scholarly journals CD-19-directed immunotherapy resistance mechanisms of B-precursor acute lymphoblastic leukemia

2019 ◽  
Vol 13 (4) ◽  
pp. 27-36
Author(s):  
E. V. Glukhanyuk ◽  
A. V. Stepanov ◽  
A. M. Popov ◽  
M. A. Maschan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Immune Escape ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Resistance Mechanisms ◽  
Great Success ◽  
Tumor Immune Escape ◽  
B Lineage

Immunotherapy is the most rapidly evolving field in clinical malignant hematology. Targeting of the B-lineage surface antigen CD19 in B-lineage acute lymphoblastic leukemia and B-cell lymphoma is a story of great success. Recently two approaches of CD19 immunotargeting were approved for clinical application: CD3 × CD19 bi-specific T-cell engager blinatumomab and CD19 chimeric antigen receptor (CAR) Tcells. Both approaches demonstrated an unprecedented activity in a cohort of patients with relapsed and refractory B-cell leukemia and lymphoma both in the adult and pediatric population. Early clinical research has showed that tumors are able to escape the immunological control and become resistant to the immune attack. Mechanisms of the tumor immune escape are being actively studied and include diverse pathways, such as alternative splicing of CD19 and immunosuppressive tumor microenvironment. Current review briefly summarizes data regarding the mechanisms of CD19-positive leukemia resistance to CD19 immune targeting and discusses potential approaches to overcome it.

Development of diffuse large B cell lymphoma during the maintenance therapy for B-lineage acute lymphoblastic leukemia

2007 ◽  
Vol 48 (2) ◽  
pp. 230-232
Author(s):  
Itaru Kato ◽  
Atsushi Manabe ◽  
Chiaki Aoyama ◽  
Takahiro Kamiya ◽  
Tsuyoshi Morimoto ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
B Lineage ◽  
Large B Cell

Gene Expression Profiling Data in Lymphoma and Leukemia: Review of the Literature and Extrapolation of Pertinent Clinical Applications

2006 ◽  
Vol 130 (4) ◽  
pp. 483-520 ◽  
Author(s):  
Cherie H. Dunphy
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Expression Profiling ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Clinical Applications

Abstract Context.—Gene expression (GE) analyses using microarrays have become an important part of biomedical and clinical research in hematolymphoid malignancies. However, the methods are time-consuming and costly for routine clinical practice. Objectives.—To review the literature regarding GE data that may provide important information regarding pathogenesis and that may be extrapolated for use in diagnosing and prognosticating lymphomas and leukemias; to present GE findings in Hodgkin and non-Hodgkin lymphomas, acute leukemias, and chronic myeloid leukemia in detail; and to summarize the practical clinical applications in tables that are referenced throughout the text. Data Source.—PubMed was searched for pertinent literature from 1993 to 2005. Conclusions.—Gene expression profiling of lymphomas and leukemias aids in the diagnosis and prognostication of these diseases. The extrapolation of these findings to more timely, efficient, and cost-effective methods, such as flow cytometry and immunohistochemistry, results in better diagnostic tools to manage the diseases. Flow cytometric and immunohistochemical applications of the information gained from GE profiling assist in the management of chronic lymphocytic leukemia, other low-grade B-cell non-Hodgkin lymphomas and leukemias, diffuse large B-cell lymphoma, nodular lymphocyte–predominant Hodgkin lymphoma, and classic Hodgkin lymphoma. For practical clinical use, GE profiling of precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, and acute myeloid leukemia has supported most of the information that has been obtained by cytogenetic and molecular studies (except for the identification of FLT3 mutations for molecular analysis), but extrapolation of the analyses leaves much to be gained based on the GE profiling data.

scholarly journals B-cell acute lymphoblastic leukemia as a secondary malignancy following diffuse large B-cell lymphoma

2019 ◽  
Vol 11 (2) ◽  
Author(s):  
Daria Gaut ◽  
Anthony Bejjani ◽  
Joshua Sasine ◽  
Gary Schiller
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Pcr Analysis ◽  
Secondary Malignancy ◽  
Large B Cell Lymphoma ◽  
First Case ◽  
Large B Cell

