Publications by authors named "Shebli Atrash"

28 Publications

  • Page 1 of 1

Thromboembolism Incidence and Risk Factors in Multiple Myeloma After First Exposure to Immunomodulatory Drug-Based Regimens.

Clin Lymphoma Myeloma Leuk 2021 Mar 28;21(3):188-198.e2. Epub 2020 Nov 28.

Division of Plasma Cell Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC.

Background: We evaluated time to thromboembolism (TE) and risk factors in multiple myeloma (MM) patients after first exposure to immunomodulatory therapy, stratified by thromboprophylaxis.

Patients And Methods: We retrospectively analyzed adult MM patients who received immunomodulatory therapy with or without dexamethasone between February 2012 and October 2017. Thromboprophylaxis included aspirin, anticoagulants (low-molecular-weight heparin, direct oral anticoagulants, or warfarin), or none. Primary endpoint was time to on-treatment TE by thromboprophylaxis type. Time to TE using death as a competing risk censored at 12 months was used in univariate and multivariable analyses to identify risk factors.

Results: Of 485 evaluable patients, 57% were white and 36% African American; median age was 66. Most received lenalidomide (97.5%) and dexamethasone (90%). Half presented with ≥ 1 comorbidities. Sixty-nine had no documented receipt of prophylaxis, 357 aspirin, and 59 anticoagulation. More patients receiving anticoagulants had ≥ 1 comorbidities compared to aspirin or no-prophylaxis groups (P < .001). There was no difference in 12-month estimated cumulative incidence of TE (7.3%; 95% confidence interval, 5.2-9.9) between thromboprophylaxis groups (none 4.4%, aspirin 8.5%, anticoagulant 3.4%) (P = .24). In multivariable analyses, male sex (hazard ratio, 2.50; 95% confidence interval, 1.21-5.17; P = .014) and presence of any comorbidity (hazard ratio, 2.35; 95% confidence interval, 1.17-4.73; P = .016) were associated with TE incidence; thromboprophylaxis type was not (P = .12).

Conclusion: Male sex and presence of any comorbidity were associated with time to TE. There were no differences in TE incidence between thromboprophylaxis groups despite a higher proportion of those in the anticoagulant group having ≥ 1 comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.11.015DOI Listing
March 2021

Outcomes of Daratumumab, Pomalidomide, and Dexamethasone, Followed by High-dose Chemotherapy and Autologous Stem Cell Transplantation, in Patients With Relapsed/Refractory Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Feb 18;21(2):e212-e219. Epub 2020 Sep 18.

Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Westwood, KS.

Background: The number of therapeutic options for patients with relapsed/refractory multiple myeloma (RRMM) has increased significantly. Our institute treated a series of patients with RRMM using DPd (daratumumab, pomalidomide, dexamethasone) as salvage therapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT).

Patients And Methods: We treated 18 patients with RRMM from May 2016 to April 2020, with DPd as salvage therapy, followed by HDCT and ASCT. DPd was administered as daratumumab 16 mg/kg weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and then every 4 weeks. Pomalidomide was given at 4 mg orally on days 1 to 21 of a 28-day cycle, and dexamethasone at 20 or 40 mg weekly.

Results: The patients had received a median of 2 (range, 1-4) previous regimens. Of the 18 patients, 13 (72%) had received ASCT before this treatment. In addition, 78% had disease refractory to proteasome inhibitors, 78% refractory to immunomodulatory agents, and 72% double refractory to immunomodulatory agents and proteasome inhibitors. The overall response rate after salvage treatment with DPd was 100% and at day 100 after ASCT was 100%; 67% had achieved a complete response or better and 78% had achieved a very good partial response or better. No treatment-related mortality had occurred by day 100. The 2-year progression-free and overall survival rates were 83.3% and 94.4%, respectively. The most common grade ≥ 3 adverse events were thrombocytopenia (100%), neutropenia (100%), and neutropenic fever (67%).

