Publications by authors named "Ashkan Emadi"

83 Publications

-ITD Allelic Burden and Acute Promyelocytic Leukemia Risk Stratification.

Biology (Basel) 2021 Mar 21;10(3). Epub 2021 Mar 21.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

The significance of -ITD in acute promyelocytic leukemia (APL) is not well-established. We performed a bi-center retrospective study of 138 APL patients, 59 (42.8%) of whom had -ITD. APL patients with -ITD had higher baseline white blood cell counts (WBCs) ( < 0.001), higher hemoglobin, ( = 0.03), higher aspartate aminotransferase ( = 0.001), lower platelets ( = 0.004), lower fibrinogen ( = 0.003), and higher incidences of disseminated intravascular coagulation ( = 0.005), M3v variant morphology ( < 0.001), and the bcr3 isoform ( < 0.001). -ITD was associated with inferior post-consolidation complete remission (CR) ( = 0.02) and 5-year overall survival (OS) of 79.7%, compared to 94.4% for -WT (wild-type) ( = 0.02). -ITD was strongly associated with baseline WBCs ≥ 25 × 10/L (odds ratio (OR): 54.4; 95% CI: 10.4-286.1; < 0.001). High -ITD allelic burdens correlated with high-risk (HR) Sanz scores and high WBCs, with every 1% increase in allelic burden corresponding to a 0.6 × 10/L increase in WBC. HR APL was associated with a 38.5% increase in allelic burden compared with low-risk (LR) APL (95% CI: 19.8-57.2; < 0.001). Our results provide additional evidence that -ITD APL is a distinct subtype of APL that warrants further study to delineate potential differences in therapeutic approach.
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http://dx.doi.org/10.3390/biology10030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003857PMC
March 2021

Increased body mass index is a risk factor for acute promyelocytic leukemia.

EJHaem 2021 02 6;2(1):33-39. Epub 2021 Jan 6.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Introduction: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community.

Methods: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center.

Results: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m and 30.3 kg/m) than those with AML (28.3 kg/m and 27.1 kg/m), ALL (29.3 kg/m and 27.7 kg/m), and others (29.3 kg/m and 27.7 kg/m) (p<0.001). Log-transformed BMI multivariable models demonstrated that APL patients had a significantly higher adjusted mean BMI by 3.7 kg/m (p<0.001) or approximately 10% (p<0.01) compared to the other groups, when controlled for sex, race, and age.

Conclusions: This study confirms that when controlled for sex, age, and race there is an independent association of higher BMI among patients with APL compared to patients with ALL, AML, and hospitalized individuals without leukemia in the same community.
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http://dx.doi.org/10.1002/jha2.163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943182PMC
February 2021

Venous thromboembolism incidence and risk factors in adults with acute lymphoblastic leukemia treated with and without pegylated E. coli asparaginase-containing regimens.

Cancer Chemother Pharmacol 2021 Mar 7. Epub 2021 Mar 7.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Purpose: Asparaginases, key agents in treatment of acute lymphoblastic leukemia (ALL), are associated with venous thromboembolism (VTE). While risks of short-acting asparaginase-related VTE is well-known, we studied VTE incidence and risk factors in adult ALL patients treated with and without long-acting pegylated asparaginase (PegA).

Methods: Single-center, retrospective analysis of 89 ALL patients treated with (n = 61) or without (n = 28) PegA at Greenebaum Comprehensive Cancer Center. Reviewed patient and disease characteristics, treatment, and VTE incidence.

Results: VTE during treatment occurred in 31 patients (35%), and was associated with PegA (p = 0.001) and Philadelphia chromosome negativity (p = 0.002). Among PegA recipients, VTE was associated with a significantly higher mean body mass index (BMI) of 31.3 kg/m (p = 0.037), and was more common with pre-T/T cell compared to pre-B/B cell ALL (68.2% vs. 33.3%, p = 0.009). Antithrombin-III (ATIII) levels were measured for 26 patients; 16 (61.5%) were < 50%. Of those, 8 (50%) experienced VTE, while 3 of 10 (30%) patients with ATIII levels ≥ 50% experienced VTE. VTE occurred in 7 of 13 (54%) of patients who received ATIII repletion. There was a trend toward a higher incidence of VTE in the PegA group among patients with non-O compared to O blood type (55.9% vs. 33.3%, p = 0.079) as well as those with a higher hemoglobin at diagnosis (9.3 vs 8.1 g/dL, p = 0.056).

