Publications by authors named "Amir T Fathi"

127 Publications

Palliative care and coping in patients with acute myeloid leukemia: Mediation analysis of data from a randomized clinical trial.

Cancer 2021 Aug 30. Epub 2021 Aug 30.

Duke University School of Medicine, Durham, North Carolina.

Background: It has been shown previously that integrated palliative care for patients with acute myeloid leukemia (AML) during intensive chemotherapy leads to improvements in quality of life (QOL) and mood. Coping has been shown to mediate palliative care interventions in advanced cancer; the mechanisms by which improvements occur among patients with AML remain unexplained.

Methods: The authors conducted a secondary analysis of data from a multisite randomized trial of integrated palliative and oncology care (IPC; n = 86) versus usual care (n = 74) for hospitalized patients with AML undergoing intensive chemotherapy. IPC patients met with palliative care at least twice weekly during their initial and subsequent hospitalizations. Patients completed the Functional Assessment of Cancer Therapy-Leukemia, the Hospital Anxiety and Depression Scale, and the Brief Coping Orientation to Problems Experienced Inventory to assess QOL, mood, and coping at the baseline and at weeks 2, 4, 12, and 24. Linear regression models were used to assess the effect of IPC on coping. Causal mediation regression models were used to examine whether changes in coping mediated intervention effects on patient-reported outcomes at week 2.

Results: One hundred sixty eligible patients (68.1%) were enrolled. Those randomized to IPC reported improvements in approach-oriented coping (P < .01) and reductions in avoidant coping (P < .05). These changes in coping mediated the intervention effects on QOL (95% CI, 2.14 to 13.63), depression (95% CI, -2.05 to -0.27), and anxiety symptoms (95% CI, -1.25 to -0.04). Changes in approach-oriented and avoidant coping accounted for 78% of the total palliative care intervention effect on QOL, for 66% of the effect on depression, and for 35% of the effect on anxiety symptoms.

Conclusions: Palliative care integrated during intensive chemotherapy for patients with AML facilitates coping strategy use. Improvement in coping skills accounts for a substantial proportion of the effect from a palliative care intervention on patient-reported outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33886DOI Listing
August 2021

Association of Thrombosis With Hypereosinophilic Syndrome in Patients With Genetic Alterations.

JAMA Netw Open 2021 Aug 2;4(8):e2119812. Epub 2021 Aug 2.

Division of Hematology Oncology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston.

Importance: Hypereosinophilic syndromes (HESs) are a rare group of disorders that result in overproduction of eosinophils, leading to tissue damage. Thrombotic complications in HES and associated risk factors in this patient population have not been extensively studied.

Objective: To investigate the rates of and risk factors associated with thrombotic events in patients with HES, including markers of clonal hematopoiesis as evidenced by molecular aberrations on next-generation sequencing.

Design, Setting, And Participants: This retrospective cohort study evaluated patients seen at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, from January 1, 2015, to January 1, 2020. Patients who had hypereosinophilia with an absolute eosinophil count of 1500 cells/μL or greater on 2 separate occasions at least 1 month apart and who underwent genetic or molecular testing as part of their work-up were included. Patients with secondary eosinophilia were excluded.

Main Outcomes And Measures: Symptomatic and asymptomatic arterial and venous thrombotic events after the diagnosis of HES and all-cause death.