Conclusions: DPd as salvage therapy, followed by HDCT and ASCT, demonstrated deep, durable, and clinically meaningful responses with a manageable safety profile in patients with RRMM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.08.026DOI Listing
February 2021

Chimeric Antigen Receptor T-cell Therapy for Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Jan 18;21(1):21-34. Epub 2020 Sep 18.

Plasma Cell Disorders Division, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC.

Relapsed/refractory multiple myeloma (MM) remains a significant clinical challenge, despite a wide array of approved therapeutic agents. Immunotherapy offers an advantage in this setting. Chimeric antigen receptor (CAR) modified T-cells have transformed care for patients with hematologic malignancies. CAR-T cells targeting CD-19 B-cell lymphoma cells have shown prominent activity in lymphoma and acute lymphoblastic leukemia. Recently, the CAR-T cell platform for MM demonstrated therapeutic benefit. Hence, it is rapidly progressing. The most commonly tested target for MM is the B-cell maturation antigen. Complexities involved in the generation and use of CAR-T cells for MM include the identification of appropriate target antigens that are specific, and tumor type restricted, in addition to the optimization of CAR constructs to mitigate toxicities including cytokine release syndrome. CAR-T cells hold immense promise as a therapeutic modality for the treatment of MM. In this article, we provide an updated review of clinical trials of MM-specific CAR-T cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.08.027DOI Listing
January 2021

Daratumumab subcutaneous formulation for the treatment of multiple myeloma.

Expert Opin Biol Ther 2020 11 16;20(11):1253-1259. Epub 2020 Aug 16.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health , Charlotte, NC, USA.

Introduction: Intravenous daratumumab has shown unprecedented anti-myeloma activity when used as a single agent or in combination with other myeloma therapies. Recently, a subcutaneous formulation of daratumumab was approved for use in both the United States and European Union based on data which showed shorter infusion times and decreased rate of infusion reactions while maintaining non-inferior efficacy.

Areas Covered: We cover the physiology behind subcutaneous daratumumab and summarize the relevant clinical data with a particular focus on the pharmacokinetics, pharmacodynamics, safety, and clinical efficacy. Articles used to generate this review were obtained by searching pubmed (https://pubmed.ncbi.nlm.nih.gov/) with the search terms 'subcutaneous daratumumab' and 'daratumumab hyaluronidase'.

Expert Opinion: Subcutaneous daratumumab is associated with lower risk of infusion reactions and decreased administration time while maintaining non-inferior efficacy. We support the use of subcutaneous daratumumab for all approved indications and for investigational use moving forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14712598.2020.1806231DOI Listing
November 2020

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

Clin Lymphoma Myeloma Leuk 2020 10 7;20(10):e777-e781. Epub 2020 Jun 7.

Department of Hematologic Oncology and Blood Disorders, Atrium Health, Levine Cancer Institute, Charlotte, NC.

Background: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs.

Patients And Methods: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion.

Results: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations.

Conclusion: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.05.024DOI Listing
October 2020

An evaluation of subcutaneous daratumumab for the treatment of multiple myeloma.

Expert Rev Hematol 2020 08 20;13(8):795-802. Epub 2020 Sep 20.

Division of Plasma Cell Disorders, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health , Charlotte, NC, USA.

Introduction: A subcutaneous formulation of daratumumab, a human immunoglobulin G1 kappa monoclonal antibody targeting CD38, recently achieved FDA approval for both newly diagnosed and relapsed refractory multiple myeloma amid promises to decrease infusion times and rates of infusion reactions in myeloma patients.

Areas Covered: In this article the biology behind subcutaneous administration of oncologic antibody therapies is reviewed and the subcutaneous formulation of daratumumab is covered in depth. The most recent results from the PAVO, COLUMBA, and PLEIADES clinical trials evaluating subcutaneous daratumumab as a single agent, and in combination, in both newly diagnosed, and relapsed and refractory myeloma patients are summarized. The efficacy, safety, and PK data from these trials are reviewed, and the potential of the subcutaneous formulation to improve quality of life in myeloma patients and decrease healthcare resource use is discussed.

