Prognostic Impact of a Novel Biomarker, Serum Soluble LR11 on Acute Leukemia

Abstract Abstract 2717 Introduction: LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding. LR11 plays a key role in the migration of undifferentiated vascular smooth muscle cells, and circulating sLR11 is known to be a biomarker of carotid intima-media thickness. Along with the fact that circulating sLR11 levels represent the accumulation of vascular immature cells, human CD34+CD38− immature hematopoietic precursors have been reported to express high levels of LR11 mRNA. We have recently found that LR11 is specifically and highly expressed on cell surface of acute leukemia cells in addition to normal leukocytes (unpublished data). These facts prompted us to evaluate the serum sLR11 level in patients with acute leukemia and other hematological malignancies to validate sLR11 as a novel circulating marker for treatment outcome and prognosis. Patients and Methods: Serum sLR11 levels were measured by ELISA method in 139 patients with acute leukemia and other hematological malignancies treated at a single institution from 1999 to 2010. Patients' laboratory data and treatment outcome were collected retrospectively in 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Results: sLR11 levels of acute leukemia patients were significantly increased [ALL, 73.5±93.5 ng mld−1 (range, 5.7–407.0), P<0.0001; AML, 26.8±29.1 ng ml−1 (range, 5.0–157.5), P<0.0001] in comparison to the control subjects (9.2±3.3 ng ml−1), while sLR11 levels in patients with chronic myeloid leukemia (17.9±11.1 ng ml−1), chronic lymphocytic leukemia (12.7±11.6 ng ml−1), multiple myeloma (10.5±4.8 ng ml−1), and POEMS syndrome (9.0±2.7 ng ml−1) were not significantly different from controls. sLR11 levels were significantly higher in ALL than those in other leukemias. Paired sample analysis of patients with AML and ALL at complete remission (CR) after chemotherapy showed significantly decreased sLR11 levels compared to the time of diagnosis (AML: 30.9±37.5 ng ml−1 vs. 10.4±4.3 ng ml−1, P=0.015, ALL: 39.1±126.0 ng ml−1 vs. 11.2±5.0 ng ml−1, P=0.0029). The multiple stepwise liner regression analysis showed that the peripheral blast proportion in both ALL and AML patients were independently associated with sLR11 at diagnosis (AML: r2= 0.21, P=0.0026, ALL: r2= 0.34, P=0.0043). Among 42 AML patients, sLR11 levels of subjects in the highest tertile of peripheral blast proportion (>67.5% of WBC) were 2.44- and 3.05-fold higher than those in the middle (23.0-64.0% of WBC) and lowest tertiles (<20.0% of WBC), respectively. Twenty out of 21 AML patients with <20 ng ml−1 sLR11 at diagnosis achieved CR after induction chemotherapy, and the CR rate was significantly higher in patients with <20 ng ml−1 sLR11 than in patients with ≥20 ng ml−1 (95.2% vs 65.5%, P=0.02). The probability of overall 5-year survival was significantly lower in AML patients with ≥20 ng ml−1 sLR11 at diagnosis than in those with <20 ng ml−1 [Figure1, 36.8% vs 63.7%, P = 0.04; hazard ratio (HR): 2.74; 95% confidence interval (CI): 1.04–8.01]. Conclusions: Serum sLR11 levels in patients with acute leukemia were significantly elevated and were associated with the peripheral blast population but not in other chronic proliferative hematological malignancies. These findings suggest that the serum sLR11 levels are predictive for pathogenic properties of immature blasts, including their migration and attachment activities, rather than simply associating with proliferating cell numbers. Especially in AML patients, serum sLR11 levels at diagnosis significantly affect CR rate and OS. Although larger scale studies including karyotype or FAB classification would be required for its patho-clinical significance, serum sLR11 is a promising novel biomarker for acute leukemia and it could play an important role as prognostic factor. Disclosures: No relevant conflicts of interest to declare.

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Epigenetic Inactivation of DBC1 in Acute Myeloid Leukaemia.

