myeloid leukemia

1999 ◽  
Vol 78 (7) ◽  
pp. 305-314 ◽  
Author(s):  
W. Zhang ◽  
G. Knieling ◽  
G. Vohwinkel ◽  
T. Martinez ◽  
R. Kuse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cultures ◽  
Acute Myeloid ◽  
Marrow Cultures

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.

Fludarabine, Cytarabine, and Attenuated-Dose Idarubicin (m-FLAI) Induction for Elderly Patients with Acute Myeloid Leukemia: Results of a Multicenter Phase II Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3626-3626
Author(s):  
Yoojoo Lim ◽  
Youngil Koh ◽  
Sung-Soo Yoon ◽  
Seonyang Park ◽  
Byoung Kook Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Free Survival ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Abstract 3626 Introduction: Although there have been remarkable improvements in treatment of acute myeloid leukemia (AML), the prognosis of AML in elderly patients remains poor, and the best induction chemotherapy for these patients remains yet unknown. To devise an effective induction regimen for elderly patients with AML, we conducted a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) regimen in these patients. Patients and Methods: Elderly (60 years or older) AML patients who did not receive previous chemotherapy were enrolled. Patients received two consecutive cycles of m-FLAI chemotherapy as an induction. The m-FLAI regimen was comprised of fludarabine (25mg/m2, days 1–4), cytarabine (1000mg/m2, days 1–4), and attenuated-dose idarubicin (5mg/m2, days 1–3). The primary end point was complete remission (CR) rate. Results: A total of 108 patients (median age 68.4 years, M:F=64:44) were enrolled. CR was achieved in 62.9% of patients, and treatment-related mortality rate (TRM) was 25.8%. Median overall survival (OS) was 9.3 months, and median event-free survival (EFS) was 6.6 months. The mortality at 30 and 60 days was 18% and 24%, respectively. Performance status and comorbidity did not have prognostic value in these patients. Bone marrow expression of CD117 was related to long EFS and OS. Conclusion: In conclusion, m-FLAI is a safe and effective induction regimen for previously untreated AML in elderly patients. Bone marrow CD117 expression is an independent good prognostic factor in these patients. (ClinicalTrials.gov number, NCT01247493) Disclosures: No relevant conflicts of interest to declare.

EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2544-2544
Author(s):  
Xiuli Wang ◽  
Haiping Dai ◽  
Qian WANG ◽  
Qinrong Wang ◽  
Yang Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Coding Region ◽  
Acute Myeloid

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

CXCR4 Invalidation Limits the MLL-ENL Induced Leucemogenesis in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4089-4089
Author(s):  
Yanyan Zhang ◽  
Hadjer Abdelouahab ◽  
Aline Betems ◽  
Monika Wittner ◽  
William Vainchenker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 4089 The receptor CXCR4 and its ligand SDF-1 play major physiological roles especially on hematopoietic stem cells homing and retention. Many studies have implicated CXCR4 in the invasion by tumor cells of organs that produce SDF-1. In acute myeloid leukemia, the physiological role of CXCR4 is not fully understood. We used retrovirus to express MLL-ENL oncogene in CXCR4+/+ and CXCR4−/− hematopoietic primitive cells (Lin- isolated from fetal liver) and showed that CXCR4 is dispensable for generation of immortalized colonies in vitro. To determine CXCR4 function in vivo, CXCR4+/+ and CXCR4−/− transformed cells were transplanted into lethally irradiated mice. Whatever their phenotype, the recipient developed a myelo-monocytique leukemia characterized by their expression of Gr-1 and Mac-1. As expected, all recipients of MLL-ENL transduced CXCR4+/+ cells were moribund within 35 to 80 days post transplant (median survival time: 50 days). Strikingly, recipients of MLL-ENL transduced CXCR4−/− cells showed significantly increased lifespan, with a median survival time of 90 days. The cellularity of the peripheral blood of recipients of MLL-ENL transduced cells displayed considerable increases over time although this increase was much lower in CXCR4−/− than in CXCR4+/+ chimera. Bone marrow of MLL-ENL transduced CXCR4−/− chimera had moderately decreased numbers of mononuclear cells. There were important numbers of leukemic CD45.2+/Gr1+/Mac1+/c-kit+ cells in spleen from MLL-ENL CXCR4+/+ chimera which suggested that CXCR4 is important for leukemic progenitors cells retention in the bone marrow and especially in the spleen. The homing capacity of transduced CXCR4+/+ cells is comparable to the CXCR4−/− cells. Finally, more DNA damages were found in the BM cells of MLL-ENL CXCR4−/− chimera. All these results were confirmed by treating of MLL-ENL CXCR4+/+ chimera with CXCR4 inhibitor (TN140). These results demonstrated that in absence of CXCR4, the cells transduced by oncogene MLL-ENL are capable of generating leukemia in the recipients. However, mice transplanted with MLL-ENL transduced CXCR4−/− FL cells developed acute myeloid leukemia with reduced aggressiveness and organ infiltration, which is associated with induced differentiation and DNA instability. These results indicated that the MLL-ENL progenitors are dependent on CXCR4 for their maintenance in the BM and spleen suggesting that CXCR4 inhibitors might have potential therapeutic applications. Disclosures: No relevant conflicts of interest to declare.

