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Monitoring residual disease in the ph-negative myeloproliferative neoplasms post-allogeneic stem cell transplantation: more mutations and more methodologies.

Langabeer SE, Haslam K, Conneally E - Front Oncol (2014)

View Article: PubMed Central - PubMed

Affiliation: Cancer Molecular Diagnostics, St. James's Hospital , Dublin , Ireland.

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Nevertheless, the only potentially curative option for these diseases, particularly PMF, is allogeneic stem cell transplantation (ASCT)... Though ASCT was previously considered only for those patients with advanced or transformed disease, improvements in candidate patient selection and stratification, timing of transplantation, and conditioning regimens have significantly reduced the transplant related morbidity and increased the overall survival for MPN patients undergoing this procedure... Development of more sensitive, JAK2 V617F-specific qPCR methodologies capable of detecting one mutant allele in 10 wild type copies has subsequently been shown to provide information on the rate of disease eradication and the identification of patients, at defined time points post-ASCT, at an increased risk of relapse... These sensitive JAK2 V617F qPCR assays have also been shown to be of value in triggering adoptive immunotherapies such as donor lymphocyte infusions that are able to elicit a graft-versus-tumor effect both preemptively and for salvage, post-relapse... In those reported MPL-mutation positive MPN who have undergone ASCT, rapid clearance of the MPL W515L mutation correlated well with peripheral blood counts and donor chimerism status... More recently, whole exome sequencing has identified insertion and/or deletion mutation in CALR, a gene that encodes the endoplasmic reticulum-associated, calcium binding protein calreticulin... These mutations, which occur exclusively in CALR exon nine, appear not to be found in PV, and are present in up to 80% of ET and PMF patients who are JAK2 V617F-and MPL-negative... As CALR mutations are likely initiating events in MPN pathogenesis, the possibility arises to assess these mutations as markers of residual disease in MPN patients post-ASCT... Apart from the common JAK2 V617F, MPL, and CALR mutations, several other recurrent mutations are observed in MPN but are also present in the myelodysplastic syndromes (MDS), MDS/MPN syndromes, and AML limiting their diagnostic utility but affording the potential for their use as markers of residual disease... A recent proof of principle study has utilized NGS to identify molecular mutations in MDS/MPN patients pre-ASCT with detection of the corresponding mutation in the post-ASCT period predictive of relapse... The goal would be the prompt recognition of those patients with an increased risk of relapse in which early therapeutic intervention is warranted, ultimately leading to gains in long-term disease-free and overall survival... The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Summary of methodologies for monitoring MPN-specific mutations post-allogeneic stem cell transplantation. ASCT, allogeneic stem cell transplantation; MPN, myeloproliferative neoplasm; qPCR, quantitative polymerase chain reaction; NGS, next generation sequencing; and dPCR, digital polymerase chain reaction.
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Figure 1: Summary of methodologies for monitoring MPN-specific mutations post-allogeneic stem cell transplantation. ASCT, allogeneic stem cell transplantation; MPN, myeloproliferative neoplasm; qPCR, quantitative polymerase chain reaction; NGS, next generation sequencing; and dPCR, digital polymerase chain reaction.

Mentions: Whether NGS technologies will be of value in routine practice in the post-ASCT setting remains to be proven. Currently, limits of detection require improvement in order to approach those achieved by qPCR necessary for clinical application (Figure 1). Furthermore, issues such as intra- and inter-laboratory will require addressing for both NGS and dPCR; preliminary studies with NGS have demonstrated technical feasibility and concordance in the diagnostic setting (18). These emerging methodologies might soon be applied to identify and monitor mutational events enabling a distinct, personalized profile in those MPN patients undergoing ASCT. The goal would be the prompt recognition of those patients with an increased risk of relapse in which early therapeutic intervention is warranted, ultimately leading to gains in long-term disease-free and overall survival.