Blood ◽

10.1182/blood.v114.22.4429.4429 ◽

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.

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Unsuccessful Cytogenetics and Outcomes in Acute Leukemia

Blood ◽

10.1182/blood-2018-99-110470 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2673-2673

Author(s):

Lauren Lee ◽

Helene Bruyere ◽

Michael J Barnett ◽

Raewyn Broady ◽

Donna L. Forrest ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

White Blood Count ◽

Prognostic Impact ◽

Intermediate Risk ◽

Steroid Use ◽

High Risk Disease

Abstract Introduction: Cytogenetic features at diagnosis have significant independent prognostic impact in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Failed or unsuccessful cytogenetics (UC) is estimated to occur in 10% of AML cases and 25-30% of ALL cases (Grimwade, 2010; Pullarkat, 2008). Previous studies suggest worse outcomes in AML patients (pts) with UC, similar to pts with unfavorable karyotype with lower response rates to induction chemotherapy and poor 5-year (yr) survival rates (Medeiros, 2014; Lazarevic, 2015). Hydroxyurea (HU) and steroids are often given urgently for cytoreduction prior to obtaining cytogenetics. The effects of such pretreatment on rates of UC have not been studied previously. In this study, we compared clinical outcomes of acute leukemia pts with UC versus successful cytogenetics (SC) and determined whether the use of HU or steroids affects cytogenetics success rates. Methods: All pts <70 yrs with de novo acute leukemia (AML or ALL) with available diagnostic bone marrow and cytogenetics testing seen at the Leukemia/Bone Marrow Transplant (BMT) Program of British Columbia between January 2010 and December 2016 were included. Pertinent information was reviewed from the program database. Cytogenetic failure was defined by the presence of <10 metaphases with a normal karyotype in the absence of a clinically actionable FISH abnormality. Pts with SC were risk stratified based on NCCN guideline criteria (NCCN, 2018). Baseline features of pts with SC and UC were compared using Chi-squared and two-tailed t-testing. Overall survival (OS) was calculated from the date of initial diagnosis to the date of death from any cause. Disease free survival (DFS) was calculated from the date of attaining first complete remission (CR1) to the date of relapse or death from any cause. Survival outcomes were estimated using the Kaplan-Meier method, with p values determined using the log rank test. A p < 0.05 was considered significant. Results: We identified 654 cases of acute leukemia (AML N=515; ALL N=139). Of these, 39 (6%) had UC (AML N=16, 3%; ALL N=23, 17%). There was no difference in age at diagnosis between groups (UC vs SC, 46 vs 51 yrs, p=0.08). AML pts with UC had higher initial white blood count (WBC) at diagnosis (71 vs 34, p<0.001). No effect of WBC was seen in ALL pts with UC versus SC. HU and/or steroid use prior to cytogenetics was similar between UC and SC groups in both AML and ALL pts (UC vs SC, HU: 8% vs 12%, p=0.61; steroids: 5% vs 1%, p=0.07. Therapy with intensive induction was also similar between groups (UC vs SC, 92% vs 90%; p=1.00). 137 (27%) of AML pts with SC had favorable risk disease, 182 (37%) intermediate, and 180 (36%) high risk. In ALL pts with SC, 32 (28%) had standard risk, and 84 (72%) had high risk disease. Follow up time in UC and SC groups was similar (32 vs 27m, p=0.18). CR rates in AML pts with UC was 81%, which was similar to pts with intermediate risk disease (84%, p=0.72) and better than CR rates of 39% observed in high risk pts (p=0.03). Compared to pts with SC, AML pts with UC had similar 5-yr OS and DFS as pts with intermediate risk disease (5-yr OS 25% vs 37%, p=0.45; 5-yr DFS 28% vs 28%, p=0.84), superior survival to high risk pts (5-yr OS 25% vs 17%, p=0.01; 5-yr DFS 28% vs 13%, p=0.036), and inferior survival to favorable risk pts (5-yr OS 25% vs 68%, p=0.07, 5-yr DFS 28% vs 52%, p=0.008), Figure 1. CR rates in ALL pts with UC was 83% and not significantly different than standard (94%, p=0.22) or high risk pts (86%, p=0.74). Compared to pts with SC, ALL pts with UC had similar 5-yr OS and DFS to pts with standard and high risk disease (UC vs standard vs high; 5-yr OS 58% vs 51% (p=0.93) vs 55% (p=0.85); 5-yr DFS 50% vs 37% (p=0.86) vs 36% (p=0.27)). Subgroup analysis of UC pts demonstrated no difference in survival in UC pts receiving BMT (N=12) vs no BMT (N=27). UC pts with high WBC >20 (N=14) had inferior survival compared to those with WBC ≤ 20 (N=25) (5-yr OS 60% vs 29%, p=0.025; 5-yr DFS 52% vs 12%, p=0.013). Conclusions: Unsuccessful cytogenetics was more frequently observed in ALL as compared to AML pts, though at lower rates than reported in previous studies. HU and steroid use had no effect on the rates of cytogenetic success. In comparison to previous reports, UC in AML was not associated with inferior outcomes, and survival was similar to intermediate risk pts. High initial WBC count was prognostic in pts with UC, and further studies are warranted to evaluate factors that affect outcomes in pts with UC. Disclosures No relevant conflicts of interest to declare.

