Ashraf Badros

University of Maryland, Baltimore, Baltimore, Maryland, United States

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Publications (98)636.08 Total impact

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    ABSTRACT: The aim of International Myeloma Working Group was to develop practical recommendations for the use of magnetic resonance imaging (MRI) in multiple myeloma (MM). An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations for the value of MRI based on data published through March 2014. MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells compared with other radiographic methods. Thus, MRI detects bone involvement in patients with myeloma much earlier than the myeloma-related bone destruction, with no radiation exposure. It is the gold standard for the imaging of axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. MRI has the ability to detect spinal cord or nerve compression and presence of soft tissue masses, and it is recommended for the workup of solitary bone plasmacytoma. Regarding smoldering or asymptomatic myeloma, all patients should undergo whole-body MRI (WB-MRI; or spine and pelvic MRI if WB-MRI is not available), and if they have > one focal lesion of a diameter > 5 mm, they should be considered to have symptomatic disease that requires therapy. In cases of equivocal small lesions, a second MRI should be performed after 3 to 6 months, and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. MRI at diagnosis of symptomatic patients and after treatment (mainly after autologous stem-cell transplantation) provides prognostic information; however, to date, this does not change treatment selection. © 2015 by American Society of Clinical Oncology.
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    ABSTRACT: Background Racial disparity in the incidence of multiple myeloma is well established; however, to the authors' knowledge, little is known regarding the impact of racial differences on disease characteristics, response to therapy, and clinical outcome.Methods The authors studied 453 patients (174 of whom were black and 279 of whom were white) who underwent transplant between 2000 and 2013. The median follow-up was 4.4 years.ResultsBlack patients were significantly younger than white patients (median age, 54 years vs 59 years; P<.0001), more frequently presented with anemia (P = .04), had more of the immunoglobulin G isotype (P<.001), and had a borderline favorable cytogenetic risk (P = .06). Overall response to induction was similar, but deeper responses were observed in more white patients compared with black patients receiving immunomodulatory drug-based induction (P = .02). Referral for transplant was significantly delayed in black individuals (median, 1.3 years vs 0.9 years; P = .003). Overall survival from the time of transplant was similar for black and white patients, with medians of 6.2 years and 5.7 years, respectively, but survival from the time of diagnosis was significantly longer among black individuals (median, 7.7 years vs 6.1 years; P = .03). Maintenance therapy was found to positively impact progression-free survival but not overall survival, irrespective of race.Conclusions The results of the current study confirm ethnic differences in age, referral patterns, response to therapy, and overall survival. Future validation of these disparities is urgently needed. Cancer 2014. © 2014 American Cancer Society.
    Cancer 12/2014; DOI:10.1002/cncr.29160 · 5.20 Impact Factor
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    ABSTRACT: Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed.
    Journal of Clinical Oncology 09/2014; DOI:10.1200/JCO.2013.52.3522 · 17.88 Impact Factor
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    ABSTRACT: Background. Peripheral neuropathy is the dose limiting toxicity of bortezomib in patients with multiple myeloma (MM). Objectives. To examine the safety, feasibility and efficacy of acupuncture in reducing bortezomib-induced peripheral neuropathy (BIPN) symptoms. Methods. Patients with MM experiencing persistent BIPN ≥grade 2 despite adequate medical intervention and discontinuation of bortezomib received 10 acupuncture treatments for 10 weeks (2×/week for 2 weeks, 1×/week for 4 weeks, and then biweekly for 4 weeks). Responses were assessed by the Clinical Total Neuropathy Score (TNSc), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire, and the Neuropathy Pain Scale (NPS). Repeated-measures analysis of variance was used to test for monotonic decline in scores on each of the measures. Serial serum levels of proinflammatory and neurotrophic cytokines were obtained at baseline and weeks 1, 2, 4, 8, and 14. Results. Twenty-seven patients with MM were enrolled in the trial. There were no adverse events associated with the acupuncture treatments. TNSc data were deemed invalid and therefore were not reported. At weeks 10 and 14, FACT/GOG-Ntx and NPS showed significant reduction suggesting decreased pain, and improved function (P values were <.0001 for both FACT/GOG-Ntx and NPS at weeks 10 and 14). However, nerve conduction studies did not significantly change between baseline assessment and end of study. There was no correlation in serum cytokines for responders versus none responders. Conclusions. Acupuncture is safe, feasible and produces subjective improvements in patients' symptoms. A follow-up randomized controlled trial is warranted.
    Integrative Cancer Therapies 05/2014; 13(5). DOI:10.1177/1534735414534729 · 2.01 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population.
    CancerSpectrum Knowledge Environment 04/2014; 106(5). DOI:10.1093/jnci/dju067 · 14.07 Impact Factor
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    ABSTRACT: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.EXPERIMENTAL DESIGN: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant.RESULTS: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%).CONCLUSIONS: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine. Clin Cancer Res; 1-11. ©2013 AACR.
    Clinical Cancer Research 02/2014; 20(5). DOI:10.1158/1078-0432.CCR-13-2817 · 8.19 Impact Factor