Multidrug-Related Protein 1 (MRP1) Polymorphisms rs129081, rs212090, and rs212091 Predict Survival In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2580-2580 ◽  
Author(s):  
Desiree Kunadt ◽  
Christian Dransfeld ◽  
Maria Schmiedgen ◽  
Michael Kramer ◽  
Christoph Röllig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Significant Influence ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Npm1 Mutation ◽  
Significant Difference ◽  
Impact On Treatment ◽  
Acute Myeloid

Abstract Background ABCB1 (=MDR1, multidrug resistance protein 1) single nucleotide polymorphisms (SNPs) were shown to have a significant impact on therapy outcome in patients with acute myeloid leukemia (AML). Furthermore, an independent significant impact on treatment response and patient survival of SNPs in the genes for ABCC4 (MRP4), ABCC5 (MRP5) and ABCC11 (MRP8) related SNPs has also been demonstrated. In contrast, therapeutic strategies trying to modulate the anthracycline efflux of these transporters have failed in most clinical trials so far. Recently, higher dosages of daunorubicin used during induction chemotherapy have been associated with a better outcome in certain subgroups of AML patients. Hence, in times of individual diagnostic genetic analyses available as point-of-care diagnostics, the goal of this study was to further investigate whether SNPs in ABC-transporter genes, which are responsible for anthracycline efflux, have an independent impact on treatment outcome. Patients and Methods DNA samples were obtained from bone marrow aspirates of 160 Caucasian patients with newly diagnosed AML as part of the prospective AML2003 trial (NCT00180102). The cohort solely consisted of patients with a normal karyotype, based on conventional G-banding, minimizing false results in case of gain or loss of chromosomal material. All patients received double induction chemotherapy with daunorubicin and cytarabine. After DNA extraction, quantitative real time PCR was performed, using a total of 49 SNP assays investigating SNPs of seven different ABC genes. The identification of the corresponding SNPs was performed in an in silico analysis using the NIH dbSNP database and HapMap while statistical univariate and multivariate analyses were performed using SPSS. Results We detected three ABCC1 (MRP1) SNPs: rs129081 (CACCCC[C/G]ACTCCA), rs212090 (TTACTG[A/T]TCCCAC), and rs212091 (ACCTTA[A/G]AGAACA) with a significant influence on disease-free survival (DFS) or overall survival (OS), respectively. Patients carrying the homozygous rs129081 GG-SNP had a significant longer 5-year OS and 5-year DFS compared to the homozygous wildtype CC and heterozygous CG patients (OS: 68% [GG] vs. 40% [CC] vs. 64%, [CG], p=.035; DFS: 64% vs. 35% vs. 50%, p=.01). SNP rs212090 revealed a statistically significant difference in DFS when comparing homozygous alleles TT and AA (wildtype), 40% vs. 68%, p=.021. SNP rs212091 showed a significant difference concerning OS, with homozygous SNP GG leading to worse OS (0% vs. wildtype AA 64% vs. heterozygous AG 59%, p=.006). Again, there was a significant difference in DFS between both homozygous alleles AA (wildtype) and GG (55% vs. 0%, p=.018). Furthermore, there were no significant differences of standard clinical and laboratory baseline characteristics, FLT3-ITD mutation, or NPM1-mutation status, or chemotherapeutic toxicities. In order to exclude false positive findings of SNPs conferred as a result of leukemic transformation, we obtained saliva germline DNA from patients in complete remission who were treated by chemoconsolidation and performed a confirmatory analysis with the investigated SNPs, including rs129081, rs212090, and rs212091. Here, all SNPs were shown to be expressed in germline DNA in remission and bone marrow samples at diagnosis alike. The multivariate models for rs129081, rs212090 (TT), rs212091(AG), and rs212091(AA) revealed significances of p=.024, p=.029, p=.042, and p=.017 respectively for DFS but not for OS (except for rs212091[AA]). After adjustment for a false discovery rate of 5% still a trend towards the association of the SNPs and DFS could be seen. Therefore, more research is necessary to strengthen this evidence. Conclusion In this study we found a significant influence of rs129081, rs212090, and rs212091 SNPs (ABCC1, MRP1) on survival in AML in univariate analyses. Interestingly, these polymorphisms were not associated with other AML specific characteristics at diagnosis and were shown to be expressed in germline DNA and AML DNA alike. Hence, we suggest a prognostic effect of these SNPs which might be responsible for differential anthracycline susceptibility. Disclosures: No relevant conflicts of interest to declare.

