Form Of Acute Lymphoblastic Leukemia Research Articles

MiR-27a downregulates 14-3-3θ, RUNX1, AF4, and MLL-AF4, crucial drivers of blast transformation in t(4;11) leukemia cells.

The chromosomal translocation t(4;11)(q21;q23), a hallmark of an aggressive form of acute lymphoblastic leukemia (ALL), encodes mixed-lineage leukemia (MLL)-AF4 oncogenic chimera that triggers aberrant transcription of genes involved in lymphocyte differentiation, including HOXA9 and MEIS1. The scaffold protein 14-3-3θ, which promotes the binding of MLL-AF4 to the HOXA9 promoter, is a target of MiR-27a, a tumor suppressor in different human leukemia cell types. We herein study the role of MiR-27a in the pathogenesis of t(4;11) ALL. Reverse transcription quantitative PCR (qPCR) reveals that MiR-27a and 14-3-3θ expression is inversely correlatedin t(4;11) ALL cell lines; interestingly, MiR-27a relative expression is significantly lower in patients affected by t(4;11) ALL than in patients affected by the less severe t(12;21) leukemia. In t(4;11) leukemia cells, ectopic expression of MiR-27a decreases protein level of 14-3-3θ and of the key transcription factor RUNX1. We show for the first time that MiR-27a also targets AF4 and MLL-AF4; in agreement, MiR-27a overexpression strongly reduces AF4 and MLL-AF4 protein levels in RS4;11 cells. Consequent to AF4 and MLL-AF4 downregulation, MiR-27a overexpression negatively affects transcription of HOXA9 and MEIS1in different t(4;11) leukemia cell lines. In agreement, we show through chromatin immunoprecipitation experiments that MiR-27a overexpression impairs the binding of MLL-AF4 to theHOXA9 promoter. Lastly, we found that MiR-27a overexpression decreases viability, proliferation, and clonogenicity of t(4;11) cells, whereas it enhances their apoptotic rate. Overall, our study identifies the first microRNAthat strikes in one hit four crucial drivers of blast transformationin t(4;11) leukemia. Therefore, MiR-27a emerges as a new promising therapeutic target for this aggressive and poorly curable form of leukemia.

FLT3-ITD in Children with Early T-cell Precursor (ETP) Acute Lymphoblastic Leukemia: Incidence and Potential Target for Monitoring Minimal Residual Disease (MRD).

Simple SummaryThe prevalence of FLT3-ITD among children with ETP-ALL must be determined. MRD monitoring in ETPs is hampered by the lack of Immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements. We determined the incidence of FLT3-ITD among children with ETP and performed MRD monitoring using FLT3-ITD sequences, successfully testing a new method of MRD detection. Moreover, we highlighted that the FLT3 pathway could represent a therapeutic target for precision therapy in patients with ETP. Early T-cell precursor (ETP) is an aggressive form of acute lymphoblastic leukemia (ALL), associated with high risk of relapse. This leukemia subtype shows a higher prevalence of mutations, typically associated with acute myeloid leukemia (AML), including RAS and FLT3 mutations. FLT3-ITD was identified in 35% cases of adult ETP-ALL, but data in the pediatric counterpart are lacking. ETPs frequently lack immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements, used for minimal residual disease (MRD) monitoring. Among 718 T-ALL enrolled in Italy into AIEOP-BFM-ALL2000, AIEOP-ALLR2006, and AIEOP-BFM-ALL2009 consecutive protocols, 86 patients (12%) were identified as ETP and 77 out of 86 children were studied for the presence of FLT3-ITD. A total of 10 out of 77 (13%) ETP cases were FLT3-ITD positive. IG/TR MRD monitoring was feasible only in four cases. FLT3-ITD MRD monitoring was performed using real-time PCR in all FLT3-ITD positive ETP cases. A comparison between IG/TR and FLT3-ITD resulted in comparable findings. Our study demonstrated that the FLT3-ITD prevalence in children was lower (13%) than that reported in adult ETP-ALL. FLT3-ITD can be used as a marker for sensitive molecular MRD monitoring in ETP-ALL when IG/TR markers are not available, potentially selecting those patients who should spare allogeneic hematopoietic stem cell transplantation (HSCT). Finally, the FLT3 pathway is a robust druggable target in this aggressive form of leukemia.

Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report

Secondary malignancy of donor origin in the form of acute lymphoblastic leukemia (ALL), post-allogeneic hematopoietic stem cell transplant (HSCT) for beta thalassemia (BT) major, is exceedingly rare. A10 year old male child, the first and only product of non-consanguineous conception, was diagnosed with BT major at the age of 9 months when he had diarrhea and his parents (both of whom had thalassemia minor) noticed yellowing of the skin. Until the age of 10 years, he received regular blood transfusion and iron chelation, when the requirements got escalated and he consequently had to undergo myeloablative haploidentical HSCT from his mother. The post-transplant period was uneventful, and follow up with short tandem repeat chimerism analysis revealed complete donor chimerism on all occasions. Five years after the transplant, he developed fever with pancytopenia. Peripheral smear (PS) and bone marrow revealed blasts that were immunophenotypically precursor B-ALL. Cytogenetics revealed twenty diploid female metaphases with modal karyotype 46, XX[20], and again, complete donor chimerism was noted. Thus, a diagnosis of donor cell leukemia (DCL) was considered. Induction chemotherapy was initiated; however, the patient succumbed to systemic sepsis midway through induction therapy. No evidence of leukemia was noted in the patient's mother, who was followed up with PSs for 5 years. DCL has a poor prognosis. Greater understanding of the disease biology could allow for appropriate donor screening, notification and shielding the recipient from DCL and its grave consequences.

Features of basic indicators of oral fluid in children after hematopoietic cell transplantation (pilot study)

Relevance. Treatment of patients with refractory forms of acute lymphoblastic leukemia causes a number of complications from the organs and tissues of the oral cavity. It can be both early complications – cytotoxic reactions with the development of oral mucositis, and late, leading to a violation of the mineralization of hard tooth tissues, and to underdevelopment of the teeth. Oral fluid plays an important role in maintaining oral homeostasis. One of the most important functions that it performs is maintaining the physiological balance of the processes of re- and demineralization of tooth enamel. Since demineralization processes begin in childhood at higher pH values than in adults, when the hydrogen index decreases below 6.4, demineralization processes begin to prevail over remineralization, and the solubility of hydroxylapatite crystals which enamel consists of increases.The objective was to assess the basic indicators of oral fluid and oral hygiene indices in this group of patients.Methods and materials. During the examination of the oral cavity, the intensity of caries and hygiene indices were determined. For the study, oral fluid was collected, followed by determination of its viscosity and hydrogen index.Results. These patients showed a lower level of oral fluid hydrogen index and a lower level of oral hygiene compared to healthy children. In addition, during the study, it was found that there is a direct relationship between the pH of the oral fluid and the time elapsed since the hematopoietic cell transplantation.Conclusion. The detected changes are factors that predispose to an increase in the intensity of caries, and require early preventive measures.Authors declare no conflict of interest.The authors confirm that they respect the rights of the people participated in the study, including obtaining informed consent when it is necessary, and the rules of treatment of animals when they are used in the study. Author Guidelines contains the detailed information.

Crosstalk between 14-3-3θ and AF4 enhances MLL-AF4 activity and promotes leukemia cell proliferation.

The t(4;11)(q21;q23) translocation characterizes a form of acute lymphoblastic leukemia with a poor prognosis. It results in a fusion gene encoding a chimeric transcription factor, MLL-AF4, that deregulates gene expression through a variety of still controversial mechanisms. To provide new insights into these mechanisms, we examined the interaction between AF4, the most common MLL fusion partner, and the scaffold protein 14-3-3θ, in the context of t(4;11)-positive leukemia. Protein-protein interactions were analyzed using immunoprecipitation and in vitro binding assays, and by fluorescence microscopy in t(4;11)-positive RS4;11 and MV4-11 leukemia cells and in HEK293 cells. Protein and mRNA expression levels were determined by Western blotting and RT-qPCR, respectively. A 5-bromo-2'-deoxyuridine assay and an annexin V/propidium iodide assay were used to assess proliferation and apoptosis rates, respectively, in t(4;11)-positive and control cells. Chromatin immunoprecipitation was performed to assess binding of 14-3-3θ and AF4 to a specific promoter element. We found that AF4 and 14-3-3θ are nuclear interactors, that 14-3-3θ binds Ser588 of AF4 and that 14-3-3θ forms a complex with MLL-AF4. In addition, we found that in t(4;11)-positive cells, 14-3-3θ knockdown decreased the expression of MLL-AF4 target genes, induced apoptosis and hampered cell proliferation. Moreover, we found that 14-3-3θ knockdown impaired the recruitment of AF4, but not of MLL-AF4, to target chromatin. Overall, our data indicate that the activity of the chimeric transcription factor MLL-AF4 depends on the cellular availability of 14-3-3θ, which triggers the transactivating function and subsequent degradation of AF4. From our data we conclude that the scaffold protein 14-3-3θ enhances the aberrant activity of the chimeric transcription factor MLL-AF4 and, therefore, represents a new player in the molecular pathogenesis of t(4;11)-positive leukemia and a new promising therapeutic target.

