Therapy-Related Acute Lymphoblastic Leukemia (t-ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4535-4535
Author(s):  
Carolina Escobar ◽  
Jerry McLarty ◽  
Oscar Ballester
Keyword(s):  
T Cell ◽  
B Cell ◽  
Median Time ◽  
Topoisomerase Ii ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Topoisomerase Ii Inhibitors ◽  
History Of ◽  
Group A

Abstract Introduction: Myelodysplasia and Acute Myeloid Leukemia are recognized and well characterized complications of cancer therapy. Much less is known about t-ALL, but an increasing number of cases are being reported. Materials and Methods: We conducted a MEDLINE search to identify patients with ALL diagnosed after exposure to chemotherapy and/or radiotherapy. Data extracted included: latency period, radiation and type of chemotherapy drug exposure, phenotype, cytogenetics and survival. Results: 74 patients were identified with a median age at the time of t-ALL of 33 years, (range 2 to 90; 16 cases age ≤ 10 and 9 cases age ≥60). History of a prior malignancy, including solid tumors in 45 (sarcomas 12, breast cancer 11, others 22) and hematological malignancies in 25 (Hodgkin’s lymphoma 17, others 8), was documeted in all patients with the exception of 4, who received chemotherapy or radiation for a non-malignant disorder. Exposure to radiotherapy was documented in 65% of patients (4 cases had exposure only to radiotherapy), 64% had recieved topoisomerase II inhibitors and 84% other chemotherapy drugs. Median time to t-ALL was 38 months. Follow up data was available in 56/74 (75.6%), 20 were reported alive (27%), 3 to 132 months from t-ALL diagnosis. Twelve patients received stem cell transplants, 7 of them were survivors (8 to 79 months). Based on phenotype and/or cytogenetics, 5 subsets of patients were identified. Group A: 32 patients (43%) with 11q23 translocations and/or MLL rearrangements: 23 of these patients (72%) presented with pro-B cell phenotype (CD19+, CD10−)(2 pre-B cell, 2 T cell, 5 unknown); 90% had history of exposure to topoisomerase II inhibitors; median time to t-ALL was 21 months in Group A, significanlty shorter (p<.0001) when compared to all other patients (median 60 months). Median overall survival was 8 months, 5 year survival 27%. Group B: 11 patients (14.8%), with L3/Burkitt’s leukemia; all with t(8;14), t(8;22) or t(2;8) abnormalities. None of them are long term survivors. Group C: 4 patients with t(9;22) (5.4%). Group D: 4 patients with T cell phenotype (5.4%). Group E: the remaining 23 patients (31%) with primarily a pre-B cell phenotype (CD19+, CD10+) with normal (21.7%), complex (21.7%) or unknown cytogenetics (56%). Of the 18 patients who received induction therapy in Group E, 9 (50%) are survivors (median 60 months from diagnosis). Conclusions: Various subsets of t-ALL can be recognized, resembling the pattern seen in patients with de novo ALL. However, high-risk subtypes such as 11q23/MLL + cases are overrepresented. Patients with t-ALL not identified by 11q23 or t(9;22) abnormalities, L3/Burkitt’s or T cell phenotype (Group E) appear to have a better prognosis: survival at 5 years 45% compared to 24% for all other patients.

scholarly journals Characterization of Acute Lymphoblastic Leukemia Subtypes in Moroccan Children

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Fatima Bachir ◽  
Sanae Bennani ◽  
Ali Lahjouji ◽  
Siham Cherkaoui ◽  
M'hamed Harif ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
High Frequency ◽  
Lymphoblastic Leukemia ◽  
Age Distribution ◽  
General Distribution ◽  
Cell Phenotype ◽  
Myeloid Antigens ◽  
Moroccan Children