Conclusion: This study confirms PegA as a risk factor for VTE in patients with ALL. Risk factors among those receiving PegA include higher BMI and pre-T/T cell ALL. ATIII repletion was not shown to be protective against VTE. There was a higher incidence of VTE in patients who received PegA with non-O compared to O blood type, but the precise correlation is uncertain.
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http://dx.doi.org/10.1007/s00280-021-04252-yDOI Listing
March 2021

1-C Metabolism-Serine, Glycine, Folates-In Acute Myeloid Leukemia.

Pharmaceuticals (Basel) 2021 Feb 26;14(3). Epub 2021 Feb 26.

Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.

Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. Glutamine depletion has also emerged as a therapeutic approach for cancers that have demonstrated dependence on glutamine for survival. Recent studies have shown that in response to glutamine deprivation leukemia cells upregulate key enzymes in the serine biosynthesis pathway, suggesting that serine upregulation may be a targetable compensatory mechanism. These new findings may provide opportunities for novel cancer treatments.
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http://dx.doi.org/10.3390/ph14030190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996867PMC
February 2021

Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax.

Blood Adv 2021 Feb;5(3):711-724

Center for Stem Cell Biology & Regenerative Medicine and.

Artemisinins are active against human leukemia cell lines and have low clinical toxicity in worldwide use as antimalarials. Because multiagent combination regimens are necessary to cure fully evolved leukemias, we sought to leverage our previous finding that artemisinin analogs synergize with kinase inhibitors, including sorafenib (SOR), by identifying additional synergistic antileukemic drugs with low toxicity. Screening of a targeted antineoplastic drug library revealed that B-cell lymphoma 2 (BCL2) inhibitors synergize with artemisinins, and validation assays confirmed that the selective BCL2 inhibitor, venetoclax (VEN), synergized with artemisinin analogs to inhibit growth and induce apoptotic cell death of multiple acute leukemia cell lines in vitro. An oral 3-drug "SAV" regimen (SOR plus the potent artemisinin-derived trioxane diphenylphosphate 838 dimeric analog [ART838] plus VEN) killed leukemia cell lines and primary cells in vitro. Leukemia cells cultured in ART838 had decreased induced myeloid leukemia cell differentiation protein (MCL1) levels and increased levels of DNA damage-inducible transcript 3 (DDIT3; GADD153) messenger RNA and its encoded CCATT/enhancer-binding protein homologous protein (CHOP), a key component of the integrated stress response. Thus, synergy of the SAV combination may involve combined targeting of MCL1 and BCL2 via discrete, tolerable mechanisms, and cellular levels of MCL1 and DDIT3/CHOP may serve as biomarkers for action of artemisinins and SAV. Finally, SAV treatment was tolerable and resulted in deep responses with extended survival in 2 acute myeloid leukemia (AML) cell line xenograft models, both harboring a mixed lineage leukemia gene rearrangement and an FMS-like receptor tyrosine kinase-3 internal tandem duplication, and inhibited growth in 2 AML primagraft models.
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http://dx.doi.org/10.1182/bloodadvances.2020003429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876886PMC
February 2021

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study.

Thromb Res 2021 02 11;198:135-138. Epub 2020 Dec 11.

Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Thrombosis and pulmonary embolism appear to be major causes of mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. However, few studies have focused on the incidence of venous thromboembolism (VTE) after hospitalization for COVID-19.

Methods: In this multi-center study, we followed 1529 COVID-19 patients for at least 45 days after hospital discharge, who underwent routine telephone follow-up. In case of signs or symptoms of pulmonary embolism (PE) or deep vein thrombosis (DVT), they were invited for an in-hospital visit with a pulmonologist. The primary outcome was symptomatic VTE within 45 days of hospital discharge.