Emerging Trends in Chimeric Antigen Receptor T-Cell Immunotherapy in Adults from the Vizient Clinical Database

Introduction Chimeric Antigen Receptor T-cell (CAR-T) Immunotherapy was approved by the FDA in 2017 for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL), as well as adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. CAR-T immunotherapy uses a patient's own T cells and modifies them in a laboratory to recognize and kill the patient's cancer. Since the CAR-T modified cells multiply and persist in the patient's bloodstream, they have the potential to protect the patient against recurrence. Beginning October 1, 2017, two new, unique ICD-10 procedure codes were assigned to CAR-T immunotherapy (XW033C3 for peripheral venous route and XW043C3 for central venous route), allowing for tracking of the procedure in administrative datasets. Objectives To describe trends in adult patient populations, outcomes, and adverse events using the CAR-T procedure codes in administrative data. Methods A retrospective cohort of 735 patients 18 years and older undergoing CAR-T procedures was identified from the Vizient Clinical Data Base / Resource Manager from 45 hospitals between October 2017 and August 2018. Results The 735 patients were largely white (77.3%), male (63.7%), commercial (55.0%) patients with large B-cell lymphoma (61.5%). Other cancer types included other B-cell lymphoma (19.3%), multiple myeloma (4.2%), follicular lymphoma (3.9%), and ALL (1.9%). The median length of stay was 15 days, the median total cost of hospitalization for CAR-T encounter was $82,059 and median direct cost was $43,108. During the initial hospitalization, 508 (69.1%) of patients had an adverse event due to the immunotherapy and 91 (12.4%) were coded for other complications following infusion, transfusion or therapeutic injection. 417 patients (56.7%) had fever, 403 (54.8%) had a change in blood pressure, 189 (25.7%) had nausea, 137 (18.6%) had a headache or migraine, 110 (15.0%) had acute kidney failure and 30 patients (1.5%) had an in-hospital death. Within 30 days, 117 patients (15.9%) had an unplanned readmission to the index hospital, with 69 (5.9%) patients being readmitted within 7 days of discharge. Conclusion Due to the recent implementation of the unique ICD-10 codes, more time and follow-up for these adult patients is needed to determine outcomes after receiving CAR-T immunotherapy, especially to track significant adverse events, including potentially cytokine release syndrome, neurologic complications and kidney/liver failure.

Emerging Trends in Chimeric Antigen Receptor T-Cell Immunotherapy in Young Adults and Pediatric Patients from the Vizient Clinical Database

Introduction Chimeric Antigen Receptor T-cell (CAR-T) Immunotherapy was approved by the FDA in 2017 for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL), as well as adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. CAR-T immunotherapy uses a patient's own T cells and modifies them in a laboratory to recognize and kill the patient's cancer. Since the CAR-T modified cells multiply and persist in the patient's bloodstream, they have the potential to protect the patient against recurrence. Beginning October 1, 2017, two new, unique ICD-10 procedure codes were assigned to CAR-T immunotherapy (XW033C3 for peripheral venous route and XW043C3 for central venous route), allowing for tracking of the procedure in administrative datasets. Objectives To describe trends in young adult patient populations, outcomes, and hospitals using the CAR-T procedure codes in administrative data. Methods A retrospective cohort of 40 patients under 25 years undergoing CAR-T procedures was identified from the Vizient Clinical Data Base / Resource Manager from 20 hospitals between October 2017 and August 2018. Results For the 40 patients, 30 of the 40 had a diagnosis of ALL. Eight of the remaining 10 patients had diagnoses of large B-cell lymphoma, one patient had blastic NK-cell lymphoma, and one patient had acute myoblastic lymphoma. The median length of stay was 17 days, the median ICU stay was 0 days, the median total cost of hospitalization for CAR-T encounter was $280,276 and median direct cost was $152,633. During the initial hospitalization, 23 (57.5%) of patients had an adverse event due to the immunotherapy. 20 patients (50.0%) had fever, 9 (22.5%) had sepsis and 7 (17.5%) had acute kidney failure and 3 patients (7.5%) had an in-hospital death. Within 30 days, 6 patients (15.0%) had an unplanned readmission to the index hospital, 2 (0.5%) with sepsis and 2 (0.5%) with an adverse event due to the immunotherapy. Conclusion Due to the recent implementation of the unique ICD-10 codes, more time and follow-up for these young adult patients is needed to determine outcomes for pediatric cancer patients receiving CAR-T immunotherapy, especially to track significant adverse events, including potentially cytokine release syndrome, neurologic complications and kidney/liver failure.