Expert Opinion: Subcutaneous daratumumab is non-inferior to conventional intravenous daratumumab with lower risk of infusion-related reactions and decreased administration time. Based on these data, and the recent FDA and European Commission approvalsthe widespread use of the subcutaneous formulation for both conventional and investigational practice is supported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17474086.2020.1795829DOI Listing
August 2020

Management of newly diagnosed transplant ineligible multiple myeloma.

Leuk Lymphoma 2020 11 4;61(11):2549-2560. Epub 2020 Jul 4.

Department of Hematologic Oncology & Blood Disorders, Division of Plasma Cell Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Multiple myeloma (MM) is a chronically managed blood cancer with a median age of 69 years at the time of diagnosis. Although high dose melphalan and autologous stem cell transplantation (ASCT) remains a standard of care for eligible patients, more than half of the newly diagnosed MM patients are deemed ineligible due to comorbidities or complications of the disease by itself. In this setting, where ASCT is deemed inappropriate, patients could still achieve durable and deep responses if given the appropriate treatment plan. The key concepts of optimizing induction and maintenance strategies while minimizing side-effects are discussed in this review, especially in the context of employing novel agent combinations. It is important to understand the balance between safety and efficacy for each regimen, utilizing maintenance strategy and the best supportive care measures (bone health, infection prevention, and treatment, pain management, etc.). Here, we examine the evidence behind each of those principles and review results from clinical trials for transplant-ineligible (TI) MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1786558DOI Listing
November 2020

Safety and Cost Benefits of the Rapid Daratumumab Infusion Protocol.

Clin Lymphoma Myeloma Leuk 2020 08 7;20(8):526-532.e1. Epub 2020 Mar 7.

Plasma Cell Disorders Division, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC. Electronic address:

Introduction: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol.

Patients And Methods: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity.

Results: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively.

Conclusion: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2020.02.014DOI Listing
August 2020

CAR-T treatment for hematological malignancies.

J Investig Med 2020 06 21;68(5):956-964. Epub 2020 Mar 21.

Department of Internal Medicine, Division of Hematological Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.

Chimeric antigen receptor (CAR)-T-cell therapy has sparked a wave of optimism in hematological malignancies, reflected by the successful results of early clinical trials involving patients with pre-B-cell acute lymphoblastic leukemia, B-cell lymphomas and multiple myeloma. CAR-T-cell therapy is considered to be a novel immunotherapy treatment that has the potential for curing certain hematological cancers. However, as use of CAR-T-cell therapy has grown, new challenges have surfaced. These challenges include the process of manufacturing the CAR-T cells, the mechanisms of resistance that underlie disease relapse, adverse effects and cost. This review describes the published results of clinical trials and expected developments to overcome CAR-T resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jim-2020-001290DOI Listing
June 2020

Outcomes of autologous stem cell transplant for cardiac AL-amyloidosis and cardiac light chain deposition disease.

J Oncol Pharm Pract 2020 Jul 3;26(5):1128-1133. Epub 2019 Dec 3.

Department of Hematology Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina, NC, USA.

Introduction: Cardiac amyloidosis and light chain deposition disease (LCDD) are the most common cause of death in AL amyloidosis or LCDD.

Methods: Our multiple myeloma database identified 50 patients with cardiac amyloidosis or LCDD between January 2004 and January 2013. Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes.

Results: The median age at diagnosis was 61 years for those who received autologous hematopoietic stem cell transplant (ASCT) and 71 years for those who received only bortezomib-based chemotherapy; 62.5% (n = 30) of patients had elevated levels of NT-proBNP ≥323 ng/L, and 29.2% (n = 14) of patients had an elevated cTnT ≥0.1 µg/L. Echocardiogram findings showed a speckled appearance in 18% (n = 9) of patients, and 60% (n = 30) of patients had an increased diastolic intra-ventricular septum (IVSD) thickness measuring ≥1.3 cm; 64.3% (n = 18) of patients who underwent cardiac MRI showed subendocardial enhancement. Out of 48 patients who received treatment, 37 patients were diagnosed with cardiac amyloidosis and 11 patients were diagnosed with cardiac LCDD. Twenty-eight patients (75.7%) with cardiac amyloidosis received ASCT, compared to 34.3% (n = 9) patients who were ineligible for ASCT and received chemotherapy only. Patients who underwent ASCT had a median OS of 4.48 years compared to 1.82 years (p = 0.69) for those receiving chemotherapy alone.