We present the incidence and the immunologic characteristics of acute lymphoblastic leukemia (ALL) subsets in Moroccan children. We studied 279 unselected patients below the age of 18 years with newly diagnosed ALL. Cases were classified according to immunophenotype: 216 (77.42%) precursor B-cell phenotype (pB-cell), mature B-cell in 4 (1.43%), and T-cell in 59 (21.15%) cases. The age distribution showed a peak in incidence between 3 and 5 years among the pB-cell ALLs subtype. There was a significantly higher frequency of males in the T-ALL subset and more females in the T-ALL CD10+ subset when compared with the T-ALL CD10– subset. Myeloid antigens occur more frequently and were expressed in 124 (57.4%) of pB-cell-ALL cases and 20 (33.9%) of T-cell ALLcases. Our results show that the distribution of ALLs in Moroccan children is similar with the general distribution pattern indeveloped countries except for the high frequency of T-ALL phenotype. The phenotypic profiles of our patients are close to thosereported in literature for B-lineage ALLs; for the T-cell ALL subgroup, the blast cells express more CD1a, surface CD3, and CD4 while expressing less TdT. The high frequency of CD1a expression resulted in an excess of the common thymocyte subtype.

scholarly journals Tumor staging in a Beagle dog with concomitant large B-cell lymphoma and T-cell acute lymphoblastic leukemia

2021 ◽  
pp. 104063872110110
Author(s):  
Alessandro Ferrari ◽  
Marzia Cozzi ◽  
Luca Aresu ◽  
Valeria Martini
Keyword(s):  
Bone Marrow ◽  
Lymph Node ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Tumor Staging ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Cell Acute Lymphoblastic Leukemia

An 8-y-old spayed female Beagle dog was presented with peripheral lymphadenomegaly. Lymph node cytology and flow cytometry led to the diagnosis of large B-cell lymphoma (LBCL). We detected minimal percentages of LBCL cells in peripheral blood and bone marrow samples. However, a monomorphic population of neoplastic cells different from those found in the lymph node was found in the bone marrow. T-cell acute lymphoblastic leukemia was suspected based on flow cytometric immunophenotyping. PCR for antigen receptor rearrangement (PARR) revealed clonal rearrangement of both B-cell and T-cell receptors, and the presence of both neoplastic clones in the lymph node, peripheral blood, and bone marrow. The dog was treated with multi-agent chemotherapy but died 46 d following diagnosis. Tumor staging and patient classification are needed to accurately establish a prognosis and select the most appropriate therapeutic protocol.

scholarly journals DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

2021 ◽  
Vol 22 (3) ◽  
pp. 1388
Author(s):  
Natalia Maćkowska ◽  
Monika Drobna-Śledzińska ◽  
Michał Witt ◽  
Małgorzata Dawidowska
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Epigenetic Modification ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Global Methylation ◽  
Current State ◽  
History Of ◽  
Cell Acute Lymphoblastic Leukemia

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

A Systematic Review of Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Engaging an Old Problem With New Solutions

2021 ◽  
pp. 106002802098841
Author(s):  
Zachery Halford ◽  
Carli Coalter ◽  
Vanessa Gresham ◽  
Tabitha Brown
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase Iii ◽  
Cytotoxic T Cell ◽  
Bispecific T Cell Engager

Objective: To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL). Data Sources: We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: blinatumomab, Blincyto, lymphoblastic leukemia, and bispecific T-cell engager. Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion. Data Synthesis: Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively. Relevance to Patient Care and Clinical Practice: Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in “chemotherapy-free” combination regimens. Conclusions: Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.

scholarly journals Pre-B cell acute lymphoblastic leukemia in the newborn

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1064-1066
Author(s):  
CM Spier ◽  
CR Kjeldsberg ◽  
R O'Brien ◽  
J Marty
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Phenotype ◽  
Cell Marker ◽  
Ultrastructural Studies ◽  
Congenital Leukemia ◽  
Laboratory Techniques ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Marker Studies

Leukemia in the newborn is an infrequent disease that has not been well defined using modern laboratory techniques. We describe two infants, one at birth and one at four weeks, with acute lymphoblastic leukemia. The blasts from each patient were studied in great detail, using a battery of cytochemical and immunologic procedures in addition to ultrastructural studies. Immunologic cell marker studies, not previously reported in congenital leukemia, showed the lymphoblasts from each infant to be of the pre-B cell phenotype. Each infant relapsed, one after a 17-week clinical remission and the other after a 44-week remission. The former has died while the latter is in a second remission. The subtype of pre-B cell acute lymphoblastic leukemia (ALL) which in childhood appears to confer an unfavorable prognosis, may have the same significance in neonatal ALL.

