Aberrant Expression Of Myeloid Antigens Research Articles

Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

Retrospective Immunophenotypic Profile of Acute Leukemias in the State of Rio Grande Do Norte, Northeast, Brazil

INTRODUCTION:The main acute leukemias (ALs) are lymphoid (B or T lineage ALL) and myeloid (AML), in addition to biphenotype AL (BAL) and undifferentiated ALL (IAL), which are rarer. This variation reflects on therapy, requiring methods to characterize these leukemias. Thus, methods such as immunophenotyping by flow cytometry (ICF), multiparametric and quantitative, help in the follow-up of these neoplasms. Objective: The aim of this study was to demonstrate the immunophenotypic diagnostic profiles in patients with AL in Rio Grande do Norte, state, Brazil by FC. Methodology: Bone marrow and peripheral blood samples from 371 patients clinically diagnosed with AL were investigated by CF, using a panel of monoclonal antibodies for the detection of lymphoid (B, T and NK) and myeloid antigens, as well as markers related to cell immaturity such as CD34, Terminal deoxynucleotidyl Transferase (TdT).At the same time, information related to clinical data, age group and sex of patients was also collected. Results: Of all LA investigates 71 were B cell-ALL, 55 T cell-ALL, 239 AML, 04 BAL and 02 IAL. Regarding the immunophenotypic pattern, the main subgroups in relation to age group and were evidenced through the FC. 06/71 were Pro-B ALL, 48/71 Common ALL, 06/71 cyt mü chain ALL and 11/71 mature sIgM+ B-ALL. In B-cell lineage ALL, 51 (71.8%) of the cases were children (less than or equal to 18 years old) and 20 (28.2%) adults (over 18 years old). In T-cell ALL, 9 (16.4%) were pre-T ALL, 12 (21.8%) intermediate ALL and 29 (52.7%) medullary T-type ALL, corresponding to a total of 36.4% children and 63.6% adults. In AML, there was a predominance of involvement in adult patients, corresponding to47 (80.7%) of cases and 192 (80.3%) in children. Biphenotypic and undifferentiated AL were detected in adult patients. DISCUSSION: The B cell-ALL were characterized by natural arrest of B-cells precursors based on the expression of antigens related to this lineage in: i) Pro-B ALL (CD19+, HLA-Dr+, CD34+, TdT+); ii) Common ALL (CD10+, CD19+, cCD79a+, cytCD22+, HLA-Dr+, TdT+/- and CD34+/-); iii) cyt mü chain+ ALL (cyt IgM+, CD19+, HLA-Dr+, cytCD79a+, cytCD22+, CD10-, CD34-) and iv) mature B-ALL (sIgM+, sCD22+, CD10+/-, CD20+ and kappa+ or lambda+). The T-ALL were classified into: i) pre-T-ALL (CD7+, cytCD3+, HLADr+, CD34+ and TdT+), ii) intermediate T-ALL (CD1a+, CD2+, CD7+, cytCD3+, TdT+ and HLADr+, CD4+/CD8+) and Medullary T-ALL (CD4+ or CD8+, sCD3+, CD1a-, TdT+, HLADr+/- and CD34-). It was also possible to observe the aberrant expression of myeloid antigens in B and T-ALL, such as CD13, CD33 and CD66b, mainly related to ALL in the context of KMT2A rearrangement with lineage switching. In addition to transferrin receptors (CD71) and IL-2 receptor (CD25), which have been reported in the context of ALL BCR+/ABL+, as well as the presence of the Philadelphia chromosome. In AMLs, the most observed subtypes were those with little differentiation and with a monocyte component. (CD64+/CD14+). CD15+/CD34+ expression was also observed, indicative of asynchrony of maturation, and phenotypic aberrancy of lymphoid antigens in some cases, predominantly CD7. In addition to other antigens such as CD2 and CD19, CD19 and CD56, In addition, ALL was more frequent in children and males, while AML in adults and females in general, with a predominant incidence in males among adult patient. Conclusion: When properly applied, ICF can have a great impact on the diagnosis, classification and prognostic analysis of neoplastic processes.