Results: Of 1529 COVID-19 patients discharged from hospital, a total of 228 (14.9%) reported potential signs or symptoms of PE or DVT and were seen for an in-hospital visit. Of these, 13 and 12 received Doppler ultrasounds or pulmonary CT angiography, respectively, of whom only one patient was diagnosed with symptomatic PE. Of 51 (3.3%) patients who died after discharge, two deaths were attributed to VTE corresponding to a 45-day cumulative rate of symptomatic VTE of 0.2% (95%CI 0.1%-0.6%; n = 3). There was no evidence of acute respiratory distress syndrome (ARDS) in these patients. Other deaths after hospital discharge included myocardial infarction (n = 13), heart failure (n = 9), and stroke (n = 9).

Conclusions: We did not observe a high rate of symptomatic VTE in COVID-19 patients after hospital discharge. Routine extended thromboprophylaxis after hospitalization for COVID-19 may not have a net clinical benefit. Randomized trials may be warranted.
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http://dx.doi.org/10.1016/j.thromres.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836837PMC
February 2021

High dose cytarabine, mitoxantrone, pegasapargase (HAM-pegA) in combination with dasatinib for the first-line treatment of Philadelphia chromosome positive mixed phenotype acute leukemia.

Am J Leuk Res 2020 15;4(1). Epub 2020 Oct 15.

University of Maryland Greenebaum Comprehensive Cancer Center, 22 S Greene St Baltimore MD 21201, USA.

The treatment of mixed phenotype acute leukemia (MPAL) is challenging due to the presence of disease characteristics of both myeloid and lymphoid leukemia. Regimens historically used to treat acute lymphoblastic leukemia are often used to treat MPAL, particularly for patients whose diseases also possess the Philadelphia chromosome (Ph+). Here we present a novel regimen, HAM-pegA plus dasatinib, for the treatment of two patients with newly diagnosed Ph+ MPAL. This regimen is a blend of both myeloid-targeted and lymphoid-targeted chemotherapy agents, and is given as a single cycle of intensive chemotherapy followed by oral dasatinib maintenance therapy. Without proceeding to allogeneic transplant, this regimen produced durable remissions of 18 months and longer. This novel regimen offers an exciting alternative to other intensive regimens that require multiple cycles of intensive chemotherapy and allogeneic transplant in first remission.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717491PMC
October 2020

Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia.

Leukemia 2020 Nov 16. Epub 2020 Nov 16.

University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.

Complex karyotype acute myeloid leukemia (CK-AML) has a dismal outcome with current treatments, underscoring the need for new therapies. Here, we report synergistic anti-leukemic activity of the BCL-2 inhibitor venetoclax (Ven) and the asparaginase formulation Pegylated Crisantaspase (PegC) in CK-AML in vitro and in vivo. Ven-PegC combination inhibited growth of multiple AML cell lines and patient-derived primary CK-AML cells in vitro. In vivo, Ven-PegC showed potent reduction of leukemia burden and improved survival, compared with each agent alone, in a primary patient-derived CK-AML xenograft. Superiority of Ven-PegC, compared to single drugs, and, importantly, the clinically utilized Ven-azacitidine combination, was also demonstrated in vivo in CK-AML. We hypothesized that PegC-mediated plasma glutamine depletion inhibits 4EBP1 phosphorylation, decreases the expression of proteins such as MCL-1, whose translation is cap dependent, synergizing with the BCL-2 inhibitor Ven. Ven-PegC treatment decreased cellular MCL-1 protein levels in vitro by enhancing eIF4E-4EBP1 interaction on the cap-binding complex via glutamine depletion. In vivo, Ven-PegC treatment completely depleted plasma glutamine and asparagine and inhibited mRNA translation and cellular protein synthesis. Since this novel mechanistically-rationalized regimen combines two drugs already in use in acute leukemia treatment, we plan a clinical trial of the Ven-PegC combination in relapsed/refractory CK-AML.
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http://dx.doi.org/10.1038/s41375-020-01080-6DOI Listing
November 2020

Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial.