Activity of CD19/CD3 Bispecific Antibodies in Chronic Lymphocytic Leukemia

▪Kinase inhibitors such as ibrutinib have advanced treatment of chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments capable of deepening response or overcoming resistance to kinase inhibitors. CD19/CD3 bispecific antibodies (bsAbs) recruit endogenous T cells to form cytolytic synapses with CD19+ tumor cells. Blinatumomab, a CD19/CD3 bsAb designed in the 54 kDa BiTE format, is FDA approved for the treatment of some forms of acute lymphoblastic leukemia, and has potential for use in other B-cell malignancies. However, due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy. We have developed a novel CD19/CD3 bsAb in the 100 kDa single chain-Fv Fc format (19/3-scFv-Fc). With a half-life of approximately 7 days, 19/3-scFv-Fc may be suitable for weekly dosing, providing a significant logistical advantage. Here we investigated the potential use of 19/3-scFv-Fc for treatment of CLL.We first cultured peripheral blood mononuclear cells (PBMCs) from treatment-naïve CLL patients with bsAbs and measured CLL cell death by flow cytometry. After 12 days of exposure, median specific-killing compared to the non-targeting control HER2/CD3-scFv-Fc was 91.2% for blinatumomab (P= 0.0009) and 92.1% for 19/3-scFv-Fc (P= 0.003)(n = 12). Both CD19/CD3 bsAbs induced over 25-fold expansion of autologous CD8 and CD4 T cells, as demonstrated by increase in absolute cell counts and by CFSE proliferation assays. Activation markers CD69 and CD25, as well as granzyme B, were also increased in both CD8 and CD4 T cell subsets cultured with blinatumomab or 19/3-scFv-Fc.As blinatumomab and 19/3-scFv-Fc demonstrated comparable activity against CLL ex vivo, we next evaluated efficacy of bsAbs in vivo using the NOD/SCID/IL2Rγnull (NSG) patient-derived xenograft model. Fifty million CLL PBMCs were injected per mouse, with 2-5 mice tested per treatment group and patient combination. bsAbs were then given once-weekly, with blinatumomab dosed at 0.25 mg/kg and 19/3-scFv-Fc at 0.5 mg/kg to achieve equal molar concentrations. Treatment with 19/3-scFv-Fc resulted in elimination of over 98% of CLL cells in the blood (P < 0.0001) and spleen (P= 0.0026) compared to treatment with HER2/CD3-scFv-Fc (n = 4). Blinatumomab failed to induce any response, either with once-weekly dosing or daily dosing for 8 days.Ibrutinib has been shown to improve T cell dysfunction characteristic of CLL, suggesting immunotherapy may work well with concurrent ibrutinib treatment. Culture of CLL PBMCs from ibrutinib-treated patients (n = 10, 12 ± 1 months on ibrutinib) with 19/3-scFv-Fc induced T cell activation and increased granzyme B expression comparable to that seen in cells obtained from treatment-naïve patients. However, treatment with 19/3-scFv-Fc drove significantly more killing of ibrutinib-treated CLL cells compared to treatment-naïve CLL cells after 3 days of exposure (43.7% versus 2.23% median specific-killing, P= 0.004). By day 7, 95.3% of ibrutinib-treated and 45.3% of treatment-naïve CLL cells were eliminated (P= 0.02).Resistance to ibrutinib has been commonly linked to mutations in BTK and/or PLCG2 and is associated with early mortality. We assessed activity of 19/3-scFv-Fc in 3 patients with acquired ibrutinib resistance, manifest 34 to 44 months from the start of ibrutinib. Multiple BTK and/or PLCG2 mutations were present in all 3 patients, with cancer cell fractions of the most abundant mutation in each patient ranging from 8-32%. 19/3-scFv-Fc treatment in culture resulted in >90% specific-killing of CLL cells from all 3 ibrutinib-resistant patients (range 91.50 - 97.83%, P= 0.0066). After engraftment of ibrutinib-resistant cells in NSG mice, 1 dose of 19/3-scFv-Fc eliminated >90% of circulating CLL cells, while HER2/CD3-scFv-Fc had no anti-leukemic activity (P < 0.0001), indicating that 19/3-scFv-Fc can effectively target mutant CLL clones resistant to ibrutinib. Taken together, these data support the investigation of 19/3-scFv-Fc as a promising immunotherapy for CLL, either in combination with ibrutinib or as rescue therapy in ibrutinib-resistant disease. DisclosuresWiestner:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding.