Conclusion: Our single institution experience shows that ASCT is feasible for cardiac amyloidosis and/or cardiac LCDD. However, careful selection of proper patients and diligent supportive care are vital to decreasing transplant-related mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155219888564DOI Listing
July 2020

Extramedullary multiple myeloma.

Leukemia 2020 01 27;34(1):1-20. Epub 2019 Nov 27.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Extramedullary multiple myeloma (EMM) is an aggressive subentity of multiple myeloma, characterized by the ability of a subclone to thrive and grow independent of the bone marrow microenvironment, resulting in a high-risk state associated with increased proliferation, evasion of apoptosis and treatment resistance. Despite improvement in survival for most patients with multiple myeloma over recent decades, outcomes are generally poor when EMM develops. Understanding the molecular underpinnings leading to homing of plasma cells in ecosystems outside the bone marrow will be crucial for therapeutically manipulating the microenvironment and targeting key signaling pathways. Herein, we discuss the evolutionary biology of EMM, underscore the importance of a uniform definition, discuss prognostic significance, and provide current and emerging treatment strategies for managing this rare subentity of multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0660-0DOI Listing
January 2020

A Review of Growth Factor Support in Bloodless Autologous Hematopoietic Stem Cell Transplant.

Biol Blood Marrow Transplant 2019 10 8;25(10):e305-e309. Epub 2019 Jul 8.

Pennsylvania Hospital, Center for Bloodless Medicine and Surgery, Philadelphia, , Pennsylvania.

Bloodless autologous hematopoietic cell transplantation is associated with risks of severe bleeding and profound anemia. RBC or platelet transfusions are often used to prevent these hematologic complications. However, in patients such as Jehovah's Witnesses who refuse major blood components, the lack of transfusion support is not an absolute contraindication to an autologous hematopoietic cell transplant. Pennsylvania Hospital performed the world's first bloodless hematopoietic cell transplant more than 15 years ago and has gradually improved its technique with a sizable patient population. Erythropoiesis-stimulating agents were successfully employed as part of their pretransplant regimen to prevent severe anemia. Thrombopoietin agonists' potential role in bloodless transplant is also currently being explored. Although there is limited literature, available reports in combination with physiologic reasoning may support the use of these growth factors to promote transplant success. These agents offer potential benefit and may be of utility in minimizing complications of a bloodless transplant. In this review, we summarize the available literature and offer insight into how we may incorporate growth factors to allow bloodless autologous hematopoietic cell transplantation to be an available option to patients who may otherwise be denied.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.07.003DOI Listing
October 2019

Daratumumab, pomalidomide and dexamethasone combination therapy in daratumumab and/or pomalidomide refractory multiple myeloma.

Br J Haematol 2019 07 11;186(1):140-144. Epub 2018 Dec 11.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15716DOI Listing
July 2019

Peripheral Immunotype Correlates with Minimal Residual Disease Status and Is Modulated by Immunomodulatory Drugs in Multiple Myeloma.

Biol Blood Marrow Transplant 2019 03 24;25(3):459-465. Epub 2018 Nov 24.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina. Electronic address:

Data indicate reversal of immune dysfunction with active treatment; however, the precise contribution of specific immune effector and immune suppressor components to achieve a minimal residual disease (MRD) state and immunomodulatory drug-mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in natural killer (NK), NK-T, and T cells, including maturation and activating/inhibitory repertoire associated with MRD versus MRD status after autologous stem cell transplantation (ASCT) and during lenalidomide-based maintenance therapy. Of the 46MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pretherapy and after cycles 1, 3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. Although the absolute number of NK cells was significantly lower in patients with MRD response, phenotypically NK cells in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRD group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRD versus MRD patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function, and acquisition of PD1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during the maintenance phase in MRD patients. Put together, these observations provide a distinctive signature for MRD and MRD groups. These data support exploration of immune profiling in prospective clinical trials according to MRD-defined responses to identify patients that may benefit from maintenance intensification/modification or maintenance withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.11.015DOI Listing
March 2019

FRAX is a robust predictor of baseline vertebral fractures in multiple myeloma patients.