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GATA-2 L359V Mutation Is Exclusively Associated with CML Progression but Not Other Hematological Malignancies and GATA-2 P250A Is a Novel Single Nucleotide Polymorphism.

Blood ◽

10.1182/blood.v114.22.2187.2187 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2187-2187

Author(s):

Su-Jiang Zhang ◽

Jing-Yi Shi ◽

Jianyong Li

Keyword(s):

Single Nucleotide Polymorphism ◽

Myeloid Leukemia ◽

Hematological Malignancies ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Chronic Phase ◽

Lymphocytic Leukemia ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Molecular Abnormalities

Abstract Abstract 2187 Poster Board II-164 Chronic myeloid leukemia (CML) progression is characterized by occurrence of new cytogenetic and molecular abnormalities. In the previous study, we have shown the important role of GATA-2 L359V mutation in CML progression. To further ascertain the truth of transcription factor GATA-2 in hematological malignancies, we expanded our study to GATA-2 full length by directly sequencing and applied MassARRAY assay into GATA-2 L359V mutation analysis. Finally, no GATA-2 L359V mutation was found in 270 acute myeloid leukemia, 30 myelodysplastic syndrome, 50 acute lymphoblastic leukemia, 12 chronic lymphocytic leukemia, 40 CML chronic phase and 286 BCR/ABL negative myeloproliferative disorders except CML blast crisis. A new variation of GATA-2 resulted in P250A change was identified, which was not found to have statistical difference between patients with hematological malignancies and healthy control. Hence, we concluded GATA-2 L359V is exclusively associated with CML progression but not other hematological malignancies and P250A is a new single nucleotide polymorphism. Disclosures: No relevant conflicts of interest to declare.

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Management of Venous Thromboembolism (VTE) in Patients with Acute Leukemia: Results from a Multicenter Study

Blood ◽

10.1182/blood.v124.21.3688.3688 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3688-3688 ◽

Cited By ~ 1

Author(s):

Mariasanta Napolitano ◽

Luca Valore ◽

Giorgia Saccullo ◽

Alessandra Malato ◽

Calogero Vetro ◽

...