Trials 2020 Oct 28;21(1):897. Epub 2020 Oct 28.

University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 South Greene Street, Room N9E06, Baltimore, Maryland, 21201, USA.

Objectives: Primary Objective: To evaluate the efficacy and safety of oral administration of imatinib combined with the Best Conventional Care (BCC) versus placebo plus BCC in hospitalized patients with COVID-19.

Hypothesis: Addition of imatinib to the BCC will provide a superior clinical outcome for patients with COVID-19 compared with BCC plus placebo. This hypothesis is on the basis of 1) intralysosomal entrapment of imatinib will increase endosomal pH and effectively decrease SARS-CoV-2/cell fusion, 2) kinase inhibitory activity of imatinib will interfere with budding/release or replication of SARS-CoV-2, and 3) because of the critical role of mechanical ventilation in the care of patients with ARDS, imatinib will have a significant clinical impact for patients with critical COVID-19 infection in Intensive Care Unit (ICU).

Trial Design: This is an individual patient-level randomized, double-blind, placebo-controlled, two-parallel arm phase 3 study to evaluate the safety and efficacy of imatinib for the treatment of hospitalized adults with COVID-19. Participants will be followed for up to 60 days from the start of study drug administration. This trial will be conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization.

Participants: Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria: 1) Ability to understand and willingness to sign a written informed consent document. Informed consent must be obtained prior to participation in the study. For patients who are too unwell to provide consent such as patients on invasive ventilator or extracorporeal membrane oxygenation (ECMO), their Legally Authorized Representative (LAR) can sign the informed consent, 2) Hospitalized patients ≥18 years of age, 3) Positive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 in the respiratory tract sample (oropharyngeal, nasopharyngeal or bronchoalveolar lavage (BAL)) by Center for Disease Control or local laboratory within 7 days of randomization, 4) Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study.

Exclusion Criteria: Patients meeting any of the following criteria are not eligible for the study: 1) Patients receiving any other investigational agents in a clinical trial. Off-label use of agents such as hydroxychloroquine is not an exclusion criterion, 2) Pregnant or breastfeeding women, 3) Patients with significant liver or renal dysfunction at the time of screening as defined as: 3.1) Direct bilirubin >2.5 mg/dL, 3.2) AST, ALT, or alkaline phosphatase >5x upper limit of normal, 3.3) eGFR ≤30 mL/min or requiring renal replacement therapy, 4) Patients with significant hematologic disorder at screen as defined as: 4.1) Absolute neutrophil count (ANC) <500/μL, 4.2) Platelet <20,000/μL, 4.3) Hemoglobin <7 g/dL, 5) Uncontrolled underlying illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled active seizure disorder, or psychiatric illness/social situations that per site Principal Investigator's judgment would limit compliance with study requirements, 6) Known allergy to imatinib or its component products, 7) Any other clinical conditions that in the opinion of the investigator would make the subject unsuitable for the study. Both men and women of all races and ethnic groups are eligible for this trial. University of Maryland Medical Center, Baltimore, MD is the initiating site. The study may be opened in other centers on the basis of the accrual rate or the magnitude of the COVID-19 pandemic.

