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With the advent of precision medicine, next-generation sequencing (NGS) is playing an increasingly important role in clinical oncology diagnosis and treatment with its advantages of high sensitivity, high accuracy, high efficiency and operability. NGS reveals the genetic characteristics of acute leukemia(AL) patients by screening for specific disease-causing genes to identify occult as well as complex genetic mutations in patients with AL, leading to early diagnosis and targeted drug therapy for AL patients, as well as to predict disease recurrence by detecting mnimal residual disease (MRD) and analyzing mutated genes to determine patient prognosis. NGS plays an increasingly important role in the diagnosis, treatment and prognosis assessment in AL, providing a direction for the pursuit of precision medicine. This paper reviews the research progress of NGS in AL.
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Humans , High-Throughput Nucleotide Sequencing , Leukemia, Myeloid, Acute/genetics , Acute Disease , Mutation , Recurrence , Neoplasm, Residual/geneticsABSTRACT
Objective:To analyze the clinical characteristics, treatment and prognosis of mixed phenotypic acute leukemia (MPAL) in children, and to provide reference for clinical optimization of diagnosis and treatment and improve the remission rate.Methods:Based on the diagnostic criteria of the World Health Organization (WHO) in 2016, the bone marrow cell morphology, immune typing, cytogenetics, molecular biological characteristics, treatment regimen, and prognosis of 15 children with MPAL who were admitted to Children′s Hospital Affiliated to Soochow University from January 2012 to December 2020 were retrospectively analyzed.The count data were compared between groups using the χ2 test, the measurement data that conformed to the normal distribution were compared using the t test, and the measurement data that were not normally distributed were compared using the rank sum test.Survival was estimated using the Kaplan- Meier ( K- M) method and the Log- rank method was used for comparison. Results:A total of 15 children with MPAL were admitted to Children′s Hospital Affiliated to Soochow University in the past 8 years, including 8 males and 7 females, with a median age of 6.8 years.Nine patients expressed B lymphocyte and myeloid phenotype, 5 patients expressed T lymphocyte and myeloid phenotype, and 1 patient expressed B and T lymphocyte phenotype.Karyotype of 11 children was examined, and the results showed that there were 2 cases of normal karyotype, 2 complex karyotype, 6 pseudodiploid and 1 subdiploid.Fusion genes were detected in 5 children, including 3 AML- ETO positive, 1 BCR- ABL positive, and 1 MLL gene positive.Thirteen patients were in complete remission (CR) after chemotherapy, with a total CR rate of 86.6% and a 2-year over survival (OS) rate of (68.2±13.4)%.Among the 15 children, 14 received induction chemotherapy and 1 gave up treatment for personal reasons.There were 10 patients with the first choice of acute lymphoblastic leukemia (ALL) chemotherapy regimen and 1 patient receiving CR, with a total CR rate of 10%.There were 4 cases of acute myeloid leukemia (AML) with the preferred chemotherapy regimen and 3 cases with CR in the first course of treatment, and the total CR rate was 75%.One case without remission was relieved after changing ALL chemotherapy regimen.The 2-year OS rates of 8 patients with hematopoietic stem cell transplantation (HSCT) and 6 patients without HSCT were (70.0±18.2)% and (66.7±19.2)%, respectively, with no significant difference ( χ2=0.318, P=0.573). Conclusions:Children with MPAL is a rare malignant tumor, mainly characterized by the co-expression of lymphoid and myeloid antigens.Chemotherapy alone or HSCT can achieve a good prognosis in the short term, but the long-term efficacy remains to be further observed.
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The background of this study is FGFR1 belongs to a family of four, high-affinity receptor tyrosine kinase and is a legitimate oncogene associated with uterine, cervical, prostate, bladder, colorectal and lung cancers. It is rarely concomitant in myeloid and lymphoid neoplasms but has an aggressive clinical course with a high mortality rate when present. Cytogenetic abnormalities involving the FGFR1 gene is most frequently observed in AML, MPN with eosinophilia, T-ALL and T-LBL with ZMYM2 gene being the most common fusion partner. Methods of this study was to authors report a series of 4 cases with FGFR1 rearrangements. Results is three patients presented as T-cell Lymphoblastic lymphoma (T-LBL) and one as mixed phenotype acute leukemia (MPAL). The T-LBL cases harboured the FGFR1/ ZMYM2 fusion and the MPAL case harbored the CNTRL/FGFR1 fusion as identified by conventional cytogenetics and confirmed by molecular studies. Conclusion is authors herewith describe the clinical, biochemical, molecular and cytogenetic features observed in these cases.
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@#Introduction: Mixed phenotype acute leukaemia (MPAL) is a rare entity of acute leukaemia. Case Report: Here we report a case of a 39-year-old lady, with an incidental finding of hyperleukocytosis (white blood cells count: 139.2 x 109 /L). Her peripheral blood film revealed 36% of blasts and a bone marrow aspiration showed 53% of blasts. Immunophenotyping showed a population of blasts exhibiting positivity of two lineages, myeloid lineage and B-lymphoid lineage with strong positivity of CD34 and terminal deoxynucleotidyl transferase (Tdt). A conventional karyotyping revealed the presence of Philadelphia chromosome. She was diagnosed with MPAL with t(9,22), BCR ABL1, which carried a poor prognosis. She was treated with acute lymphoblastic leukaemia (ALL) chemotherapy protocol coupled with a tyrosine kinase inhibitor and was planned for an allogeneic stem cells transplant. Conclusion: This MPAL case was diagnosed incidentally in an asymptomatic patient during medical check-up. We highlight this rare case report to raise the awareness about this rare disease. Understanding the pathogenesis of the disease with the underlying genes responsible for triggering the disease, uniform protocols for diagnosis and targeted treatment will help for proper management of these patients.
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BACKGROUND: Acute leukemia (AL), not clearly assigned to myeloid, B-lymphoid, or T-lymphoid lineage, is classified as either biphenotypic acute leukemia (BAL) based on the European Group for Immunological Classification of Leukemias (EGIL) or acute leukemia of ambiguous lineage (ALAL) encompassing acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemia (MPAL) based on the World Health Organization (WHO) criteria. METHODS: Medical records of children newly diagnosed with BAL or ALAL, based on the EGIL or the 2008/2016 WHO criteria, respectively, admitted at Chonnam National University Hospital in 2001–2017 were retrospectively reviewed. RESULTS: Twelve (3.2%) of 377 AL patients satisfied the BAL or ALAL definitions based on the EGIL or the WHO criteria, respectively. Among 12 patients including 11 with BAL and another with undefined case based on the EGIL criteria, 7 (1.9%) had ALAL based on more stringent 2016 WHO criteria (AUL, 2; MPAL, 5). One patient had MPAL with t(9;22)(q34;q11.2), BCR-ABL+, and two had MLL gene abnormality. ALL-directed regimen was associated with better complete remission rate compared with AML-directed regimen (100.0% vs. 16.7%; P=0.015). The 5-year overall survival (OS) and event-free survival (EFS) were 51.1±15.8% and 51.9±15.7%, respectively. AUL was associated with poor OS and EFS compared with MPAL (0.0% vs. 75.0±21.7%; P=0.008). CONCLUSION: Due to the rarity of the cases, future multicenter, prospective studies incorporating large number of cases are urgently warranted to identify the clinical, biologic, and molecular markers for the prediction of prognosis and determine the best tailored therapy for each patient.
Subject(s)
Child , Humans , Classification , Disease-Free Survival , Immunophenotyping , Leukemia , Leukemia, Biphenotypic, Acute , Medical Records , Prognosis , Prospective Studies , Retrospective Studies , World Health OrganizationABSTRACT
Objective To investigate the clinical and biological features of patients with mixed﹣phenotype acute leukemia (MPAL). Methods The clinical data of 24 de novo adult patients with MPAL who were admitted to Fujian Medical University Union Hospital from January 2012 to October 2018 were retrospectively analyzed. These patients were diagnosed according to the World Health Organization (WHO) 2016 criteria. The clinical and biological characteristics of the patients were analyzed by morphological and cytochemical staining, immunophenotyping, cytogenetics and molecular biology. Results Of the 24 patients, 16 were male and 8 were female, and the median age of the patients at diagnosis was 27 years old (5-66 years old). The average blasts of bone marrow were (57.41 ±23.20)% . Thirteen cases (54.2% ) were diagnosed as MPAL morphologically, while 5 cases (20.8% ) were diagnosed as acute myeloid leukemia (AML), 5 cases (20.8%) were diagnosed as acute lymphoblastic leukemia (ALL) and 1 case (4.2%) was inconclusive. Eighteen patients (75.0%) co﹣expressed B﹣lymphoid and myeloid markers, while 5 patients (20.8%) with T﹣lymphoid and myeloid markers and 1 patient (4.2%) with B﹣lymphoid and T﹣lymphoid markers, respectively. The positive rate [median (range)] of CD38, HLA﹣DR and CD34 was 90.5% (0.1%-99.7%), 90.1% (1.1%-98.8% ) and 81.3% (0.1%-97.8%), respectively. Eighteen cases underwent chromosome examination, of which 5 cases carried with t(9;22)(q34;q11), 3 cases with t(v;11q23.3), 2 cases with complex karyotypes, and 2 cases with t(9;22)(q34;q11) and complex karyotypes, respectively. Twenty﹣one cases underwent genetic examination, of which 6 cases were positive for