Immunophenotype of Acute Lymphoblastic Leukemia: The Experience of University Hospital Centre Casablanca - Morocco.

Acute lymphoblastic leukemia (ALL) encompasses a group of lymphoid neoplasms that morphologically and immunophenotypically resemble B-lineage and T-lineage precursor cells. Our objective is to describe the immunophenotypic aspects of acute lymphoblastic leukemia (All) diagnosed by flow cytometry at the hematology laboratory of IBN ROCHD University Hospital Center and to compare them with those reported in other series. This is a descriptive study over a period from August 2016 to October 2021, during a 5 year-and-2-month period. Immunophenotyping was performed at the flow cytometry unit on a Beckman-Coulter with 6 colors and 2 lasers in the hematology laboratory of the same hospital and data was collected retrospectively from the patients' files, their medical prescription files, kalisil software, and a data collection form we have established. The 440 patients had ages ranging from 1 month to 76 years, with a median of 9.5 years and the overall male-to-female ratio was 1.44. The immunological subtyping revealed that 82.5% of cases were B-ALL and 17.5% were T-ALL; of these B-ALL cases 230 (63.36%) were children (range: 0.1 - 15 years) and 134 (36.91%) were adults (range: 16 - 76 years); T-ALL were distributed in both age groups, 49 cases (37.7%) were children (range: 2 - 15 years) and 28 (21.56%) were adults (range: 18 - 63 years). All patients presented at least one abnormal blood count; thrombocytopenia has been observed in 89.4% of cases, anemia in 86.5% of cases, hyperleukocytosis in 79.8% of cases, leukopenia in 10.6% of cases, and pancytopenia in 4.8% of cases. The frequency of B-cell markers in B-ALL was found to be 363 (100%) for CD19, 323 (88.94%) for CD10, 290 (80%) for CD79a, and 73 (20%) for CD20. CD34 expression was found in 73 (20%) cases of B-ALL. HLA-DR was found in 54 (15%) cases, while TdT was found in 43 (13%) cases. Aberrant expression of myeloid antigens was found in 94 (26%) cases of B-ALL. Among T-ALL, the positivity of CD3 and CD7 was 100% (77 cases), while CD5 was positive in 58 (75%) cases. CD34 expression was found in only 19 cases of T-ALL. CD4 and CD8 expression was checked in only 9 adult patients and 4 pediatric cases. Out of them, 77.82% of cases were negative for both CD4 and CD8. CD4 and CD8 double positivity was seen in only 11.1% of cases, and 22.4% of cases showed either CD4 or CD8 positivity. We concluded that our study was similar to reports in the Americas and Europe, and it was the first large one that describes the immunophenotypic profile of ALL in the Moroccan population.

Aberrant expression of myeloid antigens in patients of acute lymphoblastic leukaemia.

To determine the immunophenotypic pattern and aberrant expression of myeloid antigens in newly diagnosed patients of acute lymphoblastic leukaemia(ALL). This descriptive cross-sectional study was carried out in Haematology / Pathology department, Army Medical College, National University of Medical Sciences (NUMS) in collaboration with Immunology and Haematology departments of Armed Forces Institute of Pathology (AFIP), Rawalpindi from 1st January, 2019 to 31st December, 2019. Seventy-three (73) recently diagnosed patients of Acute Lymphoblastic leukaemia of all age groups and both genders were included in the study. A proforma was used to note demographic data. CBC, cytochemical stains and bone marrow examinations were carried out and assessed for morphology and percentage of blasts using a microscope. Flow cytometry was used to perform immunophenotyping on samples of peripheral blood and bone marrow, using a standard panel. The most commonly expressed markers were weak CD45, TdT, CD19, CD10 and HLA-DR. Weak CD45 was present in almost all blast cells and there was no remarkable difference in its positivity among various subtypes of ALL. Myeloid expression was observed in 13 (17.8%) cases. CD13 and CD33 were aberrantly expressed in 11 and 12.3 of all cases of ALL respectively. Expression of aberrant myeloid CD markers in acute lymphocytic leukaemia has prognostic significance and should be documented during lineage assignment of acute leukaemias while performing immunophenotyping.

