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2.
Ann Hematol ; 102(1): 99-106, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36409328

ABSTRACT

The prognostic impact of monocytosis has not yet been determined in patients with myelodysplastic syndromes (MDS). We examined absolute monocyte counts in the peripheral blood at the time of diagnosis in 1949 patients with a bone marrow blast count < 5%, a condition we call MDS < EB1 (MDS with a blast percentage lower than that of MDS with excess blasts 1, according to the WHO classification). Monocytosis (> 600/µl) was associated with higher median hemoglobin, WBC, and ANC, and more favorable karyotype (p = .001). Nevertheless, monocytosis was associated with shorter overall survival (OS) (108 vs. 126 months, p = .002) and earlier transformation into AML (p < .001). In patients with sideroblastic phenotype, the percentage of ring sideroblasts significantly correlated with the monocyte count (p = .005), and OS was significantly shorter when monocytosis was documented (88 vs. 132 months, p = .004). The survival disadvantage of patients with MDS < EB1 and peripheral blood monocytosis suggests that these patients suffer from a CMML-like disease. Even though they are generally classified as MDS with persistent monocytosis, such patients should be considered candidates for therapeutic options employed in CMML.


Subject(s)
Bone Marrow , Myelodysplastic Syndromes , Humans , Prognosis , Myelodysplastic Syndromes/therapy , Myelodysplastic Syndromes/drug therapy , Leukocytosis , Leukocyte Count
3.
Mol Ther Oncolytics ; 26: 120-134, 2022 Sep 15.
Article in English | MEDLINE | ID: mdl-35795096

ABSTRACT

Chimeric antigen receptor (CAR) T cell therapy has demonstrated unprecedented success with high remission rates for heavily pretreated patients with hematological malignancies. The hinge connecting the extracellular antigen recognition unit to the transmembrane domain provides the length and flexibility of the CAR constructs and ensures that the CAR can reach the target antigen and mediate recognition and killing of target cells. The hinge can also include specific amino acid sequences to improve CAR expression, influence T cell proliferation, and facilitate CAR T cell detection, enrichment, and even elimination. Here, we report the generation of two novel hinge domains derived from the low-affinity p75 chain of the human nerve growth factor receptor (NGFR), termed N3 and N4, which, when incorporated into the CAR backbone, allow detection as well as high-grade enrichment of CAR T cells with GMP-compatible immunomagnetic reagents. After optimizing the MACS protocol for excellent CAR T cell purity and yield, we demonstrated that N3- and N4-hinged CAR T cells are as efficacious as their CD8-hinged counterparts in vitro against hematological blasts and also in vivo in the control of acute monocytic leukemia in an immunodeficient mouse xenograft model. Thus, both hinges could potentially be an integral part of future CAR designs and universally applicable in clinical applications.

4.
Ann Hematol ; 101(5): 1031-1038, 2022 May.
Article in English | MEDLINE | ID: mdl-35262868

ABSTRACT

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (both p < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1-99) and tMDS (13 months; range 0-160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0-345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.


Subject(s)
Leukemia, Myeloid, Acute , Multiple Myeloma , Myelodysplastic Syndromes , Neoplasms, Second Primary , Humans , Karyotyping , Leukemia, Myeloid, Acute/chemically induced , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Multiple Myeloma/complications , Multiple Myeloma/therapy , Myelodysplastic Syndromes/chemically induced , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/therapy , Neoplasms, Second Primary/etiology
5.
Ann Hematol ; 100(2): 455-463, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33159566