Results: A total of 71 patients (median age, 58 years [interquartile range (IQR), 43-67 years]; 36 women [51%]; 57 White patients [80%]) were included. Patients had a median follow-up time of 29 months (IQR, 19-49 months). Seventeen patients (24%) had 1 or more thrombotic events, including 11 venous thromboembolic events and 11 arterial thrombotic events (8 patients had ≥1 event and 3 patients had recurrent events). Patients with 1 or more thrombotic events had a higher median Eastern Cooperative Oncology Group performance status (median, 1 [IQR, 1-2] vs 0 [IQR, 0-1]; P = .002), had more frequent cardiac involvement (7 of 17 events [41%] vs 6 of 54 events [11%]; P = .01), more frequently received treatment (17 of 17 events [100%] vs 40 of 54 events [74%]; P = .02), and had more molecular aberrations on next-generation sequencing (12 of 17 [71%] vs 12 of 54 [26%]; P = .003) vs patients without thrombosis. After multivariable analysis, the presence of molecular aberration was associated with increased odds of thrombosis (adjusted odds ratio, 5.4; 95% CI, 1.1-27.7). Death occurred more frequently in patients with thrombotic events compared with those without (6 of 17 [35%] vs 2 of 54 [4%]; P = .002) and in patients with molecular aberrations compared with those without (6 of 24 [25%] vs 1 of 40 [3%]; P = .009), although only thrombotic events were significantly associated with increased odds of death after multivariable analysis.

Conclusions And Relevance: In this cohort study, thrombosis was common in patients with HES and was significantly associated with increased risk of death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.19812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346937PMC
August 2021

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Blood 2021 Aug;138(5):387-400

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008812DOI Listing
August 2021

First Reported Case of Invasive Cutaneous Infection in a Patient With Acute Myelogenous Leukemia: A Case Report and Literature Review.

Open Forum Infect Dis 2021 Jul 23;8(7):ofab265. Epub 2021 May 23.

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Certain species are emerging opportunistic pathogens. While these can be common causes of airborne contamination of clinical cultures, an increasing number of reports describe clinically significant disease in the immunocompromised population, particularly in patients with hematologic malignancy. The typical site of infection is respiratory, but disseminated infection is also reported with some frequency. Therefore, culture growth of in respiratory and other clinical samples from immunocompromised patients requires thorough investigation with clinical correlation. Here we report a case of angioinvasive infection of the right shin in a patient with acute myeloid leukemia and review reported cases of invasive infection (excluding ) in hematologic malignancy patients to characterize the emerging pathogen in this vulnerable population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofab265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271139PMC
July 2021

Acute Myeloid Leukemia: Historical Perspective and Progress in Research and Therapy Over 5 Decades.

Clin Lymphoma Myeloma Leuk 2021 Sep 29;21(9):580-597. Epub 2021 May 29.

Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, Australia.

With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2021.05.016DOI Listing
September 2021

Arsenic toxicity manifesting as profuse watery diarrhea during induction therapy for acute promyelocytic leukemia.

Clin Case Rep 2021 May 15;9(5):e04115. Epub 2021 May 15.

Division of Hematology/Oncology Massachusetts General Hospital Boston MA USA.

Arsenic trioxide (ATO) is generally well tolerated for treatment of APL. We present a patient with severe watery diarrhea and pancreatitis thought to be due to ATO toxicity in the setting of obesity and acute kidney injury. Future studies evaluating ATO levels in patients experiencing toxicities may help guide dose modifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.4115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122218PMC
May 2021

Multi-Site 11-Year Experience of Less-Intensive versus Intensive Therapies in Acute Myeloid Leukemia.

Blood 2021 04 28. Epub 2021 Apr 28.

University of Washington School of Medicine, United States.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia, assuming they are better than intensive induction. Using an AML-composite model (AML-CM) that assigns higher scores to older age, increased comorbidity-burdens and adverse cytogenetic-risks, we defined three distinct prognostic groups, and within each, compared outcomes after less-intensive versus intensive induction therapies in a multicenter retrospective cohort (n=1292) treated at six institutions from 2008-2012 and a prospective cohort (n=695) treated at thirteen institutions from 2013-2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physicians' perceptions of cure. In the retrospective cohort, recipients of less-intensive therapies were older, had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks for mortality in AML-CM scores of 4-6, 7-9, and ≥10. Results were independent from receipt of allogeneic transplants and similar in those aged 70-79 years old. In the Prospective cohort, the two groups were similar in baseline QOL, geriatric assessment, and patients' outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS and chances of cure, mortality risks and QOL were similar. Less-intensive recipients had lessened length of hospitalization (LOH). Our studies question the survival or QOL, except LOH, benefits from less-intensive therapies in patients with AML, including those aged 70-79 years or with high comorbidity-burden. A randomized trial in older/medically infirm patients is needed to better assess the value of less-intensive, intensive, or a combination of both therapies. ClinicalTrials.gov #NCT01929408.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008812DOI Listing
April 2021

Outcomes for Patients With IDH-Mutated Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 06 25;27(6):479.e1-479.e7. Epub 2021 Feb 25.

