ABSTRACT
Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg (p = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19-3.07, p = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease.
Subject(s)
Acute Kidney Injury , Arsenicals , Drug-Related Side Effects and Adverse Reactions , Leukemia, Promyelocytic, Acute , Humans , Arsenic Trioxide/adverse effects , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/adverse effects , Obesity/complications , Acute Kidney Injury/chemically induced , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Arsenicals/adverse effects , Oxides/adverse effectsABSTRACT
The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.
Subject(s)
Idarubicin , Leukemia, Myeloid, Acute , Humans , Middle Aged , Sorafenib/therapeutic use , Cladribine/therapeutic use , Cytarabine/therapeutic use , Remission Induction , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/geneticsABSTRACT
BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.
Subject(s)
Leukemia, Hairy Cell , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Leukemia, Hairy Cell/drug therapy , Leukemia, Hairy Cell/genetics , Pyridones/adverse effects , Pyrimidinones/adverse effects , Oximes/adverse effects , Mutation , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Myeloid, Acute , Risk Assessment , Stem Cell Transplantation , fms-Like Tyrosine Kinase 3/genetics , Allografts , Disease-Free Survival , Female , Humans , Infant , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Mutation , Survival RateABSTRACT
Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10-year survival, ≥90%). Acute promyelocytic leukemia is curable at a rate of 80% to 90% with a nonchemotherapy regimen of all-trans retinoic acid and arsenic trioxide. The cure rate for core-binding factor acute myeloid leukemia (AML) is ≥75% with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin. Survival for patients with chronic myeloid leukemia is close to that for an age-matched normal population with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may now be potentially curable with a finite duration of therapy with Bruton tyrosine kinase inhibitors and venetoclax. The estimated 5-year survival rate for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third-generation BCR-ABL1 TKI, and more recent nonchemotherapy regimens using dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 (blinatumomab), and CD22 (inotuzumab) to chemotherapy. Several recent drug discoveries (venetoclax, FLT3 and IDH inhibitors, and oral hypomethylating agents) are also improving outcomes for younger and older patients with AML and for those with higher risk myelodysplastic syndrome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Leukemia, Myeloid, Acute , Cytarabine , Fusion Proteins, bcr-abl , Gemtuzumab , Humans , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase InhibitorsABSTRACT
The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Age Factors , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Cladribine/therapeutic use , Core Binding Factors , Cytarabine/therapeutic use , Daunorubicin/therapeutic use , Gemtuzumab/therapeutic use , Humans , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Maintenance Chemotherapy , Mutation , Myelodysplastic Syndromes/complications , Myeloproliferative Disorders/complications , Neoplasm, Residual , Sulfonamides/therapeutic use , Survival Rate , Translational Research, Biomedical , Tretinoin/therapeutic use , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Myeloid, Acute , Mutation , fms-Like Tyrosine Kinase 3 , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzylamines , Cyclams , Disease-Free Survival , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/adverse effects , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/adverse effects , Humans , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Sorafenib/administration & dosage , Sorafenib/adverse effects , Survival Rate , fms-Like Tyrosine Kinase 3/blood , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzothiazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Neoplasm Recurrence, Local/drug therapy , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/genetics , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzothiazoles/therapeutic use , Disease Models, Animal , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm/genetics , Gene Duplication , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/genetics , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: The addition of midostaurin to induction chemotherapy improves survival in younger patients with newly diagnosed, FLT3-mutated acute myeloid leukemia (AML). Sorafenib is a potent multikinase inhibitor with efficacy when given as monotherapy. The authors investigated whether the addition of sorafenib to intensive induction chemotherapy