ABSTRACT
Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Hematopoietic Stem Cell Transplantation/standards , Leukemia, Myeloid, Acute/therapy , Medical Oncology/standards , Age Factors , Aged , Antineoplastic Combined Chemotherapy Protocols/standards , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Cytogenetic Analysis/standards , Disease-Free Survival , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Histocompatibility Testing/standards , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Middle Aged , Remission Induction/methods , Risk Assessment/standards , Transplantation, Homologous/adverse effects , United StatesABSTRACT
We used next-generation sequencing (NGS) of the immunoglobulin genes to evaluate residual disease in 153 specimens from 32 patients with adult B cell acute lymphoblastic leukemia enrolled in a single multicenter study. The sequencing results were compared with multiparameter flow cytometry (MFC) data in 66 specimens (25 patients) analyzed by both methods. There was a strong concordance (82%) between the methods in the qualitative determination of the presence of disease. However, in 17% of cases, leukemia was detected by sequencing but not by MFC. In 54 bone marrow (BM) and peripheral blood (PB) paired specimens, the burden of leukemia detected by NGS was lower in PB than in BM, although it was still detectable in 68% of the 28 paired specimens with positive BM. Lastly, patients without disease detected by NGS or MFC had a 5-year relapse free survival of > 80%. The results suggest that residual disease detection by immunoglobulin gene sequencing is an extremely sensitive technique and may identify patients that might benefit from transplantation. Moreover, the increased sensitivity of the method may allow frequent peripheral blood testing to supplement marrow sampling to measure disease response.
Subject(s)
High-Throughput Nucleotide Sequencing/methods , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Adolescent , Adult , B-Lymphocytes/pathology , Bone Marrow/pathology , Flow Cytometry , Humans , Immunoglobulins/genetics , Middle Aged , Peripheral Blood Stem Cells/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Young AdultABSTRACT
Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis, TP53 alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in TP53 or in any other of the high-risk genes (EZH2, ETV6, RUNX1, ASXL1: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with de novo disease despite higher-risk features. While TP53 alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.
Subject(s)
Myelodysplastic Syndromes/therapy , Stem Cell Transplantation/methods , Tumor Suppressor Protein p53/genetics , Female , Humans , Male , Middle Aged , Mutation , Myelodysplastic Syndromes/chemically induced , Myelodysplastic Syndromes/mortality , Transplantation, HomologousABSTRACT
Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.
Subject(s)
Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Age Factors , Disease Management , HumansABSTRACT
The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches.
Subject(s)
Anemia/drug therapy , Hematinics/therapeutic use , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/therapy , Anemia/etiology , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Humans , Immunologic Factors/therapeutic use , Induction Chemotherapy/methods , Medical Oncology/standards , Mutation , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Survival RateABSTRACT
The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.
Subject(s)
Myelodysplastic Syndromes/diagnosis , Cost-Benefit Analysis , Disease Management , Genetic Testing , Humans , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , PrognosisABSTRACT
Two major prognostic factors for outcomes with acute myeloid leukemia (AML) therapy center on cytogenetic/molecular markers and patient age. With the paucity of novel agents available for the treatment of AML, clinicians are forced to fine-tune existing treatment strategies based on risk status to achieve the best results. Dr. Margaret R. O'Donnell of the City of Hope Cancer Center explored the prognostic implications of molecular mutations and other risk factors in the treatment of AML and presented an update of the current treatment strategies, sharing relevant clinical trial data on which recommendations are based. She also provided a glimpse of a novel non-chemotherapy approach to acute promyelocytic leukemia, which has had a major impact on treatment guidelines for this hematologic malignancy.
Subject(s)
Leukemia, Myeloid, Acute/therapy , Age Factors , Humans , Leukemia, Myeloid, Acute/diagnosis , Practice Guidelines as Topic , PrognosisABSTRACT
These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Promyelocytic, Acute/drug therapy , HumansABSTRACT
The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.
Subject(s)
Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/drug therapy , Anemia/etiology , Antineoplastic Agents/therapeutic use , Hematinics/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Immunologic Factors/therapeutic use , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/therapy , Prognosis , Transplantation, HomologousABSTRACT
Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ≥ 65 years) adult patients, and key supportive care considerations.
Subject(s)
Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Practice Guidelines as Topic , Adult , HumansABSTRACT
These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.
Subject(s)
Myelodysplastic Syndromes/therapy , Clinical Trials as Topic/standards , HumansABSTRACT
Acute lymphoblastic leukemia (ALL) with high-risk features has a poor prognosis in adults despite aggressive chemotherapy. Reduced-intensity conditioning (RIC) is a lower toxicity alternative for high-risk patients requiring hematopoietic cell transplantation (HCT); however, it has not been widely used for ALL. We conducted a retrospective study of 24 high-risk adult ALL patients who received an RIC regimen of fludarabine (Flu)/melphalan (Mel) prior to allogeneic peripheral blood stem cell transplantation (PBSCT) between 6/14/02 and 6/15/07 at the City of Hope. Indications for the RIC regimen were: (1) aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of a previous HCT (37.5%). Patients had a median age of 47.5 years and the median follow-up was 28.5 months for living patients. Both overall survival (OS) and disease-free survival (DFS) at 2 years was 61.5%. Relapse incidence was 21.1% and nonrelapse mortality (NRM) was 21.5% at 2 years. Chronic graft-versus-host (cGVHD) developed in 86% of evaluable patients. In this series, no significant correlations were made between outcomes and patient age, presence of Philadelphia chromosome, relatedness of donor source, or prior HCT. These high survival rates for high-risk ALL patients following RIC HCT may offer a promising option for patients not eligible for a standard myeloablative transplant.
