ABSTRACT
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.
Subject(s)
Hematologic Neoplasms , Myeloproliferative Disorders , Skin Neoplasms , Child , Humans , Aged , Standard of Care , Interleukin-3 Receptor alpha Subunit , Dendritic Cells/pathology , Neoplasm Recurrence, Local/pathology , Myeloproliferative Disorders/pathology , Hematologic Neoplasms/pathology , Skin Neoplasms/pathology , Acute Disease , North AmericaABSTRACT
Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. In this study, we found that the silencing of protein phosphatase 2A (PP2A) directly blocks differentiation in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling revealed that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent, OSU-2S, in parallel with genetic approaches, we discovered that PP2A enforced c-Myc and p21 dependent terminal differentiation, proliferation arrest, and apoptosis in AML. Finally, we demonstrated that PP2A activation decreased leukemia-initiating stem cells, increased leukemic blast maturation, and improved overall survival in murine Tet2-/-Flt3ITD/WT and human cell-line derived xenograft AML models in vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/metabolism , Leukemia, Myeloid, Acute/metabolism , Protein Phosphatase 2/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Knockout , Protein Phosphatase 2/genetics , Proto-Oncogene Proteins c-myc/geneticsABSTRACT
BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.
Subject(s)
Leukemia, Myeloid, Acute , Tumor Suppressor Protein p53 , Humans , Decitabine , Tumor Suppressor Protein p53/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Karyotype , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Agents/therapeutic use , Glycine/analogs & derivatives , Leukemia, Myeloid, Acute/drug therapy , Pyridines/therapeutic use , Triazines/therapeutic use , Adult , Aged , Aminopyridines/adverse effects , Antineoplastic Agents/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation/drug effects , Pyridines/adverse effects , Treatment Outcome , Triazines/adverse effects , Young AdultABSTRACT
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.
Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Skin Neoplasms , Adult , Humans , Dendritic Cells/pathology , Hematologic Neoplasms/diagnosis , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/pathology , Medical Oncology , Skin Neoplasms/diagnosisABSTRACT
Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
Subject(s)
Glycine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Mutation/genetics , Pyridines/therapeutic use , Aged , Aged, 80 and over , Blood Transfusion , Female , Glycine/adverse effects , Glycine/therapeutic use , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Pyridines/adverse effects , Remission Induction , Survival Analysis , Translational Research, Biomedical , Treatment OutcomeABSTRACT
T-cell bispecific antibodies (T-BsAbs) are a new class of cancer immunotherapy drugs that can simultaneously bind to tumor-associated antigens on target cells and to the CD3 subunit of the T-cell receptor (TCR) on T cells. In the last decade, numerous T-BsAbs have been developed for the treatment of both hematological malignancies and solid tumors. Among them, blinatumomab has been successfully used to treat CD19 positive malignancies and has been approved by the FDA as standard care for acute lymphoblastic leukemia (ALL). However, in many clinical scenarios, the efficacy of T-BsAbs remains unsatisfactory. To further improve T-BsAb therapy, it will be crucial to better understand the factors affecting treatment efficacy and the nature of the T-BsAb-induced immune response. Herein, we first review the studies on the potential mechanisms by which T-BsAbs activate T-cells and how they elicit efficient target killing despite suboptimal costimulatory support. We focus on analyzing reports from clinical trials and preclinical studies, and summarize the factors that have been identified to impact the efficacy of T-BsAbs. Lastly, we review current and propose new approaches to improve the clinical efficacy of T-BsAbs.
Subject(s)
Antibodies, Bispecific , Neoplasms , Humans , Antibodies, Bispecific/therapeutic use , Neoplasms/therapy , T-Lymphocytes , Antigens, Neoplasm , ImmunotherapyABSTRACT
BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
Subject(s)
Enzyme Inhibitors/administration & dosage , Glycine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Pyridines/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Cell Count , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Follow-Up Studies , Glycine/administration & dosage , Glycine/adverse effects , Glycine/pharmacokinetics , Hemoglobins/analysis , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Pyridines/adverse effects , Pyridines/pharmacokinetics , Recurrence , Remission Induction , Survival Rate , Young AdultABSTRACT
The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.
