scholarly journals Characterization of the Relationship of Inotuzumab Ozogamicin Exposure With Efficacy and Safety End Points in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia

2020 ◽  
Author(s):  
Joseph Chen ◽  
May Haughey ◽  
Erik Vandendries ◽  
Daniel J. DeAngelo ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Efficacy And Safety ◽  
Inotuzumab Ozogamicin ◽  
End Points ◽  
Relationship Of ◽  
The Relationship

Loffler's Endomyocardial Fibrosis, Eosinophilia, and Acute Lymphoblastic Leukemia

PEDIATRICS ◽  
1977 ◽  
Vol 59 (6) ◽  
pp. 950-951
Author(s):  
Fabio Pereira ◽  
Hernan Moreno ◽  
William Crist ◽  
Rufino Ermocilla
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Normal Karyotype ◽  
Endomyocardial Fibrosis ◽  
Constant Feature ◽  
Cytogenetic Evidence ◽  
The Subject ◽  
Relationship Of ◽  
The Relationship ◽  
Peripheral Blood Eosinophilia

Eosinophilia is a constant feature of Loffler's endomyocardial fibrosis.1,2 Three cases of this syndrome have been described in which acute lymphoblastic leukemia was concurrently present.3,4 Cytogenetic evidence in one of these cases suggested that the eosinophilia was "reactive" because the eosinophils had a normal karyotype while the lymphoblasts showed chromosomal aneuploidy.4 The subject of eosinophilia and eosinophilic syndromes has been extensively reviewed by others.5-8 The purpose of this report is to describe a boy with long-standing eosinophilia who presented with intractable heart failure, striking peripheral blood eosinophilia, and 38% lymphoblasts in the bone marrow. Current thoughts concerning the relationship of endomyocardial fibrosis, acute lymphoblastic leukemia, and eosinophilia are summarized.

scholarly journals Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE

Cancer ◽  
2018 ◽  
Vol 124 (8) ◽  
pp. 1722-1732 ◽  
Author(s):  
Elias J. Jabbour ◽  
Daniel J. DeAngelo ◽  
Matthias Stelljes ◽  
Wendy Stock ◽  
Michaela Liedtke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Safety Analysis ◽  
Efficacy And Safety ◽  
Inotuzumab Ozogamicin ◽  
Age Cohort

scholarly journals Genetic Heterogeneity and Evolution in Lymphoid Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-34-SCI-34
Author(s):  
Charles G. Mullighan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Drug Exposure ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Genomic Analysis ◽  
Disease Recurrence ◽  
Relationship Of ◽  
The Relationship ◽  
Limiting Dilution