BCR﹣ABL, 3 cases were positive for MLL, 1 case was positive for MLL and BCR﹣ABL, 1 case was positive for BCR﹣ABL and TP53, and 1 case was positive for PHF6 and ASXL1 respectively. Of the 24 patients, 7 refused chemotherapy and 17 received induction chemotherapy. Of the patients receiving chemotherapy, 9 cases achieved complete remission (CR), 1 case was partial remission (PR), and 7 cases were not relieved (NR). In 11 patients treated by ALL﹣type induction regimen and 6 patients treated by ALL and AML﹣type induction regimen, 8 cases and 1 case achieved CR, the difference in CR rate was statistically significant (P<0.05). In 6 patients with Philadelphia chromosome (Ph) positive and 11 patients with Ph negative, 1 case and 8 cases achieved CR, the difference in CR rate was statistically significant (P<0.05). The median follow﹣up time was 5.5 months (0-36 months). The 3﹣year overall survival (OS) rate was 17.5% and the median OS time was 6 months. The 3﹣year OS rates in the allogeneic hematopoietic stem cell transplantation and non﹣transplanted groups were 75.2% and 0, respectively, and the median OS time was not reached and 4 months (P< 0.05). Conclusions MPAL is rare, it mostly co﹣expresses lymphoid and myeloid antigens and shows a much higher incidence of CD34, CD38 and HLA﹣DR. MPAL is often associated with Ph positive and complex karyotypes. MPAL has a low remission rate and poor prognosis, and a reasonable and effective treatment plan should be further explored.
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Objective To investigate the clinical and molecular biological characteristics of mixed_phenotypic acute leukemia (MPAL) with SET_NUP214 fusion gene positive and extramedullary infiltration. Methods The clinical characteristics, diagnosis and treatment of one MPAL patient with SET_NUP214 and extramedullary infiltration who was admitted to Hebei Yanda Ludaopei Hospital in November 2017 were analyzed, and the literature was reviewed. Results The patient was diagnosed as MPAL with extramedullary infiltration. Gene detection found SET exon7_NUP214 exon17 fusion positive accompanied with PHF6, SRSF2 and NRAS mutations. After intensive chemotherapy, the patient achieved complete remission, and then received hematopoietic stem cell transplantation (HSCT), followed by early extramedullary relapse after transplantation, and achieved secondary remission after consolidation chemotherapy. Conclusions MPAL with SET_NUP214 fusion gene positive and extramedullary infiltration has a poor prognosis, and it is easy to relapse. Currently, HSCT is the best available treatment strategy for such patients.
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A 46-year-old female patient was diagnosed as mixed phenotype acute leukemia with chief complaints of intermittent gingival swelling and bleeding for 1 week. The induction chemotherapy was not effective. During the second course chemotherapy, the patient had sudden convulsion and coma. She was transferred to the intensive care unit with worsened condition after transient improvement. Her final diagnosis was secondary adrenocortical insufficiency, adrenal crisis, intractable hyponatremia and cerebral edema.
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BACKGROUND: Different criteria have been used to diagnose mixed-phenotype acute leukemia (MPAL), which has impacted the number of individuals diagnosed with this pathology. Better outcomes have been reported when using acute lymphoblastic leukemia (ALL)-type chemotherapy in the treatment of MPAL. METHODS: We compared the outcome of 4 groups of patients with MPAL. Group 1 included patients diagnosed using the 2008/2016 World Health Organization (WHO) classification; group 2 included patients diagnosed using the European Group for the Immunological Characterization of Leukemias (EGIL) criteria; group 3 included patients diagnosed using either the EGIL or the 2008/2016 WHO criteria; and group 4 was comprised of patients diagnosed with MPAL using the EGIL classification only. RESULTS: We found a significantly worse disease-free survival (groups 1-4) and overall survival (OS) (groups 2 and 3) when comparing MPAL patients to other acute leukemia (AL) patients. A significantly better OS was obtained in patients (groups 2-4) treated with ALL-type chemotherapy compared to acute myeloid leukemia (AML)-type regimens. CONCLUSION: In light of these results, and because a trend (P=0.06) was found with regard to a better OS in group 4 when compared to other AL patients, an argument can be made that the 2008/2016 WHO classification is underpowered to diagnose all MPAL cases, potentially resulting in the suboptimal treatment of some individuals with AL.
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Humans , Classification , Disease-Free Survival , Drug Therapy , Leukemia , Leukemia, Myeloid, Acute , Pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma , World Health OrganizationABSTRACT
No abstract available.
