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- Bernell, Per
(author)
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Interphase cytogenetics and cytokine therapy in myelodysplastic syndromes and acute myeloid leukemia
- 1996
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Doctoral thesis (other academic/artistic)abstract
- Myelodysplastic syndromes (MDS) comprise a group of clonal hematopoietic bone marrow cell disorders, characterized by a variable degree of anemia, granulocytopenia and/or thrombocytopenia and with a substantial risk of transformation to acute myeloid leukemia (MDS-AML). In the present thesis a method based on fluorescence in situ hybridization (FISH) was developed which allows cytogenetic studies on morphological identified peripheral blood and bone marrow cells (MGG/FISH). The purpose was to study cytogenetic aberrations in different cell lineages in the bone marrow of patients (pts) with MDS and AML. Another aim was to scrutinise the role of therapy with GM-CSF, given together with EPO to MDS patients with anemia, and together with chemotherapy to patients with MDS-AML. The MGG/FISH method was used in the evaluation of lineage involvement in 12 pts with MDS, 14 with MDS-AML and 6 with de novo AML. In all cases of MDS and MDS-AML, both the myelopoietic and the erythropoietic cell lineages were involved but not the Iymphoid cells. In de novo AML, the abnormal chromosomal clone was generally confined to the immature myeloid cells. MGG/FISH was also evaluated as a method to detect minimal residual disease (MRD) in 12 pts with acute leukemia in complete remission (CR). Using MGG/FISH it was possible to detect MRD in 5 pts in CR, which was not detected using conventional methods. All these S pts subsequently relapsed within two to nine months. In the clinical studies, MDS pts were first treated with EPO (n=37) and non-responders were later given the combined GM-CSF/EPO (n=13) treatment. Fourteen of 37 MDS pts (38%) increased their hemoglobin levels by > l5 g/l during EPO therapy. Responders were more often of FAB subtypes RA or RAS, showed lower s-ElPO and s-LDH and had less pronounced transfusion requirements while their baseline hemoglobin levels were higher. Three of 13 pts (23%) increased their hemoglobin levels and their physical well-being during GM-CSF/EPO, suggesting possible synergism during the combined treatment. Five pts were studied before and after EPO therapy by MGG/FISH and the two responders showed an increase in non-clonal erythroid BM cells. Accordingly, it is likely that one important effect of EPO could be stimulation of remaining normal erythroid precursor cells. Pts with MDS-AML (n=14) were treated with GM-CSF before, during and after chemotherapy (TAD) and eight (58%) entered CR. We found higher CR rates, fewer early deaths, fewer fever days and fewer days with both neutropenia and thrombocytopenia among the responding pts compared to the historical control group, suggesting a better response of the combined GM-CSF/TAD treatment in MDS-AML. The MGG/FISH method is clinically useful and allows studies of cell lineage involvement and detection of MRD in MDS and acute leukemia as well as investigations into the nature of the hematological responses to growth factors.
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| 3. |
- Grövdal, Michael, et al.
(author)
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Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy
- 2010
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 150:3, s. 293-302
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Journal article (peer-reviewed)abstract
- This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.
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| 4. |
- Grövdal, Michael, et al.
(author)
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Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome
- 2007
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:23, s. 7107-7112
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Journal article (peer-reviewed)abstract
- PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
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| 6. |
- Kozlowski, Piotr, 1969-, et al.
(author)
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Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden
- 2017
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In: European Journal of Haematology. - : Wiley-Blackwell Publishing Inc.. - 0902-4441 .- 1600-0609. ; 99:2, s. 141-149
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Older/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials.METHODS: Using Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85 years, diagnosed with ALL 2005-2012.RESULTS: Of 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype. Philadelphia chromosome positivity (Ph+) occurred in 35%. Of the 155 B- and T- ALL patients, 80% were treated with intensive protocols, and 20% with a palliative approach. Higher age and WHO performance status ≥2 influenced the choice of palliation. Intensive, palliative, and both approaches, resulted in complete remission rate 83/16/70%, and 3 year overall survival (OS) 32/3/26%. The age-adapted protocol did not improve outcome. With intensive treatment, platelet count ≤35 × 10(9) /L, and age ≥75 years were adverse prognostic factors for OS, Ph+ was not. Male sex was an adverse prognostic factor in the 55-64 year group.CONCLUSIONS: We report a high frequency of Ph+ in older/elderly patients, with no evidence of poorer outcome compared to Ph negative disease. Overall prognosis for elderly patients with ALL remains dismal, despite the use of age-adapted treatment. This article is protected by copyright. All rights reserved.
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| 8. |
- Kozlowski, Piotr, 1969-, et al.
(author)
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High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-2007
- 2012
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In: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 97:9, s. 1414-1421
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Journal article (peer-reviewed)abstract
- Background less thanbrgreater than less thanbrgreater thanA minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission. less thanbrgreater than less thanbrgreater thanDesign and Methods less thanbrgreater than less thanbrgreater thanBetween 2003-2007, 76 adults (andlt;66 years) with relapsed acute lymphoblastic leukemia (Burkitts leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated. less thanbrgreater than less thanbrgreater thanResults less thanbrgreater than less thanbrgreater thanReinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13-32) and 15% (95% CI: 7-24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2-8.3) after relapse, whereas all patients over 35 years old at diagnosis have died. less thanbrgreater than less thanbrgreater thanConclusions less thanbrgreater than less thanbrgreater thanAllogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis.
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| 9. |
- Kozlowski, Piotr, 1969-, et al.
(author)
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High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden
- 2014
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In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 92:5, s. 377-381
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Journal article (peer-reviewed)abstract
- Background Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first-line therapy in patients with T-cell ALL (T-ALL). Patients and methods Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol. Results The median age was 32yr (range 18-72yr). Complete remission (CR) was obtained in 17 of 19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two- and 5-yr leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two- and 5-yr overall survival (OS) in whole cohort was 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-yr LFS for 15 patients who did not receive allogeneic SCT upfront were 20% (95% CI: 0-40), although 14 of 15 completed the protocol (eight cycles). Relapse occurred in 2 of 4 upfront-transplanted patients and in 12 of 15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age >= 35yr influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7). Conclusions Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden.
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