187 Anaplastic Multiple Myeloma (AMM) With Aberrant Myeloid Antigen Expression

187 Anaplastic Multiple Myeloma (AMM) With Aberrant Myeloid Antigen Expression

EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells.

ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.

Impact of Aberrant Myeloid Antigen Expression on Outcomes of Patients with T-cell Acute Lymphoblastic Leukemia.

To evaluate the impact of myeloid antigen expression on complete remission (CR), event-free survival (EFS), and overall survival (OS) in patients with T-cell acute lymphoblastic leukemia (T-ALL) treated with intensive chemotherapy. We retrospectively reviewed consecutive patients diagnosed with T-ALL and treated in Sultan Qaboos University Hospital and Royal Hospital in Oman between 2004 and 2010. The diagnosis of T-ALL was established using French-American-British classification or World Health Organization criteria. Patients were considered having myeloid antigen expression if they expressed CD13, CD33, or both (My+ and My-). Of the 39 patients, 38 were included in the study (25 patients with My- and median age of 18.4 years, 13 patients with My+ and median age of 22.0 years). Median follow-up was 12 months. Thirty-two out of the total cohort were eligible for response-rate assessment. Twenty-nine patients (90.6%) achieved CR with one or two courses of chemotherapy with similar CR rates between the two groups (p = 0.880). Twenty-five percent (5/20) of the patients with My- required two courses of induction, whereas 58.3% (7/12) of My+ required two courses of induction and the difference was statistically significant (p = 0.040). In the multivariable analysis; age, gender, initial white blood cell count, central nervous system disease, and myeloid antigen expression were not statistically significant predictors of CR. The EFS and OS were similar between the My+ and My- groups p = 0.180 and p = 0.440, respectively. Patients with T-ALL with myeloid antigen expression need more courses of induction; however, rates of CR, EFS, and OS are not different from those without myeloid antigen expression. Larger prospective studies are required to confirm these findings.

Multi-Institution Review of Adult Early T-Cell Precursor Acute Lymphoblastic Leukemia/Lymphoma (ETP-ALL)