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Aged, 80 and over , Female , Humans , Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/analogs & derivatives , Biomarkers, Tumor/analysis , Biopsy , Bone Marrow Examination , Cell Lineage , Leukemia, Biphenotypic, Acute/drug therapy , Phenotype , Remission Induction , Treatment OutcomeABSTRACT
Introduction: Mixed phenotype acute leukemia (MPAL) is a rare subset of acute leukemia where the blasts exhibit lineage specifi c antigens of more than one lineage. Flow cytometric immunophenotyping is essential for the diagnosis of MPAL and the accurate diagnosis highly depends on the panel of markers used. The precise incidence of MPAL is uncertain as various institutions use different combinations of antibodies to assign the blasts to a particular lineage. Aim: The aim was to study the immunoprofi le of acute leukemia including aberrant antigen expressions and to study the incidence, clinical features, laboratory fi ndings, and immunophenotype of MPAL in our institution. Materials and Methods: All cases of acute leukemias in which fl ow cytometric analysis during 1-year period from July 2012 to July 2013 were included in this study. Results: During the study period, fl ow cytometric analysis of 506 cases was performed. B lymphoblastic leukemia was the most common subtype of acute leukemia. CD13 was the most common aberrant antigen expression in acute lymphoblastic leukemia and CD7 was the most common aberrant antigen expression in acute myeloid leukemia. A diagnosis of MPAL was made in 15 cases, which accounted for 2.96% of all leukemias. 9 cases were diagnosed as T/myeloid, 5 cases as B/myeloid and 1 case as B/T. Conclusion: Mixed phenotype acute leukemia is a rare subset of acute leukemia. Flow cytometry is critical in establishing a diagnosis of MPAL. The panel of antibodies used is important in the identifi cation of the “mixed” phenotype. Cytoplasmic markers (cytoplasmic MPO, cytoplasmic 79a, cytoplasmic 22 and cytoplasmic CD3) should be included in the primary flow cytometric panel.
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BACKGROUND: We evaluated the clinical significance of revised 2008 WHO classification needed to diagnose mixed phenotype acute leukemia (MPAL). METHODS: A total of 22 MPAL patients, previously diagnosed by applying the scoring system of the European Group for Immunological Classification of Acute Leukemias (EGIL) were reclassified based on the 2008 WHO classification. RESULTS: In 2008 WHO classification, the number of monoclonal antibodies (mAbs) required for assigning more than one lineage was markedly decreased, from 26 to 11, compared with that of EGIL. Seventeen of the 22 MPAL patients were reclassified as MPAL with following details: 6 MPAL with t(9;22)(q34;q11.2); BCR-ABL1, 1 MPAL with t(v;11q23); MLL rearranged, 7 MPAL, B/Myeloid, not otherwise specified (NOS) and 3 MPAL, T/Myeloid, NOS. Five patients were excluded from MPAL in the revised classification: 4 cytoplasmic myeloperoxidase (cMPO)-negative and 1 CD19-negative. The failure of complete remission achievement and occurrence of relapse were associated with poor prognosis (P=0.0002 and P=0.009, respectively). But the presence of Philadelphia chromsome was not significantly related with patient outcome (P=0.082). One patient with cCD79a, CD20, CD38, cMPO and CD15, whose diagnosis was reclassified from MPAL to AML has survived during the study period. CONCLUSIONS: Because of decreased number of mAbs needed, it is possible that acute leukemia panel is designed to include all mAbs required to diagnose MPAL according to 2008 WHO classification. When diagnosing MPAL, it is critical to figure out positivity in either cMPO or CD19, and AML expressing more than 2 lymphoid antigens are considered as MPAL.
Subject(s)
Adolescent , Adult , Aged , Child , Female , Humans , Infant , Male , Middle Aged , Acute Disease , Antibodies, Monoclonal/immunology , Chromosomes, Human , Fusion Proteins, bcr-abl/metabolism , Leukemia/classification , Phenotype , Philadelphia Chromosome , Survival Analysis , World Health OrganizationABSTRACT
The immunophenotypic profile of hematological malignancies is usually consistent among different sites of involvement; this consistency allows reliable diagnosis from peripheral blood, bone marrow, or lymph node, especially in cases of acute leukemia. Although in a minority of lymphoma patients, two or more different populations with discordant immunophenotypes have been described, either at the same or distinct sites. Here, we report two Korean patients with acute leukemia where the results of immunophenotypic analysis of the bone marrow specimen were different from those of immunohistochemical studies of a biopsy sample of a cervical lymph node, particularly with respect to myeloperoxidase and CD3. The clinical significance of the immunophenotypic disparity found in the patients still remains unknown; however, discrepancies between the different anatomic sites that are simultaneously involved can occur in a subset of leukemia patients. Therefore, integration of all the relevant results, including those of the bone marrow studies, may be helpful for accurate diagnosis and selecting appropriate treatment modalities.