Center for Leukemia, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy after HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, clinical outcomes of IDH1- and IDH2-mutated AML patients after HCT have not been well described. The primary objective of this study was to describe the clinical characteristics and post-HCT outcomes of IDH-mutated AML patients. Survival outcomes included progression-free survival (PFS), overall survival, and cumulative incidences of relapse and nonrelapse mortality. In this multicenter retrospective analysis, 112 adult patients with IDH1- or IDH2-mutated AML who underwent HCT and did not receive an IDH inhibitor as maintenance therapy after HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their survival outcomes were analyzed. Univariate and multivariate analyses were performed. The median patient age was 64.1 years. The median follow-up was 27.5 months. Among patients, 78.5% had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Fifty-eight percent of patients received intensive induction chemotherapy, 82% of patients underwent HCT during first complete remission (CR) or CR with incomplete hematologic recovery (CRi), and 34% of patients received myeloablative conditioning. Frequently detected co-mutations were DNMT3A (35.7%), NPM1 (33.1%), and FLT3-ITD (13.4%); TP53 mutations were detected in 3.6% of patients. For IDH1-mutated patients transplanted during first CR/CRi, the 1- and 2-year PFS was 75% and 58%, respectively. For IDH2-mutated patients transplanted in first CR/CRi, the 1- and 2-year PFS was 64% and 58%, respectively. The 2-year cumulative incidence of relapse was 31% and 25% for IDH1- and IDH2-mutated cohorts, respectively. Multivariable analysis suggested first CR/CRi and age ≤60 was associated with improved outcomes for IDH2-mutated patients. To date, this is the largest multicenter study of outcomes of IDH-mutated AML patients after HCT. Our analysis provides important benchmarks for analysis and interpretation of results emerging from clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients after HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.02.028DOI Listing
June 2021

Posttraumatic stress disorder symptoms in patients with acute myeloid leukemia.

Cancer 2021 Jul 25;127(14):2500-2506. Epub 2021 Mar 25.

Harvard Medical School, Boston, Massachusetts.

Background: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy face a life-threatening illness, isolating hospitalization, and substantial physical and psychological symptoms. However, data are limited regarding risk factors of posttraumatic stress disorder (PTSD) symptoms in this population.

Methods: The authors conducted a secondary analysis of data from 160 patients with high-risk AML who were enrolled in a supportive care trial. The PTSD Checklist-Civilian Version was used to assess PTSD symptoms at 1 month after AML diagnosis. The Brief COPE and the Functional Assessment of Cancer Therapy-Leukemia were to assess coping and quality of life (QOL), respectively. In addition, multivariate regression models were constructed to assess the relation between PTSD symptoms and baseline sociodemographic factors, coping, and QOL.

Results: Twenty-eight percent of patients reported PTSD symptoms, describing high rates of intrusion, avoidance, and hypervigiliance. Baseline sociodemographic factors significantly associated with PTSD symptoms were age (B = -0.26; P = .002), race (B = -8.78; P = .004), and postgraduate education (B = -6.30; P = .029). Higher baseline QOL (B = -0.37; P ≤ .001) and less decline in QOL during hospitalization (B = -0.05; P = .224) were associated with fewer PTSD symptoms. Approach-oriented coping (B = -0.92; P = .001) was associated with fewer PTSD symptoms, whereas avoidant coping (B = 2.42; P ≤ .001) was associated with higher PTSD symptoms.

