ABSTRACT
Measurable residual disease (MRD) is a powerful predictor of outcome in acute myeloid leukemia. In the early phases of treatment, MRD refines initial disease risk stratification and is used for the allocation to allogeneic transplant. Despite its well-established role, a relatively high fraction of patients eventually relapses albeit achieving MRDneg status. The aim of this work was to assess specifically the influence of baseline features and treatment intensity on the predictive value of an MRDneg status, particularly focusing on MRD2, measured after two consecutive chemotherapy cycles. Among baseline features, younger MRD2neg patients (<55 years) had a significantly longer disease-free survival (median not reached) compared to their older counterparts (median 25.0 months, P=0.013, hazard ratio=2.08). Treatment intensity, specifically the delivery of a high dose of cytarabine in induction or first consolidation, apparently had a pejorative effect on the outcome of MRD2neg patients compared to standard dose (P=0.048, hazard ratio=1.80), a finding also confirmed by the analysis of data extracted from the literature. The combination of age and treatment intensity allowed us to identify categories of patients, among those who reached a MRD2neg status, characterized by significantly different disease-free survival rate. Our data showed that variables such as age and intensity of treatment administered can influence the predictive value of MRD in patients with acute myeloid leukemia. In addition to underscoring the need for further improvement of MRD analysis, these findings call for a reasoned application of MRD data, as currently available, to modulate consolidation therapy on adequately estimated relapse rates.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adult , Humans , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/drug therapy , Recurrence , Transplantation, Homologous , Disease-Free Survival , Chronic Disease , Neoplasm, Residual/drug therapy , Hematopoietic Stem Cell Transplantation/adverse effects , PrognosisABSTRACT
Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).
Subject(s)
Leukemia, Myeloid, Acute , Myeloproliferative Disorders , Aged , Chromatin/genetics , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/epidemiology , Leukemia, Myeloid, Acute/genetics , Prognosis , Prospective Studies , SpliceosomesABSTRACT
AMELIORATE is a Phase III, randomized trial aiming to personalize treatment intensity in FLT3-mutated acute myeloid leukemia. The current study provides an early appraisal of chemosensitivity based on peripheral blasts clearance, as assessed by multiparameter flow cytometry, from baseline to day 4 of induction. This biomarker was previously demonstrated to predict complete remission achievement and measurable residual disease status. For patients experiencing low peripheral blast cells (i.e., ≤2.0 logs), two major adjustments of treatment as compared with current standard of care are envisioned in the experimental arm: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m2 b.i.d. on days 5-7 of induction); and the early allocation of the patient to high-risk disease category, to be further refined later based on postinduction measurable residual disease status.
Lay abstract The initial treatment of acute myeloid leukemia is called induction and aims to reduce significantly the number of leukemic cells in the bone marrow. In young adults, this phase comprises several agents, including conventional chemotherapy, monoclonal antibodies, and targeted drugs. Conventionally, induction is delivered as a single block of therapy, the response to which can be appreciated 34 weeks after its completion. The authors previously showed that the response to induction can be anticipated by the speed of disappearance of leukemic cells from peripheral blood after four days of therapy. In the AMELIORATE study, the authors aim to personalize the intensity of treatment based on this biomarker, by early intensification of treatment in patients who are predicted to have a poor response.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , fms-Like Tyrosine Kinase 3/genetics , Female , Humans , Male , Middle Aged , Mutation , Neoplasm, Residual , Precision Medicine , Prospective Studies , Remission Induction , Risk AssessmentABSTRACT
Minimal residual disease (MRD) assessment in acute myeloid leukemia (AML) is increasingly used in risk stratification. However, several issues around this use are unresolved, including, among others, the most suitable time-point(s) for its application. Overall, late assessments appear more effective at distinguishing outcome but, in some studies, the early evaluations were already highly informative, anticipating the value of later ones. Our work integrated MRD with peripheral blast clearance (PBC), a treatment-related biomarker previously demonstrated to be a powerful predictor of response. From 2007 to 2014, we have studied 120 patients treated according to the NILG 02-06 trial and who achieved CR after induction. Patients in PBC-defined categories (separated by a 1.5-log threshold) showed significantly different probabilities of attaining MRD negativity, after either induction (MRD1) or consolidation (MRD2). Peripheral blast clearance combined with MRD1 largely anticipated MRD2-related information: when both biomarkers predicted chemosensitive disease (PBChigh /MRD1neg ), the rate of MRD2-negativity was 90%, and DFS and OS estimates were 68% and 76% at 3 years, respectively. When both markers were unfavorable (PBClow /MRD1pos ), rates of MRD2 negativity, DFS, and OS were 20%, 34%, and 24%, respectively, at 3 years. In fact, MRD2 added prognostic value only in cases with discordant PBC/MRD1 data. Our data support a reasoned timing for MRD-based therapeutic decisions, modulated on individual chemosensitivity, an approach we have implemented in a forthcoming prospective multi-center trial by Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA).
