Publications by authors named "Eva Jäger"

21 Publications

  • Page 1 of 1

Myelomonocytic skewing in chronic myelomonocytic leukemia: phenotypic, molecular and biologic features and impact on survival.

Eur J Haematol 2021 May 8;106(5):627-633. Epub 2021 Mar 8.

Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO), Medical University of Vienna, Vienna, Austria.

Background: Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined.

Methods: Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures.

Results: There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%). Patients with CMML with myelomonocytic skewing had higher white blood cell and peripheral blast cell counts, and lower platelet values. The number of mutations in genes of the epigenetic and/or splicing category was higher in CMML patients with as compared with patients without skewing. Patients with myelomonocytic skewing had more frequently mutations in RASopathy genes and higher growth factor independent myeloid colony formation. Interestingly, the lack of myelomonocytic skewing discriminated patients with CMML with a particularly favorable prognosis (60 vs 19 months, P = .003) and a minimal risk of transformation.

Conclusion: Myelomonocytic skewing as determined by semisolid cultures can discriminate subgroups of patients with CMML with a different phenotype, a different genotype, and a different prognosis.
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http://dx.doi.org/10.1111/ejh.13577DOI Listing
May 2021

Retrospective analysis of the prevalence of specialised palliative care services for patients with metastatic breast cancer.

ESMO Open 2020 09;5(5):e000905

Department of Internal Medicine 2, UH Krems, Krems, Austria. Electronic address:

Background: Patients with metastatic breast cancer (MBC) have a considerable symptom burden and may require extensive care for a long period of time. Palliative care (PC) has the potential to improve their quality of care and reduce their use of medical services. However, the role of specialised PC (SPC) in patients with MBC remains unclear.

Patients And Methods: We performed a retrospective analysis of the medical records of patients diagnosed with breast cancer (BC) from 2008 to 2018 at an university-based referral centre to examine the extent of early and late integration of SPC services for patients with MBC. A descriptive analysis of the patients was also established.

Results: In all, 932 patients were diagnosed with BC from 2008 to 2018; 225 of these patients had or developed metastases related to their BC. In addition, 132 patients received SPC (58.7%) and 93 patients did not receive SPC (41.3%). The median probability of overall survival (OS) for patients who did not receive SPC services was 3.6 years (95% CI 2.0 to 5.1) and 1.8 years (95% CI 1.3 to 2.3) (p<0.0001) for patients who did receive SPC. In multivariate analysis, referral to SPC services was independently associated with OS (HR 1.60, 95% CI 1.16 to 2.22, p=0.004).

Conclusion: Patients who received SPC lived significantly shorter amounts of time than patients not referred for SPC services at our hospital. We concluded that the referral to SPC services was often too late and should be implemented earlier in the course of the disease. We suggest that patients with MBC should participate in a consultation by a SPC team ≤60 days after the start of systemic palliative anticancer therapy in addition to endocrine treatment. Larger prospective studies are needed to evaluate the benefit of the early integration of SPC services for patients with MBC.
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http://dx.doi.org/10.1136/esmoopen-2020-000905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511635PMC
September 2020

Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia.

Int J Mol Sci 2020 Aug 22;21(17). Epub 2020 Aug 22.

Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO), Medical University of Vienna, 1090 Vienna, Austria.

We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in , and that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated but not was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival ( < 0.00001) and time to transformation ( = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including , however, was predictive for inferior survival ( = 0.00059) as well as for increased risk of transformation ( = 0.01429). In conclusion, we show that the composite molecular profile derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML.
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http://dx.doi.org/10.3390/ijms21176057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504428PMC
August 2020

Myelomonocytic Skewing In Vitro Discriminates Subgroups of Patients with Myelofibrosis with A Different Phenotype, A Different Mutational Profile and Different Prognosis.

Cancers (Basel) 2020 Aug 14;12(8). Epub 2020 Aug 14.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation towards the myelomonocytic over erythroid commitment in 81 patients with myelofibrosis (MF). MF patients had significantly increased numbers of circulating CFU-GM and BFU-E. Myelomonocytic skewing as indicated by a CFU-GM/BFU-E ratio ≥ 1 was found in 26/81 (32%) MF patients as compared to 1/98 (1%) in normal individuals. Patients with myelomonocytic skewing as compared to patients without skewing had higher white blood cell and blast cell counts, more frequent leukoerythroblastic features, but lower hemoglobin levels and platelet counts. The presence of myelomonocytic skewing was associated with a higher frequency of additional mutations, particularly in genes of the epigenetic and/or splicing machinery, and a significantly shorter survival (46 vs. 138 mo, < 0.001). The results of this study show that the in vitro detection of myelomonocytic skewing can discriminate subgroups of patients with MF with a different phenotype, a different mutational profile and a different prognosis. Our findings may be important for the understanding and management of MF.
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http://dx.doi.org/10.3390/cancers12082291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464756PMC
August 2020

Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype.