Monitoring residual disease in the ph-negative myeloproliferative neoplasms post-allogeneic stem cell transplantation: more mutations and more methodologies.

Langabeer SE, Haslam K, Conneally E - Front Oncol (2014)

Summary of methodologies for monitoring MPN-specific mutations post-allogeneic stem cell transplantation. ASCT, allogeneic stem cell transplantation; MPN, myeloproliferative neoplasm; qPCR, quantitative polymerase chain reaction; NGS, next generation sequencing; and dPCR, digital polymerase chain reaction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126362&req=5

Figure 1: Summary of methodologies for monitoring MPN-specific mutations post-allogeneic stem cell transplantation. ASCT, allogeneic stem cell transplantation; MPN, myeloproliferative neoplasm; qPCR, quantitative polymerase chain reaction; NGS, next generation sequencing; and dPCR, digital polymerase chain reaction.
Mentions: Whether NGS technologies will be of value in routine practice in the post-ASCT setting remains to be proven. Currently, limits of detection require improvement in order to approach those achieved by qPCR necessary for clinical application (Figure 1). Furthermore, issues such as intra- and inter-laboratory will require addressing for both NGS and dPCR; preliminary studies with NGS have demonstrated technical feasibility and concordance in the diagnostic setting (18). These emerging methodologies might soon be applied to identify and monitor mutational events enabling a distinct, personalized profile in those MPN patients undergoing ASCT. The goal would be the prompt recognition of those patients with an increased risk of relapse in which early therapeutic intervention is warranted, ultimately leading to gains in long-term disease-free and overall survival.

View Article: PubMed Central - PubMed

Affiliation: Cancer Molecular Diagnostics, St. James's Hospital , Dublin , Ireland.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Nevertheless, the only potentially curative option for these diseases, particularly PMF, is allogeneic stem cell transplantation (ASCT)... Though ASCT was previously considered only for those patients with advanced or transformed disease, improvements in candidate patient selection and stratification, timing of transplantation, and conditioning regimens have significantly reduced the transplant related morbidity and increased the overall survival for MPN patients undergoing this procedure... Development of more sensitive, JAK2 V617F-specific qPCR methodologies capable of detecting one mutant allele in 10 wild type copies has subsequently been shown to provide information on the rate of disease eradication and the identification of patients, at defined time points post-ASCT, at an increased risk of relapse... These sensitive JAK2 V617F qPCR assays have also been shown to be of value in triggering adoptive immunotherapies such as donor lymphocyte infusions that are able to elicit a graft-versus-tumor effect both preemptively and for salvage, post-relapse... In those reported MPL-mutation positive MPN who have undergone ASCT, rapid clearance of the MPL W515L mutation correlated well with peripheral blood counts and donor chimerism status... More recently, whole exome sequencing has identified insertion and/or deletion mutation in CALR, a gene that encodes the endoplasmic reticulum-associated, calcium binding protein calreticulin... These mutations, which occur exclusively in CALR exon nine, appear not to be found in PV, and are present in up to 80% of ET and PMF patients who are JAK2 V617F-and MPL-negative... As CALR mutations are likely initiating events in MPN pathogenesis, the possibility arises to assess these mutations as markers of residual disease in MPN patients post-ASCT... Apart from the common JAK2 V617F, MPL, and CALR mutations, several other recurrent mutations are observed in MPN but are also present in the myelodysplastic syndromes (MDS), MDS/MPN syndromes, and AML limiting their diagnostic utility but affording the potential for their use as markers of residual disease... A recent proof of principle study has utilized NGS to identify molecular mutations in MDS/MPN patients pre-ASCT with detection of the corresponding mutation in the post-ASCT period predictive of relapse... The goal would be the prompt recognition of those patients with an increased risk of relapse in which early therapeutic intervention is warranted, ultimately leading to gains in long-term disease-free and overall survival... The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

No MeSH data available.


Related in: MedlinePlus