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Söderlund, Stina
Publications (10 of 13) Show all publications
Kreutzman, A., Yadav, B., Brummendorf, T. H., Gjertsen, B. T., Hee, M. L., Janssen, J., . . . Mustjoki, S. (2019). Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line. Oncoimmunology, 8(9)
Open this publication in new window or tab >>Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line
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2019 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 9Article in journal (Refereed) Published
Abstract [en]

Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2019
Keywords
CML, imatinib, bosutinib, Sokal, BCR-ABL
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-396139 (URN)10.1080/2162402X.2019.1638210 (DOI)000476301700001 ()31428530 (PubMedID)
Available from: 2019-11-08 Created: 2019-11-08 Last updated: 2019-11-08Bibliographically approved
Grootens, J., Ungerstedt, J. S., Ekoff, M., Rönnberg, E., Klimkowska, M., Amini, R.-M., . . . Dahlin, J. S. (2019). Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis. EBioMedicine, 43, 150-158
Open this publication in new window or tab >>Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed) Published
Abstract [en]

Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Systemic Mastocytosis, Single-cell, Mast cell, Mast cell progenitor, CD45RA, Haematopoiesis, Haematopoietic stem cells, KIT D816V
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-387962 (URN)10.1016/j.ebiom.2019.03.089 (DOI)000470091600028 ()30975542 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Cancer Research Funds of RadiumhemmetMagnus Bergvall FoundationTore Nilsons Stiftelse för medicinsk forskningStockholm County Council
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Söderlund, S., Dahlén, T., Sandin, F., Olsson-Strömberg, U., Creignou, M., Dreimane, A., . . . Höglund, M. (2017). Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register. European Journal of Haematology, 98(1), 57-66
Open this publication in new window or tab >>Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register
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2017 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 57-66Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.

METHODS: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.

RESULTS: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.

CONCLUSION: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-310827 (URN)10.1111/ejh.12785 (DOI)000393166600009 ()27428357 (PubMedID)
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-02-26Bibliographically approved
Ilander, M., Olsson-Strömberg, U., Schlums, H., Guilhot, J., Brück, O., Lähteenmäki, H., . . . Mustjoki, S. (2017). Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.. Leukemia, 31(5), 1108-1116
Open this publication in new window or tab >>Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, p. 1108-1116Article in journal (Refereed) Published
Abstract [en]

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.Leukemia advance online publication, 16 December 2016; doi:10.1038/leu.2016.360.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-310824 (URN)10.1038/leu.2016.360 (DOI)000400464800009 ()27890936 (PubMedID)
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-02-26Bibliographically approved
Skoglund, K., Richter, J., Olsson-Strömberg, U., Bergquist, J., Aluthgedara, W., Ubhayasekera, S. J., . . . Gréen, H. (2016). In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients. Therapeutic Drug Monitoring, 38(2), 230-238
Open this publication in new window or tab >>In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
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2016 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.

METHODS: Forty-three CML patients were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.

RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to non-optimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P=0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.

CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Keywords
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Cancer and Oncology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-270505 (URN)10.1097/FTD.0000000000000268 (DOI)000376938000006 ()26693810 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2015-12-29 Created: 2015-12-29 Last updated: 2018-01-10Bibliographically approved
Söderlund, S., Christiansson, L., Persson, I., Hjorth-Hansen, H., Richter, J., Simonsson, B., . . . Loskog, A. (2016). Plasma Proteomics In Chronic Myeloid Leukemia Patients Before And After Initiation Of Tyrosine Kinase Inhibitor Therapy Reveals Induced Th1 Immunity And Loss Of Angiogenic Stimuli. Paper presented at 21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK. Haematologica, 101, 730-730
Open this publication in new window or tab >>Plasma Proteomics In Chronic Myeloid Leukemia Patients Before And After Initiation Of Tyrosine Kinase Inhibitor Therapy Reveals Induced Th1 Immunity And Loss Of Angiogenic Stimuli
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 730-730Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-301462 (URN)000379484602600 ()
Conference
21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK
Available from: 2016-08-23 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
Söderlund, S., Christiansson, L., Persson, I., Hjorth-Hansen, H., Richter, J., Simonsson, B., . . . Loskog, A. (2016). Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 50, 95-103
Open this publication in new window or tab >>Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli
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2016 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 50, p. 95-103Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation.

METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek.

RESULTS: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX.

CONCLUSIONS: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

Keywords
Proteomics, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Th1, Angiogenesis
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:uu:diva-310831 (URN)10.1016/j.leukres.2016.09.019 (DOI)000388315500015 ()27710869 (PubMedID)
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2017-11-29Bibliographically approved
Hjorth-Hansen, H., Stenke, L., Söderlund, S., Dreimane, A., Ehrencrona, H., Gedde-Dahl, T., . . . Richter, J. (2015). Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006). European Journal of Haematology, 64(3), 243-250
Open this publication in new window or tab >>Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006)
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2015 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 64, no 3, p. 243-250Article in journal (Refereed) Published
Abstract [en]

We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR(3.0) was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR(4.5) was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-233784 (URN)10.1111/ejh.12423 (DOI)000350357900008 ()25082346 (PubMedID)
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-12-05Bibliographically approved
Ilander, M., Schlums, H., Olsson-Strömberg, U., Lahteenmaki, H., Kasanen, T., Koskenvesa, P., . . . Mustjoki, S. (2015). Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission. Paper presented at 57th Annual Meeting of the American-Society-of-Hematology, DEC 05-08, 2015, Orlando, FL. Blood, 126(23)
Open this publication in new window or tab >>Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-284662 (URN)000368019001095 ()
Conference
57th Annual Meeting of the American-Society-of-Hematology, DEC 05-08, 2015, Orlando, FL
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Christiansson, L., Söderlund, S., Mangsbo, S., Hjorth-Hansen, H., Höglund, M., Markevarn, B., . . . Olsson-Strömberg, U. (2015). The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses. Molecular Cancer Therapeutics, 14(5), 1181-1191
Open this publication in new window or tab >>The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
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2015 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed) Published
Abstract [en]

Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. 

National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-269778 (URN)10.1158/1535-7163.MCT-14-0849 (DOI)000358053000010 ()25761894 (PubMedID)
Available from: 2015-12-18 Created: 2015-12-18 Last updated: 2017-12-01Bibliographically approved
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