ABSTRACT
Over the past two decades, there have been significant advances in the treatment of multiple myeloma which has led to an improvement in overall survival (OS) (1,2). However, a notable proportion of patients continue to experience early mortality (EM), defined as two years from the time of diagnosis. This raises the possibility that improvements in myeloma survival have not extended equally to all groups. Using the latest data drawn from the Surveillance Epidemiology and End Results (SEER) database of patients in the United States spanning 2000-2019, we study impact of important sociodemographic factors on EM. Through regression modeling, we demonstrate that patients diagnosed from 2000-2005, of older age, male sex, and of certain racial minority status (non-Hispanic Black and Hispanic) have higher odds of EM. Of these factors, minority status contributed to worse 2-year overall survival as well. We evaluate whether income, as a surrogate to access to care, could potentially explain this finding, but find that race has a distinct relationship with EM that is not modified by income. This is further reinforced by subgroup analysis. After characterizing groups vulnerable to EM, we examine reasons for these disparities and potential avenues to address them.
ABSTRACT
INTRODUCTION: Myeloid malignancies are a heterogeneous group of clonal bone marrow disorders that are complex to manage in the community and therefore often referred to subspecialists at tertiary oncology referral centers. Many patients do not live in close proximity to tertiary referral centers and are unable to commute long distances due to age, comorbidities, and frailty. Interventions that minimize the travel time burden without compromising quality of care are an area of unmet need. We describe a cancer care delivery model for patients with myeloid malignancies that is built around telehealth and enables this vulnerable population access to care at an NCI-designated cancer center while receiving majority of their care close to home. METHODS AND MATERIALS: We report on a cohort of patients with myeloid malignancies who were co-managed by a general community oncologist and an academic leukemia subspecialist at Montefiore Einstein Cancer Center in New York. Patients were initially referred to our institute for a second opinion by community practices that are in partnership with Montefiore Health System, and initial visits were in-person or via telehealth. Treatment plans were made after discussion with patient's local community oncologist. Patients then continued to receive majority of their treatment and supportive care including transfusion support with their local oncologist, and follow-up visits were mainly via telehealth with the academic leukemia subspecialist. RESULTS: Our cohort of 12 patients had a median age of 81 years (range, 59-88 years). Patients remained on active treatment for a median time of 357 days (range, 154-557 days). Most of our patients had a performance status of ECOG 2 or higher. Three patients had myelodysplastic syndromes, 7 patients had acute myeloid leukemia, and 2 patients had myelofibrosis. The median number of hospitalizations over the total treatment time period was one. CONCLUSION: We demonstrate a shared academic and community care co-management model for the treatment of myeloid malignancies in elderly, frail patients using telehealth as a backbone with a very low hospitalization rate.
Subject(s)
COVID-19 , Delivery of Health Care , Disease Management , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Primary Myelofibrosis , Aged , Aged, 80 and over , Humans , Middle Aged , COVID-19/epidemiology , COVID-19/therapy , Delivery of Health Care/methods , Frail Elderly , Health Services Accessibility , Hospitalization/statistics & numerical data , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/epidemiology , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/therapy , Pandemics , Primary Myelofibrosis/epidemiology , Primary Myelofibrosis/therapy , Telemedicine , New York City/epidemiology , Academic Medical Centers , Community Health Services , ComorbidityABSTRACT
PURPOSE: Antenatal detection of limb anomalies is not uncommon, and pregnancies are usually terminated in view of the expected physical handicap. The aim of this retrospective observational study is to delineate the spectrum of fetal limb anomalies and provide evidence in support of complete postnatal evaluation in establishing recurrence risk. METHODS: We present 54 cases of limb malformations detected antenatally and discuss the spectrum of abnormalities, the utility of fetal autopsy, and genetic testing to establish recurrence risk in subsequent pregnancies. RESULTS: 16/54 cases were isolated radial ray anomalies. There were five cases of amniotic band syndrome, five limb body wall complex cases, three VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) associations, one case of sirenomelia, two cases of limb pelvis hypoplasia, and one case of OEIS (Omphalocele Exstrophy Imperforate anus and spinal defects). Four fetuses with non-isolated radial ray anomaly had trisomy 18. One case with bilateral radial ray defect had a mutation in the FANC-E gene confirming fanconi anemia. Twelve cases were unclassified. CONCLUSION: Autopsy is the most important investigation in fetuses with limb anomalies. We suggest chromosomal microarray (CMA) as a first-tier test after autopsy. However, in cases of bilaterally symmetrical limb anomalies, in case of previous similarly affected child, or history of consanguinity, whole exome sequencing (WES) can be offered as the primary investigation, followed by CMA if WES is normal.