Subject(s)
Biomarkers, Tumor/blood , Blast Crisis , Leukemia, Myeloid, Acute , Adolescent , Adult , Aged , Blast Crisis/blood , Blast Crisis/mortality , Blast Crisis/therapy , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Neoplasm, Residual , Survival RateABSTRACT
BACKGROUND: The Mediterranean area is endemic for the zoonotic form of visceral leishmaniasis (VL) caused by Leishmania infantum, a species which has been recently associated with unexpected epidemiological and clinical features. METHOD: We report the result of a systematic review of the literature on VL unusually presenting with spleen focal lesions, including three previously unpublished cases. RESULTS: A total of 28 cases of VL with multiple spleen focal lesions were retrieved. Twenty-six (93%) were acquired in the Mediterranean area, where L. infantum is endemic. Thirteen cases were diagnosed in children, and the remaining 15 cases in middle-aged adults, of whom 9 were immunosuppressed. Four patients (14%) underwent diagnostic splenectomy, while the diagnosis was confirmed by less invasive techniques in the remaining patients. The most common radiological patterns were: multiple subcentimetric or centimetric spleen lesions (size ≤ 1 cm in 14 of 19 cases, 74%), hypoechoic at ultrasonography (25 of 26 cases, 99%) and hypodense at CT scan (9 of 10 cases, 90%). PET-CT (available for four patients) showed an intense FDG spleen uptake. MRI and contrast-enhanced ultrasonography, available for two and one cases each, showed complex patterns. CONCLUSIONS: VL must be added to the list of possible differential diagnosis of spleen focal lesions and health care provider awareness about this condition will avoid unnecessary invasive diagnostic procedures.
Subject(s)
Leishmaniasis, Visceral/pathology , Neglected Diseases/pathology , Spleen/pathology , Splenic Diseases/pathology , Adult , Diagnosis, Differential , Humans , Italy , Leishmaniasis, Visceral/diagnostic imaging , Male , Middle Aged , Neglected Diseases/diagnostic imaging , Spleen/diagnostic imaging , Splenic Diseases/diagnostic imagingABSTRACT
Mutations in CCAAT/enhancer binding protein α (CEBPA) occur in 5-10% of cases of acute myeloid leukemia. CEBPA-double-mutated cases usually bear biallelic N- and C-terminal mutations and are associated with a favorable clinical outcome. Identification of CEBPA mutants is challenging because of the variety of mutations, intrinsic characteristics of the gene and technical issues. Several screening methods (fragment-length analysis, gene expression array) have been proposed especially for large-scale clinical use; although efficient, they are limited by specific concerns. We investigated the phenotypic profile of blast and maturing bone marrow cell compartments at diagnosis in 251 cases of acute myeloid leukemia. In this cohort, 16 (6.4%) patients had two CEBPA mutations, whereas ten (4.0%) had a single mutation. First, we highlighted that the CEBPA-double-mutated subset displays recurrent phenotypic abnormalities in all cell compartments. By mutational analysis after cell sorting, we demonstrated that this common phenotypic signature depends on CEBPA-double-mutated multi-lineage involvement. From a multidimensional study of phenotypic data, we developed a classifier including ten core and widely available parameters. The selected markers