Background:The Early T-cell precursor (ETP) variant of acute lymphoblastic lymphoma/leukemia (ALL) is a recognized high risk variant, recognized by the absence of CD1a, with aberrant myeloid antigen expression (CD13, CD33, CD117, and CD34), and frequent absence of CD4 or CD8. Treatment intensification may improve outcome in this subset. We undertook a multi-center retrospective analysis to explore clinical features, treatment exposure, and outcomes in ETP ALL as compared to non-ETP variants.MethodsAdult T-ALL/T-LBL cases were compiled from 3 high volume cancer centers between the years 2003-2015. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. ETP cases were defined as definite (CD1a-/CD8-/myeloid+) or probable (CD1a unk/CD8-/myeloid+, or CD1a-/myeloid+ with CD4+ and/or CD8+). All other cases were defined as non-ETP. Demographic data were compared using independent t-test assuming non-equal variance. OS and PFS were calculated from diagnosis and compared by Kaplan Meier and log-rank testing.ResultsAmong 95 cases, 33 met criteria for definite/probable ETP (35%). OS and PFS data were indistinguishable between these groups (p=0.24, p=0.34), and were subsequently analyzed as a single group.Within the ETP group, no factors were associated with OS, including histology (CD1a+ vs unk, CD3cyt vs CD3sur, CD5dim vs CD5+, CD1a+/13+ vs CD1a+/13-, or CD13, CD33, CD117, CD34, & TdT status), marrow blast burden, peripheral blast burden, white blood cell count (wbc), hemoglobin (hgb), platelet count (plt), cytogenetics/FISH status, chemotherapy choice, or allogeneic transplant (in CR1 or at any time). With regards to PFS, only the inclusion of asparaginase with induction was associated with outcome (p=0.009), while all other covariates failed to show any significance.The ETP group was compared with the non-ETP subset (table 1). ETP were more likely to abuse marijuana, possibly reflecting unrecognized pesticide exposure, and were more likely to abnormalities of chrom 5 & 7. ETP trended towards lower response and higher rate of relapse, with lower PFS. Comparison of OS was not significant, likely related to small numbers (5y OS 37% vs 22%, figure 1). Non-ETP failed to show PFS benefit with frontline asparaginase, otherwise no treatment differences were apparent.ConclusionsIn this muti-center cohort we were able to identify and characterize ETP cases, confirming poor outcomes. Improvement in PFS among ETP patients treated with frontline asparaginase warrants attention and prospective confirmation. Unfortunately, OS remains poor independent of treatment or receipt of allogeneic transplant, suggesting a critical need remains for development and study novel therapies.Table 1ETPNon-ETPp-valueMedian Age37.4534.740.42Male82%66%0.89FamilyHx of Lymph/Leuk21%8%0.112FamilyHx of Ca42%25%0.09THC24%5%0.021P blasts40%28%0.158>25% M blasts30%55%0.0571WBC78.4576.550.948wbc>10024%24%0.995Hgb10.7211.780.148hgb<1267%47%0.097plt151.59138.660.644Chrom 5/740%7%0.005Remission61%79%0.096Relapse76%58%0.073OS27.0022.000.595PFS13.0017.000.048PFS AspETP (asp no vs yes)12590.009non-ETP (asp no vs yes)17150.777 [Display omitted] DisclosuresShah:Acetylon: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding. Hathaway:OnQ Health: Research Funding.

Outcome of B-Cell Acute Lymphoblastic Leukemia in Brazilian Children: Immunophenotypical, Hematological, and Clinical Evaluation.

The aim of this study is to investigate the clinical, hematological, and immunophenotypic characteristics of Brazilian children with B-cell acute lymphoblastic leukemia (B-ALL) to identify prognostic biomarkers of the disease. Thirty-three children newly diagnosed with B-ALL were followed between March 2004 and December 2009. Information about the demographic profile, diagnosis, immunophenotype, clinical manifestations, and disease outcome were gathered from the patients' medical records. Of the 33 patients with B-ALL, 18 were male and 15 female. Eighteen patients were classified as high risk; 13 as low risk, and 2 as true low risk. The frequencies of cluster of differentiation (CD)10, CD19, and CD20 antigens were 69.7%, 81.8%, and 18.2%, respectively. Six patients (18.2%) had aberrant expression of myeloid antigens. At diagnosis, patients immunopositive for CD20 had elevated white blood cell counts (P = 0.018) and lower platelet counts (P = 0.017). The 6-year overall survival was 67.5%± 3.47%. Our results demonstrate the distinct immunophenotypic and prognostic characteristics of patients with B-ALL, which can be related to the Brazilian racial admixture. Consequently, these results will most likely aid in the selection of additional prognostic markers and their use in monitoring the clinical manifestations and treatment response among B-ALL patients.

Immunophenotypic Diagnosis of Acute Lymphoblastic Leukemia Using Flow Cytometry : Experience at King Hussein Medical Center

