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1.
Blood Adv ; 6(22): 5857-5865, 2022 11 22.
Article in English | MEDLINE | ID: covidwho-2043101

ABSTRACT

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).


Subject(s)
COVID-19 , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myeloproliferative Disorders , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/drug therapy , Recurrence
2.
Int J Mol Sci ; 23(15)2022 Aug 06.
Article in English | MEDLINE | ID: covidwho-1994086

ABSTRACT

Non-relapse mortality due to GVHD and infections represents a major source of morbidity and mortality in pediatric HSCT recipients. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD and relapse-free survival in matched (related and unrelated) and mismatched haploidentical HSCT adult recipients. However, there are no published data in pediatric patients with acute myeloid leukemia who received matched-donor HSCT with PTCy. We demonstrate, in this case series, that the use of PTCy in this population is potentially safe, effective in preventing acute GVHD, does not impair engraftment, is associated with reduced non-relapse mortality, and does not hinder immune reconstitution post HSCT.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adult , Child , Cyclophosphamide/therapeutic use , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Humans , Leukemia, Myeloid, Acute/drug therapy , Recurrence , Retrospective Studies , Siblings , Unrelated Donors
7.
FEBS J ; 288(21): 6087-6094, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526365

ABSTRACT

Anthony Letai is Professor in Medicine at Harvard Medical School and Dana Farber Cancer Institute, and President of The Society for Functional Precision Medicine. Among Tony's scientific achievements, work from his lab contributed toward the FDA approval of Venetoclax combination treatment for adult acute myeloid leukemia (AML) patients. Moreover, his studies on cancer cell death have led to the development of BH3 profiling, an assay that allows for the definition of how close a cell is to the threshold required to commit to apoptosis, which can be used to improve clinical outcomes for cancer patients. In this interview, Tony relays the story behind some of his scientific breakthroughs, discusses the importance of function when designing targeted cancer therapies, gives an overview of BH3 profiling and its application to cancer therapy, and recalls the key events and collaborations that drove his successful research career.


Subject(s)
Precision Medicine/methods , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Sulfonamides/therapeutic use
8.
Elife ; 102021 08 05.
Article in English | MEDLINE | ID: covidwho-1513039

ABSTRACT

For an emerging disease like COVID-19, systems immunology tools may quickly identify and quantitatively characterize cells associated with disease progression or clinical response. With repeated sampling, immune monitoring creates a real-time portrait of the cells reacting to a novel virus before disease-specific knowledge and tools are established. However, single cell analysis tools can struggle to reveal rare cells that are under 0.1% of the population. Here, the machine learning workflow Tracking Responders EXpanding (T-REX) was created to identify changes in both rare and common cells across human immune monitoring settings. T-REX identified cells with highly similar phenotypes that localized to hotspots of significant change during rhinovirus and SARS-CoV-2 infections. Specialized MHCII tetramer reagents that mark rhinovirus-specific CD4+ cells were left out during analysis and then used to test whether T-REX identified biologically significant cells. T-REX identified rhinovirus-specific CD4+ T cells based on phenotypically homogeneous cells expanding by ≥95% following infection. T-REX successfully identified hotspots of virus-specific T cells by comparing infection (day 7) to either pre-infection (day 0) or post-infection (day 28) samples. Plotting the direction and degree of change for each individual donor provided a useful summary view and revealed patterns of immune system behavior across immune monitoring settings. For example, the magnitude and direction of change in some COVID-19 patients was comparable to blast crisis acute myeloid leukemia patients undergoing a complete response to chemotherapy. Other COVID-19 patients instead displayed an immune trajectory like that seen in rhinovirus infection or checkpoint inhibitor therapy for melanoma. The T-REX algorithm thus rapidly identifies and characterizes mechanistically significant cells and places emerging diseases into a systems immunology context for comparison to well-studied immune changes.


Subject(s)
COVID-19/immunology , Leukemia, Myeloid, Acute/immunology , Melanoma/immunology , Picornaviridae Infections/immunology , Unsupervised Machine Learning , Adolescent , Adult , Algorithms , CD4-Positive T-Lymphocytes/immunology , Humans , Leukemia, Myeloid, Acute/drug therapy , Melanoma/drug therapy , Neoplasms , Rhinovirus/isolation & purification , SARS-CoV-2/isolation & purification , Young Adult
10.
J Pediatr Hematol Oncol ; 44(2): e532-e536, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1270768

ABSTRACT

A 15-year-old male presented with fatigue and weight loss for 1 month, petechiae and bruising for 2 weeks. He was diagnosed with concurrent new acute myeloid leukemia and coronavirus disease 2019. He was febrile and chest computed tomography scan showed ground glass opacities. Fever resolved after 4 days. Polymerase chain reaction test for coronavirus disease 2019 became negative after 2 days. Induction chemotherapy was initiated on day 8 and was complicated by multisystem inflammatory syndrome in children. The multisystem inflammatory syndrome in children was managed with symptomatic treatment and continued chemotherapy. Patient recovered and end of induction bone marrow showed remission of the leukemia.