Bone 2019 04 19;121:134-138. Epub 2018 Sep 19.

Myeloma Institute for Research & Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America. Electronic address:

FRAX is a commonly used tool to evaluate patient fracture risk based on individual patient models that integrate the risks associated with clinical risk factors with or without bone mineral density (BMD) at the femoral neck. Retrospectively, factors identified by the FRAX scoring algorithm were used to predict the risk for vertebral compression fractures at baseline in newly diagnosed multiple myeloma patients. The data were derived from myeloma patients enrolled in Total Therapy Protocols (TT4 & TT5) between 8/2008 and 9/2017. FRAX scores were calculated and baseline PET and MRI imaging obtained. Univariate and multivariate logistic regression analyses determined the association between FRAX components and the existence of vertebral compression fractures, both pathologic and osteoporotic. The patient population had a median age of 61 years (43-76), 37% female, and 87% white. The median major osteoporotic score (MOS) and Hip fracture scores (HFS) for TT4 patients (low-risk myeloma) were 5.6 and 0.5, respectively, while median MOS and HFS for TT5 (high risk myeloma) patients were 6.2 and 0.7, respectively. The odds ratio for fracture at diagnosis in patients with elevated MOS (>2), and HFS (>4.5) was significant OR (1.48, 95% confidence interval (1.35,1.62)) and OR (1.61, 95% confidence interval (1.42, 1.81)), respectively. In sum, an elevated baseline FRAX score was highly predictive of baseline vertebral fractures in MM patients at presentation. In addition, patients with higher FRAX scores had significantly shorter survival in the low-risk (TT4) group but this survival effect was not seen in the high-risk (TT5) group. These findings suggest that FRAX assessment of baseline fracture risk is beneficial in MM patients to identify an individual patients' risk of vertebral fracture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2018.09.013DOI Listing
April 2019

Clinical Presentation and Gene Expression Profiling of Immunoglobulin M Multiple Myeloma Compared With Other Myeloma Subtypes and Waldenström Macroglobulinemia.

J Glob Oncol 2018 09 9;4:1-8. Epub 2017 May 9.

Shebli Atrash, Qing Zhang, Xenofon Papanikolaou, Caleb Stein, Al-Ola Abdallah, and Bart Barlogie, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Qing Zhang, Levine Cancer Institute, Charlotte, NC.

Purpose: Multiple myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated postgerminal B cells. It is a heterogeneous disease both at the genetic level and in terms of clinical outcome. Immunoglobulin M (IgM) MM is a rare subtype of myeloma. Similar to Waldenström macroglobulinemia (WM), patients with MM experience IgM monoclonal gammopathy; however, both diseases are distinct in terms of treatment and clinical behavior.

Materials And Methods: To shed light on the presentation of IgM MM, its prognosis, and its gene expression profiling, we identified and characterized 21 patients with IgM MM from our database.

Results: One of these patients presented with a rare IgM monoclonal gammopathy of undetermined significance that progressed to smoldering myeloma. The median survival of the 21 patients was 4.9 years, which was comparable to a matched group of patients with non-IgM MM with similar myeloma prognostic factors (age, gender, albumin, creatinine, anemia, lactate dehydrogenase, β-microglobulin, cytogenetics abnormalities), but much less than the median survival reported for patients with WM (9 years). We identified a cluster of genes that differ in their expression profile between MM and WM and found that the patients with IgM MM displayed a gene expression profile most similar to patients with non-IgM MM, confirming that IgM MM is a subtype of MM that should be differentiated from WM.

Conclusion: Because the prognosis of IgM MM and WM differ significantly, an accurate diagnosis is essential. Our gene expression model can assist with the differential diagnosis in controversial cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JGO.2016.008003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180798PMC
September 2018

Complement Regulatory Genetic Mutations in the Setting of Autoimmune Thrombotic Thrombocytopenic Purpura: A Case Series.