Cancers (Basel) 2020 Jul 14;12(7). Epub 2020 Jul 14.

Department of Internal Medicine V with Hematology, Oncology and Palliative Care, Hospital Hietzing, 1130 Vienna, Austria.

Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from -mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (-mutated, 28 months; -nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
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http://dx.doi.org/10.3390/cancers12071891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409251PMC
July 2020

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia-A Retrospective Analysis in 337 Patients.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, = 236) and with (B, = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% ( < 0.0001), and of high colony growth (≥20/10 peripheral blood mononuclear cells) 31%, 44%, and 80% ( < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.
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http://dx.doi.org/10.3390/ijms21083025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215883PMC
April 2020

Genotypic and phenotypic evolution in a patient with chronic myelomonocytic leukemia.

Leuk Res Rep 2019 5;12:100185. Epub 2019 Oct 5.

Department of Laboratory Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

The correlation of molecular and phenotypic evolution in individual patients with chronic myelomonocytic leukemia (CMML) is poorly investigated. The longitudinal follow up of a CMML patient for more than 10 years illustrates that the emergence of clones harboring mutations in and finally in multiple genes, respectively, was mirrored by thrombocytopenia, thrombocytosis, myeloproliferation and transformation into acute myeloid leukemia. Moreover, molecular aberrations of the genes were associated with markedly increased spontaneous in vitro myeloid colony formation which has been shown to be a functional indicator of RAS pathway hyperactivation.
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http://dx.doi.org/10.1016/j.lrr.2019.100185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904770PMC
October 2019

The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) : A representative and useful real-life data source for further biomedical research.

Wien Klin Wochenschr 2019 Sep 18;131(17-18):410-418. Epub 2019 Jul 18.

Department of Internal Medicine I with Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Barmherzige Schwestern - Elisabethinen, Linz, Austria.

In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.
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http://dx.doi.org/10.1007/s00508-019-1526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748886PMC
September 2019

Is ruxolitinib a potentially useful drug in hematological malignancies with RAS pathway hyperactivation?

Haematologica 2016 12;101(12):e492

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Austria.

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http://dx.doi.org/10.3324/haematol.2016.156448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479601PMC
December 2016

Evaluation of efficacy of alemtuzumab in 5 patients with aplastic anemia and/or myelodysplastic neoplasm.

Wien Klin Wochenschr 2017 Jun 14;129(11-12):404-410. Epub 2016 Oct 14.

Department of Internal Medicine I, Division of Hematology & Hemostaseology, AKH, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Patients with aplastic anemia or hypoplastic myelodysplastic syndrome (MDS) may respond to immunosuppressive therapy, including the anti-CD52 antibody alemtuzumab. We analyzed treatment responses to alemtuzumab in 5 patients with MDS or aplastic anemia (AA) evolving to MDS. Two patients with hypoplastic MDS (hMDS) showed a partial response (PR) to alemtuzumab. In both responding patients, a concomitant paroxysmal nocturnal hemoglobinuria (PNH) clone was detected before therapy. One responder relapsed after 15 months and underwent successful allogeneic stem cell transplantation. Both patients are still alive and in remission after 40 and 20 months, respectively. The other patients showed no response to alemtuzumab. One patient died from pneumonia 4 months after treatment. In summary, our data confirm that alemtuzumab is an effective treatment option for a subset of patients with MDS, even in the presence of a PNH clone.
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http://dx.doi.org/10.1007/s00508-016-1091-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486731PMC
June 2017

In vitro and in vivo effects of JAK2 inhibition in chronic myelomonocytic leukemia.

Eur J Haematol 2016 Dec 15;97(6):562-567. Epub 2016 Jun 15.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

In chronic myelomonocytic leukemia (CMML), colony-forming units granulocyte/macrophage (CFU-GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM-CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML. We investigated the in vitro effects of the specific JAK2 inhibitor TG101209 on the autonomous CFU-GM formation from peripheral blood mononuclear cells of patients with CMML. TG101209 was found to either block or strongly inhibit spontaneous CFU-GM growth in all 10 patients tested. This inhibitory effect was dose dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU-GM growth from normal individuals. In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU-GM formation ex vivo. Pharmacological JAK2 inhibition may be an interesting approach to be systematically studied in patients with CMML.
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http://dx.doi.org/10.1111/ejh.12773DOI Listing
December 2016

Interleukin-10 inhibits autonomous myelopoiesis in patients with myelofibrosis.