Haploidentical hematopoietic stem cell transplantation in the treatment of children and adolescents with resistant forms of acute leukemia

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is one of the effective methods of treatment of patients with malignant disorders of hematopoietic system. Because of absence of related and unrelated donors at the majority of Russian patients, search for alternative grafts for allo-HSCT is actual now. HSCT from partially HLA-matched related (haploidentical, haplo-HSCT) is the fast and universal method of treatment. Fifty six children and young adults 1–21 years old (age median – 9 years old) with resistant forms of acute lymphoblastic leukemia (ALL) (n = 32) and acute myeloid leukemia (AML) (n = 24) were transplanted with haploidentical donor from December 2007 to June 2013. In preparative therapy and graft-versus-host disease (GvHD) prevention the following regimens were used: myeloablative conditioning regimen (MAC) + Antithymocyte Immunoglobulin (ATGAM) (n = 20), MAC + Cyclophosphamide (CpH) (n = 5), reduce-intensity regimen (RIC) + ATGAM (n = 14), RIC + Alemtuzumab (n = 4), RIC + CpH (n = 13). All patients received base immunosuppressive therapy with Tacrolimus and Cyclosporin A. The following types of haplo-transplants were used: combination of stimulated with G-CSG unmanipulated bone marrow (BM) and peripheral blood stem cells (PBSC) with positive CD34+ selection (n = 23) or stimulated with G-GSF unmanipulated BM (n = 33). Overall survival (OS) in this group of patients was 33.3 %. Statistically better OS (р = 0.03) was revealed in a group of patients transplanted with G-CSF stimulated unmanipulated BM – 45.5 % versus 13 % in case of combined transplant. Other factors influenced on the results of haplo-HSCT (age, status at the moment of HSCT, conditioning regimen, posttransplant therapy, engraftment, cells dose) are described in the article.

Blinatumomab for hard-to-treat form of acute lymphoblastic leukemia

Blinatumomab for hard-to-treat form of acute lymphoblastic leukemia

Blinatumomab: New therapy treats rare form of acute lymphoblastic leukemia

Blinatumomab: New therapy treats rare form of acute lymphoblastic leukemia

Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement.

Distinct from other forms of acute lymphoblastic leukemia (ALL), infant ALL with mixed lineage leukemia (MLL) gene rearrangement, the most common leukemia occurring within the first year of life, might arise without the need for cooperating genetic lesions. Through Ig/TCR rearrangement analysis of MLL-AF4+ infant ALL at diagnosis and xenograft leukemias from mice transplanted with the same diagnostic samples, we established that MLL-AF4+ infant ALL is composed of a branching subclonal architecture already at diagnosis, frequently driven by an Ig/TCR-rearranged founder clone. Some MLL-AF4+ clones appear to be largely quiescent at diagnosis but can reactivate and dominate when serially transplanted into immunodeficient mice, whereas other dominant clones at diagnosis can become more quiescent, suggesting a dynamic competition between actively proliferating and quiescent subclones. Investigation of paired diagnostic and relapse samples suggested that relapses often occur from subclones already present but more quiescent at diagnosis. Copy-number alterations identified at relapse might contribute to the activation and expansion of previously quiescent subclones. Finally, each of the identified subclones is able to contribute to the diverse phenotypic pool of MLL-AF4+ leukemia-propagating cells. Unraveling of the subclonal architecture and dynamics in MLL+ infant ALL may provide possible explanations for the therapy resistance and frequent relapses observed in this group of poor prognosis ALL.