Abstract Patterns of mutation and clonal evolution in relapsed acute lymphoblastic leukemia Relapsed acute lymphoblastic leukemia remains a major cause of childhood cancer death, and this remains true despite the advent of new targeted and immunotherapeutic approaches. Recent years have witnessed the use of broad and deep serial genomic profiling approaches to dissect the relationship of genetic variegation to clonal evolution and relapse. Studies of over 90 children treated on St Jude Total Therapy protocols, incorporating genome, exome and transcriptome sequencing, coupled with limiting dilution xenografting to formally elucidate clonal structure have provided multiple key insights. In the majority of cases, the relapse-fated clone is a minor clone at diagnosis, that harbors resistance-enriched (and thus relapse-promoting) mutations at diagnosis, and/or acquires additional mutations the confer resistance after initial therapy. Approximately one third of cases relapse from a major clone, or show polyclonal evolution, and such cases typically have a shorter time to disease recurrence and relapse. A subset of cases exhibit complete discordance for somatic non-silent mutations, DNA copy number alterations and antigen receptor rearrangements between diagnosis and relapse, suggesting relapse represents a second leukemia; however such cases typically preserve the founding chromosomal rearrangement and a subset of non-coding mutations, indicating that relapse arises from an ancestral clone that has undergone divergent evolution early in leukemogenesis. Conversely, a subset of cases relapse with myeloid or lineage ambiguous leukemia but preserve genomic alterations indicating a common clonal origin but lineage plasticity: thus, careful genomic analysis is required to interpret the nature of disease recurrence/relapse. Approximately 15% of cases exhibit hypermutation, particularly in aneuploid leukemia and second or later relapse, associated with distinct mutational signatures and kinetics of hypermutation, thus identifying this process as a driver of treatment failure in a subset of ALL cases. Integrated analysis has identified over 80 recurrent targets of alteration at relapse that show variable patterns of enrichment in rising and falling clones. Importantly, several targets (e.g. NT5C2) are never identified at diagnosis despite deep sequencing approaches, suggesting adverse effects on leukemic fitness, and/or an absolute requirement of prior drug exposure to initiate mutagenesis. Integration of limiting dilution xenografting, coupled with genomic analysis of xenografts and drug exposure has not only formally confirmed and extended inferential clonal structures, but shown that in a subset of cases resistance is present at initial diagnosis, rather than being acquired after drug exposure. Finally, several groups have shown that the relationship of relapse-enriched mutations and relapse by be drug agnostic (e.g. IKZF1) or drug specific (e.g. NT5C2 and thiopurine resistance, and CREBBP and glucocorticoid resistance). As such mutations may now be detected at levels suitable for tracking of minimal residual disease, these insights offer the opportunity to identify the relapse-fated clone early in disease evolution, and modulate therapy accordingly to circumvent relapse. Disclosures Mullighan: Pfizer: Honoraria, Research Funding, Speakers Bureau; Cancer Prevention and Research Institute of Texas: Consultancy; Loxo Oncology: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Speakers Bureau.

scholarly journals Molecular analysis of clonality and bcr rearrangements in Philadelphia chromosome-positive acute lymphoblastic leukemia

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1495-1498 ◽  
Author(s):  
AG Turhan ◽  
CJ Eaves ◽  
DK Kalousek ◽  
AC Eaves ◽  
RK Humphries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Chromosome 22 ◽  
Cell Of Origin ◽  
A Cell ◽  
Relationship Of ◽  
The Relationship

Abstract Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) patients consistently show a rearrangement in a 5.8-kilobase length of chromosome 22, referred to as the breakpoint cluster region (bcr). In Ph1-positive acute lymphoblastic leukemia (ALL), the breakpoint in chromosome 22 is more heterogeneous and, in some instances, does not occur within this region. In such cases the cell of origin of the neoplastic clone and the relationship of the disease to CML has remained obscure. We have analyzed the bcr rearrangement in the malignant cells from three patients who presented with Ph1-positive ALL and who in cytogenetic studies had shown evidence of variable involvement of myeloid cells in the Ph1-positive clone. Rearrangements in bcr typical of most cases of CML were detected in purified granulocyte preparations from two of the ALL patients (nos. 1 and 2) and in the blasts from patient 3 at the time of her terminal relapse. In the same analysis the simultaneously obtained granulocytes from patient 3, however, did not show any evidence of bcr rearrangement. Patient 3 was also heterozygous for the BamHI polymorphism in the X- linked hypoxanthine phosphoribosyltransferase (HPRT) gene, thus permitting a different method of clonal analysis based on methylation differences in active and inactive alleles. When DNA from her granulocytes that had shown no bcr rearrangement was hybridized to an HPRT probe, a pattern typical of a polyclonal population was seen. A similar pattern was exhibited by her marrow fibroblasts. In marked contrast, her simultaneously isolated blasts showed an unambiguous monoclonal pattern. These findings demonstrate the origin of the disease in the first two patients in a cell with myelopoietic as well as lymphopoietic potential and confirm the restricted lymphoid cell origin of the neoplastic clone in the third Ph1-positive ALL patient. Furthermore, they indicate that different target cells for transformation within the hematopoietic system may be affected by very similar bcr rearrangements.

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