Conclusions: A substantial proportion of patients with AML report clinically significant PTSD symptoms 1 month after initiating intensive chemotherapy. Patients' baseline QOL, coping strategies, and extent of QOL decline during hospitalization emerge as important risk factors for PTSD, underscoring the need for supportive oncology interventions to reduce the risk of PTSD in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33524DOI Listing
July 2021

Differentiation syndrome with lower-intensity treatments for acute myeloid leukemia.

Am J Hematol 2021 06 18;96(6):735-746. Epub 2021 Mar 18.

Gustave Roussy, Villejuif, France.

Differentiation Syndrome (DS) has been identified in a subset of patients undergoing treatment with novel classes of differentiating therapies for acute myeloid leukemia (AML) such as IDH and FLT3 inhibitors. While DS is a well-known treatment-related complication in acute promyelocytic leukemia (APL), efforts are still ongoing to standardize diagnostic and treatment parameters for DS in AML. Though the rates of incidence vary, many of the signs and symptoms of DS are common between APL and AML. So, DS can lead to fatal complications in AML, but prompt management is usually effective and rarely necessitates interruption or discontinuation of AML therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26142DOI Listing
June 2021

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

J Natl Compr Canc Netw 2021 01 6;19(1):16-27. Epub 2021 Jan 6.

O'Neal Comprehensive Cancer Center at UAB.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2021.0002DOI Listing
January 2021

Effectiveness of Integrated Palliative and Oncology Care for Patients With Acute Myeloid Leukemia: A Randomized Clinical Trial.

JAMA Oncol 2021 Feb;7(2):238-245

Massachusetts General Hospital, Boston.

Importance: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy experience substantial decline in their quality of life (QOL) and mood during their hospitalization for induction chemotherapy and often receive aggressive care at the end of life (EOL). However, the role of specialty palliative care for improving the QOL and care for this population is currently unknown.

Objective: To assess the effect of integrated palliative and oncology care (IPC) on patient-reported and EOL outcomes in patients with AML.

Design, Setting, And Participants: We conducted a multisite randomized clinical trial of IPC (n = 86) vs usual care (UC) (n = 74) for patients with AML undergoing intensive chemotherapy. Data were collected from January 2017 through July 2019 at 4 tertiary care academic hospitals in the United States.

Interventions: Patients assigned to IPC were seen by palliative care clinicians at least twice per week during their initial and subsequent hospitalizations.

Main Outcomes And Measures: Patients completed the 44-item Functional Assessment of Cancer Therapy-Leukemia scale (score range, 0-176) to assess QOL; the 14-item Hospital Anxiety and Depression Scale (HADS), with subscales assessing symptoms of anxiety and depression (score range, 0-21); and the PTSD Checklist-Civilian version to assess posttraumatic stress disorder (PTSD) symptoms (score range, 17-85) at baseline and weeks 2, 4, 12, and 24. The primary end point was QOL at week 2. We used analysis of covariance adjusting and mixed linear effect models to evaluate patient-reported outcomes. We used Fisher exact test to compare patient-reported discussion of EOL care preferences and receipt of chemotherapy in the last 30 days of life.

Results: Of 235 eligible patients, 160 (68.1%) were enrolled; of the 160 participants, the median (range) age was 64.4 (19.7-80.1) years, and 64 (40.0%) were women. Compared with those receiving UC, IPC participants reported better QOL (adjusted mean score, 107.59 vs 116.45; P = .04), and lower depression (adjusted mean score, 7.20 vs 5.68; P = .02), anxiety (adjusted mean score, 5.94 vs 4.53; P = .02), and PTSD symptoms (adjusted mean score, 31.69 vs 27.79; P = .01) at week 2. Intervention effects were sustained to week 24 for QOL (β, 2.35; 95% CI, 0.02-4.68; P = .048), depression (β, -0.42; 95% CI, -0.82 to -0.02; P = .04), anxiety (β, -0.38; 95% CI, -0.75 to -0.01; P = .04), and PTSD symptoms (β, -1.43; 95% CI, -2.34 to -0.54; P = .002). Among patients who died, those receiving IPC were more likely than those receiving UC to report discussing EOL care preferences (21 of 28 [75.0%] vs 12 of 30 [40.0%]; P = .01) and less likely to receive chemotherapy near EOL (15 of 43 [34.9%] vs 27 of 41 [65.9%]; P = .01).