scholarly journals Corticosteroids Do Not Influence the Efficacy and Kinetics of CAR-T Cells for B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 228-228 ◽  
Author(s):  
Shuangyou Liu ◽  
Biping Deng ◽  
Jing PAN ◽  
Zhichao Yin ◽  
Yuehui Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Car T Cells ◽  
Steroid Group ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Kinetics Of

Cytokine release syndrome (CRS) is the most prominent and potentially life-threatening toxicity caused by chimeric antigen receptor (CAR) T cell therapy, therefore, effectively controlling severe CRS is critical to ensure patient safety. Tocilizumab, an interleukin-6 receptor antagonist, has been widely used to treat CRS, whereas it is not clear if corticosteroids could be as another optimal choice for managing CRS. We applied corticosteroids instead of tocilizumab as the first-line agent to control CRS in patients with relapsed/refractory B-cell acute lymphoblastic leukemia during CAR-T therapy. The impacts of steroids on treatment efficiency and kinetics of CAR-T cells were assessed by comparing two groups of patients who did (42 cases) or did not (26 cases) receive steroids. Patients followed up less than one month (went to other hospitals for transplantation or died within one month) were excluded. Treatment effects were evaluated on day 30 after T-cell infusion and then monthly in follow-up patients. Minimal residual disease (MRD) was detected by multiparameter flow cytometry (FCM) and quantitative PCR for fusion genes. The dynamic monitoring of CAR-T cells was performed through flow cytometric quantitation of FITC+CD3+ T cells. B-cell aplasia (BCA) was assayed by FCM. Dexamethasone or methylprednisolone or both (alternately) were administrated. Dexamethasone was used in most cases especially for patients with neurologic symptoms; methylprednisolone was preferred for patients with pulmonary or liver dysfunction, and patients accepting high dose steroids. Steroids started with low dose and could be increased if symptoms were not resolved, for severe CRS, steroids would be escalated up to dexamethasone 20mg/m2/d or more higher up to methylprednisolone 10mg/kg/d. Once CRS was improved, steroids were rapidly reduced and stopped. A total of 68 patients (28 adults and 40 children younger than 18 years) were included, 22 (32.4%) presented with extramedullary diseases (EMD), bone marrow blasts in patients without EMD varied between 5%-96.5%, 31 (45.6%) patients had an allogeneic transplantation, 54 (79.4%) cases received CD19-specific and 14 (20.6%) received CD22-specific CAR-T therapy. Forty-two (61.8%) cases, including all (10) of grade III CRS, 68.2% (30/44) of grade II CRS and 2 patients with no CRS but with GVHD (1 case) or neurotoxicity (1 case), were administered steroids, among them, 23/42 (54.8%) received high dose steroids (&gt;10mg/m2/d dexamethasone or equivalent), the duration of steroid use was 1-16 days (78.6% &lt;= 7 days); whereas 26 (38.2%) patients were not given any steroids but the supportive care. We found that there was no difference either in complete remission (CR) rate (95.2% vs 92.3%, p=.344) or in MRD negative CR rate (80.0% vs 79.2%, p=.249) between steroid and non-steroid group, verified that corticosteroids even high dose steroids did not influence the treatment response. Furthermore, we investigated the dynamics of CAR-T cells. Firstly, the expansion of CAR-T cells in peripheral blood (PB) was evaluated, the average CAR-T cell counts in steroid group were significantly higher than those in non-steroid group on D11 (p=.0302), D15 (p=.0053), D20 (p=.0045) and D30 (p=.0028), except for D7 when CAR-T cells began to expand (p=.9815), this demonstrated that steroids did not suppress the proliferation of CAR-T cells in PB. Secondly, the percentages of patients with detectable CAR-T cells in bone marrow (BM) and cerebrospinal fluid (CSF) were compared between steroid and non-steroid group, there were no differences both in BM (85.2% vs 78.6%, p=.923) and in CSF (68.6% vs 57.9%, p=.433), which implied steroids did not influence the trafficking of T-cells to BM and CSF. Thirdly, we monitored B-cell aplasia (BCA) in part of patients followed-up more than 2 months without further treatments, the percentages of patients with BCA in steroid group had no significant differences compared to non-steroid group at 2-month (p=.086) and 3-month (p=.146). Later, although limited cases left, in the steroid group, 100% of patients (4-month, 7/7; 5-month, 7/7; 6-month, 5/5) still maintained BCA and CR, indicating that corticosteroids did not impact the duration of functional CAR-T cells. In conclusion, corticosteroids do not compromise the treatment efficacy and kinetics of CAR-T cells, could be as a feasible and effective approach to manage CAR-T associated CRS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Novel CD19/CD22 Bicistronic Chimeric Antigen Receptors Outperform Single or Bivalent Cars in Eradicating CD19+CD22+, CD19-, and CD22- Pre-B Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 810-810 ◽  
Author(s):  
Haiying Qin ◽  
Sang M Nguyen ◽  
Sneha Ramakrishna ◽  
Samiksha Tarun ◽  
Lila Yang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Chain ◽  
Dual Targeting ◽  
Single Antigen ◽  
Therapeutic Function