improves outcomes in patients with FLT3-internal tandem duplication (ITD)-mutated AML. METHODS: In total, 183 patients who were newly diagnosed with FLT3-ITD-mutated AML between February 2001 and December 2017 were identified. Of these, 79 patients (43%) underwent intensive chemotherapy with the addition of sorafenib, and 104 (57%) received intensive chemotherapy alone. Propensity score matching identified 42 patients in each cohort. RESULTS: The overall response rate was 98% in the sorafenib cohort and 83% in the intensive chemotherapy cohort (P = .057). The median follow-up was 54 months. The median event-free survival was 35 months in the sorafenib cohort and 8 months in the intensive chemotherapy cohort (P = .019), and the median overall survival was 42 and 13 months, respectively (P = .026). With censoring at the time of allogeneic stem cell transplantation, the median event-free survival was 31 and 8 months in the sorafenib and intensive therapy cohorts, respectively (P = .031), and the median overall survival was not reached and 10 months, respectively (P = .001). Multivariate Cox proportional hazards models confirmed that treatment with sorafenib was a favorable prognostic factor (P = .009; hazard ratio, 0.558; 95% CI, 0.360-0.865). CONCLUSIONS: The addition of sorafenib improves survival in patients with FLT3-ITD-mutated AML regardless of whether they undergo allogeneic stem cell transplantation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid/therapy , Mutation , Tandem Repeat Sequences/genetics , fms-Like Tyrosine Kinase 3/genetics , Acute Disease , Adult , Cohort Studies , Combined Modality Therapy , Female , Humans , Induction Chemotherapy/methods , Kaplan-Meier Estimate , Leukemia, Myeloid/genetics , Male , Middle Aged , Remission Induction , Sorafenib/administration & dosage , Staurosporine/administration & dosage , Staurosporine/analogs & derivatives , Transplantation, Homologous , Young AdultABSTRACT
Acute myeloid leukemia (AML) is a heterogeneous disease and remains a therapeutic challenge. Cytogenetics is a well-established prognostic factor. Recent discovery of molecular mutations has gained momentum with some being potential therapeutic targets. FLT3 mutation seen in approximately one third of the cytogenetically normal AML confers high risk of relapse and poor survival. Quizartinib is the first drug developed specifically as a FLT3 inhibitor. It has confirmed safety and efficacy in phase I and II clinical trials and has shown survival benefit over conventional chemotherapy in patients with FLT3 ITD mutated relapsed/refractory AML. Despite such promise, disease relapses are still seen. Besides the complex nature of AML itself, resistance mechanisms blunting the efficacy of quizartinib have been identified and are being investigated including TKD mutations, alternate signaling pathways and the bone marrow microenvironment. Strategies using combination of quizartinib with other TKIs/agents like crenolinib, PIM kinase, and MEK inhibitors should be further explored.
Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzothiazoles/chemistry , Benzothiazoles/therapeutic use , Biomarkers, Tumor , Clinical Studies as Topic , Combined Modality Therapy , Drug Development , Drug Discovery , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/therapy , Molecular Targeted Therapy , Phenylurea Compounds/chemistry , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on 2 separate protocols of AZA plus sorafenib were analyzed. The clinical trials were registered at clinicaltrials.gov (NCT02196857 and NCT01254890). Overall, 27 patients with untreated FLT3 mutated AML (median age of 74 years, range, 61-86) were enrolled. The overall response rate was 78% (7 [26%] CR, 12 [44%] CRi/CRp, and 2 [7%] PR). Patients received a median of 3 treatment cycles (1-35). The median duration of CR/CRp/CRi is 14.5 months (1.1-28.7 months). Three (11%) responding patients (1 CR, 2 CRi) proceeded to allogeneic stem cell transplant. The median follow-up for surviving patients was 4.1 months (3.0-17.3 months). The median overall survival for the entire group was 8.3 months, and 9.2 months in the 19 responders. The regimen was well tolerated in elderly patients with untreated FLT3 mutated AML with no early deaths.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/therapy , fms-Like Tyrosine Kinase 3/genetics , Age Factors , Aged , Aged, 80 and over , Azacitidine/therapeutic use , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Middle Aged , Mutation , Remission Induction , Salvage Therapy/methods , Sorafenib/therapeutic use , Stem Cell Transplantation , Survival Analysis , Transplantation, Homologous , Treatment OutcomeABSTRACT
Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients' age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40-50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30 to 40% up to 80 to 90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the "7+3"regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the "7+3" regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Adult , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Leukemia, Myeloid, Acute/diagnosis , Prognosis , Survival RateABSTRACT
INTRODUCTION: The outcomes of patients with relapsed or refractory acute myeloid leukemia (AML) are dismal, and effective treatment options in this patient population are therefore desperately needed. Vosaroxin is a first-in-class anticancer quinolone derivative that has shown promising activity in patients with relapsed or refractory AML. AREAS COVERED: Studies in relapsed/refractory AML, including a large randomized phase III trial, have shown improved response rates when vosaroxin was combined with cytarabine, which translated to prolonged survival in certain subsets of patients, including older patients. Given the encouraging results of vosaroxin in the relapsed/refractory setting, several studies are also evaluating vosaroxin in older patients with untreated AML who are not candidates for intensive chemotherapy. The results from clinical trials evaluating vosaroxin in both treatment naïve and relapsed/refractory AML will be reviewed. Expert Commentary: Vosaroxin has shown significant promise in the management of AML, especially in older patients with relapsed/refractory disease. As vosaroxin has been associated with increased toxicity in some studies, appropriate dosing and patient selection will be crucial to determine the future role of vosaroxin in AML.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Naphthyridines/therapeutic use , Thiazoles/therapeutic use , Age Factors , Animals , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Humans , Naphthyridines/pharmacology , Recurrence , Retreatment , Thiazoles/pharmacology , Treatment OutcomeSubject(s)
Imatinib Mesylate/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Propensity Score , Protein Kinase Inhibitors/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Dasatinib/therapeutic use , Humans , Imatinib Mesylate/pharmacology , Leukemia, Myeloid, Chronic-Phase/mortality , Middle Aged , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/therapeutic use , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
AML with FLT3 ITD mutations are associated with poor outcome. We reviewed outcomes of patients with FLT3 ITD mutated AML to investigate trends over time. We analyzed 224 AML patients (excluding patients with core binding factor and acute promyelocytic leukemia) referred to our institution between 2000 and 2014. Patients were divided into five cohorts by era: 2000-2002 (Era 1, n = 19), 2003-2005 (Era 2, n = 41), 2006-2008 (Era 3, n = 53), 2009-2011 (Era 4, n = 55), and 2012-2014 (Era 5, n = 56) to analyze differences in outcome. The baseline characteristics were not statistically different across Eras. The response rate (CR/CRp) from Era 1-5 was 68%, 49%, 72%, 73%, and 75%, respectively. The overall response rate (all Eras) with chemotherapy alone versus chemotherapy plus FLT3 inhibitor was 67% and 72.5%, respectively (P = 0.4). The median time to relapse was 6, 3.6, 7.9, 8.1 months and not reached from Eras 1 through 5, respectively (P = 0.001). The median OS has improved: 9.6, 7.6, 14.4, 15.7, and 17.8 month from Eras 1-5, respectively (P = <0.001). Stem cell transplant as a time-dependent variable, showed better OS in the univariate analysis (HR: 0.57, 95% CI: 0.39-0.84, P = 0.004) but did not retained its significance in multivariate analysis (HR: 0.75, 95% CI: 0.50-1.13, P = 0.16). Our data suggest improvement in outcome of FLT3 ITD mutated AML patients over the last 15 years. This is probably due to improvement in treatment strategies, including but not limited to integration of FLT3 inhibitors and increased use of SCT.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Analysis of Variance , Female , Gene Expression , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Recurrence , Remission Induction , Retrospective Studies , Sorafenib , Survival Analysis , Transplantation, Homologous , Treatment OutcomeABSTRACT
INTRODUCTION: Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development. AREAS COVERED: This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents. EXPERT OPINION: The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/therapeutic use , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Benzimidazoles/therapeutic use , Benzothiazoles/therapeutic use , Drug Resistance, Neoplasm , Humans , Imidazoles/therapeutic use , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , Piperidines/therapeutic use , Pyridazines/therapeutic use , Sorafenib , Staurosporine/analogs & derivatives , Staurosporine/therapeutic use , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