Keyword(s):

Venous Thromboembolism ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Sinus Thrombosis ◽

Lymphoblastic Leukemia ◽

Laboratory Data ◽

Induction Phase ◽

Severe Thrombocytopenia ◽

Significant Difference ◽

Clinical Records

Abstract Background In the last decades, evaluation of thrombotic complications secondary to acute leukemia (AL) has been poorly investigated. Only scant data are available on management and prevention of thrombosis in this setting. We performed a multicenter retrospective study with the aim to evaluate the management of venous thromboembolism (VTE) in patients with AL and to report the most commonly adopted regimens of treatment. Materials and methods Available clinical records of out and in-patients diagnosed with AL from January 2008 to June 2013 in 7 Reference Regional Hospitals were analyzed. Cases of VTE, including thrombosis in atypical sites [Retinal occlusion (RO) and Cerebral Sinus Thrombosis (SCT)], were reported. All data were recorded in a dedicated electronic database. The patient’s basic demographic data (age, gender, race), medical history, disease-related information, and laboratory data were extracted. Instrumental diagnosis of deep vein thrombosis (DVT), pulmonary embolism (PE) and RO and SCT was performed according to ACCP guidelines. Data were collected and analysed by the IBM SPSS Software 21.0 version (SPSS, Inc., Chicago, Ill, US) and the Epi Info software, version 3.2.2, (Centers for Disease Control and Prevention). Statistical analysis of quantitative and qualitative data, included descriptive statistics, was performed for all the items. Results Over a population of 1461 patients with AL, 99 (6.8%) cases of VTE were recorded, mainly in hospitalized patients: 72 cases were associated with Acute Myeloid Leukemia (AML) and 27 with Acute Lymphoblastic Leukemia (ALL), with a mean age of 52.2 ± 15.4 years (median age: 53years). In particular the incidence/ratio over the sub-population of AML-patients was 6.0%, that is 72/1191 cases; with a mean age of 54.7 ± 14.3 years (median age: 57 years). VTE occurred during chemotherapy (CHT) in 90/99 (90%) cases, mainly during the induction phase of treatment (in 70% of cases ),the remaining 9 cases were diagnosed in concomitance with acute leukemia. In both subgroups with VT, there was no statistical significant difference between time at diagnosis of VT and time at diagnosis of AL. Treatment of VTE was mainly based on Low Molecular Weight Heparin (LMWH), in accordance with results from previous studies and current guidelines (full dosage for the first month from diagnosis and reduced dosage at 75% for the following months). Thrombocytopenia occurred in 55 patients at diagnosis of AL, in 33 cases platelets were <50x109/L. Most VTE episodes (73/99, 73.7%) were treated with LMWH as above reported . In patients with moderate/severe thrombocytopenia, a dose adjusted to platelet count was adopted; most of the investigators used LMWH at prophylactic dosage. Two cases received fondaparinux, one patient was treated with unfractioned heparin; six cases did not receive any treatment due to severe thrombocytopenia. No cases of VT–related deaths nor fatal complications during treatment for VTE were reported. All treatments with LMWH lasted from 3 to 6 months. All patients clinically recovered from VTE, only 2 late recurrences (PEs) were observed. Conclusion VTE can complicate the clinical course of AL in a not negligible percentage of cases. Anticoagulant treatment schedules and duration in patients with AL are influenced by many factors, mainly related to chemotherapy and severe thrombocytopenia. In the analyzed subset of patients, full dose treatment with LMWH for at least one month followed by a dose reduction for at least three months was appropriate. Disclosures No relevant conflicts of interest to declare.

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Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

Clinical Epigenetics ◽

10.1186/s13148-021-01011-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

A. D. van Dijk ◽

F. W. Hoff ◽

Y. H. Qiu ◽

J. Chandra ◽

E. Jabbour ◽

...

Keyword(s):

Acute Leukemia ◽

Histone Methylation ◽

Myeloid Leukemia ◽

Outcome Prediction ◽

Epigenetic Modification ◽

Molecular Genetic ◽

Proliferative Potential ◽

Prognostic Impact ◽

Adult Onset ◽

H3k27 Methylation

Abstract Background Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia. Results Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior. Conclusion This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

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Spinal Cord Compression in Patients with Acute Myeloid and Lymphoid Leukemia

Blood ◽

10.1182/blood-2020-137446 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-27

Author(s):

Shehab Fareed Mohamed ◽

Elabbass Abdelmahmuod ◽

Elrazi Awadelkarim A Ali ◽

Abdulqadir Jeprel Nashwan ◽

Dina Sameh Soliman ◽

...

