Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation

Ferri, Cristian Alberto; Bianchini, Michele; Bengió, Raquel; Moiraghi, Elena Beatriz; Gonzalez, Mariana Selena; Noriega, Maria Fernanda; Larripa, Irene

doi:10.1111/ejh.12358

Cited by 5 publications

(3 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fifteen months later, the patient maintains a sustained MR 5.0 with no detectable disease. Ponatinib efficacy was previously observed in a CML e19a2 patient refractory to both imatinib and dasatinib therapy due to the presence of a T315I mutation [ 20 ]. These results suggest that ponatinib could be an excellent therapeutic option in the treatment of e19a2 CML harbouring the T315I mutation refractory to previous therapies including HSCT, although more studies are necessary to draw a definitive conclusion.…”

Section: Discussionmentioning

confidence: 99%

Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report

Cerveira¹,

Ferreira²,

Bizarro³

et al. 2018

BMC Cancer

View full text Add to dashboard Cite

BackgroundAtypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib.Case presentationHere we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation (HSCT).ConclusionThis case illustrates the major interest of ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after HSCT.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5100-4) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report

Cerveira¹,

Ferreira²,

Bizarro³

et al. 2018

BMC Cancer

View full text Add to dashboard Cite

show abstract

“…The constitutive expression gene β-Actin was used to normalize sample-to-sample differences in cDNA input, RNA quality and RT efficiency [31]. For all targets, the thermal cycling conditions were 2 minutes at 50°C, followed by 2 minutes at 95°C; continued by 45 cycles at 95°C for 20 seconds and 60°C for 1 minute, ending with a melting curve from 50°C to 99°C.…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia

et al. 2017

View full text Add to dashboard Cite

Telomeres are protective repeats of TTAGGG sequences located at the end of human chromosomes. They are essential to maintain chromosomal integrity and genome stability. Telomerase is a ribonucleoprotein complex containing an internal RNA template (hTR) and a catalytic subunit (hTERT). The human hTR gene consists of three major domains; among them the H/ACA domain is essential for telomere biogenesis. H/ACA ribonucleoprotein (RNP) complex is composed of four evolutionary conserved proteins, including dyskerin (encoded by DKC1 gene), NOP10, NHP2 and GAR1. In this study, we have evaluated the expression profile of the H/ACA RNP complex genes: DKC1, NOP10, NHP2 and GAR1, as well as hTERT and hTR mRNA levels, in patients with chronic lymphocytic leukemia (CLL). Results were correlated with the number and type of genetic alteration detected by conventional cytogenetics and FISH (fluorescence in situ hybridization), IGHV (immunoglobulin heavy chain variable region) mutational status, telomere length (TL) and clinico-pathological characteristics of patients. Our results showed significant decreased expression of GAR1, NOP10, DKC1 and hTR, as well as increased mRNA levels of hTERT in patients compared to controls (p≤0.04). A positive correlation between the expression of GAR1-NHP2, GAR1-NOP10, and NOP10-NHP2 (p<0.0001), were observed. The analysis taking into account prognostic factors showed a significant increased expression of hTERT gene in unmutated-IGHV cases compared to mutated-CLL patients (p = 0.0185). The comparisons among FISH groups exhibited increased expression of DKC1 in cases with two or more alterations with respect to no abnormalities, trisomy 12 and del13q14, and of NHP2 and NOP10 compared to those with del13q14 (p = 0.03). The analysis according to TL showed a significant increased expression of hTERT (p = 0.0074) and DKC1 (p = 0.0036) in patients with short telomeres compared to those with long TL. No association between gene expression and clinical parameters was found. Our results suggest a role for these telomere associated genes in genomic instability and telomere dysfunction in CLL.

show abstract

“…The substitution of a threonine by an isoleucine impairs the formation of a hydrogen bond with the TKI, thus preventing the binding of the drug ( Bose et al, 2013 ). Recent studies ( Ferri et al, 2015 ) have shown that only the third generation TKI (ponatinib) is able to inhibit BCR-ABL with the T315I mutation. However, even ponatinib fails when facing compound mutations ( Zabriskie et al, 2014 ).…”

Section: The Impact Of Point Mutations Of Specific Targets On Drug Dementioning

confidence: 99%

The study of homology between tumor progression genes and members of retroviridae as a tool to predict target-directed therapy failure

Fernandes

2015

Front. Pharmacol.

View full text Add to dashboard Cite

Oncogenes are the primary candidates for target-directed therapy, given that they are involved directly in the progression and resistance of tumors. However, the appearance of point mutations can hinder the treatment of patients with these new molecules, raising costs and the need to development new analogs that target the novel mutations. Based on an analysis of homologies, the present study discusses the possibility of predicting the failure of a protein as a pharmacological target, due to its similarities with retrovirus sequences, which have extremely high mutation rates. This analysis was based on the molecular evidence available in the literature, and widely-used and well-established PSI-BLAST, with two iterations and maximum of 500 aligned sequences. The possibility of predicting which newly-discovered genes involved in tumor progression would likely result in the failure of targeted therapy, using free, simple and automated bioinformatics tools, could provide substantial savings in the time and financial resources needed for long-term drug development.

show abstract

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation

Abstract: Here, we report the hematological, cytogenetic, and molecular response of a patient with refractory CML in chronic phase with e19a2 transcripts, carrying T315I mutation that was successfully treated with ponatinib.

Cited by 5 publications

References 11 publications

Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report

Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report

Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia

The study of homology between tumor progression genes and members of retroviridae as a tool to predict target-directed therapy failure

Contact Info

Product

Resources

About