Intervention And Comparator: Imatinib: All doses of imatinib should be administered with a meal and a large glass of water. Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. In this study, patients with confirmed positive COVID-19 tests receive imatinib for a total of 14 days; 400 mg orally daily Days 1-14. Imatinib 400 mg tablets will be encapsulated using size 000 capsules and cellulose microcrystalline filler. For patients on ventilator or ECMO, imatinib will be given as oral suspension (40 mg/mL). To make the oral suspension, imatinib tablets will be crushed and mixed in Ora-sweet solution to yield a concentration of 40 mg/mL suspension by pharmacy. Additionally, in the absence of supportive microbiological testing results, we confirm that the in-use stability period for the prepared imatinib suspensions will be 24 hours at room temperature or 7 days at refrigerated conditions. The pharmacy staff will follow the American Society Health-System Pharmacists (ASHP) guidelines for handling hazardous drugs. Placebo: The matching placebo will be packaged by Investigational Drug Service Pharmacy at University of Maryland Medical Center. The placebos will be prepared using size 000 capsules and cellulose microcrystalline filler. Imatinib 400 mg capsules and placebo capsules will be identical form and color. For patients on ventilator or ECMO, placebo will be given as oral suspension with similar process for making imatinib suspension. Concomitant Medications/supportive care: In both arms, patients can receive concomitant available local standard of care antipyretics, antibacterials, antivirals, antifungals and anti-inflammatory including hydroxychloroquine at the discretion of the treating physician as necessary. For other drug-drug interactions particularly with CYP P450, the treating physician should consider the risk and benefit of drug administration based on available information. Co-administration of off-label immunomodulatory treatments for COVID-19 including but not limited to corticosteroids, sarilumab, clazakizumab, tocilizumab, and anakinra will be allowed but may affect interpretability of study outcomes. The timing, dosing, and duration of these treatments will be meticulously collected, including any of these treatments that may be used for participants who experience progression of COVID-19 disease after study enrollment. Two analyses will be performed, the primary analysis will compare the primary endpoint in the two trial arms irrespective of any other treatment; the second analysis will be stratified for co-administration of immunomodulatory drugs.

Main Outcomes: The primary endpoint is the proportion of patients with a two-point improvement at Day 14 from baseline using the 8-category ordinal scale. The ordinal scale is an evaluation of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or ECMO; 8) Death. The secondary endpoints include: All-cause mortality at Day 28, All-cause mortality at Day 60, Time to a 2-point clinical improvement difference over baseline, Duration of hospitalization, Duration of ECMO or invasive mechanical ventilation (for subjects who are on ECMO or mechanical ventilation at Day 1), Duration of ICU stay (for subjects who are in ICU at Day 1), Time to SARS-CoV-2 negative by RT-PCR, Proportion of patients with negative oropharyngeal or nasopharyngeal swab for SARS-CoV-2 by RT-PCR on days 5, 10, 14, 21, and 28 after starting treatment, Proportion of subjects with serious adverse events, Proportion of subjects who discontinue study drug due to adverse events. The exploratory endpoints include: Determine the impact of treatment arms on IL-6 levels, Obtain blood/peripheral blood mononuclear cells (PBMCs) for storage to look at transcriptomics in severe disease, Association of major histocompatibility complex (MHC) with severity of illness, Mean change in the ordinal scale from baseline, Time to an improvement of one category from admission using an ordinal scale, Duration of hospitalization, Duration of new oxygen use, Number of oxygenation free days, Duration of new mechanical ventilation, Number of ventilator free days.

Randomization: Eligible patients will be uniformly randomized in 1:1 ratio to receive either imatinib or placebo for 14 days. Both groups will receive the BCC. The randomized treatment allocations use stratified, permuted block randomization with a variable block size; blocks are generated using a validated random number generator. In order to balance the severity of the respiratory illness between the two arms, randomization will be stratified based on radiographic findings and oxygen requirements: 1) Severe disease: evidence of pneumonia on chest X-ray or CT scan OR chest auscultation (rales, crackles), and SpO ≤92% on ambient air or PaO/FiO <300 mmHg, and requires supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device; 2) Critical disease: requires supplemental oxygen delivered by non-rebreather mask or high flow cannula OR use of invasive or non-invasive ventilation OR requiring treatment in an intensive care unit, use of vasopressors, extracorporeal life support, or renal replacement therapy.

Blinding (masking): The participants, caregivers, and the statistician are blinded to group assignment. The only people who are not blinded are Site Pharmacists. Blinding will be performed via a specific randomization process. Centralized, concealed randomization will be executed by the Primary Site's Pharmacist. Data on eligible consented cases will be submitted electronically on the appropriate on-study form to the pharmacy, where the patient is randomized to imatinib or placebo. Imatinib 400 mg capsules and placebo capsules will be identical form and color. For patients on ventilator or ECMO, placebo will be given as oral suspension with similar process for making imatinib suspension.

