Leukemic stem cell quantification in newly diagnosed chronic myeloid leukemia patients predicts response to nilotinib therapy
(2016) In Clinical Cancer Research 22(16). p.4030-4038- Abstract
PURPOSE: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We identified Philadelphia chromosome (Ph) positive CD34+CD38- bone marrow cells (here denoted LSCs) and addressed their response-predictive value in CML patients (n=48) subjected to nilotinib in the ENEST1st trial (NCT01061177).
EXPERIMENTAL DESIGN: Two flow cytometry-based cell sorting methods were employed with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.
RESULTS: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score,... (More)
PURPOSE: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We identified Philadelphia chromosome (Ph) positive CD34+CD38- bone marrow cells (here denoted LSCs) and addressed their response-predictive value in CML patients (n=48) subjected to nilotinib in the ENEST1st trial (NCT01061177).
EXPERIMENTAL DESIGN: Two flow cytometry-based cell sorting methods were employed with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.
RESULTS: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC, FISH), 6 (MPFC), 9 (FISH) and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34+CD38- cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions.
CONCLUSION: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in CML patients subjected to first-line nilotinib therapy.
(Less)
- author
- organization
- publishing date
- 2016-08-15
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Clinical Cancer Research
- volume
- 22
- issue
- 16
- pages
- 9 pages
- publisher
- American Association for Cancer Research
- external identifiers
-
- pmid:27006491
- scopus:84982170188
- pmid:27006491
- wos:000382265900008
- ISSN
- 1078-0432
- DOI
- 10.1158/1078-0432.CCR-15-2791
- language
- English
- LU publication?
- yes
- id
- ab856ed0-a683-469e-bead-cf78b07b571f
- date added to LUP
- 2016-04-12 12:27:16
- date last changed
- 2024-09-20 12:02:52
@article{ab856ed0-a683-469e-bead-cf78b07b571f, abstract = {{<p>PURPOSE: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We identified Philadelphia chromosome (Ph) positive CD34+CD38- bone marrow cells (here denoted LSCs) and addressed their response-predictive value in CML patients (n=48) subjected to nilotinib in the ENEST1st trial (NCT01061177).</p><p>EXPERIMENTAL DESIGN: Two flow cytometry-based cell sorting methods were employed with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.</p><p>RESULTS: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC, FISH), 6 (MPFC), 9 (FISH) and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34+CD38- cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions.</p><p>CONCLUSION: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in CML patients subjected to first-line nilotinib therapy.</p>}}, author = {{Thielen, Noortje and Richter, Johan and Baldauf, Matthias and Barbany, Gisela and Fioretos, Thoas and Giles, Francis and Gjertsen, Bjørn Tore and Hochhaus, Andreas and Schuurhuis, Gerrit Jan and Sopper, Sieghart and Stenke, Leif and Thunberg, Sarah and Wolf, Dominik and Ossenkoppele, Gert and Porkka, Kimmo and Janssen, Jeroen and Mustjoki, Satu}}, issn = {{1078-0432}}, language = {{eng}}, month = {{08}}, number = {{16}}, pages = {{4030--4038}}, publisher = {{American Association for Cancer Research}}, series = {{Clinical Cancer Research}}, title = {{Leukemic stem cell quantification in newly diagnosed chronic myeloid leukemia patients predicts response to nilotinib therapy}}, url = {{http://dx.doi.org/10.1158/1078-0432.CCR-15-2791}}, doi = {{10.1158/1078-0432.CCR-15-2791}}, volume = {{22}}, year = {{2016}}, }