Mayo Clin Proc Innov Qual Outcomes 2018 Mar 20;2(1):69-73. Epub 2017 Dec 20.

Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock.

Objective: To explore the benefits of adding eculizumab for the treatment of refractory autoimmune thrombotic thrombocytopenic purpura (iTTP) with complement dysregulation.

Patients And Methods: From January 1, 2014, through July 1, 2017, we identified patients with iTTP defined by ADAMTS13 (disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels less than 5% and the presence of ADAMTS13 inhibitor. Patients who progressed after receiving standard of care management for iTTP were subjected to a comprehensive evaluation to look for evidence of complement activation. Herein, we share our single-institute experience regarding the clinical course and treatment algorithm for 3 patients with refractory iTTP.

Results: All the patients had clinical deterioration despite treatment with plasma exchange, corticosteroids, rituximab, and vincristine, which prompted us to look for evidence of complement activation and associated genetic mutations. Complement-related genetic aberrations were present in all 3 patients, who had had different degrees of complement activation. The first 2 patients did not benefit from eculizumab when treatment was started before complete clearance of inhibitors to ADAMTS13. However, they had durable remissions when eculizumab was introduced after clearance of ADAMTS13 inhibitors. The third patient started eculizumab therapy after inhibitor levels were undetectable.

Conclusion: We found eculizumab therapy to be effective in all 3 patients. However, its efficacy was prominent only after clearance of antibodies against ADAMTS13 via therapeutic plasma exchange.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocpiqo.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124327PMC
March 2018

Chronic Lymphocytic Leukemia with Translocation (2;14)(p16;q32): A Case Report and Review of the Literature.

Case Rep Oncol Med 2016 3;2016:9037436. Epub 2016 Nov 3.

Department of Medicine, Division of Hematology Oncology, University of Arkansas for Medical Science, Little Rock, AR, USA.

We report the case of a young African American male with no significant past medical history presenting with low back and bilateral leg pain; presenting CBC and chemistries revealed elevated white blood cell count of 250,000, with anemia (Hb 6.8 g/dL) and thrombocytopenia (platelets 9 K/L), and elevated LDH, 1008. Physical examination findings were notable for diffuse lymphadenopathy and lower extremity skin nodules. Interestingly the bone marrow biopsy revealed involvement by CLL/SLL with translocation (2;14)(p16;q32) and trisomy 12. The patient was treated with fludarabine-based chemotherapy and steroids for CLL-related ITP with excellent response. After three cycles of chemotherapy, all the enlarged lymph nodes and skin nodules disappeared, and patient had achieved complete hematologic response. In this paper we also reviewed the available literature of CLL patients with translocation (2;14).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2016/9037436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112301PMC
November 2016

A rare case of blastic plasmacytoid dendritic cell neoplasm with deletion 7q.31, in the setting of heavy pre-treatment with alkylating chemotherapy.

J Oncol Pharm Pract 2017 Oct 24;23(7):552-556. Epub 2016 Aug 24.

1 Department of Internal Medicine, Division of Hematology Oncology, University of Arkansas for Medical Science, Little Rock, AR, USA.

Blastic plasmacytoid dendritic cell neoplasm is rare myeloid malignancy clinically characterized by non-pruritic, violaceous and papulo-nodular skin lesions, together with bone marrow and lymph node involvement. Histologically, there is infiltration of dermis by neoplastic mono-nuclear CD4, CD56, CD123 co-expressing cells with epidermal sparing. Most commonly blastic plasmacytoid dendritic cell neoplasm presents as a de-novo condition, and treatment-related blastic plasmacytoid dendritic cell neoplasm is a rare phenomenon. Due to rarity of the disease, there is no established standard of care treatment. Both acute myeloid leukemia and acute lymphoid leukemia type induction regimens have been used for treatment of blastic plasmacytoid dendritic cell neoplasm, with initial response rate of 50%-80%. We present a rare case of therapy-associated blastic plasmacytoid dendritic cell neoplasm in a patient with remote history alkylating agent systemic therapy. A lag period of five to seven years and presence of deletion 7q.31 seen in bone marrow biopsy specimen in our patient are consistent with a likely therapy-associated etiology of his blastic plasmacytoid dendritic cell neoplasm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155216665245DOI Listing
October 2017

Response of metastatic mucosal melanoma to immunotherapy: It can get worse before it gets better.