Numbers To Be Randomized (sample Size): The trial is designed as a double-blind, two-parallel arm, randomized controlled trial with a uniform (1:1) allocation ratio to: Arm A) Imatinib or Arm B) Placebo. Patients in both arms will receive the BCC per local institutional standards at the discretion of the treating physician. Group sample sizes of 102 in Arm A and 102 in Arm B achieve 80.6% power to detect a difference between the group proportions of 0.20. The proportion in Arm A (imatinib treatment arm) is assumed to be 0.30 under the null hypothesis and 0.50 under the alternative hypothesis. The proportion in Arm B (placebo control arm) is 0.30. The test statistic used is the two-sided Fisher's Exact Test. The significance level of the test is targeted at 0.05. The significance level actually achieved by this design is α=0.0385. The power of the test is calculated using binomial enumeration of all possible outcomes. The primary analysis will be conducted using an intention to treat principle (ITT) for participants who at least receive one dose of study drug or placebo. The sample size is not inflated for dropouts. All patients will be evaluable irrespective of the clinical course of their disease.

Trial Status: Current protocol version is 1.2 from May 8, 2020. The recruitment started on June 15, 2020 and is ongoing. We originally anticipated that the trial would finish recruitment by mid 2021. We are aware of the enrollment requirement of approximately 200 patients, which is required to provide scientific integrity of the results. We are also aware of the fact that enrolling this number of patients in a single-site at University of Maryland Medical Center (UMMC) may take longer than expected, particularly taken into account other competing studies. For this reason, we are actively considering opening the protocol in other sites. After identification of other sites, we will fulfill all regulatory requirements before opening the protocol in other sites.

Trial Registration: ClinicalTrials.gov Identifier: NCT04394416 . First Posted: May 19, 2020; Last Update Posted: June 4, 2020. FDA has issued the "Study May Proceed" Letter for this clinical trial under the Investigational New Drug (IND) number 149239.

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04819-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594416PMC
October 2020

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Blood 2021 Feb;137(6):751-762

Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.
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http://dx.doi.org/10.1182/blood.2020007732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885824PMC
February 2021

Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

Pharmaceuticals (Basel) 2020 Jun 16;13(6). Epub 2020 Jun 16.

Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.
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http://dx.doi.org/10.3390/ph13060124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345996PMC
June 2020

Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia.

J Clin Med 2020 Feb 16;9(2). Epub 2020 Feb 16.

Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA.

Currently, no standard of care exists for the treatment of relapsed or refractory acute myeloid leukemia (AML). We present our institutional experience with using either CLAG-M or HAM-pegA, a novel regimen that includes pegaspargase. This is a retrospective comparison of 34 patients receiving CLAG-M and 10 receiving HAM-pegA as first salvage cytotoxic chemotherapy in the relapsed or refractory setting. Composite complete response rates were 47.1% for CLAG-M and 90% for HAM-pegA ( = 0.027). Event-free survival was significantly different in favor of HAM-pegA ( = 0.045), though overall survival was similar between groups. There were no significant differences in toxicities experienced by patients treated with the two regimens, including adverse events of special interest related to pegaspargase (venous thromboembolism, hemorrhage, hepatotoxicity, pancreatitis, and hypersensitivity reactions). HAM-pegA is a novel regimen for relapsed or refractory AML that resulted in improved response rates and similar toxicities compared to CLAG-M.
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http://dx.doi.org/10.3390/jcm9020536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074083PMC
February 2020

Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse?

Leukemia 2020 03 8;34(3):671-681. Epub 2020 Jan 8.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