Secondary acute lymphoblastic leukemia (ALL) is a rare disease that has not been well characterized compared with secondary myelodysplastic syndrome or secondary acute myeloid leukemia. We present a report of two patients who developed ALL following complete remission of diffuse large B-cell lymphoma (DLBCL). The first case is more consistent with a therapy-related ALL as a PCR analysis of bone marrow aspirate revealed a distinct clone and the mixed-lineage leukemia gene rearrangement, commonly associated with exposure to topoisomerase II inhibitors. The second case is more consistent with clonal evolution given positive MYC and BCL2 fusion signals in the original diagnosis of DLBCL and the secondary ALL.

scholarly journals Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1731-1737 ◽  
Author(s):  
A Manabe ◽  
E Coustan-Smith ◽  
M Kumagai ◽  
FG Behm ◽  
SC Raimondi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Programmed Cell Death ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Fatal Outcome ◽  
Interleukin 4 ◽  
B Lineage

Abstract We investigated the effects of interleukin-4 (IL-4) on the survival of leukemic and normal B-cell progenitors cultured on bone marrow stroma. IL-4 (at 100 U/mL) was cytotoxic in 16 of 21 cases of B-lineage acute lymphoblastic leukemia, causing reductions in CD19+ cell numbers that ranged from 50% to greater than 99% (median 83.5%) of those in parallel cultures not exposed to the cytokine. All nine cases with the t(9;22)(q34;q11) or the t(4;11)(q21;q23), chromosomal features that are often associated with multidrug resistance and a fatal outcome, were susceptible to IL-4 toxicity. IL-4 cytotoxicity resulted from induction of programmed cell death (apoptosis); there was no evidence of cell killing mediated by T, natural killer, or stromal cells. IL-4 cytotoxicity extended to a proportion of normal B-cell progenitors. After 7 days of culture with IL-4 at 100 U/mL, fewer CD19+, CD34+ normal lymphoblasts (the most immature subset) survived: in five experiments the mean (+/- SEM) reduction in cell recoveries caused by IL-4 was 60.0% +/- 6.0%. By contrast, reductions in recovery of more differentiated bone marrow B cells (CD19+, CD34-, surface Ig+) were low (6.6% +/- 2.2%; P < .001 by t-test). Our findings indicate that IL-4 is cytotoxic for human B-cell precursors and support clinical testing of IL-4 in cases of high-risk lymphoblastic leukemia resistant to conventional therapy.

Outcome of Relapse After Allogeneic Transplantation for Childhood Acute Lymphoblastic Leukemia In Complete Remission. A Study of the Pediatric Diseases and Acute Leukemia Working Parties of the EBMT Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1291-1291
Author(s):  
Adriana Balduzzi ◽  
Myriam Labopin ◽  
Vanderson Rocha ◽  
Nabila Elarouci ◽  
Giorgio Dini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Prognostic Impact ◽  
Dismal Prognosis ◽  
B Lineage ◽  
Donor Lymphocyte Infusions