Subject(s)
Heart Defects, Congenital , Limb Deformities, Congenital , Tracheoesophageal Fistula , Female , Humans , Pregnancy , Fetus/diagnostic imaging , Heart Defects, Congenital/diagnostic imaging , Heart Defects, Congenital/genetics , Kidney/abnormalities , Limb Deformities, Congenital/diagnostic imaging , Limb Deformities, Congenital/genetics , Trachea/abnormalities , Tracheoesophageal Fistula/diagnostic imaging , Tracheoesophageal Fistula/genetics , Prenatal DiagnosisABSTRACT
Antenatal posterior fossa cystic lesions are intimidating due to overlapping imaging features of benign and severe malformations. Sonographic assessment of the posterior fossa with good resolution median sagittal and axial views, either primary or secondarily reconstructed, plays the lead role in antenatal evaluation, further enhanced when sequential assessments are added. We present 10 cases of fetal posterior fossa cystic lesions diagnosed in the first and second trimesters that were sequentially analyzed and followed up till delivery or termination. The ultrasound imaging appearance, evolution, and morphometry have been presented in this article.
Subject(s)
Cysts , Dandy-Walker Syndrome , Humans , Female , Pregnancy , Cranial Fossa, Posterior/diagnostic imaging , Cranial Fossa, Posterior/abnormalities , Cranial Fossa, Posterior/pathology , Pregnancy Trimester, Second , Fetus/pathology , Cysts/pathology , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Globally, 5 million to 10 million people are infected with human T-cell leukemia virus type 1, which causes adult T-cell leukemia/lymphoma (ATLL) in 2% to 5% of the carriers. ATLL is a rare but extremely aggressive malignancy that can be challenging to diagnose. Very little data exist on the incidence patterns of ATLL in the United States. METHODS: ATLL cases reported to the National Program of Cancer Registries, the Surveillance, Epidemiology, and End Results (SEER) program, and the New York State Cancer Registry were used for the study. Age-adjusted incidence rates were calculated by age, race/ethnicity, sex, and year of diagnosis. The 5-year survival rate was compared among race/ethnicity groups with the SEER data. RESULTS: During 2001-2015, 2148 ATLL cases were diagnosed in the United States, 18% of which were in New York State. New York State had the highest incidence rate for ATLL, with a rising trend especially among non-Hispanic blacks (NHBs), whereas the incidence was stable across the remainder of the United States. NHBs were diagnosed at a younger median age (54 years) and had a shorter overall survival (6 months). In New York City, only 22.6% of the ATLL cases diagnosed were born in North America. CONCLUSIONS: This is the largest epidemiological study of ATLL in the United States and shows a rising incidence in New York City. NHBs have a younger age at presentation and poor overall survival. The rising incidence is largely due to NHBs originating from the Caribbean.
Subject(s)
Leukemia-Lymphoma, Adult T-Cell/epidemiology , Lymphoma/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/therapy , Lymphoma/pathology , Lymphoma/therapy , Male , Middle Aged , New York City/epidemiology , North America/epidemiology , SEER Program , United States/epidemiology , White People , Young AdultABSTRACT
Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher, whereas the mutation frequency in JAK/STAT and T-cell receptor/NF-κB pathway genes was significantly lower. The most common type of epigenetic mutation is that affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA sequencing analysis of 9 primary patient samples. ATLL samples with a mutated EP300 gene have decreased total and acetyl p53 protein and a transcriptional signature reminiscent of p53-mutated cancers. Most importantly, decitabine has highly selective single-agent activity in the EP300-mutated ATLL samples, suggesting that decitabine treatment induces a synthetic lethal phenotype in EP300-mutated ATLL cells. In conclusion, we demonstrate that North American ATLL has a distinct genomic landscape that is characterized by frequent epigenetic mutations that are targetable preclinically with DNA methyltransferase inhibitors.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Decitabine/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/genetics , Adult , Aged , Aged, 80 and over , Apoptosis/drug effects , E1A-Associated p300 Protein/genetics , Epigenesis, Genetic , Female , Humans , Japan/epidemiology , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/epidemiology , Male , Middle Aged , Mutation Rate , Prognosis , Transcriptome , Tumor Suppressor Protein p53/genetics , United States/epidemiologyABSTRACT