J Oncol Pharm Pract 2017 Apr 8;23(3):215-219. Epub 2016 Jul 8.

University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Immune therapy with checkpoint inhibitors has revolutionized the management of metastatic melanoma. Ipilimumab, nivolumab, and pembrolizumab are all FDA-approved immune checkpoint inhibitors to treat metastatic melanoma. Responses to immune checkpoint inhibitors are usually delayed. An interim progression on restaging computed tomography scans "pseudo-progression" may be observed before response to treatment occur. In this case, we report a significant interim progression of metastatic mucosal melanoma before meaningful responses to immunotherapy occurred. The patient developed significant immune therapy-related colitis and new onset vitiligo. Further restaging computed tomography scans showed sustained tumor response despite stopping the immune therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155215627503DOI Listing
April 2017

Thrombotic thrombocytopenic purpura.

J Ark Med Soc 2015 Feb;111(9):187-9

View Article and Find Full Text PDF

Download full-text PDF

Source
February 2015

Patterns of central nervous system involvement in relapsed and refractory multiple myeloma.

Clin Lymphoma Myeloma Leuk 2014 Jun 16;14(3):211-4. Epub 2013 Nov 16.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR. Electronic address:

Background: Invasion of CNS in MM is an extremely rare occurrence that is associated with advanced disease with poor prognosis.

Patients And Methods: Our MM database identified 35 CNS MM cases presenting between January 1996 and March 2012. Descriptive analyses were performed on available data on patient characteristics, disease course, and outcomes.

Results: The mean age at diagnosis was 55.4 years; 23.5% (n = 8) patients had elevated levels of beta-2-microglobulin > 5.5 mg/L; 68.6% (n = 24) of patients had elevated lactate dehydrogenase (LDH) levels (≥ 2 times upper limit of normal); and 14% (n = 5) of patients had secondary plasma cell leukemia. Magnetic resonance imaging (MRI), which was performed in 34 patients, showed diffuse or localized leptomeningeal disease in 20 patients (58.8%). Monoclonal malignant plasma cells were found by CSF analysis in all 35 patients. In total, 31 patients received chemotherapy, including intrathecal chemotherapy as a part of their treatment, with a median survival of 4 months after CNS MM diagnosis.

Discussion: In our experience, CNS MM is an aggressive terminal disease feature associated with high beta-2-microglobulin level, high LDH level, and secondary plasma cell leukemia. This study highlights an unmet need in this subset of patients with high-risk, relapsed or refractory MM.

Conclusion: Achieving adequate CSF penetration while limiting the off-target effects needs to be considered in MM-specific novel drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2013.11.004DOI Listing
June 2014

Successful treatment of Bing-Neel syndrome using intrathecal chemotherapy and systemic combination chemotherapy followed by BEAM auto-transplant: a case report and review of literature.

Clin Lymphoma Myeloma Leuk 2013 Aug 5;13(4):502-6. Epub 2013 Jun 5.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2013.03.002DOI Listing
August 2013

Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance.