Abstract Abstract 1291 Introduction. Childhood acute lymphoblastic leukemia (ALL) relapse occurring after hematopoietic cell transplantation (HCT) has a very dismal prognosis. Its treatment is still controversial and ranges from palliative treatment or chemotherapy to donor lymphocyte infusions, second transplant or experimental approaches. Objectives. The aim of this study is to assess the actual outcome in a pediatric population. The primary endpoint of this study is the 2-year probability of survival of children with ALL relapsing after allogeneic HCT; the secondary endpoint is the relationship between outcome and time of relapse after transplant, for which the following categories were considered: <3, 3–6, 6–12, > 12 months. Patients. Patients younger than 18 years of age undergoing first HCT from any allogeneic donor for ALL in first (CR1) or second (CR2) remission between January 1st 1998 and December 31st 2007 reported to the EBMT were eligible for the study. Results. Out of 3628 transplanted children with ALL reported to the EBMT, 836 (median age 9 years, male 66%) relapsed at a median of 6 months (range 1–67; 25th, 75th 4, 12 months) after HCT. The HCT was performed in CR1 (60%) or CR2 (40%) for a B-lineage (60%) or T- (13%) or unknown (27%) immunophenotype ALL, from an HLA-matched related (44%), unrelated (59%) or mismatched related (7%) donor, with marrow (61%), peripheral (28%) or umbilical (11%) stem cells. Out of 836, 81% died at a median of 2 months (25th,75th centiles:1,7) and 19% were reported as alive at last follow-up at a median of 22 months after relapse (range: 1–130). The 3-year probability of overall survival (3y-OS) was 14% (SE 1). As to immunophenotype, disease phase and donor type, 3y-OS was 15% (SE 2) in B-lineage and 8% (SE 3) in T-ALL, 18% (SE 2) in patients transplanted in CR1 and 11% (SE 6) in CR2 and 17% (SE 2) in patients transplanted from an HLA-identical sibling and 12% (SE 2) from any other donor. According to time of relapse after transplant, 3-year OS was 6% (SE 2), 10% (SE 2), 15% (SE 2) and 27% (SE 4) in those who relapsed in the first quarter, second quarter, second semester or after the first year, respectively. Donor lymphocyte infusions were reported for 7% and a second HCT for 16% of the 836 relapsed children. The probability of undergoing a second HCT within 1 year after relapse was 17% (SE 1); this probability was 6% for relapses occurring <6 months and 25% for later relapses. 3y-OS of those who underwent a second HCT was 32% (SE 5). Conclusions. The multivariate analyses confirmed the prognostic role of disease phase and immunophenotype, but not of the type of donor, assessed the strong prognostic impact of the time elapsed in CR after HCT before relapse, being earlier relapses at worse outcome compared with later relapses, possibly due to the chance of undergoing a second HCT, which role per se was not statistically significant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clonal evolution in B-lineage acute lymphoblastic leukemia by contemporaneous VH-VH gene replacements and VH-DJH gene rearrangements

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2506-2512 ◽  
Author(s):  
Y Choi ◽  
SJ Greenberg ◽  
TL Du ◽  
PM Ward ◽  
PM Overturf ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Gene Segment ◽  
Gene Replacement ◽  
Gene Rearrangements ◽  
Region Gene ◽  
Vh Gene ◽  
B Lineage

B-cell acute lymphoblastic leukemia (B-ALL), more frequently than any other B-lineage neoplasm, exhibits oligoclonal Ig heavy chain (IgH) gene rearrangement in 15% to 43% of all cases studied. To study the molecular processes that promote multiple IgH rearrangements, a comprehensive sequence analysis of a B-ALL case was performed in which seven clonal IgH gene rearrangements were identified. The genetic profiles suggested that a single leukemic progenitor clone evolved into several subclones through dual processes of variable (VH) to preexisting diversity-joining (DJH) gene segment rearrangement and VH to VH gene replacement. Predominant IgH-V usage and the uniquely rearranged clonotype-specific VHDJH region gene sequences were identified using a novel DNA-based gene amplification strategy. Polymerase chain reaction (PCR) was directed by an IgH-J generic primer and a complement of family-specific IgH-V primers that defined the major B-cell IgH-V gene usage. Clonality of rearranged VHDJH bands was substantiated by high resolution denaturant gel electrophoretic analysis. Sequence patterns of the amplified VHDJH fragments segregated into two groups defined by common DJH sequences. Partial N region homology at the VHD junction as well as shared DJH sequences firmly established VH to VHDJH gene replacement as a mechanism generating clonal evolution in one group. In the second subset, oligoclonality was propagated by independent VH gene rearrangements to a common DJH precursor. The contributions of all clonal Ig-VHDJH repertoires for each group was approximately 50% and reflected a symmetric distribution of leukemic subclones generated by either process. Thus, oligoclonal rearrangements evolved by two independent, yet seemingly contemporaneous molecular genetic mechanisms. All seven clones displayed nonfunctional Ig-VHDJH recombinations. These observations may have relevance to the recombinatorial opportunities available during normal B-cell maturation.

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