Inhibition of HDAC8 Reactivates p53 and Abrogates Leukemia Stem Cell Activity in CBFβ-SMMHC Associated Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 363-363
Author(s):  
Jing Qi ◽  
Qi Cai ◽  
Sandeep Singh ◽  
Ling Li ◽  
Hongjun Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Acute Myeloid

Abstract The inv(16)-created CBFβ-SMMHC fusion protein inhibits differentiation of hematopoietic stem and progenitor cells (HSPCs) and creates pre-leukemic populations predisposed to acute myeloid leukemia (AML) transformation. However, the molecular mechanism underlying the leukemogenic function of CBFβ-SMMHC has been elusive. Given the low TP53 mutation rate in AML, alternative mechanisms disrupting p53 function are expected. We showed thatCBFβ-SMMHC impairs p53 acetylation and p53 target gene activation through formation of an aberrant protein complex with p53 and HDAC8 (Blood, 120: A772; 122(21): 224). We now show that CBFβ-SMMHC binds to p53 and HDAC8 independently through distinct regions and that HDAC8 mediates the deacetylation of p53 associated with CBFβ-SMMHC. In addition, we generated mice carrying a floxed Hdac8 (Hdac8f) allele and crossed with Cbfb56M/+/Mx1-Cre (Kuo YH et al, Cancer Cell 2006). Deletion of Hdac8 signifiacntly (p<0.0001) reduced the incidence of AML and prolonged disease-free survival. Pharmacologic inhibition of HDAC8 activity with HDAC8-selective inhibitors (HDAC8i) reactivates p53 and selectively induces apoptosis of inv(16)+ AML CD34+ cells while sparing normal HSPCs. To test the effect of HDAC8i on LSC engraftment and leukemia-initiating capacity, we generated Cbfb56M/+/Mx1-Cre mice with a Cre-reporter line expressing tdTomato fluorescence protein following Cre-mediated recombination. AML cells (dTomato+/cKit+) treated with HDAC8i (22d) ex vivo showed reduced engraftment (p=0.025) and enhanced survival (p=0.025) in transplanted mice. To examine whether HDAC8i 22d treatment affects the engraftment capacity on surviving cells, we transplanted equal number (2 x 106) of AML cells treated with either 22d or vehicle in another cohort of mice (n=4). We show that HDAC8i 22d treatment reduced the engraftment of dTomato+/cKit+ AML cells and enhanced survival, suggesting that the engraftment capacity is altered in addition to reducing AML cell survival. We next performed preclinical studies to determine the efficacy of in vivo administration of HDAC8i 22d. AML transplanted mice were randomized into two groups, one group treated with vehicle and the other treated with HDAC8i 22d for 2 weeks. Flow cytometry analysis revealed significantly reduced frequency (p=0.0097) and number (p=0.0101) of dTomato+/cKit+ AML cells in the bone marrow and spleen of 22d treated mice compared to vehicle treated group. To further assess the impact on LSC activity, we transplanted bone marrow cells from these treated mice into secondary recipients and analyzed for AML engraftment. Significant reduction in the frequency (p<0.0001) and the number (p=0.0006) of dTomato+/cKit+ AML cells was observed in the bone marrow and spleen. Furthermore, HDAC8i 22d treated transplants showed no signs of leukemia while vehicle treated transplants are moribund with aggressive AML. These results indicate that HDAC8 inhibition by 22d treatment effectively eliminates engraftment and leukemia-initiating capacity of AML LSCs. In conclusion, our studies identify a novel post-translational p53-inactivating mechanism and demonstrate selective HDAC8 inhibition as a promising approach to target inv(16)+ AML LSCs. Disclosures No relevant conflicts of interest to declare.