Blood 2012 Aug 6;120(8):1597-600. Epub 2012 Jun 6.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Thalidomide and lenalidomide constitute an important part of effective myeloma therapy. Recent data from the Intergroup Francophone du Myélome, Cancer and Leukemia Group B, and Gruppo Italiano Malattie Ematologiche dell Adulto MM-015 trials suggest that lenalidomide maintenance therapy is associated with a higher incidence of second primary malignancies (SPMs), including both hematologic and solid malignancies. In the present study, we analyzed data from the Total Therapy 2 (TT2) trial, along with the 2 Total Therapy 3 (TT3) trials. TT2 patients were assigned randomly to either a control group (no thalidomide) or to the experimental group (thalidomide during induction, between transplantations, and during consolidation and maintenance). The 2 TT3 trials used thalidomide and bortezomib during induction, before and in consolidation after tandem melphalan-based transplantation; TT3A applied VTD (bortezomib, thalidomide, dexamethasone) in the first year of maintenance and TD for 2 more years, whereas TT3B used VRD (bortezomib, lenalidomide, dexamethasone) maintenance for 3 years. The cumulative incidence of SPMs did not differ significantly among the TT trial components when measured from enrollment (P = .78) or from initiation of maintenance (P = .82). However, a pairwise comparison of the TT2 arms suggested a lower incidence of hematologic SPMs in the thalidomide maintenance arm (hazard ratio = 0.38; P = .09). These trials are registered at www.clinicaltrials.gov as NCT00573391 (TT2), NCT00081939 (TT3A), and NCT00572169 (TT3B).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2012-04-421883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429303PMC
August 2012

Unilateral conjunctival AL kappa amyloidosis with trace evidence of systemic amyloidosis.

Am J Case Rep 2012 6;13:102-5. Epub 2012 Jun 6.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.

Background: Amyloidosis is a systemic disorder that results from the tissue deposition of various proteins with distinctive morphological characteristics. Conjunctival amyloidosis is a rare variant which is generally localized and not associated with systemic involvement.

Case Report: We present here a case of 47-year-old female patient with right eyelid swelling that progressed over a 12 year period and eventually underwent surgery with pathology showing AL conjunctival amyloidosis. Unlike in most other reported cases of localized amyloidosis, she was noted to have amyloid deposition in the bone marrow and gastrointestinal tract upon extensive evaluation without any evidence of underlying plasma cell dyscrasia. She has been on observation without evidence of systemic progression or recurrence of conjunctival amyloid.

Conclusions: Although it initially appeared that our case represented an isolated form of AL (kappa)-type conjunctival amyloidosis, systemic evaluation revealed trace amount of amyloid in the bone marrow and GI tract. It is feasible that upon very close scrutiny patients with seemingly localized AL amyloidosis may have trace amounts of amyloid involving other organs and based on experience from this single patient we believe that it is safe to observe such patients closely rather than pursue systemic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12659/AJCR.883022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615912PMC
April 2013

Comparing outcomes of HIV versus non-HIV patients requiring mechanical ventilation.

Clin Med Res 2012 May 26;10(2):57-64. Epub 2011 Oct 26.

Pulmonary Disease and Critical Care Medicine, University of North Carolina School of Medicine, 130 Mason Farm Rd, Chapel Hill, NC 27599, USA.

Background: Mechanical ventilation (MV) is a predictor of mortality in patients infected with human immunodeficiency virus (HIV) in the intensive care unit (ICU). Patients with HIV-infections are admitted to the ICU for a variety of reasons that frequently require intubation. While survival rates for HIV-infected patients continue to improve, ICU admission rates have remained consistent.

Methods: To observe the consequences of MV in HIV-infected patients, we conducted a retrospective chart review on patients with HIV (n=55) vs. matched HIV-negative patients (n=55) who required MV over a one-year period and compared the groups for differences in outcome and complications.

Results: The HIV group had twice the number of deaths (44% vs. 22%, all-cause mortality) (P=0.01). Among the HIV-positive group, 5 of 55 patients required tracheostomy and prolonged MV, compared to 15 of 55 in the control group (9% and 27%, respectively). Successful extubation was virtually identical (47% MV vs. 50% control). Ventilator-associated pneumonia (VAP) was significantly higher among HIV-positive cases (39 of 55 HIV vs. 14 of 55 non-HIV) (P=0.05). Regression analysis revealed that hypotension, hypoalbuminemia, and fever predicted a poorer outcome. Low CD4 cell counts were strongly associated with mortality.

Conclusion: HIV-infected patients requiring MV have significantly higher mortality and VAP rates than HIV-negative patients. Since VAP is associated with a poor prognosis, discovering ways to prevent it in the HIV-infected patient may improve outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3121/cmr.2011.987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355737PMC
May 2012