In the United States adult T cell lymphoma-leukemia (ATLL) carries a dismal prognosis and mainly affects immigrants from human T cell lymphotropic virus 1 endemic areas. Allogeneic hematopoietic stem cell transplant (alloHSCT) can be effective and is recommended as an upfront treatment in the National Comprehensive Cancer Network guidelines. We studied the barriers to alloHSCT in one of the largest ATLL populations in the United States. Comprehensive chart and donor registry reviews were conducted for 88 ATLL patients treated at Montefiore Medical Center from 2003 to 2018. Among 49 patients with acute and 32 with lymphomatous subtypes, 48 (59.5%) were ineligible for alloHSCT because of early mortality (52%), loss to follow-up (21%), uninsured status (15%), patient declination (10%), and frailty (2%). Among 28 HLA-typed eligible patients (34.6%), matched related donors were identified for 7 (25%). A matched unrelated donor (MUD) search yielded HLA-matched in 2 patients (9.5%), HLA mismatched in 6 (28.5%), and no options in 13 (62%). Haploidentical donors were identified for 6 patients (46%) with no unrelated options. There were no suitable donors for 7 (25%) alloHSCT-eligible patients. The main limitation for alloHSCT after donor identification was death from progressive disease (82%). AlloHSCT was performed in 10 patients (12.3%) and was associated with better relapse-free survival (26 versus 11 months, Pâ¯=â¯.04) and overall survival (47 versus 10 months, Pâ¯=â¯.03). Early mortality and progressive disease are the main barriers to alloHSCT, but poor follow-up, uninsured status, and lack of suitable donor, including haploidentical, are also substantial limitations that might disproportionally affect this vulnerable population. AlloHSCT can achieve long-term remissions, and strategies aiming to overcome these barriers are urgently needed to improve outcomes in ATLL.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Human T-lymphotropic virus 1/pathogenicity , Leukemia-Lymphoma, Adult T-Cell/therapy , Transplantation, Homologous/methods , Adult , Cohort Studies , Female , Humans , Male , Middle Aged , Tertiary Care Centers , United StatesABSTRACT
Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers are also seen in a stage-specific manner in human MDS samples as well as in murine models of the disease. Overexpression of several markers such as interleukin-1 (IL-1) receptor accessory protein (IL1RAP), CD99, T-cell immunoglobulin mucin-3, and CD123 have begun to differentiate MDS HSPCs from healthy counterparts. Overactivation of innate immune components such as Toll-like receptors, IL-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor-6, IL8/CXCR2, and IL1RAP signaling pathways has been demonstrated in MDS HSPCs and is being targeted therapeutically in preclinical and early clinical studies. Other dysregulated pathways such as signal transducer and activator of transcription 3, tyrosine kinase with immunoglobulinlike and EGF-like domains 1/angiopoietin-1, p21-activated kinase, microRNA 21, and transforming growth factor ß are also being explored as therapeutic targets against MDS HSPCs. Taken together, these studies have demonstrated that MDS stem cells are functionally critical for the initiation, transformation, and relapse of disease and need to be targeted therapeutically for future curative strategies in MDSs.
Subject(s)
Hematopoietic Stem Cells/pathology , Myelodysplastic Syndromes/pathology , Animals , Biomarkers, Tumor/analysis , Disease Progression , Humans , Immunity, Innate , Myelodysplastic Syndromes/genetics , Neoplastic Stem Cells/pathologyABSTRACT
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.
Subject(s)
Hematopoietic Stem Cells/metabolism , Interleukin-8/metabolism , Leukemia, Myeloid, Acute/metabolism , Myelodysplastic Syndromes/metabolism , Receptors, Interleukin-8B/metabolism , Signal Transduction , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Cluster Analysis , Disease Models, Animal , Gene Expression , Gene Expression Profiling , Humans , Interleukin-8/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Mice , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Neoplastic Stem Cells/metabolism , Prognosis , Receptors, Interleukin-8B/antagonists & inhibitors , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the ß3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 106 CD34+ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 106 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 106 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation.