Keyword(s):

Spinal Cord ◽

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Spinal Cord Compression ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Cord Compression ◽

Myeloid Sarcoma ◽

Acute Myeloid

Introduction Acute leukemias can be divided into acute myeloid leukemia and acute lymphoblastic leukemia. Common presentations of acute leukemia include fever, symptoms of anemia, bleeding, bone pain palpable Lymph nodes or spleen and symptoms due inflation or leukocystasis. Extramedullary mass is rare and can be of myeloid tissue and known as Chloroma or myeloid (granulocytic) sarcoma which one of the WHO classifications for acute myeloid leukemia. Common sites of occurrence are skin, sinuses, bone and other. It's rarely involve central nervous system. Spinal cord involvement usually manifest as epidural mass causing cord compression. Spinal epidural tumor with acute leukemia and myeloid sarcoma is rare and can be found in 3-9% in patients with leukemia. In this review we decide to review the cases of spinal cord compression caused by acute myeloid leukemia (including Chloroma) and acute lymphoblastic leukemia due to the significance of such presentation in addition to reports that Myeloid sarcoma of the spine has very poor prognosis Methodology: We have reviewed the literature using: PubMed, google scholar, Scopus for patient with spinal cord compression and acute leukemia. We used the search term and synonyms : : acute myeloid leukemia , acute myelocytic leukemia , acute monocytic leukemia , acute lymphoblastic leukemia , acute lymphoid leukemia, chloroma , myeloid sarcoma ,granulocytic sarcoma, spinal cord compression .We included adult patients above 18 years old only cases we exclude pediatrics cases and cases of chronic leukemia's and other myeloproliferative disorders as well as cases of central nervous system involvement other than spinal cord Results We gathered the information from 98 cases with general demographics, presentation, image modality, cytogenetics and molecular in addition to management and outcome. We have found mean age for the patients is 38 years old with male predominance with 70% of the cases. The most presenting symptom was back pain in around 75% of the cases. Neurological findings showed sensory loss and parapreresis in most of the documented cases. MRI was most performed modality of imaging 63% followed by Computed tomography(CT) 15 % and then myelogram 13 %, which is least used due to invasive nature and before the era of MRI. The most common affected site on spinal cord were thoracic followed by lumbar. Cytogenetics and molecular data was not reported in most of the cases. Patients were treated with either steroids or surgery or radiotherapy and or chemotherapy while few underwent bone marrow transplant, but the most common approach was surgery+ radiotherapy + chemotherapy combination. Steroids used in most of the cases especially in the cases of acute lymphoblastic leukemia and dexamethasone was the steroids of the choice mainly. The outcome of the patients were variable, 30 % were alive at the time of the reports 30 % died and 30 % between relapse and complete remission. Conclusions Acute leukemia can be presented as mass causing spinal cord compression which is very serious. There are is no standardized management of patients with acute leukemia who presented with spinal cord compression nether guidelines or steps to follow. Some reports speculated also specific morphology and cytogenetics association with predisposition to have Extramedullary mass, however there lack of reporting of such a valuable information. Large studies including all adjusted variables required to determine if spinal cord compression presentation can be an independent risk facto or not Effective diagnosis and prompt action should take place. Figure Disclosures No relevant conflicts of interest to declare.

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IKZF1 Deletion Is An Independent Predictor of Outcome In Pediatric Acute Lymphoblastic Leukemia Treated According to the ALL-BFM 2000 Protocol

Blood ◽

10.1182/blood.v116.21.409.409 ◽

2010 ◽

Vol 116 (21) ◽

pp. 409-409

Author(s):

Petra Breithaupt ◽

Barbara Meissner ◽

Martin Zimmermann ◽

Anja Möricke ◽

André Schrauder ◽

...