Subject(s)
Melphalan/administration & dosage , Myeloablative Agonists/administration & dosage , Peripheral Blood Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzamides , Combined Modality Therapy , Dasatinib , Disease-Free Survival , Drug Administration Schedule , Female , Follow-Up Studies , Graft Survival , Graft vs Host Disease/epidemiology , Humans , Imatinib Mesylate , Male , Middle Aged , Neoplasms, Second Primary/drug therapy , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/surgery , Piperazines/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Pyrimidines/administration & dosage , Reoperation , Retrospective Studies , Risk , Thiazoles/administration & dosage , Transplantation, Homologous , Vidarabine/administration & dosage , Young AdultABSTRACT
The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force to critically review the evidence for iron chelation and the rationale for treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS). The task force was charged with addressing issues related to tissue iron toxicity; the role of MRI in assessing iron overload; the rationale and role of treating transfusional iron overload in patients with MDS; and the impact of iron overload on bone marrow transplantation. This report summarizes the background data and ensuing discussion from the NCCN Task Force meeting on transfusional iron overload in MDS.
Subject(s)
Iron Overload , Myelodysplastic Syndromes/therapy , Transfusion Reaction , Advisory Committees , Chelation Therapy , Humans , Iron Chelating Agents/therapeutic use , Iron Overload/etiology , Iron Overload/pathology , Iron Overload/therapy , Magnetic Resonance Imaging , Myelodysplastic Syndromes/drug therapy , ThalassemiaSubject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Aged , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab , Female , Humans , Male , Middle Aged , Recurrence , Thalidomide/administration & dosage , Treatment Outcome , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVES: Pulmonary invasive fungal infections (IFIs) are associated with high mortality in patients being treated for haematological malignancy. There is limited understanding of the role for surgical lung resection and outcomes in this patient population. METHODS: This is a retrospective cohort of 50 immunocompromised patients who underwent lung resection for IFI. Patient charts were reviewed for details on primary malignancy and treatment course, presentation and work-up of IFI, reasons for surgery, type of resection and outcomes including postoperative complications, mortality, disease relapse and survival. Analysis was also performed on two subgroups based on year of surgery from 1990-2000 and 2001-2014. RESULTS: The median age was 39 years (range: 5-64 years). Forty-seven patients (94%) had haematological malignancies and 38 (76%) underwent haematopoietic stem cell transplantation (HSCT). Surgical indications included haemoptysis, antifungal therapy failure and need for eradication before HSCT. The most common pathogen was Aspergillus in 34 patients (74%). Wedge resections were performed in 32 patients (64%), lobectomy in 9 (18%), segmentectomy in 2 (4%) and some combination of the 3 in 7 (14%) for locally extensive, multifocal disease. There were 9 (18%) minor and 14 (28%) major postoperative complications. Postoperative mortality at 30 days was 12% (n = 6). Acute respiratory distress syndrome was the most common cause of postoperative death. Overall 5-year survival was 19%. Patients who had surgery in the early period had a median survival of 24 months compared with 5 months for those who had surgery before 2001 (P = 0.046). At the time of death, 15 patients (30%) had probable or proven recurrent IFI. Causes of death were predominantly related to refractory malignancy, fungal lung disease or complications of graft versus host disease (GVHD). Patients who had positive preoperative bronchoscopy cultures had a trend towards worse survival compared with those with negative cultures (hazard ratio: 1.80, P = 0.087). CONCLUSIONS: Surgical resection of IFI in immunocompromised patients is associated with high perioperative mortality. Long-term survival is limited by recurrent malignancy, persistent fungal infection and GVHD but has improved in recent years. Selection for surgical resection is difficult in this patient population, but should be carefully considered in those who are symptomatic, or have failed antifungal treatment.
Subject(s)
Immunocompromised Host , Lung Diseases, Fungal/surgery , Opportunistic Infections/surgery , Pneumonectomy/methods , Adolescent , Adult , Child , Child, Preschool , Female , Hematologic Neoplasms/complications , Hematologic Neoplasms/immunology , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Humans , Lung Diseases, Fungal/complications , Lung Diseases, Fungal/immunology , Male , Middle Aged , Opportunistic Infections/complications , Opportunistic Infections/immunology , Pneumonectomy/adverse effects , Postoperative Complications , Prognosis , Retrospective Studies , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
PURPOSE: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation. PATIENTS AND METHODS: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 x 10(6) U/m(2)/24 h for 4 days, followed by 10 days of IL-2 1.6 x 10(6) U/m(2)/24 h on hematologic recovery. RESULTS: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate. CONCLUSION: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin-mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Interleukin-2/therapeutic use , Leukemia, Myeloid/drug therapy , Stem Cell Transplantation , Adult , Antineoplastic Agents/adverse effects , Confidence Intervals , Cytarabine/administration & dosage , Female , Humans , Idarubicin/administration & dosage , Interleukin-2/adverse effects , Leukemia, Myeloid/therapy , Male , Middle AgedABSTRACT
We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD; of these 35 were extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result.