Objective: To identify the importance of flow cytometry (FCM) in diagnosis and subclassifying acute lymphoblastic leukemia, and to highlight its capability to detect antigen aberration. Method: The Results of flow cytometry for 165 patients, between January 2006 and December 2011 who were diagnosed with acute lymphoblastic leukemia (ALL) were retrospectively reviewed with respect to age and gender distribution and immunophenotypic findings. Results: 63% of patients were children (104 out of 165 patients) with age less than fourteen years old. 114 patients were male while 51 patients were female with male to female ratio 2.2: 1. PrecursorB- acute lymphoblastic leukemia represents eighty percent (132 patients) of cases, of 106 patients (87.6%) were [CD10/CD19] positive,125 patients (94.7%) were positive for cytoplasmic CD79a, 126/129 (97.6%) were positive for HLA-DR, and 15 patients (11.36%) were CD10 negative. Aberrant myeloid antigen expression was noted; CD33 and CD13 were positive in 15/113 (13.3%) and 2/108 (1.85%) respectively. On the other hand precursor-T- acute lymphoblastic leukemias were found in thirty three patients, 84.4% of them were Anti-TdT positive, and all were negative for B-cell markers. Myeloid antigen expression results were as follows; 1/29 (3.4%) and 2/29 (6.9%) positive for CD33 and CD13 respectively Conclusion: Flow cytometry is a golden tool in diagnosis and identifying ALL subtypes. PrecursorB- acute lymphoblastic leukemia represents most of ALL cases with minority of cases are CD10negative. Aberrant myeloid antigen expression would not change the diagnosis of ALL in either B- or T- subtypes. Further clinical correlation is needed to figure out aberrant markers prognostic implications.

Aberrant myeloid antigen co-expression is correlated with high percentages of CD34-positive cells among blasts of acute lymphoblastic leukemia patients: an Indian tertiary care center perspective.

BackgroundAberrant myeloid antigen (MA) co-expression and high expression of CD34 antigen on the blasts of acute lymphoblastic leukemia (ALL) patients are independently reported to have a role in pathogenesis and prognosis. This study was conducted to determine whether these two parameters are related.MethodsA total of 204 cases of ALL were included in an analysis of blast immunophenotypic data. CD34 expression was categorized as low when less than 50% of blasts were CD34-positive (CD34low) and as high when 50% or more were CD34-positive (CD34high).ResultsOf 204 cases of ALL, 163 and 41 were of B-cell origin (B-ALL) and T-cell origin (T-ALL), respectively. Of all cases, 132 (64.7%) showed co-expression of MA and among these, 101 (76.51%) were CD34high, while the remaining 31 (23.48%) were CD34low. Of 72 cases without MA co-expression, 25 (34.72%) were CD34high and 47 (67.25%) were CD34low. Furthermore, of 163 cases of B-ALL, 111 showed co-expression of MA and 84 of these were CD34high. Of 52 cases of B-ALL without MA expression, 22 were CD34high. Among 41 cases of T-ALL, 21 co-expressed MA, 17 of which were CD34high. Moreover, all 20 cases of T-ALL without co-expression of MA were CD34low. These differences were statistically significant.ConclusionWe observed a strong correlation between aberrant MA expression and CD34high expression on the blasts of ALL. We hypothesize that these different patient subsets may represent unique prognostic characteristics.

Philadelphia chromosome positive precursor T acute lymphoblastic leukemia.

To the Editor, 26 year old male presented with generalized bulky lymphadenopathy, raised white blood cell count, anemia and thrombocytopenia in December of 2009. The peripheral smear and bone marrow were morphologically consistent with acute lymphoblastic leukaemia. Immunophenotype showed that the blast cells were positive for CD3 and CD7. All the B lineage markers were absent. In addition the blast cells were positive for CD13 and CD 33, but negative for CD117 and cytoplasmic myeloperoxidase. Cytoplasmic CD 3 was positive. We therefore made a diagnosis of acute T lymphoblastic leukemia with aberrant myeloid antigen expression. Conventional cytogenetics showed 9;22 translocation. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the presence of minor BCR–ABL transcript at high levels which is shown in the Fig. 1. Fig. 1 Band at 106 bp is patient’s sample which is positive for minor break point e1a2 (lane 5) corresponding to p190KD protein. The previous lane (lane 4) showing the band at 330 bp is internal control for the ABL region of the patient’s ... T lymphoblastic leukemia with Philadelphia positivity is very rarely reported in the literature [1–4]. There is a debate whether it is de novo leukemia or blastic phase of chronic myeloid leukemia [5]. Our patient did not have a palpable spleen. Absence of splenomegaly and the presence of minor BCR–ABL transcript probably favours an acute lymphoblastic leukemia of precursor T cell lineage. The presence of aberrant myeloid markers makes our case more interesting. The patient was treated with a combination of chemotherapy and imatinib. He achieved morphologic remission but has not achieved molecular remission and hence switched over to second line tyrosine kinase inhibitor dasatinib. There was no BCR–ABL mutation detected. Bone marrow transplantation could not be offered as the patient does not have a histocompatible sibling and an alternative donor transplantation was not feasible due to various logistic constraints.