Eur J Haematol 2015 Sep 7;95(3):239-43. Epub 2015 Jan 7.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

The spontaneous formation of colony-forming units granulocyte/macrophage (CFU-GM) in semisolid cultures has been shown to be due to the endogenous release of cytokines and/or to the hypersensitivity of cells against growth factors. We have reported that increased autonomous CFU-GM growth is an in vitro characteristic of myelofibrosis (MF) which may reflect aberrant hematopoiesis in vivo. Because of its cytokine synthesis-inhibiting action, we speculated that interleukin-10 (IL-10) may inhibit pathological overproduction of myeloid cells in MF by suppression of autonomous myelopoiesis. In this study, IL-10 significantly inhibited autonomous CFU-GM formation in vitro from peripheral blood mononuclear cells (PB MNC) in 10 of 11 patients with MF tested. In all patients, there was a mean inhibition of 69% ranging from 35% to 100%. Suppression of autonomous CFU-GM formation by IL-10 was dose dependent and reversible by the addition of anti-IL-10 antibodies. Our results indicate that IL-10 is a potentially useful molecule to affect aberrant myelopoiesis in patients with MF.
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http://dx.doi.org/10.1111/ejh.12486DOI Listing
September 2015

Circulating hematopoietic progenitor cells in essential thrombocythemia versus prefibrotic/early primary myelofibrosis.

Am J Hematol 2014 Dec 27;89(12):1157-8. Epub 2014 Aug 27.

5th Department of Internal Medicine - Oncology/Hematology, Hospital Hietzing, Vienna, Austria; Ludwig Boltzmann Institute for Clinical Oncology, Vienna, Austria.

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http://dx.doi.org/10.1002/ajh.23829DOI Listing
December 2014

Evaluation of treatment responses and colony-forming progenitor cells in 50 patients with aplastic anemia after immunosuppressive therapy or hematopoietic stem cell transplantation: a single-center experience.

Wien Klin Wochenschr 2014 Feb 18;126(3-4):119-25. Epub 2014 Jan 18.

Division of Hematology & Hemostaseology, Department of Internal Medicine I, AKH, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria,

We analyzed the clinical course and outcome in 50 patients (27 males, 23 females) suffering from aplastic anemia (AA), treated in our department between 1987 and 2007. The median age was 37 years (range: 14-70 years). A total of 42 patients received antithymocyte globulin and cyclosporine A (CSA). Seven patients were transplanted using a matched sibling donor upfront, and one patient was treated with CSA and growth factors only. A total of 34 patients (68 %) achieved a complete remission, and 7 (14 %), a partial remission. Eight patients (16 %) did not respond to treatment, and one died shortly after transplantation. Relapses of AA occurred in eight patients (20 %). No obvious correlations between clinical parameters, including age, karyotype, existence of paroxysmal nocturnal hemoglobinuria clones, pretreatment blood counts, progenitor cell counts, and the response to immunosuppressive therapy (IST), were found. We also examined the numbers of colony-forming progenitor cells (CFUs) before and after therapy. In most responding patients, CFU numbers increased substantially after successful therapy. However, even in patients without a substantial increase in CFU, stable remissions were observed. Together, both IST and stem cell transplantation are reasonable treatment options for patients with AA.
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http://dx.doi.org/10.1007/s00508-013-0484-2DOI Listing
February 2014

Recombinant human interleukin-10 in patients with chronic myelomonocytic leukemia.

Ann Hematol 2014 Oct 18;93(10):1775-6. Epub 2014 Jan 18.

5th Department of Internal Medicine-Oncology/Hematology, Krankenhaus Hietzing, Wolkersbergenstraße 1, 1130, Vienna, Austria.

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http://dx.doi.org/10.1007/s00277-014-2012-5DOI Listing
October 2014

High spontaneous granulocyte/macrophage-colony formation in patients with myelofibrosis.

Leuk Res 2014 Jan 14;38(1):116-20. Epub 2013 Oct 14.