Subject(s)
Leukemia, Myeloid, Acute , Adult , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Mutation , PrognosisABSTRACT
PURPOSE OF REVIEW: Treatment of relapsed and refractory acute myeloid leukemia (AML) is still very challenging, with poor response rates and low chance for cure. This is especially true when treating patients who are elderly, have multiple comorbidities, or who are too unfit for traditional salvage chemotherapy regimens. RECENT FINDINGS: Recently, advances in the treatment of relapsed/refractory AML utilizing novel chemotherapy combinations, hypomethylating, and targeted therapies have shown promising results. SUMMARY: Several early-phase studies with novel targeted therapy combinations have demonstrated encouraging results warranting larger, comparative studies. This has expanded the access of treatment for patients with relapsed/refractory AML who cannot receive traditional salvage chemotherapy. These newer treatments have the potential to outperform traditional chemotherapy as well.
Subject(s)
Leukemia, Myeloid, Acute/therapy , Humans , RecurrenceABSTRACT
Recent years have seen tremendous advances in treating acute myeloid leukemia (AML), largely because of progress in understanding the genetic basis of the disease. The US Food and Drug Administration approved 7 agents for AML in the last 2 years: the first new drugs in decades. In this review, the authors discuss these new approvals in the backdrop of an overall strategy for treating AML today. Treating AML in the modern era requires: 1) access to and use of upfront genetic and cytogenetic testing, not only to describe prognosis but also to help identify the best available therapy; 2) effectively working new therapies into a conventional backbone of treatment, including transplantation; and 3) continued commitment to clinical trials designed to capitalize on advances in genetics and immunology to foster the next wave of drug approvals.
Subject(s)
Leukemia, Myeloid, Acute/therapy , Humans , Middle AgedABSTRACT
Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.
Subject(s)
Antineoplastic Agents/therapeutic use , Bridged-Ring Compounds/therapeutic use , Janus Kinase 2/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bridged-Ring Compounds/adverse effects , Bridged-Ring Compounds/pharmacokinetics , Bridged-Ring Compounds/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cytarabine/adverse effects , Cytarabine/therapeutic use , Daunorubicin/adverse effects , Daunorubicin/therapeutic use , Decitabine/adverse effects , Decitabine/therapeutic use , Drug Resistance, Neoplasm/drug effects , Female , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Pilot Projects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m2 cytarabine D5-8, and 8 mg/m2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Disease-Free Survival , Female , Humans , Idarubicin/administration & dosage , Idarubicin/adverse effects , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/mortality , Survival RateABSTRACT
PURPOSE OF REVIEW: The majority of patients with acute myeloid leukemia (AML) die from disease recurrence and historically, treatment options in both the relapsed and refractory settings of this disease have been limited. However, new insights into the molecular characterization and biology of relapsed and refractory AML have led to novel therapeutics and improvement in outcomes in these settings. The current understanding of mechanisms of disease resistance and status of treatment options both currently available and under exploration in relapsed and refractory AML are summarized in this review. RECENT FINDINGS: The rapid approval of multiple therapeutic agents since 2017 has led to improvement in selected populations such as isocitrate dehydrogenase and fms-like tyrosine kinase 3-mutated relapsed and refractory AML with agents such as enasidenib, ivosidenib, and gilteritinib. Despite these advancements, the only current curative approach remains allogeneic transplantation and only for those minority of patients that are candidates. However, encouraging results are being seen with a multitude of novel small molecular inhibitors and immunotherapeutic approaches currently in clinical trials both as single agents and combination strategies in both upfront and relapsed/refractory AML. SUMMARY: Continued advancements in the knowledge of various mechanisms of relapse and resistance in AML are ongoing, leading to the realization that diverse treatment strategies are needed to both prevent and manage relapsed and refractory disease.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Immunotherapy , Leukemia, Myeloid, Acute/therapy , Small Molecule Libraries/pharmacology , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathologyABSTRACT
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
Diseases with clonal hematopoiesis such as myelodysplastic syndrome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or hematopoietic stem cells in myelodysplastic syndrome. CD123, the alpha chain of the interleukin-3 receptor heterodimer, is expressed on the majority of leukemic stem cells and myelodysplastic syndrome hematopoietic stem cells and in 80% of acute myeloid leukemia. Here, we report indiscriminate killing of CD123+ normal and acute myeloid leukemia / myelodysplastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123- lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 significantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition to primary samples, studies on normal cord blood and healthy marrow show that SL-401 has activity against normal hematopoietic progenitors. These findings indicate potential use of SL-401 as a "bridge-to-transplant" before allogeneic hematopoietic cell transplantation in acute myeloid leukemia / myelodysplastic syndrome patients.
Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Interleukin-3 Receptor alpha Subunit/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Recombinant Fusion Proteins/pharmacology , Animals , Cell Line, Tumor , Heterografts , Humans , Interleukin-3 Receptor alpha Subunit/analysis , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Recombinant Fusion Proteins/therapeutic use , Tumor Cells, CulturedABSTRACT
KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).