ABSTRACT

The European Leukemia Net (ELN) guidelines for treatment of myelodysplastic syndromes (MDS) connect heterogeneous MDS subgroups with a number of therapeutic options ranging from best supportive care to allogeneic stem cell transplantation (alloSCT). However, it is currently unknown whether adherence to guideline recommendations translates into improved survival. The sizeable database of the Duesseldorf MDS Registry allowed us to address this question. We first performed a retrospective analysis including 1698 patients (cohort 1) to whom we retrospectively applied the ELN guidelines. We compared patients treated according to the guidelines with patients who deviated from it, either because they received a certain treatment though it was not recommended or because they did not receive that treatment despite being eligible. We also performed a prospective study with 381 patients (cohort 2) who were seen in our department and received guideline-based expert advice. Again, we compared the impact of subsequent guideline-adherent versus non-adherent treatment. For the majority of treatment options (best supportive care, lenalidomide, hypomethylating agents, low-dose chemotherapy, and intensive chemotherapy), we found that adherence to the ELN guidelines did not improve survival in cohort 1. The same was true when patient management was prospectively enhanced through guideline-based treatment advice given by MDS experts (cohort 2). The only exceptions were alloSCT and iron chelation (ICT). Patients receiving ICT and alloSCT as recommended fared significantly better than those who were eligible but received other treatment. Our analysis underscores the limited survival impact of most MDS therapies and suggests to pursue alloSCT in all suitable candidates. Graphical abstract.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Databases, Factual , Guideline Adherence , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Female , Humans , Male , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Prospective Studies , Retrospective Studies , Survival Rate , Transplantation, Homologous
6.
Leuk Res ; 72: 27-33, 2018 09.
Article in English | MEDLINE | ID: mdl-30075323

ABSTRACT

The IPSS-R proved to be a powerful tool for the assessment of prognosis in MDS patients. We aimed at a validation of the IPSS-R for patients with MDS harboring deletion (5q) isolated or accompanied by additional aberrations. The study was based on 444 MDS patients from MDS centers in Europe. 67% of the patients were female, median age was 69 years. 43.5% had MDS del(5q), 5.9% were diagnosed with RCUD, 2.0% RARS, 18.4% RCMD, 14.6% RAEB-I and 15.5% RAEB-II. According to the IPSS-R, there were 9.9% very low, 39.6% low, 16.6% intermediate, 12.8% high, 20.9% very high risk patients. For very low risk patients survival was 7.5 years, low 9.0 years, intermediate 6.5 years, high 1.5 years and very high 0.7 years (p < 0.001). For low and intermediate risk, the probability of AML evolution was significantly different (p = 0.03) as well as for high versus very high risk groups (p = 0.002). The IPSS-R proved to be an appropriate prognostic tool for MDS with del(5q).


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Risk Factors , Survival Rate
7.
Leuk Res ; 65: 1-4, 2018 02.
Article in English | MEDLINE | ID: mdl-29216536

ABSTRACT

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/µl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/µl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p=n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population.


Subject(s)
Bone Marrow/pathology , Leukemia, Myelomonocytic, Chronic/genetics , Leukemia, Myelomonocytic, Chronic/pathology , Monocytes/pathology , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Bone Marrow/enzymology , Carrier Proteins/genetics , Cell Proliferation , Core Binding Factor Alpha 2 Subunit/genetics , DNA-Binding Proteins/genetics , Dioxygenases , Esterases/metabolism , Female , Genes, ras , Genetic Testing , Humans , Male , Middle Aged , Monocytes/enzymology , Mutation , Mutation Rate , Nuclear Proteins/genetics , Prognosis , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Serine-Arginine Splicing Factors/genetics
8.
Leukemia ; 31(7): 1525-1531, 2017 07.
Article in English | MEDLINE | ID: mdl-28218239

ABSTRACT

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/psychology , Male , Middle Aged , Pyrimidines/adverse effects , Quality of Life
9.
Leukemia ; 31(4): 889-895, 2017 04.
Article in English | MEDLINE | ID: mdl-27774990

ABSTRACT

Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms. Pomalidomide, an immune-modifying drug, is reported to improve anaemia and thrombocytopenia in some patients with MPN-associated myelofibrosis. We designed a phase 2 study of pomalidomide in patients with MPN-associated myelofibrosis and anaemia and/or thrombocytopenia and/or neutropenia. Subjects received pomalidomide 2.0 mg/day in cohort 1 (n=38) or 0.5 mg/day in cohort 2 (n=58). Prednisolone was added if there was no response after 3 months in cohort 1 and based on up-front randomization in cohort 2 if there was no response at 3 or 6 months. Response rates were 39% (95% confidence interval (CI), 26-55%) in cohort 1 and 24% (95% CI, 15-37%) in cohort 2. In a multivariable logistic regression model pomalidomide at 2.0 mg/day (odds ratio (OR), 2.62; 95% CI, 1.00-6.87; P=0.05) and mutated TET2 (OR, 5.07; 95% CI, 1.16-22.17; P=0.03) were significantly associated with responses. Median duration of responses was 13.0 months (range 0.9-52.7). There was no significant difference in response rates or duration in subjects receiving or not receiving prednisolone. Clinical trial MPNSG 01-09 is registered at ClinicalTrials.gov (NCT00949364) and clinicaltrialsregister.eu (EudraCT Number: 2009-010738-23).