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    ABSTRACT: We retrospectively evaluated the tolerability and efficacy of fractionated total body irradiation (TBI) (1,200 cGy) and melphalan (MEL) (100-110 mg/m(2)) myeloablative conditioning in 48 patients with nonremission AML (n = 14), ALL (n = 10), NHL (n = 18), and other refractory hematologic malignancies (n = 6) who received allogeneic stem cell transplantation (SCT) between 2002 and 2011. Median age was 48 years (22 to 68); 14 out of 26 leukemia patients (54 %) had circulating blasts at transplant, 20 (50 %) evaluable patients had poor-risk cytogenetics, 12 (25 %) had prior SCT, and 10 (21 %) received stem cells from a mismatch donor. All patients received tacrolimus with or without methotrexate for GVHD prophylaxis. At the time of analysis, 13 patients (27 %) were alive and disease free. Engraftment was complete in all patients. The median time to ANC recovery (>500) was 12 days (range, 6-28). The most common grade III and IV toxicities were mucositis and infections. Eighteen patients (43 %) developed grade II-IV acute GVHD, and eight (26 %) had extensive chronic GVHD. Of 44 evaluable patients for response, 28 (64 %) achieved a complete remission (CR), and seven (15 %) had a partial remission after the transplant. With a median follow-up of 30 months (4 to 124 months) for surviving patients, the cumulative incidence of relapse was 45 % at 1 year, and the probability of overall survival (OS) at 5 years was 22.5 %. Multivariate analysis showed that platelet count (<80,000/mL) and lactic dehydrogenase (>500 IU/L) at SCT were associated with relapse. Age less than 53 years and CR after SCT were associated with better OS. Our data suggest that TBI-MEL can result in CR in two thirds, durable remission in one third, and 5-year survival in about one quarter of patients with nonremission hematologic malignancies. Further studies with TBI-MEL in standard risk transplant patients are warranted.
    Annals of Hematology 10/2013; 93(4). DOI:10.1007/s00277-013-1908-9 · 2.40 Impact Factor
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    ABSTRACT: Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in 1 of 4 phase 2 studies (PX-171-003-A0, PX- 171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%) including in patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.
    Haematologica 08/2013; DOI:10.3324/haematol.2013.089334 · 5.94 Impact Factor
  • Vishal Bhatnagar, Ashraf Badros
    Leukemia & lymphoma 07/2013; DOI:10.3109/10428194.2013.821704 · 2.61 Impact Factor
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    ABSTRACT: This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80, 50-80, 30-49, <30 ml/min, and chronic hemodialysis. Carfilzomib was administered on Days 1, 2, 8, 9, 15, and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2), and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%), and fatigue (14.0%). Adverse events were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.Leukemia accepted article preview online, 31 January 2013; doi:10.1038/leu.2013.29.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2013; DOI:10.1038/leu.2013.29 · 10.16 Impact Factor
  • HAA 2013 SBOC October 23-26, Brasilia, Brasil Società Italiana di Ematologia (SIE) 2013 – October 20-23; Verona, Italy Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO) 2013 October 19-23, Vienna, Austria; 01/2013
  • MASCC/ISOO International Symposium on Supportive Care in Cancer, Berlin, Germany; 01/2013
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    ABSTRACT: Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (20%) and absolute number (2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.Leukemia advance online publication, 4 January 2013; doi:10.1038/leu.2012.336.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2012; 27(4). DOI:10.1038/leu.2012.336 · 10.16 Impact Factor
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    ABSTRACT: Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant anti-tumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 min, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on cytochrome (CYP)3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner following intravenous administration. The systemic half life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was mainly cleared by extrahepatic metabolism via peptidase cleavage and epoxide hydrolysis. CYP-mediated metabolism played a minor role, suggesting that co-administration of CYP inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the unique PK properties of carfilzomib limit clinically significant DDI.
    Drug metabolism and disposition: the biological fate of chemicals 11/2012; 41(1). DOI:10.1124/dmd.112.047662 · 3.74 Impact Factor
  • Rashid Z Khan, Ashraf Badros
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    ABSTRACT: The introduction of bortezomib, a first-generation proteasome inhibitor, changed the standard-of-care for newly diagnosed and relapsed multiple myeloma patients. The next generation of proteasome inhibitors, such as carfilzomib, provides a novel pharmacokinetic and pharmacodynamic profile. In vitro data suggest a more specific and irreversible inhibition of the proteasome. Based on the clinical trials conducted to date, carfilzomib has activity in heavily pretreated as well as bortezomib-refractory/relapsed patients. The safety profile, specifically a lower incidence of peripheral neuropathy, efficacy in the high-risk setting, as defined cytogenetically, and the durability of responses indicate a great potential for carfilzomib as a promising therapy. Several trials are underway involving carfilzomib in the newly diagnosed setting and in combination with other active myeloma drugs such as immunomodulatory derivatives of thalidomide, alkylating agents and targeted therapies such as histone deacetylase inhibitors. The introduction of this agent is yet another step in improving the overall outcome of multiple myeloma patients.
    Expert Review of Hematology 08/2012; 5(4):361-72. DOI:10.1586/ehm.12.26 · 2.38 Impact Factor
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    Ashraf Z Badros
    New England Journal of Medicine 05/2012; 366(19):1836-8. DOI:10.1056/NEJMe1202819 · 54.42 Impact Factor
  • Lymphoma Myeloma Conference 2012, New York, NY; 01/2012

Publication Stats

4k Citations
636.08 Total Impact Points

Institutions

  • 2002–2014
    • University of Maryland, Baltimore
      • Greenebaum Cancer Center
      Baltimore, Maryland, United States
  • 2005–2013
    • Loyola University Maryland
      Baltimore, Maryland, United States
  • 2010
    • Weill Cornell Medical College
      New York City, New York, United States
  • 2002–2010
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
  • 2003–2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2000–2006
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2001–2002
    • University of Arkansas for Medical Sciences
      Little Rock, Arkansas, United States