5th Department of Internal Medicine - Oncology/Hematology, Hospital Hietzing, Vienna, Austria; Ludwig Boltzmann Institute for Clinical Oncology, Vienna, Austria. Electronic address:

Unstimulated methylcellulose cultures in 25 myelofibrosis (MF) patients were performed to better understand the role of cytokines in the proliferation of MF cells. Compared to controls MF patients show a variable but highly increased spontaneous CFU-GM formation (66 vs 4.8/10(5) PBMNC). There was a marked reduction of autonomous CFU-GM growth by the cytokine-synthesis-inhibiting molecule IL-10 as well as by antibodies against GM-CSF whereas antibodies against IL-3, G-CSF, M-CSF and IL-1β showed heterogeneous effects. Spontaneous CFU-GM growth >100/10(5) PBMNC predicted shorter survival. Constitutive release of GM-CSF seems to contribute to proliferation of MF cells in vitro and possibly in vivo.
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http://dx.doi.org/10.1016/j.leukres.2013.10.003DOI Listing
January 2014

CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin.

Haematologica 2012 Feb 11;97(2):219-26. Epub 2011 Oct 11.

Ludwig Boltzmann Cluster Oncology, Vienna, Austria.

Background: CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.

Design And Methods: We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined.

Results: As assessed by flow cytometry, stem cell-enriched CD34(+)/CD38(-)/CD123(+) leukemic cells expressed significantly higher levels of CD33 compared to normal CD34(+)/CD38(-) stem cells. Moreover, highly enriched leukemic CD34(+)/CD38(-) cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34(+)/CD38(-) cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells.

Conclusions: CD33 is expressed abundantly on immature CD34(+)/CD38(-) stem cells and may serve as a stem cell target in chronic myeloid leukemia.
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http://dx.doi.org/10.3324/haematol.2010.035006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269481PMC
February 2012

Idiopathic bone marrow dysplasia of unknown significance (IDUS): definition, pathogenesis, follow up, and prognosis.

Am J Cancer Res 2011 16;1(4):531-41. Epub 2010 Mar 16.

Minimal diagnostic criteria for myelodysplastic syndromes (MDS) include constant cytopenia recorded for at least 6 months, dysplasia, and exclusion of other causes of cytopenia and dysplasia. However, there are patients with dysplastic bone marrow features with or without a karyotype, who have only mild if any cytopenia. This condition has been termed idiopathic dysplasia of unknown significance (IDUS). Out of a series of 1,363 patients with suspected MDS or mild cytopenia seen between 1997 and 2010, we have identified 10 patients with IDUS, and analyzed their clinical course and outcome as well as features potentially involved in disease-evolution. Follow-up ranged between 2 and 13 years. Progression to an overt myeloid neoplasm was observed in 4 patients: two progressed to frank MDS, one to chronic myelomonocytic leukemia, and one to a myelodysplastic/myeloproliferative neoplasm exhibiting 5q-and JAK2 V617F. Consecutive studies revealed that most IDUS patients have an adequate production of erythropoietin (EPO) and sufficient numbers of EPO-responsive erythroid progenitors, features rarely seen in MDS. The erythropoiesis-promoting JAK2 mutation V617F was only detectable in one case. We hypothesize that the dysplastic clone in IDUS cannot manifest as frank MDS because i) the clone retains responsiveness against EPO, and ii) an adequate EPO-production counteracts anemia. Evolution of IDUS to low risk MDS may thus depend on the biological properties of the clone as well as patient-related factors such as EPO production. The latter often decreases with age and may thus explain why MDS often manifests in the elderly.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186051PMC
November 2011

Targeted drug delivery by gemtuzumab ozogamicin: mechanism-based mathematical model for treatment strategy improvement and therapy individualization.

PLoS One 2011 7;6(9):e24265. Epub 2011 Sep 7.

Institute for Medical BioMathematics, Bene Ataroth, Israel.