on blasts (CD34, CD117, CD7, CD15, CD65), neutrophil (SSC, CD64), monocytic (CD14, CD64) and erythroid (CD117) compartments were able to cluster CEBPA-double-mutated cases. In a validation set of 259 AML cases from three independent centers, our classifier showed excellent performance with 100% specificity and 100% sensitivity. We have, therefore, established a reliable screening method, based upon multidimensional analysis of widely available phenotypic parameters. This method provides early results and is suitable for large-scale detection of CEBPA-double-mutated status, allowing gene sequencing to be focused in selected cases.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Mutation , Phenotype , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Bone Marrow/pathology , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cluster Analysis , Cytogenetic Analysis , DNA Mutational Analysis , Female , Genetic Association Studies , Genotype , Humans , Immunophenotyping , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Prognosis , Reproducibility of Results , Sensitivity and Specificity , Young AdultSubject(s)
Antimetabolites, Antineoplastic/administration & dosage , Azacitidine/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Dendritic Cells/drug effects , Neoplasm Recurrence, Local/drug therapy , Skin Neoplasms/drug therapy , Sulfonamides/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dendritic Cells/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Skin Neoplasms/diagnosis , Treatment OutcomeABSTRACT
We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0-1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤ 25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤ 60 years with performance score 0-1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Agents/administration & dosage , Burkitt Lymphoma/diagnosis , Burkitt Lymphoma/drug therapy , Leukemia/diagnosis , Leukemia/drug therapy , Adolescent , Adult , Aged , Burkitt Lymphoma/epidemiology , Drug Administration Schedule , Female , Follow-Up Studies , Germany/epidemiology , Humans , Italy/epidemiology , Leukemia/epidemiology , Male , Middle Aged , Prospective Studies , Remission Induction/methods , Rituximab , Survival Rate/trends , Young AdultABSTRACT
The prognostic significance of CD20 expression in acute lymphoblastic leukemia has been investigated in children and adults but is still a subject of debate. The aim of our study was to correlate CD20 expression with clinical-biological characteristics and outcome in 172 Philadelphia chromosome negative patients prospectively treated in a multicenter trial introducing the molecular evaluation of minimal residual disease for therapeutic purposes. We considered 20% as the threshold for CD20 positivity. Complete remission rate, minimal residual disease negativity rate at weeks 10, 16 and 22, and disease-free and overall survival were similar among CD20-positive and -negative patients, even considering minimal residual disease results and related therapeutic choices. Our study failed to demonstrate any prognostic significance for CD20 expression in Philadelphia chromosome negative acute lymphoblastic leukemia. This conclusion is supported for the first time by a comparable minimal residual disease response rate among CD20-positive and -negative and positive patients.