BACKGROUND: FLT3-internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 inhibitors have shown clinical activity in AML with FLT3-ITD, but responses are usually short-lived. METHODS: This study examined 69 FLT3-mutated patients with AML, who were treated with different FLT3 inhibitors to analyze emergence of new mutations. RESULTS: At baseline, 87% of patients had an ITD mutation, 7% had a D835/I836 mutation, and 6% had combined ITD and D835/I836 mutations. Responses occurred in 32% of patients, all with FLT3-ITD; none of the patients with D835/I836 or ITD+D835/I836 responded. Mutational assessment at the time of FLT3 inhibitor discontinuation showed that 68% of patients were unchanged, 10% had become undetectable, and 22% of patients progressed from a single ITD to have combined ITD+D835/I836 mutations. In those patients with unchanged FLT3 mutation at progression, the median survival was 5 months, whereas in those with undetectable and with combined ITD+D835/I836 mutations, the median survival was 7 months, respectively. CONCLUSIONS: These data confirm in vitro observations that a secondary tyrosine kinase domain mutation may arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with resistance and a poor prognosis.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , fms-Like Tyrosine Kinase 3/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Benzothiazoles/therapeutic use , Carbazoles/therapeutic use , DNA Mutational Analysis , Female , Furans , Humans , Leukemia, Myeloid, Acute/mortality , Male , Medical Records , Middle Aged , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/pharmacology , Retrospective Studies , Sorafenib , Survival Analysis , Treatment OutcomeABSTRACT
B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited also CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL.
Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Hairy Cell/pathology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptors, Antigen, B-Cell/metabolism , Adenine/analogs & derivatives , Adult , Agammaglobulinaemia Tyrosine Kinase , Aged , Antineoplastic Agents/administration & dosage , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemokine CCL3/metabolism , Chemokine CCL4/metabolism , Chemokine CXCL12/antagonists & inhibitors , Chemokine CXCL12/physiology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Female , Humans , Leukemia, Hairy Cell/genetics , Leukemia, Hairy Cell/metabolism , Male , Middle Aged , Mutation , Neoplasm Proteins/metabolism , Phosphorylation/drug effects , Piperidines , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins B-raf/genetics , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Receptors, Antigen, B-Cell/physiology , Signal Transduction/drug effects , Tumor Cells, CulturedABSTRACT
Abstract With improved outcome for patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), treatment discontinuation has become increasingly attractive to patients. We analyzed the outcomes of patients who chose to discontinue TKI therapy regardless of their ongoing response. Thirty-five patients with chronic phase CML discontinued TKI in complete cytogenetic response. Of them, 51% discontinued due to adverse effects, 23% due to long complete molecular response (CMR) (> 5 years), 9% due to pregnancy and 17% due to financial problems. After TKI discontinuation, patients were followed for a median of 16 months. Among 27 patients (77%) who discontinued TKIs in CMR, 11 (41%) had a molecular relapse after a median of 3.5 months. In univariate analysis we observed that patients with ≥ 64 months of CMR before TKI discontinuation had superior cumulative proportions of sustained CMR and major molecular response (MMR) at 12 months after discontinuation: 88.9% vs. 45.5% (p = 0.02) and 100% vs. 75% (p = 0.05), respectively. Patients treated with high dose imatinib or second generation TKIs had a higher cumulative proportion of sustained MMR at 12 months after discontinuation than patients treated with standard dose imatinib: 100% vs. 72.2% (p = 0.03), respectively. Of the five patients who stopped TKI in MR(4.5) (molecular response of 4.5-log reduction) one lost cytogenetic response. All three patients who discontinued TKIs in MMR lost cytogenetic response; one progressed to accelerated phase. Thirteen patients (37%) restarted TKIs after loss of response: 11 improved their response, and for two it is too early to assess. Treatment discontinuation can lead to sustained CMR in some patients, but risk of relapse is higher if patients discontinue TKIs when not in CMR.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Chronic-Phase/genetics , Leukemia, Myeloid, Chronic-Phase/mortality , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Recurrence , Retreatment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.