Treatment Acute Myeloid Leukemia Using Cytoreductive Chemotherapy Cytarabine (Ara-C) Followed Azacitidine (AZA) Maintenance: A Real Life Single Center Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5204-5204
Author(s):  
Rosa Greco ◽  
Annamaria Petrungaro ◽  
Anna Grazia Recchia ◽  
Laura De Stefano ◽  
Sabrina Bossio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Real Life ◽  
Response To Therapy ◽  
Significant Activity ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Abstract Background: Older patients (pts) with acute myeloid leukemia (AML) have a particularly dismal outcome, because of adverse features of AML in the elderly and frailty. The median duration of complete remission (CR) last less than 1 year. The optimal management of older AML pts in daily clinical practice has not been determined. Regular treatment options include best support care, low dose cytarabine (Ara-c) and intensive chemotherapy (anthracycline combined with ara-c). Recently, the DNA methyltransferase inhibitor Azacitidine (AZA) has demonstrated significant activity and favorable tolerability in AML pts also showing a survival advantage. Materials and Methods: Between May 2013 and July 2016, at our institution, 19 pts with a diagnosis of AML (13 males and 7 females) were judged to be ineligible for intensive chemotherapy due to age or comorbidities. They received a 5-day regimen of cytoreductive chemotherapy with ara-c at a dosage of 100 mg\mq\day i.v. continuous infusion. On the sixth day, on termination of Ara-c infusion, all pts had ≤30% bone marrow blasts. Therefore, AZA was administered at a dosage of 75 mg\mq\day subcutaneously for 7 days, continuing the therapy every 28 days. The median age of pts was 75 years (range, 49 to 79 years), with 17 pts (89%) aged over 65 years. Six pts (32%) had poor molecular and cytogenetic risks markers, and six other pts (32%) had either antecedent myelodisplastic/myeloproliferative diseases or therapy related AML. The response to therapy according to the AML IWG criteria was assessed by bone marrow aspiration immediately after Ara-c infusion, after one AZA cycle and every 6 months thereafter. Baseline pts characteristics are summarized in Table 1. Results: The median number of administered AZA cycles was 6 (range, 1-25 cycles). Fifty eight percent (11/19) of pts received ≥6 AZA clycles. The median overall survival was 6 months (range, 1-26 months). According to AML IWG criteria, 8 pts (42%) achieved CR after Ara-c and a single AZA cycle. Of these, 5 pts (62%) are currently alive in CR, with median duration of response of 7 months (range: 5-12 months), while 3 pts (38%) died after 4, 12, and 22 months after diagnosis. One pt (5%) achieved a partial response (PR) after one AZA cycle, maintaining at present the same response after 3 months of therapy. Other 8 pts (42%) obtained stable disease (SD). Of these, 3 pts (37%) are currently in SD after 2, 8 and 10 months of therapy, while 5 pts (64%) died within a median of 5 months (range: 2 - 18 months) after AML diagnosis. Finally 1 pt (5%) was refractory dying after 2 months of diagnosis, and another pt (5%) died after first AZA cycle for sepsis. Fever and infections were the most common non-hematologic toxic events after Ara-c chemotherapy and first AZA cycle (17/19 pts, 90%). While subsequent AZA cycles were well tolerated. Conclusion: We suggest that the use of Ara-c-AZA combination is feasible in elderly AML pts. However, the relatively small number of pts studied and short follow up preclude definitive conclusion. The study is still accruing patients. Disclosures No relevant conflicts of interest to declare.