Subject(s)
Antigens, CD20/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Adult , Aged , Gene Expression , Humans , Middle Aged , Neoplasm, Residual , Philadelphia Chromosome , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
Clofarabine has been shown to be effective in AML patients, either as single agent or, mainly, in association with intermediate dose cytarabine. Based on these reports, we conducted a preliminary study combining clofarabine and intermediate dose cytarabine in AML patients who relapsed or failed to respond to at least two induction therapies. We treated 47 patients affected by relapsed/refractory AML with a regimen including clofarabine at 22.5 mg/m(2) daily on days 1-5, followed after 3 hr by cytarabine at 1 g/m(2) daily on days 1-5. Ten patients received a further consolidation cycle with clofarabine at 22.5 mg/m(2) and cytarabine at 1 g/m(2) day 1-4. Among the 47 patients, 24/47 (51%) achieved a complete remission, 5/47 (10.5%) a partial response, 10/47 (21%) had a resistant disease, and 6/47 (13%) died of complications during the aplastic phase. The most frequent nonhematologic adverse events were vomiting, diarrhea, transient liver toxicity, febrile neutropenia, and infections microbiologically documented. Among the 24 patients who obtained a CR 13 underwent allogeneic bone marrow transplantation. In 14 patients, complete remission duration was shorter than 12 months, whereas 10 patients experienced longer complete remission duration. These very preliminary results suggest that clofarabine-cytarabine regimen is effective in this particularly poor prognosis category of patients, representing a potential "bridge" toward bone marrow transplant procedures. Safety data were consistent with previously reported salvage therapies. Further studies and a longer follow up are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adenine Nucleotides/administration & dosage , Adenine Nucleotides/adverse effects , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Arabinonucleosides/administration & dosage , Arabinonucleosides/adverse effects , Clofarabine , Cytarabine/administration & dosage , Cytarabine/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Recurrence , Remission Induction , Treatment Outcome , Young AdultABSTRACT
Paroxysmal nocturnal haemoglobinuria (PNH) is a serious form of acquired haemolytic anaemia with several features that make it unique, including the fact that it is caused by clonal expansion, in the context of bone marrow failure, of a haematopoietic stem cell that has a somatic mutation in a gene crucial for the synthesis of glycosylphosphatidylinositol anchors; and that this also produces a life-threatening acquired thrombophilic state. Until recently, the two only main options for patients with PNH were either allogeneic bone marrow transplantation or supportive management, including blood transfusion: both options require some skill and good patient-doctor collaboration. Since the start of this millennium a major advance has been the introduction of eculizumab, a monoclonal antibody that targets the C5 protein of the complement system: blockade of C5 prevents activation of the complement distal pathway, and thus abrogates the complement-mediated intravascular haemolysis that severely plagues patients with PNH. This review outlines an approach to the management of all three major components of the clinical picture of PNH--namely haemolysis, thrombosis and bone marrow failure--based on the literature and on personal experience. We consider specifically how the use of eculizumab has modified other aspects of the management of PNH, and even the pathophysiology itself of this disease. Finally, we develop a treatment algorithm which others might find helpful.
Subject(s)
Hemoglobinuria, Paroxysmal/therapy , Anemia, Aplastic , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Anticoagulants/therapeutic use , Bone Marrow Diseases , Bone Marrow Failure Disorders , Bone Marrow Transplantation , Female , Hematopoietic Stem Cell Transplantation , Hemolysis , Humans , Pregnancy , Pregnancy Complications, Hematologic/drug therapy , Thrombolytic Therapy/methods , Thrombosis/drug therapyABSTRACT
In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59(-)). The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.
Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Complement C3/metabolism , Erythrocytes/metabolism , Hemoglobinuria, Paroxysmal/metabolism , Hemoglobinuria, Paroxysmal/therapy , Immunotherapy , Antibodies, Monoclonal, Humanized , Cell Survival , Erythrocytes/pathology , Female , Flow Cytometry , Hemoglobinuria, Paroxysmal/immunology , Humans , MaleABSTRACT
Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRD(neg)) or SCT (in MRD(pos)). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRD(neg), 54 MRD(pos), and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRD(neg) group compared with 0.33/0.14 in MRD(pos) (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10(-4) or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.
Subject(s)
Neoplasm, Residual/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Stem Cell Transplantation , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Prospective Studies , Risk Factors , Survival Rate , Translocation, Genetic , Transplantation Conditioning , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical need, owing to the lack of standardized, effective treatment approaches, resulting in an overall dismal outcome. The only curative option for R/R AML patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is only applicable in a fraction of patients due to the scarce efficacy and high toxicity of salvage regimens. Recently, a number of targeted agents with relatively favorable toxicity profiles have been explored in clinical trials for R/R AML patients. The Bcl-2 inhibitor venetoclax, in combination with hypomethylating agents or low dose cytarabine, has produced impressive results for newly diagnosed AML, while its role in R/R disease is not well defined yet. We retrospectively analyzed the clinical outcomes of 47 R/R AML patients treated with venetoclax-based regimens between March 2018 and December 2020 at our institution. Overall, we report a composite complete response rate of 55% with an overall acceptable toxicity profile. Outcomes were particularly favorable for NPM1 mutated patients, unlike for FLT3-ITD positive patients irrespective of NPM1 status. For patients treated with intention to transplant, the procedure could be finally performed in 54%. These findings suggest a role for venetoclax-based regimens in R/R AML patients and support the design of prospective studies.