Subject(s)
Immunologic Factors/therapeutic use , Myeloproliferative Disorders/complications , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/etiology , Thalidomide/analogs & derivatives , Aged , Aged, 80 and over , Alleles , Biomarkers , Chromosome Banding , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Male , Middle Aged , Mutation , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Phenotype , Prednisolone/administration & dosage , Prednisolone/adverse effects , Prednisolone/therapeutic use , Primary Myelofibrosis/diagnosis , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/therapeutic use , Treatment Outcome
10.
Ann Hematol ; 95(9): 1399-410, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27334946

ABSTRACT

Philadelphia-negative myeloproliferative neoplasms (MPN) comprise a heterogeneous group of chronic hematological malignancies with significant variations in clinical characteristics. Due to the long survival and the feasibility of oral or subcutaneous therapy, these patients are frequently treated outside of larger academic centers. This analysis was performed to elucidate differences in MPN patients in three different health care settings: university hospitals (UH), community hospitals (CH), and office-based physicians (OBP). The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences were used. Besides a different distribution of MPN subtypes between the settings, patients contributed by UH showed an impaired medical condition, a higher comorbidity burden, and more vascular complications. In the risk group analyses, the majority of polycythemia vera (PV) and essential thrombocythemia (ET) patients from UH were classified into the high-risk category due to previous vascular events, while for PV and ET patients in the CH and OBP settings, age was the major parameter for a high-risk categorization. Regarding MPN-directed therapy, PV patients from the UH setting were more likely to receive ruxolitinib within the framework of a clinical trial. In summary, the characteristics and management of patients differed significantly between the three health care settings with a higher burden of vascular events and comorbidities in patients contributed by UH. These differences need to be taken into account for further analyses and design of clinical trials.


Subject(s)
Delivery of Health Care/statistics & numerical data , Myeloproliferative Disorders/therapy , Severity of Illness Index , Symptom Assessment/statistics & numerical data , Aged , Aged, 80 and over , Chi-Square Distribution , Delivery of Health Care/methods , Female , Hospitals, Community/statistics & numerical data , Hospitals, University/statistics & numerical data , Humans , Male , Middle Aged , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/genetics , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Philadelphia Chromosome , Physicians/statistics & numerical data , Physicians' Offices/statistics & numerical data , Prospective Studies , Registries/statistics & numerical data , Risk Factors , Symptom Assessment/methods
11.
J Hematol Oncol ; 9: 18, 2016 Mar 05.
Article in English | MEDLINE | ID: mdl-26944254

ABSTRACT

BACKGROUND: Patients with Ph-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices) are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN. METHODS: The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events. RESULTS: MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length). While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95% CI = 1.39-8.48) and splenomegaly (OR 1.76; 95% CI = 1.15-2.71). Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95% CI = 1.36-5.40), splenomegaly (OR = 2.22; 95% CI 1.01-4.89), and the administration of heparin (OR = 5.64; 95% CI = 1.84-17.34). Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups. CONCLUSIONS: Together, this report on an unselected "real-world" cohort of German MPN patients reveals important data on the prevalence, diagnosis, and treatment of thromboembolic and major bleeding complications of MPN.