Clinical and Pathological Features and Differential Diagnosis of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): a Series of Cases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5183-5183 ◽  
Author(s):  
Gabriela Cesarman-Maus ◽  
Carmen Lome ◽  
Karla Adriana Espinosa ◽  
Carmen Marcela Quezada-Fiallos ◽  
Silvia Rivas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Differential Diagnosis ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Plasmacytoid Dendritic Cell ◽  
Cell Neoplasm ◽  
Skin Infiltration ◽  
Acute Myeloid

Abstract Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is a recently recognized highly aggressive malignant proliferation of plasmacytoid dendritic-cell (PDC) precursors which consistently express CD4, CD56 and CD123. Mortality is high despite transplant and the response to treatment is poor, except for preliminary results with conjugated anti-CD123. Clinically, cutaneous involvement is the most common feature with or without the presence of initial bone marrow infiltration, however patients may present with bone marrow-only disease. BPDCN is underdiagnosed, and can be confused with several entities, including acute myeloid leukemia. We describe our experience with 7 cases of BPDCN, their clinical and pathological presentation, and describe possible misdiagnosis and the antibodies that may help in corroborating BPDCN. See table for clinical characteristics at diagnosis. Diagnosis of BPDCN must take into account clinical, morphological and immunohistochemical analysis (IHC), since these tumors variably express markers that may be shared with other neoplasias including CD56 and TCL-1. When IHC is not categorical for BPDCN, the WHO recommends reporting the cases as AML of ambiguous lineage. The typical IHC includes CD4, CD43, CD45RA, CD56, CD123, TCL1, CLA and CD68. The absence of CD56 does not exclude the diagnosis. Markers shared with other hematological tumors include: CD7, CD33, CD2,CD36 and CD38 and TdT. Thus differential diagnosis should be done primarily with A) Skin infiltration by acute myeloid leukemia (myeloperoxidase +, 7- lysozyme +, CD34 +, CD117 +/-) B) Skin Infiltration by T / NK extra nodal lymphoma ( CD8 , cytotoxic cytoplasmic granules [CCG] , granzyme B, perforin, TIA1 and EBER) C) cutaneous peripheral T lymphoma ( +/- CD8, CD2 +/-, +/- CD5, CD7 +/- and variably positive CCG´s). D) Other histiocytic and dendritic cell-neoplasms may also be considered in the differential diagnosis however the histological appearance is usually characteristic. BPDCN is a poorly known entity that should be suspected by both clinician and pathologist in order to make a correct diagnosis. Table Table. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document