Aberrant Expression of Myeloid Antigens Identifies a Subgroup of Standard-Risk Adult Acute Lymphoblastic Leukemia Patients with Short Survival

Aberrant Expression of Myeloid Antigens Identifies a Subgroup of Standard-Risk Adult Acute Lymphoblastic Leukemia Patients with Short Survival

Therapy-related pro-B cell acute lymphoblastic leukemia: report of two patients with MLL amplification

Improvements in chemotherapy and medical support of patients treated with chemotherapy and radiation have led to an ever-increasing number of cancer survivors. Unfortunately, a small fraction of these patients develop secondary hematologic malignancies as a consequence of their exposure to genotoxic anti-cancer regimens. Most of these are myeloid malignancies, therapy-related acute myeloid leukemia (t-AML) or myelodysplasia (t-MDS); however, a small but growing body of literature exists, which describes therapy-related acute lymphoblastic leukemias (t-ALL). Nearly all these cases are reportedly associated with translocations involving chromosome 11q23, the site of the MLL gene. We herein report two cases of ALL occurring after chemotherapy for other malignancies that showed complex karyotypic abnormalities and distinct MLL amplification by fluorescence in situ hybridization analysis. Immunophenotypic analysis showed that both cases expressed a pro-B cell (CD10-) phenotype with aberrant myeloid antigen expression. Although MLL amplification has been reported in therapy-related myeloid disease, to our knowledge this is the first report of MLL amplification occurring in therapy-related B cell ALL.

Successful treatment of lymphoid blastic crisis in chronic myelogenous leukemia with the additional bcr/abl transcript using imatinib-combined chemotherapy and high-dose chemotherapy with allogeneic bone marrow stem cell transplantation

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome. Although the major BCR/ABL transcript is present in majority of CML patients, the minor BCR/ABL transcript is rarely reported as an additional chromosomal abnormality related to the progression of CML. We describe the case of a 37-year-old woman who had CML and pain in the extremities. She was diagnosed with lymphoid blast crisis of CML on the basis of the following findings: presence of promyelocytes, myelocytes, and metamyelocytes in peripheral blood smear; detection of major and minor BCR/ABL transcripts by polymerase chain reaction analysis; proliferation of lymphoblastic cells with abnormal B-cell phenotype; and aberrant expression of myeloid antigens in the bone marrow. The patient underwent one course of idarubicin and cytosine arabinose therapy combined with imatinib followed by daunorubicin/cyclophosphamide plus vincristine and prednisone/L: -asparaginase (DNR/COP/L: -ASP) therapy, high-dose cytosine arabinose, and CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Subsequently, the patient underwent high-dose chemotherapy (total body irradiation and cyclophosphamide) followed by allogeneic bone marrow stem cell transplantation from a human leukocyte antigen (HLA)-matched unrelated donor. After these treatments, the patient was disease-free for 19 months. Our case suggests that these treatments may be feasible, safe, and effective for the treatment of patients with blast crisis CML expressing the minor BCR/ABL transcript.