Subject(s)
Blood Coagulation/physiology , Hemorrhage/physiopathology , Myeloproliferative Disorders/physiopathology , Registries/statistics & numerical data , Thrombosis/physiopathology , Adult , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Female , Germany/epidemiology , Hemorrhage/diagnosis , Hemorrhage/prevention & control , Humans , Logistic Models , Male , Middle Aged , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/epidemiology , Prevalence , Prospective Studies , Splenomegaly/diagnosis , Splenomegaly/physiopathology , Thrombosis/diagnosis , Thrombosis/prevention & control
13.
Leuk Res ; 38(12): 1413-9, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25444076

ABSTRACT

Since 2001, chronic myelomonocytic leukemia (CMML) is classified by the WHO as myeloproliferative/myelodysplastic neoplasm. Herein we tried to better describe CMML patients with regard to hematological characteristics and prognosis using data of the Duesseldorf registry. We created 6 CMML subgroups, by dividing dysplastic and proliferative CMML at the cut-off of white blood cell count of 13,000/µL and splitting these two groups into 3 subgroups: CMML 0 with <5% blasts (n=101), CMML I with 5-9% blasts (n=204) and CMML II with 10-19% blasts (n=81). For comparison we included patients with RCMD, RAEB I and II. The newly created CMML 0 group had better prognosis than CMML I and II, median survival times were 31 months (ms), 19ms and 13ms, respectively (p<0.001). Median survival times between the corresponding dysplastic and proliferative subgroups 0 and 1 differed significantly: CMML 0 dysplastic 48ms and CMML 0 proliferative 17ms (p=0.03), CMML I dysplastic 29ms and CMML I proliferative 15ms (p=0.008), CMML II dysplastic 17ms and CMML II proliferative 10ms (p=0.09). Outcome of CMML patients worsens with increasing medullary blasts and when presenting as proliferative type. Therefore it is justified to separate CMML with <5% medullary blasts.


Subject(s)
Blast Crisis , Cell Proliferation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Blast Crisis/blood , Blast Crisis/classification , Blast Crisis/mortality , Disease-Free Survival , Female , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/classification , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Leukocyte Count , Male , Retrospective Studies , Survival Rate
15.
Leukemia ; 27(9): 1841-51, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23797473

ABSTRACT

Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.


Subject(s)
Mesenchymal Stem Cells/metabolism , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cell Differentiation , Cell Proliferation , Cellular Senescence , Cluster Analysis , Colony-Forming Units Assay , DNA Methylation , Epigenesis, Genetic , Female , Gene Expression Profiling , Humans , Immunophenotyping , Male , Mesenchymal Stem Cells/cytology , Middle Aged , Osteogenesis/genetics , Phenotype
16.
Leukemia ; 27(1): 107-12, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22763385

ABSTRACT

Nilotinib (Tasigna) is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after imatinib resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to imatinib.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Leukemia, Myeloid, Chronic-Phase/drug therapy , Piperazines/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Salvage Therapy , Adolescent , Adult , Aged , Aged, 80 and over , Benzamides , Female , Follow-Up Studies , Humans , Imatinib Mesylate , International Agencies , Leukemia, Myeloid, Chronic-Phase/mortality , Male , Maximum Tolerated Dose , Middle Aged , Prognosis , Survival Rate , Young Adult
17.
Ann Hematol ; 92(2): 191-8, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23073603

ABSTRACT

The majority of patients with myelodysplastic syndrome (MDS) present with anemia and will become dependent on regular transfusions of packed red blood cells (PRBC) with the risk of iron overload (IOL). Liver iron content best reflects the total body iron content, and measurement of liver iron concentration (LIC) by MRI is a validated tool for detection, but data in MDS is rather limited. Here we present the results of a multi-center trial evaluating the efficacy and safety of deferasirox (DFX) in low and intermediate-1 risk MDS patients with transfusion-dependent IOL. Three patients with transfusion frequency of > 4 units PRBC per month were initially treated with 30 mg/kg/day while in 46 patients with a lower transfusion burden deferasirox was initiated at 20 mg/kg/day, due to patient related reasons one patient received DFX in a dose of 6 mg/kg/day only. LIC was measured by MRI at baseline and end of study using the method by St. Pierre et al. The intention to treat population consisted of 50 MDS patients (28 male; 22 female) with a median age of 69 years who were treated with DFX for a median duration of 354 days. Mean daily dose of DFX was 19 mg/kg/day. Median serum ferritin level (SF) at baseline was 2,447 ng/mL and decreased to 1,685 ng/mL (reduction by 31 %) at end of study (p = 0.01). In 7 (13 %) patients the initially chosen dose had to be increased due to unsatisfactory efficacy of chelation therapy. For 21 patients, LIC measurement by liver MRI was performed at baseline and for 19 of these patients at the end of study: mean LIC decreased significantly from 16,8 mg/g dry tissue weight (± 8.3 mg/g dry tissue weight) at study entry to 10,8 mg/g dry tissue weight (± 10.4 mg/g dry tissue weight) at end of study (p = 0.01). Of all patients exposed to the study drug (n = 54), 28 (52 %) did not complete the 12 month study period most commonly due to AEs in 28 % (n = 15) and abnormal laboratory values in 7 % (n = 4), respectively. The most common adverse events (≥ 10 % of all patients) with suspected drug relationship were diarrhea (n = 25, 46 %), nausea (n = 13, 24 %), upper abdominal pain (n = 8, 15 %), serum creatinine increase (n = 16, 30 %) and rash (n = 5, 9 %). Adverse events making dose adjustments or interruption of study drug necessary occurred in 33 patients (61 %). Hematologic improvement according to IWG criteria (2006) was observed in 6 patients (11 %). Initiation of treatment of IOL with DFX depending on the transfusion burden yields sufficient reduction of excess iron indicated by serum ferritin levels and most importantly by liver MRI. The safety profile of DFX was comparable to previous observations.


Subject(s)
Benzoates/therapeutic use , Chelation Therapy , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Myelodysplastic Syndromes/therapy , Transfusion Reaction , Triazoles/therapeutic use , Administration, Oral , Adult , Aged , Aged, 80 and over , Benzoates/administration & dosage , Benzoates/adverse effects , Chelation Therapy/adverse effects , Creatinine/blood , Deferasirox , Drug Eruptions/etiology , Female , Ferritins/blood , Gastrointestinal Diseases/chemically induced , Humans , Iron/analysis , Iron Chelating Agents/administration & dosage , Iron Chelating Agents/adverse effects , Iron Overload/etiology , Liver/chemistry , Magnetic Resonance Imaging , Male , Middle Aged , Myelodysplastic Syndromes/epidemiology , Risk , Treatment Outcome , Triazoles/administration & dosage , Triazoles/adverse effects
18.
Leukemia ; 27(4): 907-13, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23174881

ABSTRACT

The purpose was to assess predictive factors for outcome in patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP) treated with nilotinib after imatinib failure. Imatinib-resistant and -intolerant patients with CML-CP (n=321) were treated with nilotinib 400 mg twice daily. Of 19 baseline patient and disease characteristics and two response end points analyzed, 10 independent prognostic factors were associated with progression-free survival (PFS). In the multivariate analysis, major cytogenetic response (MCyR) within 12 months, baseline hemoglobin ≥ 120 g/l, baseline basophils <4%, and absence of baseline mutations with low sensitivity to nilotinib were associated with PFS. A prognostic score was created to stratify patients into five groups (best group: 0 of 3 unfavorable risk factors and MCyR by 12 months; worst group: 3 of 3 unfavorable risk factors and no MCyR by 12 months). Estimated 24-month PFS rates were 90%, 79%, 67% and 37% for patients with prognostic scores of 0, 1, 2 and 3, respectively, (no patients with score of 4). Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Aged, 80 and over , Drug Resistance, Neoplasm , Female , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/physiopathology , Male , Middle Aged , Multivariate Analysis , Prognosis , Young Adult
20.
Eur J Med Res ; 16(10): 437-44, 2011 Oct 10.
Article in English | MEDLINE | ID: mdl-22024422

ABSTRACT

Patients with ESCC (squamous cell carcinoma of the esophagus) are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.


Subject(s)
Carcinoma, Squamous Cell/therapy , Esophageal Neoplasms/therapy , Esophagectomy , Neoadjuvant Therapy , Carcinoma, Squamous Cell/pathology , Chemotherapy, Adjuvant , Combined Modality Therapy , Esophageal Neoplasms/pathology , Humans , Meta-Analysis as Topic , Neoplasm Staging , Radiotherapy, Adjuvant , Standard of Care , Survival Rate , Treatment Outcome
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