Conclusions And Relevance: In this randomized clinical trial of patients with AML, IPC led to substantial improvements in QOL, psychological distress, and EOL care. Palliative care should be considered a new standard of care for patients with AML.

Trial Registration: ClinicalTrials.gov Identifier: NCT02975869.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.6343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747042PMC
February 2021

A new era of immuno-oncology in acute myeloid leukemia - antibody-based therapies and immune checkpoint inhibition.

Best Pract Res Clin Haematol 2020 12 4;33(4):101220. Epub 2020 Nov 4.

Massachusetts General Hospital / Harvard Medical School, Zero Emerson Place, Suite 118, Boston, MA, 02114, USA. Electronic address:

Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy with high rate of relapse and poor outcomes. There has been increased understanding of the molecular characteristics of AML and the various roles of the immune system in its pathogenesis, the result of which has led to the study and development of multiple immune-based approaches for this disease. In this review, we aim to provide an overview of the recent advancements made in antibody-based approaches to the treatment of AML including monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibition. In addition, we provide insight and discuss the promise of these agents, some of which may soon enter the therapeutic armamentarium we currently employ against this lethal disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.beha.2020.101220DOI Listing
December 2020

New directions for emerging therapies in acute myeloid leukemia: the next chapter.

Blood Cancer J 2020 10 30;10(10):107. Epub 2020 Oct 30.

MD Anderson Cancer Center, Houston, TX, USA.

Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-020-00376-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599225PMC
October 2020

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.

J Clin Oncol 2021 01 29;39(1):57-65. Epub 2020 Oct 29.

University of Oxford, Oxford, United Kingdom.

Purpose: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of -mutant (m) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.

Patients And Methods: This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m on days 1-7 in 28-day cycles in patients with newly diagnosed m AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922).

Results: Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission.

Conclusion: Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m mutation clearance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771719PMC
January 2021

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.

Blood 2021 04;137(13):1792-1803

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020007233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020270PMC
April 2021

Incidence of Invasive Fungal Infections in Acute Myeloid Leukemia Without Antifungal Prophylaxis.

Clin Lymphoma Myeloma Leuk 2020 11 26;20(11):e883-e889. Epub 2020 Jun 26.

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA.

Background: Antifungal prophylaxis during induction for acute myeloid leukemia (AML) varies according to local rates of invasive fungal infections (IFIs). We evaluated fluconazole prophylaxis and no antifungal prophylaxis, as a natural interrupted time-series study to assess survival and infection complications.

Patients And Methods: We identified patients with AML ≥ 18 years old undergoing induction chemotherapy during 2 time periods: period 1, fluconazole prophylaxis from August 1, 2013 to September 30, 2015, and period 2, no prophylaxis from October 1, 2015 to December 31, 2017. The primary outcome was incidence of proven or probable IFI. Secondary outcomes included types of IFIs and 60-day overall survival (OS). IFI was defined by the 2002 European Organization for Research and Treatment of Cancer/Mycoses Study Group Consensus criteria.

Results: One hundred forty-four patients received induction chemotherapy over the 2 time periods. In the prophylaxis versus no-prophylaxis groups, the rate of proven or probable IFIs was 4 (5%) of 87 versus 12 (21%) of 57 (P = .01). The total number of proven IFIs was 3 (3%) of 87 versus 4 (7%) of 57 (P = .44), whereas probable IFIs were 1 (1%) of 87 versus 8 (14%) of 57 (P < .01). No difference was observed in fungemia. Incidence of IFIs was too low to detect resistance patterns. OS at 60 days was improved in with fluconazole prophylaxis compared with no prophylaxis (hazard ratio, 0.329; 95% confidence interval, 0.12-0.89; P = .028).