Aberrantly expressed CEACAM6 is involved in the signaling leading to apoptosis of acute lymphoblastic leukemia cells

The aberrant expression of myeloid antigens on acute lymphoblastic leukemia (ALL) cells is a well-documented phenomenon. So far, there have been no reports of a functional consequence of this aberrant expression. The granulocytic marker carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6, CD66c) is a GPI-anchored molecule that is reported to be the most frequently aberrantly expressed myeloid marker in ALL with a strong correlation with genotype. We mimicked CEACAM6 signaling in ALL cells by cross-linking with anti-CEACAM6 antibody. Next, we measured a response to CEACAM6 signaling by integrin subunits expression, integrin ligand binding, phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2), Akt, and p38 mitogen-activated protein kinase (MAPK) and apoptosis by flow cytometry. Following CEACAM6 cross-linking in ALL cells, we detected Erk1/2, Akt, and p38 MAPK phosphorylation and integrin upregulation, as well as enhanced binding of integrin ligands (vascular cell adhesion molecule-1 [VCAM-1] and intercellular cell adhesion molecule-1 [ICAM-1]). However, CEACAM6 signaling resulted in an increase in apoptosis, unlike other GPI-anchored molecules, such as CD24. The present study is the first to demonstrate the functional consequences of CEACAM6 cross-linking in B-cell precursor ALL cells.

Specific induction of CD33 expression by E2A–HLF: the first evidence for aberrant myeloid antigen expression in ALL by a fusion transcription factor

Specific induction of CD33 expression by E2A–HLF: the first evidence for aberrant myeloid antigen expression in ALL by a fusion transcription factor

Prognostic significance of minimal residual disease detected by a simplified flow cytometric assay during remission induction chemotherapy in children with acute lymphoblastic leukemia

PurposeOur study attempted to determine the prognostic significance of minimal residual disease (MRD) detected by a simplified flow cytometric assay during induction chemotherapy in children with B-cell acute lymphoblastic leukemia (B-ALL).MethodsA total of 98 patients were newly diagnosed with precursor B-ALL from June 2004 to December 2008 at the Asan Medical Center (Seoul, Korea). Of those, 37 were eligible for flow cytometric MRD study analysis on day 14 of their induction treatment. The flow cytometric MRD assay was based on the expression intensity of CD19/CD10/CD34 or aberrant expression of myeloid antigens by bone marrow nucleated cells.ResultsThirty-five patients (94.6%) had CD19-positive leukemic cells that also expressed CD10 and/or CD34, and 18 (48.6%) had leukemic cells with aberrant expression of myeloid antigens. Seven patients with ≥1% leukemic cells on day 14 had a significantly lower relapse-free survival (RFS) compared to the 30 patients with lower levels (42.9% [18.7%] vs. 92.0% [5.4%], P=0.004). Stratification into 3 MRD groups (≥1%, 0.1-1%, and <0.1%) also showed a statistically significant difference in RFS (42.9% [18.7%] vs. 86.9% [8.7%] vs. 100%, P=0.013). However, the MRD status had no significant influence on overall survival. Multivariate analysis demonstrated that the MRD level on day 14 was an independent prognostic factor with borderline significance.ConclusionAn MRD assay using simplified flow cytometry during induction chemotherapy may help to identify patients with B-ALL who have an excellent outcome and patients who are at higher risk for relapse.

Bcl-2 in Combination to Myeloid Antigen Expression in Adult Acute Lymphoblastic Leukemia and Prognostic Outcome

The present study was performed to find the importance of two myeloid (CD13 and CD33) antigens aberrantly expressed on the blasts of acute lymphoblastic leukemia (ALL) patients and Bcl-2 expression in relation to clinical and biological features and treatment outcome. Bone marrow or peripheral blood samples of 50 patients were assessed for the expression of markers by immunostaining methods. Twenty-one patients (42%) showed more than 20% positivity for Bcl-2. Aberrant expression of myeloid antigens was found in 14% of cases. The expression of Bcl-2 was associated with shorter survival (p = 0.009). A significant correlation between expression of myeloid antigens (MY) and survival and complete remission duration was found. The mean survival was 656 + 301 days for MY+ cases and 1009 +/- 230 days for MY- patients (p < 0.0001). Expression of Bcl-2 in combination to myeloid antigens was associated with a poorer outcome. Survival of MY+ patients expressing Bcl-2 was shorter than MY- Bcl-2+ and MY+ Bcl-2- ALL cases (p = 0.038). In conclusion, results of this study indicated the prognostic value of Bcl-2 and myeloid antigen expression in ALL patients. Presence of these markers together on the leukemic cells was associated with a poorer response to therapy and may implicate modified therapeutic strategies in the patients.