Since 2017 the US Food and Drug Administration (FDA) has approved glasdegib, venetoclax, ivosidenib, midostaurin, CPX- 351, and gemtuzumab ozogamicin (GO) to treat persons with newly diagnosed acute myeloid leukemia. The European Medicines Agency (EMA) has done likewise for midostaurin, CPX-351, and GO. While increasing options for persons, particularly older ones, for whom current therapy is unsatisfactory, or simply not given, these approvals raise several concerns. Although the venetoclax and glasdegib approvals were for persons considered "unfit" for intensive induction, the criteria for fitness were not well defined (age ≥75 per se being insufficient) and are frequently subjective, making it likely that many subjects in the venetoclax and glasdegib registration trials were fit for intensive induction; for example, none had performance status 3-4. Fitness must be assessed together with the potential efficacy of a proposed therapy. We note the modest complete remission rates and durations in the venetoclax + hypomethylating agent trial. Although these formed the basis for FDA approval, it is unclear that better results might not have obtained with more intense induction, as several studies, with considerably longer-follow up, have suggested. Hence, we question the venetoclax (and glasdegib) approvals absent randomized comparisons with intense induction. Given the uncertain relation in older individuals between survival and complete remission (CR), much less responses less than CR, we are skeptical of the sole use of these responses in the ivosidenib and venetoclax approvals; we also question the use of survival, without event-free survival, in the glasdegib approval. Noting the midostaurin and CPX-351 approvals included populations not participating in the registration studies we suggest means to address this issue as well as those involving fitness, randomization, and endpoints.
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http://dx.doi.org/10.1038/s41375-019-0704-5DOI Listing
March 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, Massachusetts General Hospital, Boston, Massachusetts.

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

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia.

Br J Haematol 2020 03 5;188(6):881-887. Epub 2019 Dec 5.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.
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http://dx.doi.org/10.1111/bjh.16261DOI Listing
March 2020

Real-world experience managing blinatumomab toxicities in adults with relapsed/refractory acute lymphoblastic leukemia.

J Oncol Pharm Pract 2020 Jul 21;26(5):1080-1085. Epub 2019 Oct 21.

Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD, USA.

Purpose: The purpose of this study was to determine the effect of blinatumomab toxicities on drug therapy modifications in an intended 28-day course of blinatumomab therapy.

Methods: Patients with acute lymphoblastic leukemia who received blinatumomab at the University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center from March 1, 2015 to April 30, 2018 were included. The primary objective of this study was to identify the frequency and severity of blinatumomab toxicities that led to drug therapy modifications; secondary objectives were to identify the frequency and duration of modifications and the total dose and duration of therapy received.

Results: This study included 23 patients. Seventy-eight percent of patients experienced cytokine release syndrome and/or neurotoxicity. Eighteen drug therapy modifications occurred due to toxicity with a median interruption time of nine hours. Drug therapy was continued for the majority of grade 1 or 2 events and discontinued during grade 3 or 4 neurotoxicity. The median number of days of therapy delivered was 28 days (range, 27-35). A median of 2 h (range, 0-16) of therapy or 0.2% (range, 0-2.4) of a total 28-day cycle was lost due to transition of care.

Conclusion: This retrospective study demonstrates a single center experience with blinatumomab toxicity management and appropriate delivery of drug during transitions of care. Overall, these results support to the importance of institutional guidelines in place to facilitate safe and effective delivery of blinatumomab.
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http://dx.doi.org/10.1177/1078155219881680DOI Listing
July 2020

A Prospective Study of Peritransplant Sorafenib for Patients with FLT3-ITD Acute Myeloid Leukemia Undergoing Allogeneic Transplantation.

Biol Blood Marrow Transplant 2020 02 21;26(2):300-306. Epub 2019 Sep 21.

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001148PMC
February 2020

Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics.

Molecules 2019 Aug 28;24(17). Epub 2019 Aug 28.

Department of Medicine Division of Hematology/Oncology University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus.
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http://dx.doi.org/10.3390/molecules24173121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749238PMC
August 2019

Characteristics and outcomes of therapy-related myeloid neoplasms after treatment for multiple myeloma.

Leuk Lymphoma 2019 12 8;60(14):3577-3580. Epub 2019 Jul 8.

Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1080/10428194.2019.1633639DOI Listing
December 2019

Refractory postallogeneic stem cell transplant pure red cell aplasia in remission after treatment with daratumumab.

Am J Hematol 2019 08 7;94(8):E216-E219. Epub 2019 Jun 7.