Gemtuzumab ozogamicin (GO) is a chemotherapy-conjugated anti-CD33 monoclonal antibody effective in some patients with acute myeloid leukemia (AML). The optimal treatment schedule and optimal timing of GO administration relative to other agents remains unknown. Conventional pharmacokinetic analysis has been of limited insight for the schedule optimization. We developed a mechanism-based mathematical model and employed it to analyze the time-course of free and GO-bound CD33 molecules on the lekemic blasts in individual AML patients treated with GO. We calculated expected intravascular drug exposure (I-AUC) as a surrogate marker for the response to the drug. A high CD33 production rate and low drug efflux were the most important determinants of high I-AUC, characterizing patients with favorable pharmacokinetic profile and, hence, improved response. I-AUC was insensitive to other studied parameters within biologically relevant ranges, including internalization rate and dissociation constant. Our computations suggested that even moderate blast burden reduction prior to drug administration enables lowering of GO doses without significantly compromising intracellular drug exposure. These findings indicate that GO may optimally be used after cyto-reductive chemotherapy, rather than before, or concomitantly with it, and that GO efficacy can be maintained by dose reduction to 6 mg/m(2) and a dosing interval of 7 days. Model predictions are validated by comparison with the results of EORTC-GIMEMA AML19 clinical trial, where two different GO schedules were administered. We suggest that incorporation of our results in clinical practice can serve identification of the subpopulation of elderly patients who can benefit most of the GO treatment and enable return of the currently suspended drug to clinic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168467PMC
February 2012

Circulating hematopoietic progenitor cells predict survival in patients with myelofibrosis with myeloid metaplasia.

Haematologica 2003 Nov;88(11):1204-12

Department of Internal Medicine I, Division of Hematology, University of Vienna, Vienna, Austria.

Background And Objectives: The levels of circulating hematopoietic progenitor cells are often increased in myelofibrosis with myeloid metaplasia (MMM). The prognostic relevance of this phenomenon is largely unknown.

Design And Methods: We determined the number of circulating myeloid (CFU-GM), erythroid (BFU-E), and pluripotent (CFU-GEMM) progenitors, in 110 patients with MMM at diagnosis using a semi-solid colony assay. Overall survival was investigated by plots of the Kaplan-Meier estimator; known risk factors and the number of circulating progenitor cells were tested by univariate and multiple Cox regression analysis.

Results: Univariate analysis showed that hemoglobin concentration (p=0.019), CFU-GM (p< 0.0001), BFU-E (p=0.002), and age (p=0.002) predicted survival. Numbers of circulating CFU-GM above the 75th percentile were associated with a significantly shorter survival than were CFU-GM levels at or below the 75th percentile (27 vs. 74 months, p=0.0007). Similarly, high numbers of BFU-E in peripheral blood (> 75th percentile) predicted a shorter survival (33 vs. 74 months; p=0.007). When myeloid and erythroid progenitor cells were calculated separately in the multiple Cox regression analysis, both CFU-GM (hazard ratio 2.8, 95% CI, 1.35 to 5.93) and BFU-E (hazard ratio 2.57, 95% CI, 1.26 to 5.21) numbers above the 75th percentile were independent adverse prognostic factors in our patients.

Interpretation And Conclusions: High levels of circulating myeloid and erythroid progenitor cells are novel risks factors in patients with MMM. The assessment of hematopoietic progenitor cells may be useful to determine risk-adjusted treatment strategies.
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November 2003

Relation of in vitro growth characteristics to cytogenetics and treatment outcome in acute myeloid leukemia: prognostic significance in patients with a normal karyotype.

Int J Hematol 2003 Oct;78(3):241-7

Department of Internal Medicine I, Division of Hematology, University of Vienna, Austria.

We analyzed in vitro growth characteristics of bone marrow mononuclear cells (BMMCs) from 322 patients with acute myeloid leukemia (AML) in relation to cytogenetic abnormalities. Median colony growth was low in each of the cytogenetic changes associated with a favorable outcome. Most karyotypic abnormalities in the intermediate prognosis group were associated with low growth potential, but 11 q23 abnormalities exhibited 8 times higher in vitro growth. Cytogenetic changes that included abn(3q) seemed to display the highest colony growth in the unfavorable prognosis group, whereas isolated -7 may have been associated with limited growth potential. In vitro growth behavior was predictive of neither rate of complete remission (CR) nor survival of AML patients within the 3 cytogenetic risk groups. In contrast, colony growth differed significantly in the subgroup of patients with a normal karyotype who achieved remission with induction treatment and those who had no remission (10 versus 81.5/10(5) BMMCs; P = .015). Significantly more patients with normal cytogenetics and colony growth below the 50th percentile went into CR than did patients with colony growth above the 50th percentile (82.8% versus 71.2%). Only 4 (6.8%) of the patients in the low growth group had no remission, compared with 12 (23.1%) of the patients with higher in vitro growth (P = .031, chi-square test). In conclusion, colony growth may prove useful as a prognostic factor for early treatment failure in AML patients with a normal karyotype.
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http://dx.doi.org/10.1007/BF02983801DOI Listing
October 2003