Subject(s)
Adrenergic Uptake Inhibitors/therapeutic use , Antigens, CD34/immunology , Desipramine/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Adolescent , Adrenergic Uptake Inhibitors/administration & dosage , Adult , Aged , Benzylamines , Cyclams , Desipramine/administration & dosage , Drug Therapy, Combination , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/adverse effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/metabolism , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/adverse effects , Heterocyclic Compounds/therapeutic use , Humans , Male , Middle Aged , Multiple Myeloma/blood , Pilot Projects , Receptors, Adrenergic, beta-3/metabolism , Young AdultABSTRACT
BACKGROUND: Single-center studies suggest that patients with cancer have similar outcomes after intracerebral hemorrhage (ICH) compared to patients without cancer. However, these studies were limited by small sample sizes and high rates of intratumoral hemorrhage. Our hypothesis was that systemic cancer patients without brain involvement fare worse after ICH than patients without cancer. METHODS: We identified all patients diagnosed with spontaneous ICH from 2002 to 2011 in the Nationwide Inpatient Sample. Our predictor variable was systemic cancer. Our primary outcome was discharge disposition, dichotomized into favorable discharge (home/self-care or rehabilitation) or unfavorable discharge (nursing facility, hospice, or death). We used logistic regression to compare outcomes and performed secondary analyses by cancer subtype (i.e., nonmetastatic solid tumors, nonmetastatic hematologic tumors, and metastatic solid or hematologic tumors). RESULTS: Among 597,046 identified ICH patients, 22,394 (3.8%) had systemic cancer. Stroke risk factors such as hypertension and diabetes were more common in patients without cancer, whereas anticoagulant use and higher Charlson comorbidity scores were more common among cancer patients. In multivariate logistic regression analysis adjusted for demographics, comorbidities, and hospital-level characteristics, patients with cancer had higher odds of death (OR 1.62, 95% CI 1.56-1.69) and lower odds of favorable discharge (OR .59, 95% CI .56-.63) than patients without cancer. Among cancer groups, patients with nonmetastatic hematologic tumors and those with metastatic disease fared the worst. CONCLUSIONS: Patients with systemic cancer have higher mortality and less favorable discharge outcomes after ICH than patients without cancer. Cancer subtype may influence outcomes after ICH.
Subject(s)
Cerebral Hemorrhage/epidemiology , Neoplasms/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/mortality , Cerebral Hemorrhage/therapy , Chi-Square Distribution , Databases, Factual , Female , Hospice Care , Hospital Mortality , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Neoplasms/diagnosis , Neoplasms/mortality , Neoplasms/therapy , Odds Ratio , Patient Discharge , Retrospective Studies , Risk Assessment , Risk Factors , Self Care , Skilled Nursing Facilities , Time Factors , Treatment Outcome , United States/epidemiology , Young AdultSubject(s)
Betacoronavirus , Coronavirus Infections/complications , Monoclonal Gammopathy of Undetermined Significance/complications , Pneumonia, Viral/complications , Aged , Aged, 80 and over , COVID-19 , Comorbidity , Fatal Outcome , Female , Humans , Male , Middle Aged , Pandemics , Prognosis , SARS-CoV-2ABSTRACT
Three hundred women presenting to a sexually transmitted infection (STI) clinic in Mumbai, India were surveyed and HIV tested. Thirty-nine percent were HIV infected; 80% were current sex workers, and HIV infection was not significantly associated with past-year sex work. Only 44% always used condoms with their noncommercial sex partners. Most believed that condom preparation is a male responsibility (58%); that condom use is a sign that partner trust is lacking (84%); and that if a woman asks her partner to use a condom, he will lose respect for her (65%). All women at STI clinics in India need HIV testing and culturally sensitive risk interventions.
Subject(s)
Ambulatory Care Facilities/statistics & numerical data , HIV Infections/epidemiology , Health Knowledge, Attitudes, Practice , Risk-Taking , Sex Workers , Sexual Behavior , Condoms/statistics & numerical data , Cross-Sectional Studies , Female , HIV Infections/transmission , Humans , India/epidemiology , Male , Prevalence , Risk Factors , Sex Work , Sexual Partners , Sexually Transmitted Diseases/epidemiology , Sexually Transmitted Diseases/transmission , Surveys and QuestionnairesABSTRACT
Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.
Subject(s)
Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Unrelated Donors , Humans , Female , Male , Middle Aged , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Adult , Graft vs Host Disease/prevention & control , Minority Groups/statistics & numerical data , Cohort Studies , HLA Antigens/immunology , AgedABSTRACT
While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR-T), and T cell engagers have improved the response rates in B cell malignancies, the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19 immunotoxin. Single-cell RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (ATAC-Seq) showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B cell acute lymphoblastic leukemia (B-ALL) that relapsed after CD19 CAR-T-targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (BTK) and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.