Keyword(s):

Treatment Outcome ◽

High Risk ◽

Cox Regression ◽

Conflicts Of Interest ◽

Residual Disease ◽

Risk Group ◽

Independent Predictor ◽

Lymphoblastic Leukemia ◽

Time Points ◽

Pediatric All

Abstract Abstract 409 Alteration of the IKZF1 gene – encoding the transcription factor IKAROS, a key player in lymphoid development and tumor suppression – has been reported to be associated with a poor outcome in pediatric precursor B-cell ALL, especially in cases positive for the BCR-ABL1 fusion gene. In order to assess the prognostic value of IKZF1 deletions in a representative cohort of pediatric ALL patients treated on the German ALL-BFM 2000 study protocol, we screened 409 patients by applying a multiplex ligation-dependent probe amplification (MLPA) assay covering all eight IKZF1 exons (P335-A3 ALL-IKZF1 probemix; MRC-Holland, Amsterdam, The Netherlands). In ALL-BFM 2000, risk group stratification (standard, SR; intermediate, MR; high, HR) was based on minimal residual disease (MRD) analysis at two different time points (TP) and required two MRD targets with sensitivities of ≤10−4 (Flohr et al. Leukemia 2008). SR patients were MRD-negative on treatment days 33 (TP1) and 78 (TP2). HR patients had residual disease (≥10−3) at TP2. MRD MR patients had positive MRD detection at either one and or both time points but at a level of <10−3 at TP2. Although MRD-based stratification criteria were introduced in ALL-BFM 2000, established high-risk parameters were also retained: patients with prednisone poor-response or ≥5% leukemic blasts in the bone marrow on day 33 or positivity for a t(9;22) or t(4;11) or their molecular equivalents (BCR/ABL1 or MLL/AF4 fusion RNA) were stratified into the high-risk group independent of their MRD results. First results on MRD and outcome were published earlier (Conter et al. Blood 2010). Out of the 409 patients analyzed in our study, 46 (11%) displayed a deletion in at least one of the eight IKZF1 exons. Forty-three out of the 46 cases showed heterozygous deletions, while 3 patients displayed homozygous loss of IKZF1 exons. MLPA results of 11 patients were validated with results derived from copy number/LOH analyses using Affymetrix SNP 6.0 arrays. IKZF1 deletion was significantly more common in precursor B compared to T cell ALL (13% vs. 4%, P = 0.03) and less frequent in TEL/AML1-positive ALL (3% vs. 13%, P = 0.004). Out of 11 BCR/ABL1-positive samples, only two were characterized by an IKZF1 deletion. Forty-four patients with IKZF1-deleted ALL had results of MRD analyses available for both informative time points (day 33 after induction and day 78 after consolidation). Despite a trend towards increasing incidence of IKZF1 deletion in patients with slow response, the distribution of IKZF1-deleted ALL patients over the risk groups was not significantly different from non-deleted ALL (SR: 40.9 vs. 41.9; MR: 45.5 vs. 52.3; HR: 13.6 vs. 5.7%; P = 0.153). Regarding treatment outcome, patients with an IKZF1 deletion had a significantly lower 5-year event-free survival (EFS) compared to non-deleted patients (0.78±0.06 vs. 0.86±0.02; P = 0.015). This result was due to a higher cumulative incidence of relapses in IKZF1-deleted patients (0.16±0.05 vs. 0.10±0.02; P = 0.031). In multivariate Cox regression analyses including known prognostic variables (gender, immunophenotype, WBC count at diagnosis, TEL/AML1 status, risk group criteria of ALL-BFM 2000), IKZF1 deletion conferred a risk of 2.16 (95% confidence interval 1.14 – 4.10; P = 0.018) for an event when compared to non-deleted patients. We conclude that IKZF1 deletion is an independent predictor of treatment outcome for patients enrolled on the ALL-BFM 2000 protocol and represents a candidate marker to be integrated in future algorithms for early risk stratification in pediatric ALL. Disclosures: No relevant conflicts of interest to declare.