Department of Medicine, Department of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1002/ajh.25515DOI Listing
August 2019

Equipotent doses of daunorubicin and idarubicin for AML: a meta-analysis of clinical trials versus in vitro estimation.

Cancer Chemother Pharmacol 2019 06 9;83(6):1105-1112. Epub 2019 Apr 9.

School of Medicine, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Room N9E24, Baltimore, MD, 21201, USA.

In the treatment of acute myeloid leukemia (AML), the "7 + 3"-based strategy, combining cytarabine 100-200 mg/m for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7-20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64-4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9-4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.
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http://dx.doi.org/10.1007/s00280-019-03825-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334867PMC
June 2019

Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management.

J Oncol Pharm Pract 2020 Jan 27;26(1):74-92. Epub 2019 Mar 27.

Division of Hematology/Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.
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http://dx.doi.org/10.1177/1078155219838316DOI Listing
January 2020

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib.

Acta Haematol 2019 29;141(2):107-110. Epub 2019 Jan 29.

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA,

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.
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http://dx.doi.org/10.1159/000495558DOI Listing
September 2019

Treatment of CD19-positive mixed phenotype acute leukemia with blinatumomab.

Am J Hematol 2019 01 25;94(1):E7-E8. Epub 2018 Nov 25.

Departments of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1002/ajh.25317DOI Listing
January 2019

High-Risk Acute Promyelocytic Leukemia with Unusual T/Myeloid Immunophenotype Successfully Treated with ATRA and Arsenic Trioxide-Based Regimen.

J Hematop 2018 09 9;11(3):67-74. Epub 2018 Aug 9.

Department of Medicine, University of Maryland School of Medicine.

We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored -ITD mutations. One additionally had a deletion in the gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation. Our report highlights the complexity and challenge of diagnosis and management of APL due to the variant immunophenotype and genetics, and underscores the importance of synthesizing information from all testing modalities. The association of the unusual immunophenotype and -ITD mutation illustrates the plasticity of the hematopoietic stem cell and the pathobiology of leukemia with mixed lineage or lineage infidelity.
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http://dx.doi.org/10.1007/s12308-018-0329-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171103PMC
September 2018

Combination of Blinatumomab and Vincristine Sulfate Liposome Injection for Treatment of Relapsed Philadelphia Chromosome Positive B-cell Acute Lymphoblastic Leukemia.

Am J Leuk Res 2018 23;2(1). Epub 2018 Mar 23.

University of Maryland School of Medicine, USA.

Relapsed Philadelphia chromosome (Ph) positive Acute Lymphoblastic Leukemia (ALL) is an aggressive lymphoid malignancy with a poor prognosis and no randomized studies demonstrating superiority of any single salvage regimen. We present the case of a 33-year-old woman with relapsed Ph positive precursor (pre) B-cell ALL with rapidly rising peripheral blasts while on blinatumomab monotherapy initially, but ultimately responded with the addition of Vincristine Sulfate Liposome Injection (VSLI). Ponatinib was added later when it became available for the patient, and she ultimately achieved a complete remission. Further study is warranted to explore mechanisms of potential synergy, and the safety and efficacy of the combination of blinatumomab and VSLI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018018PMC
March 2018

Promyelocytic sarcoma of the right humerus: an unusual clinical presentation with unique diagnostic and treatment considerations.

Clin Case Rep 2017 11 29;5(11):1874-1877. Epub 2017 Sep 29.

Department of Pathology University of Maryland School of Medicine Baltimore Maryland.

Promyelocytic leukemia is a known medical emergency and requires rapid diagnosis and expedient therapy with differentiating agents. We present an unusual case in which the diagnosis is based on a fine needle aspirate of a humeral mass. Despite lack of systemic involvement, the sarcoma responded to traditional differentiation agents.
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http://dx.doi.org/10.1002/ccr3.1212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676285PMC
November 2017

Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia.

Cancer Chemother Pharmacol 2018 01 8;81(1):217-222. Epub 2017 Nov 8.

University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA.

Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 μmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 μmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.
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http://dx.doi.org/10.1007/s00280-017-3459-6DOI Listing
January 2018