Abstract Treatment of pre-B cell acute lymphoblastic leukemia (ALL) using chimeric antigen receptor expressing T cells (CART) targeting CD19 have demonstrated impressive clinical results in children and young adults with up to 70-90% complete remission rate in multiple clinical trials. However, about 30% of patients relapse due to loss of the targeted epitope on CD19 or CART failure. Our CD22-targeted CAR trial has generated promising results in relapsed/refractory ALL, including CD19 antigen negative ALL, but relapse associated with decreased CD22 site density has occurred. Thus, developing strategies to prevent relapses due to changes in antigen expression have the potential to increase the likelihood of durable remissions. In addition, dual targeting of both CD19 and CD22 on pre-B ALL may be synergistic compared to targeting a single antigen, a potential approach to improve efficacy in patients with heterogeneous expression of CD19 and CD22 on leukemic blasts. We describe the systematic development and comparison of the structure and therapeutic function of three different types (over 15 different constructs) of novel CARs targeting both CD19 and CD22: (1) Bivalent Tandem CAR, (2) Bivalent Loop CAR, and (3) Bicistronic CAR. These dual CARs were assembled using CD19- and CD22-binding single chain fragment variable (scFv) regions derived from clinically validated single antigen targeted CARs. They are structurally different in design: both tandem and loop CARs have the CD19 and CD22 scFv covalently linked in the same CAR in different orders, whereas, bicistronic CARs have 2 complete CAR constructs connected with a cleavable linker. The surface expression on the transduced T cell of the CD19/CD22 dual CARs was detected with CD22 Fc and anti-idiotype of CD19 and compared to single CD19 or CD22 CARs. Activities of dual CARs to either CD19 or CD22 were evaluated in vitro with cytotoxicity assays or killing assays against K562 cells expressing either CD19 or CD22 or both antigens and also tested against a leukemia CD19+/CD22+ cell line, NALM6, and NALM6 with CRISPER/CAS9 knockout of CD19 or CD22 or both antigens. Therapeutic function of the top candidates of the dual CARs was then validated in vivo against these NALM6 leukemia lines. Some of these dual CARs were also further tested against patient-derived xenografts. Finally, we tested the dual targeting CARs in an artificial relapse model in which mice were co-injected with a mix of CD19 knockout and CD22 knockout NALM6 leukemia lines. From these studies, we established that the order of the scFv, size of the linker, type of leader sequence, and co-stimulatory domain in the CAR constructs all impact the efficacy of the dual targeting CARs. Tandem, Loop, and Bicistronic CARs all demonstrate some levels of in vitro and in vivo activities, but the bicistronic CAR was most effective at clearing leukemia and preventing relapse. In the CD19+/CD22+ NALM6 model, bicistronic CAR treated mice remain disease free while CD19 CAR or CD22 CAR treated mice already died or relapsed on day 27. In the relapse model, as expected, CD19 or CD22 single CAR T cell treatment resulted in progression of the corresponding antigen-negative NALM6. Treatment with dual targeted bicistronic CARs resulted in clearance of both CD19 and CD22 negative ALL with durable remission. In summary, we described novel CD19/CD22 dual targeting CARs with robust pre-clinical activity against pre-B cell ALL, and validated this approach in the prevention of resistance to single-antigen targeted CARs in preclinical models. Disclosures No relevant conflicts of interest to declare.

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