A Randomised Phase II Study of Pegylated Liposomal Doxorubicine in Elderly Patients with Acute Lymphoblastic Leukemia (ALL): The GRAALL-SA1 Study.

The GRAALL-SA1 study aimed to randomly compare the efficacy and toxicity of liposomal pegylated doxorubicin (Peg-Dox) vs continuous infusion doxorubicin (CI-Dox) in elderly patients with Philadelphia chromosome-negative ALL. Induction chemotherapy, supported by G-CSF, comprised either CI-Dox 12 mg/m2/d and CI-VCR 0.4 mg/d on d1-4 or Peg-Dox 40 mg/m2 IV and standard VCR 2 on d1, in combination with dexamethasone. A second cycle, reinforced by cyclophosphamide 1 g/m2, was started at d28. Consolidation included two additional cycles using reduced doses of CI-Dox (12mg/m2/d d1-3) or Peg- Dox (30 mg/m2 d1) with VCR in both treatment arms (5 minutes infusion on d1,8,15) alternating with two cyclophosphamide (650 mg/m2 d1) /thioguanine (60 mg/m2 d2- d15) /cytarabine (75 mg/m2/d4-7 and d11-14) cycles. Maintenance included 6-MP and methotrexate for 2 years. CNS prophylaxis was based on 6 triple ITs and cranial irradiation. From March 2002 to October 2006, 60 patients aged 55 years or more from 26 centers were enrolled in this multicenter study. The median age was 66 years (range 55–80), 17% had initial WBC 3 30 x109/l, 2 patients had CNS leukemia and 6.6% had mediastinal involvement. Immunophenotyping showed 85% B-lineage ALL, 12% T-ALL, and 3% aberrant expression of myeloid antigens. Patient characteristics were comparable in the two randomization groups except for a small unbalance with more T-ALL and more steroids resistant leukemia in the Peg-Dox group (6/29 vs 1/31, P = .05 and 5/29 vs 1/31, P = .1, respectively). Tolerance was improved in the Peg-Dox arm with less Grade 3–4 infectious events during induction (27% vs 48%; P = .04), less Gram negative bacteriemia during induction (1 vs 9, P = .02) and consolidation courses (2 vs 7, P = .07) and less cardiac toxicities (1/29 vs 6 /31, P = .12). Duration of neutropenia was reduced from 7 days in the CI-Dox arm to 6 days in the Peg-Dox arm (P= .06). RBC units transfused were reduced from 7.2 to 4.5 during induction (P= .02) and from 2.9 to 1.1 during consolidation course (P= .003). Days with platelets < 50.109/L were reduced from 13.4 to 6.4 (P=0.03). After the 2 induction cycles, CR rate was 82%, with 10% failures and 8% induction deaths. With a median follow-up of 40 months, median OS for the entire population was 10 months and 19% of the patients were alive in CR at 3 years (95% CI, 9–30). Despite the better tolerance, there was a trend for a worse 2-year OS in the Peg-Dox arm (11 vs 27% ; P=0.07), due to higher induction failure (17 vs 3%) as well as relapse incidence rates (62 vs 39%). Younger age, B-lineage, and steroid sensitivity were the three factors identified for a higher CR rate in multivariate analysis. The decreased toxicity of Peg-Dox over CI-Dox was thus offset by a decreased efficacy. Further studies should evaluated higher doses of pegylated versus conventional formulations of anthracycline in patients with ALL.