Conclusion: Observed rates of proven or probable IFI were lower in the fluconazole prophylaxis group versus the no-prophylaxis group. Sixty-day OS was higher with fluconazole prophylaxis. Further study is required to evaluate how fluconazole may impart the differences in survival seen in this analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.06.008DOI Listing
November 2020

Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.

Cancer Cell 2020 07 11;38(1):79-96.e11. Epub 2020 Jun 11.

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.

Fat mass and obesity-associated protein (FTO), an RNA N-methyladenosine (mA) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363590PMC
July 2020

Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML.

Blood Adv 2020 05;4(9):1894-1905

Agios Pharmaceuticals, Inc., Cambridge, MA.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG-restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020001503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218420PMC
May 2020

Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation.

Curr Cancer Drug Targets 2020 ;20(7):490-500

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568009620666200424145622DOI Listing
July 2021

Enasidenib in patients with mutant IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicentre, AG221-C-001 trial.

Lancet Haematol 2020 Apr 5;7(4):e309-e319. Epub 2020 Mar 5.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial.

Methods: The multicentre, open-label, phase 1-2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60-300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov, NCT01915498, status ongoing but closed to recruitment.

Findings: 17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5-73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8-23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2-15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3-4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28-77]), with a median duration of response of 9·2 months (95% CI 1·0-not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5-32·3), and median event-free survival was 11·0 months (1·5-16·7).

Interpretation: Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful.

Funding: Celgene and Agios Pharmaceuticals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(19)30284-4DOI Listing
April 2020

Management of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study.

Leukemia 2020 12 4;34(12):3149-3160. Epub 2020 Mar 4.

University of Illinois Cancer Center, Chicago, IL, USA.

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 10/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0783-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155811PMC
December 2020

Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangement.

Blood Adv 2020 01;4(1):106-111

Harvard Medical School, Boston, MA.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subtype of Ph-negative ALL that molecularly resembles Ph-positive ALL. It shares the adverse prognosis of Ph-positive ALL, but lacks the BCR-ABL1 fusion oncogene. Instead, Ph-like ALL is associated with alternative mutations in signaling pathways. We describe a case of Ph-like ALL that harbored 2 genomic alterations, which activated signaling, an NRASGly12Asp mutation, and an ETV6-NTRK3 rearrangement. Initially, the NRAS mutation was detected at high frequency, whereas the gene fusion was only detectable with a targeted next-generation sequencing-based fusion assay, but not by fluorescence in situ hybridization analysis. The disease failed to respond to multiagent chemotherapy but investigational CD19-directed chimeric antigen receptor T-cell therapy resulted in a complete remission. However, the leukemia relapsed after 6 weeks. Intriguingly, the NRAS mutation was extinguished during the chimeric antigen receptor T-cell therapy and did not contribute to the relapse, which was instead associated with a rise in ETV6-NTRK3. The relapsed leukemia progressed with further chemo- and immunotherapy but was controlled for 6 weeks with substantial leukemic cytoreduction using the TRK inhibitor larotrectinib. Unfortunately, recovery of normal hematopoiesis was only marginal and the patient eventually succumbed to infections. These results demonstrate that larotrectinib has clinical activity in ETV6-NTRK3-associated Ph-like ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960464PMC
January 2020

A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

Cancer 2020 03 20;126(6):1264-1273. Epub 2019 Dec 20.

Division of Hematology/Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.

Background: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML.

Methods: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7.

Results: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion.

Conclusions: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777).

Lay Summary: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32657DOI Listing
March 2020

Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.

Blood 2020 02;135(7):463-471

Agios Pharmaceuticals, Inc, Cambridge, MA; and.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019002140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019193PMC
February 2020
-->