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Acute Leukemia

10.2310/im.1247 ◽

2016 ◽

Author(s):

Richard A. Larson ◽

Roland B Walter

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Lymphoblastic Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Who Classification ◽

Lymphoblastic Leukemia ◽

World Health ◽

Acute Leukemias ◽

Acute Myeloid

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classiﬁcation of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 1 highly rendered figure, 9 tables, and 117 references.

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Uncommon CD markers in acute myeloid leukemia

Bangabandhu Sheikh Mujib Medical University Journal ◽

10.3329/bsmmuj.v11i4.37281 ◽

2018 ◽

Vol 11 (4) ◽

pp. 267-269

Author(s):

Azad Abul Kalam ◽

Md. Rafiquzzaman Khan ◽

A. B. M. Hassan Habib ◽

Masuda Begum

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Leukemia ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Color Flow ◽

Mixed Phenotype Acute Leukemia ◽

International Data ◽

Mixed Phenotype ◽

Cd Markers ◽

Acute Myeloid

This study was done to assess the unusual CD expression in 100 cases of acute myeloid leukemia from October 2016 to April 2018. The age limit was from 3 to 50 years. Four color flow cytometry was used to diagnose the fresh aspirated bone marrow or peripheral blood sample of acute leukemia. The unusual lymphoid CD expression on myeloblasts was analyzed. Among the cases, 44% were acute myeloid leukemia, 52% of patients were of acute lymphoblastic leukemia and mixed phenotype acute leukemia was 4%. Aberrant CD expression was observed in 58% acute myeloid leukemia patients. Both aberrant CD5 and CD7 lymphoid markers expressed in acute myeloid leukemia patients were 4.2%. Aberrant CD7, CD5, cCD79a and cCD3 were in 45.8%, 33.3%, 8.3%, 8.3% of acute myeloid leukemia patients respectively. In acute myeloid leukemia, the frequency of aberrant CD expression was compared with recent international data.

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Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia

Blood ◽

10.1182/blood.v65.1.142.142 ◽

1985 ◽

Vol 65 (1) ◽

pp. 142-148 ◽

Cited By ~ 79

Author(s):

PB Neame ◽

P Soamboonsrup ◽

G Browman ◽

RD Barr ◽

N Saeed ◽

...

Keyword(s):

Acute Leukemia ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Lymphoblastic Leukemia ◽

Differentiation Markers ◽

Lymphoid Leukemia ◽

Chromosome Marker ◽

Fab Classification ◽

Blast Cells ◽

French American British

Abstract Acute mixed myeloid-lymphoid leukemia is uncommon. We report four cases in which myeloid and lymphoid cell markers were observed simultaneously or sequentially when 94 patients with acute leukemia were phenotyped according to the French-American-British (FAB) classification system, with cytochemical stains, and with immunologically defined differentiation markers (identified by monoclonal antibodies and antiterminal deoxynucleotidyl transferase [TdT]). In one case, conversion from acute lymphoblastic leukemia to acute myeloid leukemia was noted (FAB L1, TdT+ to FAB M4, Auer rods, TdT-). In another patient, two distinct populations of myeloid and lymphoid blast cells were observed simultaneously (TdT-, LeuM1+/TdT+, LeuM1-). In two additional patients, acute leukemia was characterized by the expression of both lymphoid and myeloid markers on the same cell (TdT+/Leu M1+, B4+/Leu M1+ and greater than or equal to 70% TdT+, T11+, My9+). The Philadelphia (Ph1) chromosome was negative in all cases, though other chromosomal abnormalities were noted in three out of four cases. Malignant transformation of a pluripotential stem cell for both lymphoid and myeloid lineages, with or without the Ph1 chromosome marker, could explain the coexistence of distinct populations of lymphoblasts and myeloblasts in acute leukemia. Acute leukemia with a biphenotypic profile may reflect genome depression accompanying neoplasia.

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