Allogeneic hematopoietic stem cells transplantation with reduced intensity conditioning regimen in children and adolescents with unfavorable forms of acute lymphoblastic leukemia

Allogeneic hematopoietic stem cells transplantation with reduced intensity conditioning regimen in children and adolescents with unfavorable forms of acute lymphoblastic leukemia

Role of Glutamine Depletion in Directing Tissue-specific Nutrient Stress Responses to L-Asparaginase

Role of Glutamine Depletion in Directing Tissue-specific Nutrient Stress Responses to L-Asparaginase

Efficient expression, purification, and characterization of C-terminally tagged, recombinant human asparagine synthetase

Several lines of evidence suggest that up-regulation of asparagine synthetase (AS) in human T-cells results in metabolic changes that underpin the appearance of asparaginase-resistant forms of acute lymphoblastic leukemia (ALL). Inhibitors of human AS therefore have potential as agents for treating leukemia and tools for investigating the cellular basis of AS expression and drug-resistance. A critical problem in developing and characterizing potent inhibitors has been a lack of routine access to sufficient quantities of purified, reproducibly active human AS. We now report an efficient protocol for preparing multi-milligram quantities of C-terminally tagged, wild type human AS in a baculovirus-based expression system. The recombinant enzyme is correctly processed and exhibits high catalytic activity. Not only do these studies offer the possibility for investigating the kinetic behavior of biochemically interesting mammalian AS mutants, but such ready access to large amounts of enzyme also represents a major step in the development and characterization of inhibitors that might have clinical utility in treating asparaginase-resistant ALL.

Acute Lymphoblastic Leukemia Presenting as Cutaneous Involvement

Primary cutaneous involvement in B-cell lymphoblastic leukemia is rare in childhood. We present a case of 2-year-old girl admitted to our hospital because of left scapular skin lesion and left axillary mass. She was looked pale and weak. Left axillary lymph node pachage of 5 cm diameter and left scapular skin lesion was revealed by physical examination. Complete blood count revealed 124.000/mm3 white blood cell count. Peripheral blood smear showed 99% lymphoblasts. Bone marrow aspiration revealed 95% blastic cells with immunophenotype and morphological characteristics of pre-B type acute lymphoblastic leukemia with L1 subtype. ALL St Jude Total XIII remission induction treatment protocol was started. Skin lesion disappeared after 15th day of the cytotoxic therapy. On the follow up, she was on remission and continued to maintenance chemotheraphy for 6 months. We would like to highlight that a small growing cutaneous lesion could be the presenting form of acute lymphoblastic leukemia.

CHRONIC NEUTROPHILIC LEUKAEMIA: A DISTINCT CLINICAL ENTITY?

CHRONIC NEUTROPHILIC LEUKAEMIA: A DISTINCT CLINICAL ENTITY?

Conjugate drug shows antileukemic activity

A conjugate drug that combines a monoclonal antibody with an enzyme inhibitor is effective in animal tests against the predominant form of acute lymphoblastic leukemia (ALL), the most common type o...

CD2+CD19+Biphenotypic Acute Lymphoblastic Leukaemia: A Report of Three Cases and a Review of the Literature

Biphenotypic acute lymphoblastic leukaemia expressing a pan-T CD2 and a pan-B CD19 antigen is very rare. In this report, we describe three such cases, focusing specially on the variable clinical and laboratory findings. We have also reviewed the literature on this unique form of acute lymphoblastic leukaemia which appears to behave differently to biphenotypic leukaemia coexpressing both myeloid and lymphoid markers.

Unusual immunophenotypes in acute leukaemias: incidence and clinical correlations.

The incidence and clinical implications of unusual patterns of expression of leucocyte differentiation antigens in acute leukaemia were assessed on 568 newly diagnosed paediatric and adult cases undergoing immunophenotyping with a panel of monoclonal antibodies at a single centre. Among patients with the precursor B (common) form of acute lymphoblastic leukaemia (ALL), the major variant seen was the group of 15 cases with expression of myeloid surface antigens. 4.5% of ALL cases tested with antibody to CD-11b were positive, 5.1% were CD-13+, and 10.8% CD-33+. All 15 patients achieved a complete remission with chemotherapy, with six of eight children and four of seven adults remaining disease free. A smaller proportion (1.5%) of precursor B ALL patients showed expression of the T lineage marker, CD-7. The only significant variant seen in the precursor T-ALL group was expression of HLA-DR antigen, which was found in five of 35 cases; although all responded to treatment, only one remains a disease-free survivor. Among patients with acute myeloid leukaemia (AML), expression of the lymphoid markers terminal transferase (TdT) and CD-7 were commonly seen (22.2% and 28.4% respectively of cases tested). Other lymphoid markers detected on AML cases were CD2 (11.1%), CD-10 (1%) and CD-19 (4.4%). These results confirm that examples of lineage infidelity are regularly seen in large series of patients with acute leukaemia. Prospective studies using uniform treatment protocols are required to establish whether these patients have significantly different disease outcomes.