Subject(s)
Antigens, CD19 , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Sialic Acid Binding Ig-like Lectin 2 , Child , Humans , Young Adult , Agammaglobulinaemia Tyrosine Kinase , Antigens, CD19/genetics , Chromatin , Immunotherapy, Adoptive , Mitogen-Activated Protein Kinase Kinases , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Chimeric Antigen , Sialic Acid Binding Ig-like Lectin 2/geneticsABSTRACT
BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Myelodysplastic Syndromes , Pneumonia , Male , Humans , Female , Decitabine/adverse effects , Treatment Outcome , Leukemia, Myelomonocytic, Chronic/drug therapy , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/etiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pneumonia/etiologyABSTRACT
BACKGROUND AND PURPOSE: The safety of thrombolysis for acute stroke in patients with cancer is not well established. Our aim is to study the outcomes after thrombolysis in patients with stroke with cancer. METHODS: Patients with acute ischemic stroke who received thrombolysis were identified from the 2009 and 2010 Nationwide Inpatient Sample. Patients with cancer-associated strokes and noncancer strokes were compared based on demographics, comorbidities, and outcomes. RESULTS: Of the 32 576 strokes treated with thrombolysis, cancer-associated strokes had significantly higher comorbidity indices overall, but fewer vascular risk factors than noncancer strokes. There was no difference in the rates of home discharge and in-hospital mortality, after adjusting for confounders. Subgroup analysis showed that compared with liquid cancers, patients with solid tumors had worse home discharge (odds ratio, 0.178; 95% confidence interval, 0.109-0.290; P<0.001) and higher in-hospital mortality (odds ratio, 3.018; 95% confidence interval, 1.37-6.646; P=0.006) after thrombolysis. Metastatic cancers had poorest outcomes, but intracerebral hemorrhage rates were similar. CONCLUSIONS: Thrombolytic therapy for acute stroke in patients with cancer is not associated with increased risk of intracerebral hemorrhage or in-hospital mortality. However, careful consideration of the cancer subtype may help delineate the subset of patients with poor response to thrombolysis. Prospective confirmation is warranted.
Subject(s)
Brain Ischemia/drug therapy , Fibrinolytic Agents/therapeutic use , Neoplasms/complications , Stroke/drug therapy , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/therapeutic use , Adult , Aged , Aged, 80 and over , Brain Ischemia/complications , Female , Fibrinolytic Agents/adverse effects , Humans , Male , Middle Aged , Risk Factors , Stroke/complications , Time Factors , Tissue Plasminogen Activator/adverse effects , Treatment OutcomeABSTRACT
Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) are clonal diseases that emerge and progress due to the expansion of disease-initiating aberrant hematopoietic stem cells, that are not eliminated by conventional cytotoxic therapies. Hypomethylating agents(HMA), azacytidine and decitabine are the first line agents for treatment of MDS and a combination with BCL-2 inhibitor, venetoclax, is approved for AML induction in patients above 75 years and is also actively being investigated for use in high risk MDS. Resistance to these drugs has become a significant clinical challenge in treatment of myeloid malignancies. In this review, we discuss molecular mechanisms underlying the development of resistance to HMA and venetoclax. Insights into these mechanisms can help identify potential biomarkers for resistance prediction, aid in the development of combination therapies and strategies to prevent resistance and advance the field of cancer therapeutics.
Subject(s)
Antineoplastic Agents , GATA2 Deficiency , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Antineoplastic Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Azacitidine/therapeutic use , Proto-Oncogene Proteins c-bcl-2/geneticsABSTRACT
PURPOSE OF REVIEW: To discuss novel targeted therapies under investigation for treatment of myelodysplastic neoplasms (MDS). RECENT FINDINGS: Over the last few years, results of phase 3 trials assessing novel therapies for high-risk MDS have been largely disappointing. Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. However, early phase trials of BCL-2, TIM3, and CD47 inhibitors have shown exciting data and are currently under phase 3 investigation. Moreover, combination of hypomethylating agents (HMA) with novel therapies targeting the mutational (IDH, FLT3, spliceosome complex) or immune (PD-1/PDL-1, TIM-3, IRAK-4) pathways are being investigated in early phase clinical trials and have shown adequate safety and promising efficacy. Myelodysplastic neoplasms (MDS) are a group of hematopoietic neoplasms defined by cytopenias and morphological dysplasia. They are characterized by clonal proliferation of aberrant hematopoietic stem cells caused by recurrent genetic abnormalities. This leads to ineffective erythropoiesis, peripheral blood cytopenias, abnormal cell maturation, and a high risk of transformation into acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, it is not a suitable option for majority patients due to their age, comorbidities, and the high rate of treatment-related complications. HMAs remain the only FDA-approved treatment option for high-risk MDS. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.