First report of clinical response to Venetoclax in Early T-cell Precursor Acute Lymphoblastic Leukemia.
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ABSTRACT:
SUBMITTER: Numan Y
PROVIDER: S-EPMC6508880 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:•The case demonstrated a rare event of clonal heterogeneity by IKZF1 gene status in BCRABL1- ALL.•IKZF1 deletions are secondary events in ALL caused by clonal evolution during the treatment.•It's prognostic significance could be more crucial in BCR-ABL- rather than in BCR-ABL + ALL.•IKZF1 gene alterations may be determined and proved at the genome, expression and protein level.•IKZF1 deletions are suitable for MRD detection but not stable compared to Ig/TCR rearrangement.
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Project description:Early precursor T cell-acute lymphoblastic leukemia (ETP-ALL) is a rare entity characterized by chemo-resistance and a paucity of data regarding optimal management. We review here the literature regarding the management of ETP-ALL and focus on the recent, emerging data, regarding the potential role of molecularly targeted approaches with a focus on venetoclax.
| S-EPMC7370557 | biostudies-literature
Project description:Minimal residual disease (MRD), where leukemic cell levels are lower than the morphologic detection threshold, is the most important prognostic factor for acute lymphoblastic leukemia (ALL) relapse during first-line chemotherapy treatment and is standard of care in treatment monitoring and decision making. Limited data are available on the prognostic value of MRD response after relapse. We evaluated the relationship between MRD response and outcomes in blinatumomab-treated adults with relapsed/refractory (R/R) B-cell precursor ALL. Of 90 patients with complete remission (CR) or CR with partial hematologic recovery (CRh), 64 (71.1%) achieved a complete MRD response (no detectable individual rearrangements of immunoglobulin/T-cell receptor genes by polymerase chain reaction [PCR] at a minimum sensitivity level of 10-4). Eleven patients had MRD <10-4. Therefore, overall, 75 (83.3%) experienced an MRD response (no detectable MRD or detectable MRD) measured by PCR within the first 2 treatment cycles. Overall survival (OS) and relapse-free survival (RFS) were significantly longer in patients who achieved CR/CRh and MRD response (median, 20.6 and 9.0 months, respectively) compared with CR/CRh patients without MRD response (median, 12.5 and 2.3 months, respectively). In conclusion, longer durations of OS and RFS associated with MRD response support the value of achieving MRD response and its use as a prognostic factor for blinatumomab treatment in R/R ALL. This trial was registered at www.clinicaltrials.gov as #NCT01466179.
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Project description:Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.
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Project description:Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations.
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Project description:Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as "best risk" if they had cleared MRD by day 8 of therapy and as "worst risk" if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing "best" and "worst" risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.
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Project description:In childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well-established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and ETV6-RUNX1 fusion, classified as good risk, while Philadelphia chromosome (Ph) positive ALL and rearrangements of the KMT2A (MLL) gene define poor risk. A poor risk subgroup of intrachromosomal amplification of chromosome 21 (iAMP21-ALL) has been described, in which intensification of therapy has greatly improved outcome. Until recently, no consistent molecular features were defined in around 30% of BCP-ALL (known as B-other-ALL). Recent studies are classifying them into distinct subgroups, some with clear potential for novel therapeutic approaches. For example, in 1 poor risk subtype, known as Ph-like/BCR-ABL1-like ALL, approximately 10% have rearrangements of ABL-class tyrosine kinases: including ABL1, ABL2, PDGFRB, PDGFRA, and CSF1R. Notably, they show a poor response to standard chemotherapy, while they respond to treatment with tyrosine kinase inhibitors, such as imatinib. In other Ph-like-ALL patients, deregulation of the cytokine receptor, CRLF2, and JAK2 rearrangements lead to activation of the JAK-STAT signaling pathway, implicating a specific role for JAK inhibitors in their treatment. Other novel subgroups within B-other-ALL are defined by the IGH-DUX4 translocation, related to deletions of the ERG gene and a good outcome, while fusions involving ZNF384, MEF2D, and intragenic PAX5 amplification (PAX5 AMP) are linked to a poor outcome. Continued genetic screening will eventually lead to complete genomic classification of BCP-ALL and define more molecular targets for less toxic therapies.
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Project description:The most common cancer in children is acute lymphoblastic leukemia (ALL) and it had high cure rate, especially for B-precursor ALL. However, relapse due to drug resistance and overdose treatment reach the limitations in patient managements. In this study, integration of gene expression microarray data, logistic regression, analysis of microarray (SAM) method, and gene set analysis were performed to discover treatment response associated pathway-based signatures in the original cohort. Results showed that 3772 probes were significantly associated with treatment response. After pathway analysis, only apoptosis pathway had significant association with treatment response. Apoptosis pathway signature (APS) derived from 15 significantly expressed genes had 88% accuracy for treatment response prediction. The APS was further validated in two independent cohorts. Results also showed that APS was significantly associated with induction failure time (adjusted hazard ratio [HR] = 1.60, 95% confidence interval [CI] = [1.13, 2.27]) in the first cohort and significantly associated with event-free survival (adjusted HR = 1.56, 95% CI = [1.13, 2.16]) or overall survival in the second cohort (adjusted HR = 1.74, 95% CI = [1.24, 2.45]). APS not only can predict clinical outcome, but also provide molecular guidance of patient management.
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Project description:UnlabelledGene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia.Trial registrationThe GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
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