Subject(s)
COVID-19/complications , Induction Chemotherapy/methods , Leukemia, Myeloid, Acute/complications , SARS-CoV-2/isolation & purification , Systemic Inflammatory Response Syndrome/pathology , Adolescent , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/virology , Male , Remission Induction , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/virology
11.
Gut Microbes ; 13(1): 1-10, 2021.
Article in English | MEDLINE | ID: covidwho-1270726

ABSTRACT

COVID-19 precautions decrease social connectedness. It has been proposed that these measures alter the gut microbiota, with potential clinical consequences. We tested this hypothesis in patients with acute myeloid leukemia (AML) receiving inpatient chemotherapy, a population with extensive exposure to the nosocomial setting and at high risk for infections. Hospitalized patients with AML contributed stool samples to a biorepository protocol that was initiated before COVID-19 and continued without change through the pandemic. Patient-, disease-, and treatment-related characteristics remained the same in the two eras and the only change in clinical care was the implementation of COVID-19 precautions in March 2020. The incidence of all-cause nosocomial infections during the pandemic was lower than in the pre-COVID-19 era. Multivariable analysis revealed an imprint of COVID-19 precautions in the gut microbiota as a viable mechanistic explanation. In conclusion, COVID-19 precautions alter the gut microbiota, thereby mediating pathogen susceptibility and nosocomial infections.


Subject(s)
COVID-19/prevention & control , Cross Infection/epidemiology , Disease Susceptibility/microbiology , Gastrointestinal Microbiome/genetics , Leukemia, Myeloid, Acute/drug therapy , Aged , Antineoplastic Agents/therapeutic use , Feces/microbiology , Humans , Length of Stay , Masks , Middle Aged , Physical Distancing , Principal Component Analysis , RNA, Ribosomal, 16S/genetics , Risk , SARS-CoV-2
13.
Transfus Clin Biol ; 28(1): 55-59, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1059459

ABSTRACT

BACKGROUND: Although the SARS-CoV-2 virus is transmitted mainly through the respiratory tract, possible transmission by transfusion from asymptomatic carriers should be explored. As yet there are no reports of transfusion transmission of COVID-19. Haemovigilance findings within a three-month surveillance period during the new coronavirus pandemic are presented. MATERIALS AND METHODS: Due to great demand and shortage, blood sessions in outpatient facilities were organized during the high prevalence period of COVID-19, alongside a national plan to monitor the evolving public health situation by random molecular screening of high-risk groups of the population. Haemovigilance protocols were implemented as well as surveillance for any COVID-19 case reported post-transfusion. A 14-day quarantine and follow-up molecular and antibody testing of any COVID-19 positive case was obligatory. RESULTS: Post-donation, post-transfusion information and molecular testing of swab samples collected from three asymptomatic donors at risk for COVID-19, revealed the case of an immunosupressed patient who had been transfused with whole blood derived platelets from a donor subsequently diagnosed with COVID-19. The recipient exhibited no symptoms of the disease. Molecular and antibody testing results were negative. CONCLUSION: Haemovigilance provided information supporting the absence of transfusion transmission of COVID-19, thus strengthening the hypothesis that, even if it cannot yet be definitively ruled out, COVID-19 is not transmitted through blood transfusion. As of early June 2020, a perfect test does not exist, therefore haemovigilance along with the implementation of strict proactive measures is crucial to identify eluding asymptomatic individuals and ensure blood safety during the pandemic.


Subject(s)
Blood Component Transfusion/adverse effects , Blood Donors , Blood Safety , COVID-19/transmission , Donor Selection/standards , Pandemics , SARS-CoV-2/isolation & purification , Viremia/transmission , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asymptomatic Infections , COVID-19/blood , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19 Testing , Contact Tracing , Female , Greece/epidemiology , Humans , Immunocompromised Host , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Platelet-Rich Plasma , Police , Viremia/blood , Viremia/diagnosis
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