ABSTRACT
We investigated the prognostic significance of early peripheral blast clearance as assessed by WT1 transcript reduction during the first days of standard induction therapy in 57 adult patients with acute myeloid leukemia (AML). Quantification of WT1 transcript by real-time quantitative PCR in peripheral blood on days 1 and 5 of treatment was performed. WT1 ratio was defined as the ratio of copy number measured on day 1 and on day 5. The median WT1 ratio was greater in patients attaining CR as compared to non-responders (11.68 vs. 2.14, respectively; P=0.0006). Furthermore, DFS and OS were significantly longer in patients displaying a WT1 ratio greater than 5.82 (i.e. the median value of whole cohort) than in patients with WT1 ratio of 5.82 or under (P=0.024 and P<0.001, respectively). These data suggest that early decrease of WT1 copy number in peripheral blood predicts for better outcome and should be considered in the management of AML patients.
Subject(s)
Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/drug therapy , Transcription, Genetic/physiology , WT1 Proteins/antagonists & inhibitors , WT1 Proteins/genetics , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/metabolism , Cytarabine/administration & dosage , Disease-Free Survival , Female , Genes, Wilms Tumor/drug effects , Genes, Wilms Tumor/physiology , Humans , Idarubicin/administration & dosage , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Predictive Value of Tests , Survival Rate/trends , Time Factors , Transcription, Genetic/drug effects , Treatment Outcome , WT1 Proteins/blood , Young AdultABSTRACT
Acute myeloid leukemia (AML) "with myelodysplasia-related changes (MRC)" is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.
ABSTRACT
Although genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov #NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP+ cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P < .0001). PBC < 1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC >1.5 (PBChigh, n = 96) and 43.6% of patients with PBC ≤1.5 (PBClow, n = 55) achieved CR after single-course induction (P < .0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P = .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy.
Subject(s)
Immunophenotyping/methods , Leukemia, Myeloid, Acute/immunology , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.
ABSTRACT
PURPOSE: We conducted a retrospective study to evaluate the efficacy and related costs of using two different molecules of granulocyte-colony stimulating factor (G-CSF) (lenograstim - LENO or filgrastim - FIL) as primary prophylaxis of chemotherapy-induced neutropenia in a hematological inpatient setting. METHODS: The primary endpoints of the analysis were the efficacy of the two G-CSFs in terms of the level of white blood cells, hemoglobin and platelets at the end of the treatment and the per capita direct medical costs related to G-CSF prophylaxis. RESULTS: Two hundred twelve patients (96 LENO, 116 FIL) have been evaluated. The following statistically significant differences have been observed between FIL and LENO: the use of a higher number of vials (11 vs 7; P<0.03) to fully recover bone marrow, a higher grade 3-4 neutropenia at the time of G-CSF discontinuation (29.3% vs 16.7%; P=0.031) and an increased number of days of hospitalization (8 vs 5; P<0.005). A longer hospital stay before discharge was necessary (12 vs 10), which reflects the higher final costs per patient (median treatment cost per cycle 10.706 for LENO, compared to 12.623 for FIL). CONCLUSION: The use of LENO has been associated with a lower number of days of hospitalization, number of vials and less incidence of grade 3-4 neutropenia at the time of G-CSF discontinuation. LENO seems to be cost-saving when compared with FIL (-15.2%).
ABSTRACT
Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.