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 CountABSTRACT
In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.
Subject(s)
Biomarkers, Tumor/analysis , Myelodysplastic Syndromes/classification , Myelodysplastic Syndromes/diagnosis , Neoplasms, Second Primary/classification , Neoplasms, Second Primary/diagnosis , Risk Assessment/methods , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Neoplasms, Second Primary/therapy , Prognosis , Retrospective Studies , Survival RateABSTRACT
The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for "hematological improvement" criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between "procedures" and "criteria" for hematologic improvement-erythroid assessment and a new categorization of transfusion-burden subgroups.
Subject(s)
Clinical Trials as Topic/standards , Hematology/methods , Hematology/standards , Myelodysplastic Syndromes/therapy , Blood Transfusion , Cell Lineage , Disease Progression , Erythrocyte Transfusion , Erythrocytes/cytology , Humans , International Cooperation , Leukocyte Count , Neutrophils , Platelet Count , Practice Guidelines as Topic , Quality of Life , Recurrence , Risk Reduction Behavior , Societies, Medical , Treatment OutcomeABSTRACT
BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Leukemia, Myeloid, Acute/therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Stem Cell Transplantation/adverse effects , Tandem Repeat Sequences , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Antineoplastic Agents/adverse effects , Disease Progression , Disease-Free Survival , Female , Germany , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Niacinamide/adverse effects , Niacinamide/therapeutic use , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Recurrence , Remission Induction , Retrospective Studies , Risk Factors , Sorafenib , Time Factors , Transplantation, Homologous , Treatment Outcome , Young AdultSubject(s)
Immunologic Factors/therapeutic use , Mutation , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Thalidomide/analogs & derivatives , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Female , Humans , Lenalidomide , Male , Middle Aged , Prevalence , Prospective Studies , Thalidomide/therapeutic useABSTRACT
We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Adult , Aminoglutethimide/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/therapeutic use , Danazol/therapeutic use , Disease-Free Survival , Granulocyte Colony-Stimulating Factor , Humans , Induction Chemotherapy , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Middle Aged , Mitoxantrone/therapeutic use , Stem Cell Transplantation , Survival Rate , Tamoxifen/therapeutic use , Transplantation, Autologous , Treatment Outcome , Young AdultSubject(s)
Immunologic Factors/therapeutic use , Myelodysplastic Syndromes/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Female , Humans , Kaplan-Meier Estimate , Lenalidomide , Male , Middle Aged , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Proportional Hazards Models , Prospective Studies , Thalidomide/therapeutic use , Treatment OutcomeABSTRACT
DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/therapeutic use , Induction Chemotherapy/methods , Leukemia, Myeloid, Acute/drug therapy , Aged , Cytarabine/therapeutic use , Cytogenetic Analysis , Daunorubicin/therapeutic use , Female , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Remission Induction , Survival AnalysisSubject(s)
Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/complications , Platelet Count , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Thrombocytopenia/drug therapy , Thrombocytopenia/etiology , Thrombopoietin/therapeutic use , Humans , Myelodysplastic Syndromes/mortality , Thrombocytopenia/mortality , Treatment OutcomeABSTRACT
Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) ≥ 8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI ≥ 8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI ≥ 8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI ≥ 8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression.
Subject(s)
Chromosome Deletion , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/genetics , Survival Analysis , Thalidomide/analogs & derivatives , Aged , Disease Progression , Erythrocyte Transfusion , Female , Humans , Lenalidomide , Leukemia, Myeloid, Acute/pathology , Male , Thalidomide/therapeutic useSubject(s)
Blood Transfusion , Erythropoietin/therapeutic use , Hydroxamic Acids/therapeutic use , Indoles/therapeutic use , Myelodysplastic Syndromes/drug therapy , Administration, Oral , Erythropoietin/administration & dosage , Humans , Hydroxamic Acids/administration & dosage , Indoles/administration & dosage , PanobinostatABSTRACT
Monosomal karyotype (MK) is associated with an adverse prognosis in patients in acute myeloid leukemia (AML). This study analyzes the prognostic impact of MK in a cohort of primary, untreated patients with myelodysplastic syndromes (MDS). A total of 431 patients were extracted from an international database. To analyze whether MK is an independent prognostic marker in MDS, cytogenetic and clinical data were explored in uni- and multivariate models regarding overall survival (OS) as well as AML-free survival. In all, 204/431 (47.3%) patients with MK were identified. Regarding OS, MK was prognostically significant in patients with ≤ 4 abnormalities only. In highly complex karyotypes (≥ 5 abnormalities), MK did not separate prognostic subgroups (median OS 4.9 months in MK+ vs 5.6 months in patients without MK, P=0.832). Based on the number of abnormalities, MK-positive karyotypes (MK+) split into different prognostic subgroups (MK+ and 2 abnormalities: OS 13.4 months, MK+ and 3 abnormalities: 8.0 months, MK+ and 4 abnormalities: 7.9 months and MK+ and ≥ 5 abnormalities: 4.9 months; P<0.01). In multivariate analyses, MK was not an independent prognostic factor. Our data support the hypothesis that a high number of complex abnormalities, associated with an instable clone, define the subgroup with the worst prognosis in MDS, independent of MK.
Subject(s)
Chromosome Aberrations , Monosomy/genetics , Myelodysplastic Syndromes/mortality , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Follow-Up Studies , Humans , Karyotyping , Male , Middle Aged , Multivariate Analysis , Myelodysplastic Syndromes/classification , Myelodysplastic Syndromes/genetics , Prognosis , Survival Rate , Young AdultABSTRACT
The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells. The transformation rate to acute myeloid leukemia reaches 30-40 %. In early phases of the disease, the clonal cells have a growth advantage but suffer from premature apoptosis, which explains the paradox of a cellular bone marrow coupled to peripheral blood cytopenias. At later stages, additional genetic aberrations accumulate and lead to proliferation with leukemic transformation. Patients with early MDS benefit from supportive therapy or growth factors. Sometimes, immunological or immunomodulatory treatments can suppress the malignant clone and strengthen normal hematopoiesis for sustained periods. Patients with advanced MDS are usually treated with cytotoxic therapy followed by allogeneic stem cell transplantation or with epigenetic therapy to initiate differentiation and slow down proliferation.
Subject(s)
Cell Transformation, Neoplastic/pathology , Hematopoietic Stem Cells/pathology , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/prevention & control , Neoplastic Stem Cells/pathology , Precancerous Conditions/diagnosis , Precancerous Conditions/therapy , HumansABSTRACT
The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461-888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT.