Ahmad Iftikhar

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• Ayoobkhan, F. S., Qureshi, R., Rahman, R. L., Faiz, Z., Irfan, S., Iftikhar, A., Ansari, B., Mushtaq, M. U., Abdallah, A., Raza, S., Shaikh, H., Lutfi, F., Atrash, S., McGuirk, J. P., Hashmi, H., Anwer, F., & Ahmed, N. (2024). Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) for Chimeric Antigen Receptor T-Cell Therapy (CAR-T) and T-Cell Engager Antibody (TCE) in Myeloma and Lymphoma. Blood, 144(Supplement 1), 5163-5163.
• Ayoobkhan, F. S., Rahman, R., Iftikhar, A., Qureshi, R., Suleman, N., Wesson, W., Mushtaq, M. U., Ouchveridze, E., Abdallah, A., Raza, S., & others, . (2024). Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome in Relapsed and Refractory Multiple Myeloma Using the FAERS Database. Clinical lymphoma, myeloma and leukemia, 24(Supplement 1), S241--S241.
• Channar, A., Naqvi, S., Khan, M. A., Bibi, A., Saxena, A., Tripathi, N., Iftikhar, A., Raina, A., Khakwani, K., Riaz, I. B., & Husnain, M. (2024). Quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma (TENDMM): A systematic review and meta-analysis.. Journal of Clinical Oncology, 42(16_suppl), e19534-e19534.
• Ebad Ur Rehman, M., Faraz, F., Cheema, H. A., Ashruf, O. S., Raheel, H., Naqvi, S. Z., Jabeen, N., Abid, A., Mumtaz Malik, H., Iftikhar, A., Ibrahim, A., & Swed, S. (2024). Impact of prior cancer history on survival in brain malignancy: A propensity score-adjusted, population-based study. Cancer reports (Hoboken, N.J.), 7(2), e1984.
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  Individuals with a Prior Cancer History (PCH) are often excluded from clinical trials. However, a growing body of evidence suggests that prior cancer history does not present adverse outcomes on cancer patients. The evidence on the survival of brain cancer patients in this regard remains widely unknown.
• Ebad Ur Rehman, M., Faraz, F., Cheema, H. A., Ashruf, O. S., Raheel, H., Naqvi, S. Z., Jabeen, N., Abid, A., Mumtaz Malik, H., Iftikhar, A., Ibrahim, A., & Swed, S. (2024). Impact of prior cancer history on survival in brain malignancy: A propensity score‐adjusted, population‐based study. Cancer Reports, 7(2). doi:10.1002/cnr2.1984
• Ebad Ur Rehman, M., Faraz, F., Cheema, H., Ashruf, O., Raheel, H., Naqvi, S., Jabeen, N., Abid, A., Mumtaz Malik, H., Iftikhar, A., Ibrahim, A., & Swed, S. (2024). Impact of prior cancer history on survival in brain malignancy: A propensity score-adjusted, population-based study. Cancer Reports, 7(2). doi:10.1002/cnr2.1984
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  Background: Individuals with a Prior Cancer History (PCH) are often excluded from clinical trials. However, a growing body of evidence suggests that prior cancer history does not present adverse outcomes on cancer patients. The evidence on the survival of brain cancer patients in this regard remains widely unknown. Methods: We conducted a retrospective cohort study to estimate the prevalence and impact of prior cancer on survival of patients diagnosed with brain cancer. Data of patients who were diagnosed with brain cancer as their first or second primary malignancy between 2000 and 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity Score Matching (PSM) was used to ensure comparable baseline characteristics among the patients. Survival analysis was conducted using the Kaplan–Meier method, as well as multivariate Cox proportional hazard and multivariate competing risk models. Results: Out of 42 726 patients, 1189 (2.78%) had PCH. Genitourinary (40.4%), Breast (13.6%), Hematologic and Lymphatic (11.4%), and Gastrointestinal malignancies (11.3%) were the most common types of prior cancer. PCH served as a significant risk factor for Overall Survival (OS) (Adjusted Hazard Ratio [AHR] 1.26; 95% CI [1.15–1.39]; p
• Iftikhar, A., Ali, M. A., Ismail, M. S., Ayoobkhan, F. S., Abiddin, Z. U., Pandey, A., Aiman, W., Dashkevych, U., Husnain, M., Gowin, K., & others, . (2024). Impact of MRD Status on Survival Rates in Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients: A Systematic Review and Meta-Analysis. Clinical Lymphoma Myeloma and Leukemia, 24, S234.
• Iftikhar, A., Shahani, H. A., Rehman, M., Hameed, M. S., Abidi, S., Ayoobkhan, F. S., Ahmad, R. U., Quadri, A., Suhaib, M., A, S. O., Anwer, F., & Husnain, M. (2024). Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy in Relapsed and Refractory Multiple Myeloma - a Meta-Analysis. Blood, 144(Supplement 1), 2008-2008.
• Osama, M., Haris, K. M., Tahir, A., Hussain, A., Ali, A., Khan, S., Hasan, M. B., Alam, I., Khan, Z., Afridi, A., Gul, A., Ur, R., Iftikhar, A., Husnain, M., & Anwer, F. (2024). Efficacy and Safety of Daratumumab-Based Quadruplet Therapy Vs Non-Daratumumab-Based Triplet Therapy in Newly Diagnosed Multiple Myeloma Patients: A Systematic Review and Meta-Analysis. Blood, 144, 6922.
• Rehman, M. E., Hameed, M., Shah, Z., Ashruf, O. S., Ali, R., Faraz, F., Basit, J., Khan, I., Fazal, F., Iftikhar, A., Nashwan, A. J., Faisal, M. S., & Anwer, F. (2024). Incidence and Risk of Secondary Malignancy in Patients with Waldenström Macroglobulinemia: A Population-Based Analysis. Clinical hematology international, 6(1), 3-12.
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  Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma which may predispose individuals to development of secondary malignancies (SMs). The Surveillance, Epidemiology, and End Results (SEER) database is a comprehensive registry of cancer patients in the United States reporting on a wide set of demographic variables. Using the SEER-18 dataset, analyzing patients from 2000 to 2018, we aimed to assess the incidence of SMs in WM patients. Patient characteristics such as gender, age, race, and latency were identified, and respective standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated to compare to the general population. Of the 4,112 eligible WM patients identified, SMs were reported in 699 (17%) patients. The overall risk of developing SM, second primary malignancy, and secondary hematological malignancy was significantly higher in WM patients compared to the general population. Our findings show that WM patients had a 53% higher risk of SMs relative to the general population, and an AER of 102.69 per 10,000. Although the exact mechanism is unclear, the risk of SM development may be due to genetic predisposition, immune dysregulation, or treatment-induced immune suppression.
• Rehman, M., Khalid, B., Khan, M. H., Waseem, M., Rehman, N., Abideen, Z. U., Jamil, M., Hamza, M., Nasir, M., Afridi, A., Masood, S., Shahram, H., Saeed, S., Haider, T., Basit, J., Akbar, U., & Iftikhar, A. (2024). Abstract 4120966: Outcomes Following Balloon Angioplasty with Drug Coated Versus Uncoated Balloons in Patients with Coronary In-Stent Restenosis: A Systematic Review and Meta-Analysis. Circulation, 150(Suppl_1), A4120966-A4120966.
• Rehman, M., Rehman, M. E., Hameed, M., Hameed, M., Shah, Z., Shah, Z., Ashruf, O., Ashruf, O. S., Ali, R., Ali, R., Faraz, F., Faraz, F., Basit, J., Basit, J., Khan, I., Khan, I., Fazal, F., Fazal, F., Iftikhar, A., , Iftikhar, A., et al. (2024). Incidence and Risk of Secondary Malignancy in Patients with Waldenström Macroglobulinemia: A Population-Based Analysis. Clinical Hematology International, 6(1). doi:10.46989/001c.90436
• Shehnaz, A. F., Wesson, W., Suleman, N., Iftikhar, A., Rahman, R., Alzatary, H., Mahmoudjafari, Z., Lufti, F., Bansal, R., Umair, M., Abdallah, A., Sun, W., Doolittle, G., McGuirk, J., Al-Rajabi, R., Baranda, J., Anwer, F., & Ahmed, N. (2024). CT-296 Unveiling the Future: Insights From the Current Landscape in Solid Tumor CAR T Clinical Trials. Clinical Lymphoma Myeloma and Leukemia, 24, S597-S598.
• Ghafoor, B., Masthan, S. S., Hameed, M., Akhtar, H. H., Khalid, A., Ghafoor, S., Allah, H. M., Arshad, M. M., Iqbal, I., Iftikhar, A., Husnain, M., & Anwer, F. (2023). Waldenström macroglobulinemia: a review of pathogenesis, current treatment, and future prospects. Annals of hematology.
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  Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity.
• Ibrahim, A., Chattaraj, A., Iqbal, Q., Anjum, A., Rehman, M. E., Aijaz, Z., Nasir, F., Ansar, S., Zangeneh, T. T., & Iftikhar, A. (2023). Pneumonia: A Review of Management in Human Immunodeficiency Virus (HIV) and Non-HIV Immunocompromised Patients. Avicenna journal of medicine, 13(1), 23-34.
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  pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has been a decline in pneumonia incidence in HIV since the introduction of antiretroviral medications. However, its incidence is increasing in non-HIV immunocompromised patients including those with solid organ transplantation, hematopoietic stem cell transplantation, solid organ tumors, autoimmune deficiencies, and primary immunodeficiency disorders. We aim to review and summarize the etiology, epidemiology, clinical presentation, diagnosis, and management of pneumonia in HIV, and non-HIV patients. HIV patients usually have mild-to-severe symptoms, while non-HIV patients present with a rapidly progressing disease. Induced sputum or bronchoalveolar lavage fluid can be used to make a definitive diagnosis of pneumonia. Trimethoprim-sulfamethoxazole is considered to be the first-line drug for treatment and has proven to be highly effective for pneumonia prophylaxis in both HIV and non-HIV patients. Pentamidine, atovaquone, clindamycin, and primaquine are used as second-line agents. While several diagnostic tests, treatments, and prophylactic regimes are available at our disposal, there is need for more research to prevent and manage this disease more effectively.
• Iftikhar, A. (2023).

  Efficacy of Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis

  . Current Problems in Cardiology. doi:10.1016/j.cpcardiol.2022.101524
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  Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic cardiomyopathy (HCM). Catheter ablation (CA) has emerged as an effective therapy for AF. We conducted a meta-analysis to update the current clinical evidence on the efficacy of CA for AF in patients with HCM. We searched PubMed, Embase, Cochrane and Clinicaltrials.gov for interventional and observational studies assessing single and multiple procedure success rate of CA in HCM patients. Our meta-analysis included 25 studies involving 1817 patients. Success rate following single procedure was 40.4% (95% CI 33.1 to 48.0%) at latest follow-up. The pooled success rate following multiple procedures was 51.4% (95% CI 42.9% to 60.0%) at latest follow-up. In the subgroup analysis for AF subtype, TCA was more successful for paroxysmal AF compared to non-paroxysmal AF. For the subset of studies reporting drug-free success rate, single and multiple procedures had a success rate of 33.4% (95% CI 19.3 to 49.1%) and 51.8% (95% CI 41.3 to 62.2%) at latest follow-up, respectively. CA is a suitable option for AF in patients with HCM. Success rate is greater in paroxysmal AF, after multiple procedures and with antiarrhythmic drugs.
• Iftikhar, A. (2023).

  Pneumocystis jiroveci Pneumonia: A Review of Management in Human Immunodeficiency Virus (HIV) and Non-HIV Immunocompromised Patients

  . Avicenna Journal of Medicine, 13(01), 023-034. doi:10.1055/s-0043-1764375
• Iftikhar, A. (2023).

  Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis

  . Clinical Lymphoma Myeloma Leukemia ., 2023 Apr;23(4):249-258.. doi:10.1016/j.clml.2023.01.004
• Iftikhar, A. (2023).

  Waldenström macroglobulinemia: a review of pathogenesis, current treatment, and future prospects

  . Avicenna Journal of Medicine. doi:10.1007/s00277-023-05345-9
• Iftikhar, A. (2023). Busulfan versus treosulfan conditioning for acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis.. Journal of Clinical Oncology, 41(16_suppl), e19032-e19032. doi:10.1200/jco.2023.41.16_suppl.e19032
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  e19032 Background: Busulfan containing myeloablative conditioning regimens are widely used before allogeneic hematological stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Treosulfan-based conditioning regimens are a potential alternative with potent myelotoxic immunosuppressive characteristics and favorable extramedullary toxicity profile compared to busulfan. In order to determine the optimal conditioning regimen, we conducted a systematic review and meta-analysis to compare the efficacy and safety outcomes of busulfan and treosulfan based conditioning regimens in patients with AML/MDS. Methods: A retrospective systematic literature search was undertaken on PubMed, Cochrane, Embase and Clinicaltrials.gov, using MeSH terms and relevant keywords for AML, MDS, busulfan and treosulfan, to retrieve studies published prior to February 5, 2023. Efficacy outcomes were overall survival (OS), disease-free survival (DFS), and relapse. Safety outcomes included non-relapse mortality (NRM), acute (a) and chronic (c) graft-versus-host disease (GvHD). The random-effects model with the Mantel-Haenszel method was used to pool risk ratios (RR) for dichotomous variables in Revman version 5.4. Results: The initial search retrieved 1094 articles. After removal of duplicates, reviews and non-relevant articles, data was extracted from seven different studies. Busulfan and treosulfan were employed in 4706 and 1979 patients, respectively. The median age ranged from 55 to 61 years, and the median follow-up ranged from 14 to 58 months. The treosulfan and busulfan doses administered ranged from 10-42 g/m2 and 0.8-12.8 mg/kg, respectively. Treosulfan was superior to busulfan in terms of OS (RR 1.39, 95% CI 1.15-1.68, p-value 0.0007, I2 58%), DFS (RR 1.39, 95% CI 1.10-1.75, p-value 0.006, I2 60%) and NRM (RR 0.95, 95% CI 0.90-1.00, p-value 0.05, I2 67%). The two regimens were comparable in terms of relapse (RR 0.96, 95% CI 0.89-1.04, p-value 0.33, I2 76%), aGvHD (RR 1.00, 95% CI 0.65-1.54, p-value 1.00, I2 94%) and cGvHD (RR 1.00, 95% CI 0.95-1.05, p-value 0.92, I2 0%). Conclusions: Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD. Treosulfan may be more favorable compared to busulfan as conditioning in AML/MDS. Large scale prospective studies are needed to confirm the most suitable option.
• Rehman, M. E., Chattaraj, A., Mahboob, A., Ijaz, Z., Franco, D., Farhan, M., Dharma, K., Mumtaz, H., Saeed, S., Basit, J., Aslam, M. M., Iftikhar, A., Faraz, F., & Anwer, F. (2023). Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis. Clinical lymphoma, myeloma & leukemia, 23(4), 249-258.
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  Allogeneic hematopoietic stem cell transplant (HSCT) is indicated in pediatric patients with acute lymphoblastic leukemia (ALL) who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning are employed before allogeneic HSCT: total body irradiation (TBI)-based regimens and chemotherapy (CHT) alone. This study compares the efficacy and safety of TBI-based regimens and CHT-based conditioning in pediatric, adolescent, and young adult patients with ALL (0-24 years old). TBI-based and CHT-conditioning regimens were evaluated in 4262 and 1367 patients, respectively, from 15 studies. Compared to CHT alone, TBI-based regimens were associated with better overall survival (OS), relative risk (RR) 1.21, better event-free survival (RR 1.34), and a reduced risk of relapse (RR 0.69). Both approaches had comparable risk of acute graft-versus-host disease (GVHD), grades 3 to 4 acute GVHD, chronic GVHD, and nonrelapse mortality (NRM). In the subgroup analysis for patients in first complete remission, TBI-based regimens and CHT alone had comparable OS and NRM. Our results demonstrate the superiority of TBI-based regimens compared to CHT alone in pediatric patients with ALL.
• Rehman, M. E., Kulsoom, A., Faraz, F., Mustafa, B., Shahid, A., Cheema, H. A., Maqbool, S., Khan, I., Hussain, T., Iftikhar, A., Awan, R. U., Swed, S., Raza, S., & Anwer, F. (2023). Analysis of risk factors and prognostic factors of brain metastasis in gastric cancer: a surveillance, epidemiology and end-results database study. Scientific reports, 13(1), 18664.
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  Brain metastasis in gastric cancer (GC) patients is a rare phenomenon that is associated with adverse clinical outcomes and poor survival rates. We conducted a retrospective cohort study to investigate the incidence, risk factors and prognostic factors of brain metastasis in GC patients. Data on sociodemographic and tumor characteristics of GC patients from 2010 to 2019 was extracted from the Surveillance, Epidemiology and End-Results (SEER) database. Descriptive statistics, multivariable logistic and Cox regression were applied on SPSS. Kaplan-Meier-Survival curves and ROC curves were constructed. A total of 59,231 GC patients, aged 66.65 ± 13.410 years were included. Brain metastasis was reported in 368 (0.62%) patients. On logistic regression, the risk of brain metastasis was significantly greater in males, patients aged 
• Faraz, F., Rehman, M. E., Sabir, B., Ghaffar, A., Iftikhar, A., Maqsood, A., Ahmad Cheema, H., Yasmin, F., Aamir, M., Ahmed, M. U., & Asghar, M. S. (2022). Efficacy of Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis. Current problems in cardiology, 48(3), 101524.
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  Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic cardiomyopathy (HCM). Catheter ablation (CA) has emerged as an effective therapy for AF. We conducted a meta-analysis to update the current clinical evidence on the efficacy of CA for AF in patients with HCM. We searched PubMed, Embase, Cochrane and Clinicaltrials.gov for interventional and observational studies assessing single and multiple procedure success rate of CA in HCM patients. Our meta-analysis included 25 studies involving 1817 patients. Success rate following single procedure was 40.4% (95% CI 33.1 to 48.0%) at latest follow-up. The pooled success rate following multiple procedures was 51.4% (95% CI 42.9% to 60.0%) at latest follow-up. In the subgroup analysis for AF subtype, TCA was more successful for paroxysmal AF compared to non-paroxysmal AF. For the subset of studies reporting drug-free success rate, single and multiple procedures had a success rate of 33.4% (95% CI 19.3 to 49.1%) and 51.8% (95% CI 41.3 to 62.2%) at latest follow-up, respectively. CA is a suitable option for AF in patients with HCM. Success rate is greater in paroxysmal AF, after multiple procedures and with antiarrhythmic drugs.
• Iftikhar, A., Rehman, M. E., Basit, J., Faraz, F., Abbas, K., Saeed, S., Fatima, M., Khanam, R., Farrukh, L., Akbar, U. A., Zulfiqar, H., & Anwer, F. (2022). Second Primary Malignancy in Waldenström Macroglobulinemia: Insights from a Population-Based Analysis. Blood, 140(Supplement 1), 10963-10964. doi:10.1182/blood-2022-165191
• Ahmed, M. B., Sami, Z. A., Razzaq, F., Ali, M. A., Fazal, A., & Iftikhar, A. (2021). Pheochromocytoma: An Incidental Finding in an Asymptomatic Older Adult With Renal Oncocytoma. Federal practitioner : for the health care professionals of the VA, DoD, and PHS, 38(12), e81-e85.
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  A high index of suspicion for pheochromocytoma is necessary during the workup of secondary hypertension as untreated pheochromocytoma may lead to significant morbidity and mortality, especially in patients who require any surgical treatment.
• Latif, A., Ahsan, M. J., Lateef, N., Kapoor, V., Fazeel, H. M., Razzaq, F., Iftikhar, A., Ashfaq, M. Z., Anwer, F., Mirza, M., & Kabach, A. (2021). Prognostic Impact of Red Cell Distribution Width on the Development of Contrast-Induced Nephropathy, Major Adverse Cardiac Events, and Mortality in Coronary Artery Disease Patients Undergoing Percutaneous Coronary Intervention. Current cardiology reviews, 17(6), e051121191160.
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  Red cell distribution width (RDW) serves as an independent predictor towards the prognosis of coronary artery disease (CAD) in patients undergoing percutaneous coronary intervention (PCI). A systematic search of databases such as PubMed, Embase, Web of Science, and Cochrane library was performed on October 10th, 2019, to elaborate the relationship between RDW and in hospital and long term follow up, all-cause and cardiovascular mortality, major adverse cardiac events (MACE) and development of contrast-induced nephropathy (CIN) in patients with CAD undergoing PCI. Twenty-one studies qualified this strict selection criterion (number of patients = 56,425): one study was prospective, and the rest were retrospective cohorts. Our analysis showed that patients undergoing PCI with high RDW had a significantly higher risk of in-hospital all-cause mortality (OR 2.41), long-term all-cause mortality (OR 2.44), cardiac mortality (OR 2.65), MACE (OR: 2.16), and odds of developing CIN (OR: 1.42) when compared to the patients with low RDW. Therefore, incorporating RDW in the predictive models for the development of CIN, MACE, and mortality can help in triage to improve the outcomes in coronary artery disease patients who undergo PCI.
• Latif, A., Lateef, N., Razzaq, F., Kapoor, V., Ahsan, M. J., Ashfaq, M., Iftikhar, A., Anwer, F., Holmberg, M., & William, P. (2021). Fundamentals of Light Chain Cardiac Amyloidosis: A Focused Review. Cardiovascular & Hematological Disorders-Drug Targets, 20(4), 274-283. doi:10.2174/1871529x20666201130110036
• Usman, R. M., Razzaq, F., Akbar, A., Farooqui, A. A., Iftikhar, A., Latif, A., Hassan, H., Zhao, J., Carew, J. S., Nawrocki, S. T., & Anwer, F. (2021). Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance. Asia-Pacific journal of clinical oncology, 17(3), 193-208.
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  A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy-induced tumorigenesis and drug resistance including Beclin-1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF-2, MEG3, LAPTM4B, mTOR, BRAF and c-MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.
• Iftikhar, A., Zar, M. A., Usman, R. M., Sohail, A., Razzaq, F., Javaid, A., Iftikhar, A., Hassan, H., Anwer, F., Anwar, M. Y., & Ali, M. A. (2020). Ixazomib Based Regimens in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials. Blood, 136(Supplement 1), 35-35. doi:10.1182/blood-2020-141620
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  Introduction: Multiple myeloma (MM) is an incurable malignancy, and clinical trials with newer agents have shown improved patient outcomes. Ixazomib (Ixa) is a proteasome inhibitor and induces apoptosis in cancer cells. It is commonly used with immunomodulators for the treatment of MM. We conducted a systematic review and meta-analysis to assess the efficacy of Ixazomib alone and in combination with other drugs for the treatment of newly diagnosed multiple myeloma (NDMM). Methods: A literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used the following MeSH and Emtree terms; "ixazomib" AND "Multiple Myeloma" from inception till 06/05/2020. We screened 1,558 articles and included 3 randomized clinical trials (RCTs) (N=901) and 12 non-randomized clinical trials (NRCT) (N=632). We excluded case reports, case series, preclinical trials, review articles, observational studies, meta-analysis, and ongoing clinical trials that did not report interim efficacy outcomes. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 15 clinical trials (N=1533), Ixa based regimens were used in patients with age range of 39-92 years. (Table 1) In 3 clinical trials (N=170), Ixa with Lenalidomide (Len) and dexamethasone (Dex) yielded a pooled overall response rate (ORR) of 90% (95% CI=0.82-0.94, I2=32%), a pooled complete response (CR) of 23% (95% CI=0.16-0.32, I2=24%) and a pooled ≥very good partial response and better (≥VGPR) of 39% (95% CI=0.24-0.57, I2 =76%) when used as induction therapy for NDMM patients. As consolidation therapy (N=88), pooled ORR was 91% (95% CI=0.79-0.97, I2=0), pooled CR was 36% (95% CI=0.27-0.47, I2=0) and pooled ≥VGPR was 70% (95% CI=0.53-0.84, I2=60%). (Fig 1-3) In 5 clinical trials (N=233), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR, CR, and ≥VGPR of 76% (95% CI=0.70-0.81, I2 =0), 12% (95% CI=0.07-0.20, I2=44%), and 25% (95% CI=0.14-0.39, I2=78%), respectively. (Fig 1-3) The lower dose of Cyc 300mg/m2 had similar efficacy as 400mg/m2 with better safety profile in elderly patients. In a RCT (N=175) of Ixa with multiple combinations, Ixa + Dex yielded ORR 55% (95% CI=0.40-0.69), CR 14% (95% CI=0.07-0.28) and ≥VGPR 24% (95% CI=0.13-0.39). Ixa+ thalidomide (Thal) + Dex fostered ORR 82% (95% CI=0.70-0.90), CR 15% (95% CI=0.08-0.26), and VGPR 43% (95% CI=0.31-0.55). Ixa + bendamustine + Dex yielded ORR of 73% (95% CI=0.41-0.91), CR 9% (95% CI=0.01-0.44), and ≥VGPR 27% (95% CI=0.09-0.59). In one clinical trial (N=53), Ixa + melphalan (Mel) + prednisone (Pred) combination yielded pooled ORR, CR, and ≥VGPR of 66% (95% CI=0.52-0.77), 13% (95% CI=0.06-0.25), and 30% (95% CI=0.19-0.44), respectively. In a phase II trial (N=40), Ixa + daratumumab (Dara) + Len + Dex yielded an ORR, CR and ≥VGPR of 97% (95% CI=0.84-1), 15% (95% CI=0.07-0.28), and 35% (95% CI=0.22-0.51) respectively. (Fig 1-3) In a phase III RCT by Dimopholous et al. (N=656), Ixa maintenance therapy after stem cell transplant (SCT) yielded an ORR, CR, and ≥VGPR of 76%, 15%, and 54%, respectively. They observed 28% reduction in the risk of progression or death with Ixa vs. placebo, median progression free survival (mPFS) was 26.5 months (95% CI 23·7-33·8) vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). Second malignancies were 3% in both ixazomib and placebo group. 27% of the patients in ixazomib group and 20% patients in placebo group experienced serious adverse events. In a clinical trial on unfit and frail patients (N=46) treated with Ixa + daratumumab (Dara) + Dex, pooled ORR and ≥VGPR were 83% (95% CI=0.69-0.91, I2=0), and 33% (95% CI=0.21-0.47, I2=0), respectively. (Fig 1-3) In the phase II trial, ORR, CR, and VGPR with ixazomib and lenalidomide were 64%, 26%, and 53%, respectively. Conclusion: Ixa in combination with Len, Dex, Cyc, Dara, Mel, Pred is effective in the treatment of NDMM patients. In early phase trials, Ixa with Dara, Len, and Dexa showed the highest overall response as induction therapy. Ixazomib maintainance therapy prolongs PFS after SCT as compared to placebo and represents an additional option for post SCT maintainace therapy in NDMM patiens. The safety profile of Ixa was acceptable with most commonly encountered adverse events were hematological including neutropenia and thrombocytopenia. Additional multicenter, double-blind, randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
• Latif, A., Lateef, N., Razzaq, F., Kapoor, V., Ahsan, M. J., Ashfaq, M., Iftikhar, A., Anwer, F., Holmberg, M., & William, P. (2020). Fundamentals of Light Chain Cardiac Amyloidosis: A Focused Review. Cardiovascular & hematological disorders drug targets, 20(4), 274-283.
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  The estimated prevalence of AL CA in the US is approximately 8-12 cases per million. Almost 30-50% diagnosed cases of AL amyloid in the US have multisystem involvement, including cardiac involvement. Even with the availability of advanced diagnostic testing and novel therapies, prognosis remains poor. It is overlooked as a cause of heart failure with preserved ejection fraction leading to a delay in diagnosis when management options are limited and associated with poor survival outcomes. Therefore, the education of physicians is needed to ensure that it would be highly considered as a differential diagnosis. The purpose of this manuscript is to review the advances in the diagnosis and management of cardiac amyloidosis with the aim of educating colleagues who provide care in the primary care setting. We have summarized the pathogenesis of amyloidosis, its association with plasma cell dyscrasias, novel diagnostic and surveillance approaches including echocardiography, cardiovascular magnetic resonance imaging, histopathologic techniques, systemic biomarkers, and advanced treatment approaches including supportive symptomatic management and standard of care chemotherapy targeting the amyloid deposits. Given the overall poor prognosis of amyloidosis, we have also discussed the role of palliative and hospice care.
• Majeed, A., Larriva, M. M., Iftikhar, A., Mushtaq, A., Campbell, P., Nadeem Malik, M., Rafae, A., Zar, M. A., Kamal, A., Lakhani, M., Khalid, N. R., Zangeneh, T. T., & Anwer, F. (2020). A Single-Center Experience and Literature Review of Management Strategies for Infection in Hematopoietic Stem Cell Transplant Patients. Infectious diseases in clinical practice (Baltimore, Md.), 28(1), 10-15.
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  The aim of our study is to evaluate risk factors associated with the development of infection (CDI) in hematopoietic stem cell transplant (HSCT) patients, determine its incidence and report outcomes of CDI in our patient population.
• Usman, R. M., Razzaq, F., Akbar, A., Farooqui, A. A., Iftikhar, A., Latif, A., Hassan, H., Zhao, J., Carew, J. S., Nawrocki, S. T., & Anwer, F. (2020). Role and mechanism of autophagy‐regulating factors in tumorigenesis and drug resistance. Asia-Pacific Journal of Clinical Oncology, 17(3), 193-208. doi:10.1111/ajco.13449
• Anwer, F., Gee, K. M., Iftikhar, A., Baig, M., Russ, A. D., Saeed, S., Zar, M. A., Razzaq, F., Carew, J., Nawrocki, S., Al-Kateb, H., Cavalcante Parr, N. N., McBride, A., Valent, J., & Samaras, C. (2019). Future of Personalized Therapy Targeting Aberrant Signaling Pathways in Multiple Myeloma. Clinical lymphoma, myeloma & leukemia, 19(7), 397-405.
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  Multiple myeloma (MM) is a genetically complex disease. Identification of mutations and aberrant signaling pathways that contribute to the progression of MM and drug resistance has potential to lead to specific targets and personalized treatment. Aberrant signal pathways include RAS pathway activation due to RAS or BRAF mutations (targeted by vemurafenib alone or combined with cobimetinib), BCL-2 overexpression in t(11:14) (targeted by venetoclax), JAK2 pathway activation (targeted by ruxolitinib), NF-κB pathway activation (treated with DANFIN combined with bortezomib), MDM2 overexpression, and PI3K/mTOR pathway activation (targeted by BEZ235). Cyclin D1 (CCND1) and MYC are also emerging as key potential targets. In addition, histone deacetylase inhibitors are already in use for the treatment of MM in combination therapy, and targeted inhibition of FGFR3 (AZD4547) is effective in myeloma cells with t(4;14) translocation. Bromodomain and extra terminal (BET) protein antagonists decrease the expression of MYC and have displayed promising antimyeloma activity. A better understanding of the alterations in signaling pathways that promote MM progression will further inform the development of precision therapy for patients.
• Hassan, H., Rafae, A., Iftikhar, N., Furqan, F., Iftikhar, A., Mushtaq, A., Ashraf, A., Majeed, A., Kashinath, S., Razzaq, F., & Anwer, F. (2019). Role of extra corporeal methods for light chain removal on renal recovery in multiple myeloma: A systematic review.. Journal of Clinical Oncology, 37(15_suppl), e19530-e19530. doi:10.1200/jco.2019.37.15_suppl.e19530
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  e19530Background: Renal impairment (RI) in Multiple Myeloma (MM) adversely affects the prognosis. Removing circulating free light chains via hemodialysis (HD) or plasma exchange (PLEX) along with c...
• Iftikhar, A., Hassan, H., Iftikhar, N., Mushtaq, A., Sohail, A., Rosko, N., Chakraborty, R., Razzaq, F., Sandeep, S., Valent, J. N., Kanate, A. S., & Anwer, F. (2019). Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development. Antibodies (Basel, Switzerland), 8(2).
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  Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively.
• Iftikhar, A., Iftikhar, A., Majeed, A., Majeed, A., Malik, M. N., Malik, M. N., Mohajer, M. A., Mohajer, M. A., Mushtaq, A., Mushtaq, A., Razzaq, F., Razzaq, F., Zahid, U., & Zahid, U. (2019). Role of Inflammatory Markers in Diagnosing Diabetic Foot Infection: A Meta-Analysis. Infectious Diseases in Clinical Practice, 27(5), 251-259. doi:10.1097/ipc.0000000000000763
• Iftikhar, A., Kumar, A., Wahab, A., Thirunagari, P., Siyahian, A., Russ, A. D., Parr, N. C., Majeed, A., Kumar, A., Iftikhar, A., Ashraf, A., & Anwer, F. (2019). The efficacy of ibrutinib-based combination therapy for mantle cell lymphoma: A systematic review.. Journal of Clinical Oncology, 37(15_suppl), e19043-e19043. doi:10.1200/jco.2019.37.15_suppl.e19043
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  e19043Background: Mantle Cell Lymphoma (MCL) is generally treated with rituximab (R) in combination with other drugs. However, treatment for relapsed or refractory (RR) MCL is challenging. For Ibru...
• Iftikhar, A., Yusufi, M. A., Yousaf, M. A., Shah, Z., Rafae, A., Mushtaq, A., Malik, M. N., Iftikhar, A., Ibrahim, A., Hassan, H., Basheer, A., Anwer, F., & Ahmad, M. E. (2019). Efficacy and Safety Profile of Bortezomib Based Regimens for Treatment of Newly Diagnosed Amyloidosis: A Systematic Review of Literature. Blood, 134(Supplement_1), 5583-5583. doi:10.1182/blood-2019-127190
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  Introduction: For more than a decade, bortezomib (V) has become an integral part of initial treatment of AL amyloidosis It is cytotoxic to plasma cells. We report published literature on efficacy and safety of bortezomib based regimens in patients (pts) with newly diagnosed amyloidosis (ND-AL). Methods: Following PRISMA guidelines, we performed a comprehensive literature search for articles published after 2007 using Pubmed, Embase, Clinical Trials.gov, Cochrane Library and Web of Science. Initially, 649 articles were identified and after a thorough screening, we finalized 9 studies involving 213 ND-AL patients. Prospective (n=91) and retrospective (n=122) studies were included. MeSH terms and keywords were bortezomib and newly diagnosed AL amyloidosis. Results: Chemotherapy followed by HDCT versus frontline HDCT / ASCT: In a retrospective study involving 31 pts by Scott et al., with induction chemotherapy with V-based regimens (n=12), with non-V-based regimens (n=6) and frontline (n=13) high dose melphalan (HDM) therapy followed by autologous stem cell transplant (ASCT). Overall hematological response (OHR) and organ response (OR) rates in the entire cohort after ASCT were 77% and 58% respectively. OHR and OR were 92% & 75% in V-pretreated group and 69% & 54% in pts who received no treatment. The trend was similar for other responses (Table 1). In a clinical trial by Huang, X., et al., induction therapy with Vd (V in combination with dexamethasone) prior to HDM/SCT was compared with frontline HDM/SCT in 58 patients. The OHR, and complete response (CR) between Vd+HDM/SCT (20 evaluable pts) and frontline HDM/SCT (23 evaluable pts) groups were 85.7% versus 53.5% and 67.9% versus 35.7% respectively. All organs showed better response in Vd+HDM/SCT group (Table 1). Vd/CyBorD (Cyclophosphamide, bortezomib, dexamethasone) prior to ASCT: In a prospective clinical trial by Sanchorawala et al., 35 pts were given induction with Vd before HDM and ASCT. Among 27 evaluable pts, OHR was 100% with CR in 76.9% and very good partial response (VGPR) in 23% pts. In a study by Hong et al., 20 patients received induction with Vd or CyBorD prior to ASCT. OHR was 89% with CR in 55%, partial response (PR) in 10% and VGPR in 33%. 5-year overall survival (OS) was 80% and 5-year progression free survival (PFS) was 69%. Vd/CyBorD without ASCT: In a retrospective study by Zhao et al., 23 pts received Vd. OHR was 100% with CR in 44% and PR in 38.9% pts. Median overall survival (mOS) was 38 months and 3-year OS was 41-72%. OR was 25% with kidney being the organ showing response in maximum pts (84%). Kikukawa et al., reported 8 pts who received CyBorD, OHR was 100% with CR in 50%, PR in 25% and VGPR in 25% pts. 63% pts showed OR in heart and/or kidney. In a study by Huang, B., et al., Vd was given to 12 renal ND-AL pts and among 10 evaluable pts, OHR was 80% with CR in 50% and PR in 10%. mOS was 8.2 months and OR was 50%. Other Regimens: In a study by Lee et al., involving 19 pts, VMP (bortezomib, melphalan, prednisone) was given as induction therapy. OHR was 84% with CR in 37%, PR in 26% and VGPR in 21% pts. OS was 39% at 2 years and PFS was 8 months. OR was 53% with heart (50%) and kidney (40%). In a retrospective review by Chari et al., 9 pts were treated with a triplet regimen (V, cyclophosphamide or lenalidomide/thalidomide and d). OHR was 88% with CR in 22% and PR in 66% pts. OR was 77% with heart and kidney both at 44%. Conclusion: In ND-AL pts, V-based combination regimens are very effective and well tolerated as induction therapy, or when used as therapy prior to HDM/ASCT and this approach resulted in better outcomes when compared to frontline HDM/ASCT. Three drug combination therapy with V is effective. Kidney and heart were the major organs to show improvement with therapy. Novel combinations need to be studied in randomized prospective clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
• Majeed, A., Majeed, A., Larriva, M. M., Larriva, M. M., Iftikhar, A., Iftikhar, A., Mushtaq, A., Mushtaq, A., Campbell, P., Campbell, P., Malik, M. N., Malik, M. N., Rafae, A., Rafae, A., Zar, M. A., Zar, M. A., Kamal, A., Kamal, A., Lakhani, M., , Lakhani, M., et al. (2019). A Single-Center Experience and Literature Review of Management Strategies for Clostridium difficile Infection in Hematopoietic Stem Cell Transplant Patients. Infectious Diseases in Clinical Practice, 28(1), 10-15. doi:10.1097/ipc.0000000000000798
• Majeed, A., Mushtaq, A., Iftikhar, A., Zahid, U., Malik, M., Razzaq, F., & Al Mohajer, M. (2019). Role of Inflammatory Markers in Diagnosing Diabetic Foot Infection: A Meta-Analysis. Infectious Diseases in Clinical Practice, 27(5). doi:10.1097/IPC.0000000000000763
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  Background Inflammatory markers including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin (PCT) are frequently ordered in suspected cases of diabetic foot infection (DFI). We did a meta-analysis to compare diagnostic performance of these inflammatory markers for detecting DFI. Materials and Methods The meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used bivariate random-effects regression model to pool the sensitivity and specificity of the targeted biomarkers. Results A comprehensive literature search identified 73 studies. Twelve studies met our inclusion criteria. The number of studies reporting data on each individual biomarker was as follows: 11 for ESR, 7 for CRP, and 5 for PCT. For Infectious Diseases Society of America grade I versus grade II, we calculated pooled sensitivity and specificity for ESR to be 0.86 and 0.82, positive likelihood ratio (LR+) of 4.7, negative likelihood ratio (LR-) of 0.17, and area under receiver operating characteristic curve (AUROC) of 0.91. Pooled sensitivity and specificity for CRP were found to be 0.54 and 0.91, LR+ of 6.2, LR-of 0.50, and AUROC of 0.80. Pooled sensitivity and specificity for PCT were 0.72 and 0.96, LR+ of 18.4, LR-of 0.29, and AUROC of 0.84. For Infectious Diseases Society of America grade II versus grade III, we calculated pooled sensitivity and specificity for ESR to be 0.81 and 0.80, LR+ of 4.0, LR-of 0.24, and AUROC of 0.84. Conclusions Erythrocyte sedimentation rate has the highest AUROC of 0.91 followed by PCT (0.84) and CRP (0.80) to diagnose DFI. For osteomyelitis, ESR has a diagnostic accuracy of 0.84. Erythrocyte sedimentation rate could be beneficial in ruling out infection in persons who have low suspicion of disease (lowest-LR). For those who have high suspicion of disease, PCT could be helpful in ruling in infection (highest +LR). All inflammatory markers need standardization of threshold levels for detecting infection.
• Majeed, A., Sagar, F., Latif, A., Hassan, H., Iftikhar, A., Darouiche, R. O., & Mohajer, M. A. (2019). Does antimicrobial coating and impregnation of urinary catheters prevent catheter-associated urinary tract infection? A review of clinical and preclinical studies. Expert review of medical devices, 16(9), 809-820.
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  : Catheter-associated urinary tract infection (CAUTI) is one of the most common nosocomial infections in hospitals, accounting for 36% of all health care-associated infections. : We aimed to address the potential impact of antimicrobial coating of catheter materials for the prevention of CAUTI and to analyze the progress made in this field. We conducted literature searches in the PubMed, Embase, and Cochrane Library databases, and found 578 articles. Data from 60 articles in either the preclinical or clinical stage were analyzed in this expert review. : The literature review revealed many promising methods for preventing CAUTI. Recent studies have suggested the combination of silver-based products and antibiotics, owing to their synergistic effect, to help address the problem of antibiotic resistance. Other coating materials that have been tested include nitric oxide, chlorhexidine, antimicrobial peptides, enzymes, and bacteriophages. Because of heterogeneity among studies, it is difficult to reliably comment on the clinical efficacy of different coating materials. Future research should focus on double-blind randomized clinical trials for evaluating the role of these potential coating agents.
• Mushtaq, A., Iftikhar, A., Hassan, H., Lakhani, M., Sagar, F., Kamal, A., Zahid, U., Ali, Z., Razzaq, F., Zar, M. A., Hassan, S. F., Safdar, A., Raychaudhuri, S., & Anwer, F. (2019). Pomalidomide-Based Regimens for Treatment of Relapsed and Relapsed/Refractory Multiple Myeloma: Systematic Review and Meta-analysis of Phase 2 and 3 Clinical Trials. Clinical lymphoma, myeloma & leukemia, 19(7), 447-461.
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  Pomalidomide (Pom) has demonstrated synergistic antiproliferative activity in combination regimens as a result of its distinct anticancer, antiangiogenic, and immunomodulatory effects. This review aimed to compare outcome measures of different Pom regimens for relapsed/refractory multiple myeloma.
• Bin Riaz, I., Umar, M., Zahid, U., Husnain, M., Iftikhar, A., McBride, A., Bilal, J., Javed, A., Akbar, S., Singh, P., Ali, Z., Sipra, Q. U., Gondal, F. R., Ahman, F., & Anwer, F. (2018). Role of one, two and three doses of high-dose chemotherapy with autologous transplantation in the treatment of high-risk or relapsed testicular cancer: a systematic review. Bone marrow transplantation, 53(10), 1242-1254.
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  Approximately 20-30% of patients with metastatic germ cell cancers (GCCs) can develop relapsed or refractory (RR) disease, about 40-50% of patients who relapse after salvage chemotherapy may reach long-term remission. The goal of this review was to identify patients who appear to benefit from high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). To access this, we performed a systematic medical literature review to evaluate the effectiveness of HDCT in the frontline setting, as well as in patients with RR testicular cancer. We searched databases for interventional clinical studies and identified 5883 studies. We selected 49 studies for inclusion, which included a total of 5985 patients. Seventeen studies reported results of newly diagnosed poor-risk GCC patients and 32 studies reported results of RR patients. For newly diagnosed patients with poor prognostic predictors, a risk adjusted strategy using unfavorable tumor marker decline with initial standard chemotherapy regimen and upfront HDCT demonstrated improved outcomes. Our data suggest a minimum of two HDCT cycles with ASCT should be standard of care for patients with RR GCC. Failure of HDCT results in a poor prognosis with only 10% of patients achieving lasting remission with salvage therapy.
• Iftikhar, A., Abdullah, H. M., Anwer, F., Lal, A., Malik, S. U., Mcbride, A., Rauf, A., Warraich, Z., Warraich, S. U., & Warraich, F. H. (2018). A Systematic Review of Conventional Therapy and Role of Stem Cell Transplantation for Primary Plasma Cell Leukemia. Biology of Blood and Marrow Transplantation, 24(3), S253-S254. doi:10.1016/j.bbmt.2017.12.229
• Iftikhar, A., Mohajer, M. A., Fraz, M. A., Majeed, A., Mushtaq, A., Sagar, F., Usman, M., & Zahid, U. (2018). 302. Role of Inflammatory Markers in Diagnosing Diabetic Foot Infection: A Meta-Analysis. Open Forum Infectious Diseases, 5(suppl_1), S122-S123. doi:10.1093/ofid/ofy210.313
• Iftikhar, A., Zahid, U., Yun, S., Warraich, Z., Tenneti, P., Sohail, A., Iftikhar, A., & Anwer, F. (2018). Role of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for Children and Young Adults with Relapsed Ewing's Sarcoma: A Systematic Review.. Sarcoma, 2018, 2640674. doi:10.1155/2018/2640674
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  Relapsed Ewing's sarcoma (RES) is an aggressive malignancy with poor survival. Although high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given after conventional chemotherapy (CC) has shown survival benefits, it is not generally used in the United States for RES. We performed a systemic review to evaluate the benefits of HDCT for RES..Literature search involved Medline, Embase, and Cochrane database. We included studies with RES patients treated with HDCT/ASCT..Twenty-four studies with total of 345 reported RES patients that got HDCT were included in final analysis. Seventeen studies had patients with multiple malignancies including RES, while seven had only RES patients. At 2 and 3-5 years, event-free survival (EFS) in studies with only RES patients ranged 42-47% and 20-61% and overall survival (OS) ranged 50-66% and 33-77%, respectively. In studies with combined patients that reported outcomes of RES separately, the EFS at 1-3 and 4 years was 36-66% and 17-50%, respectively. The OS at 1-2 and 3-4 years was 40-60% and 50-70%..Most studies using HDCT/ASCT as consolidation regimen showed improved survival benefits compared to CC. Randomized controlled studies are needed to determine true clinical benefits of HDCT followed by ASCT in patients with RES.
• Iftikhar, A., Zar, M. A., Zahid, U., Sagar, F., Safdar, A., Razzaq, F., Mushtaq, A., Malik, S. U., Lakhani, M., Kamal, A., Iftikhar, A., Hassan, S. F., Hassan, H., Chaudhary, M. B., Bakr, M. M., Anwer, F., & Ali, Z. (2018). Pomalidomide Based Regimens for Treatment of Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials. Blood, 132(Supplement 1), 2022-2022. doi:10.1182/blood-2018-99-111439
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  Abstract Introduction Bortezomib, a proteasome inhibitor and lenalidomide (Len), an immunomodulatory drug are the backbone of established treatment regimens for newly diagnosed MM. Patients with dual-refractory (refractory to both bortezomib and lenalidomide) disease have a poor prognosis with overall survival estimated to be less than one year. Pomalidomide (Pom) has distinct anticancer, antiangiogenic and immunomodulatory properties and has demonstrated synergistic antiproliferative activity in combination regimens. The aim of our study is to compare different Pom based regimens to identify the most effective regimen for relapsed refractory multiple myeloma (RRMM) patients. Methods A comprehensive literature search was performed on PubMed, Cochrane library, Web of Science, Embase and AdisInsight databases on 03/29/2018 which identified a total of 1374 studies. We included phase II/III clinical trials on pomalidomide based regimens that have clearly documented efficacy outcomes. All statistical analyses were performed using Comprehensive Meta-analysis (CMA) Version 3. We used the Cochrane Q statistics (p0.05 or I2 >50%). Studies were classified into subgroups according to the therapeutic regimen: dual and triplet combinations. A separate stratified analysis of triplet regimens based on type of regimen was also performed. Results A total of 35 studies (n = 4623 patients) were included. The most commonly studied regimen was Pom + LoDex (Low dose dexamethasone) with a total of 16 studies on this regimen. All patients included in our study had ≥ 2 prior lines of therapy. Mean number of prior lines of therapy was 6. Most patients were lenalidomide refractory, with 10 patient cohorts of 100% refractoriness and 8 cohorts of ≥ 90% refractoriness. Pooled analysis showed an overall response rate (ORR) of 47.1% across all Pom regimens including both doublet and triplet regimens. An I2 value of 87.3 was found, indicating high heterogeneity across all Pom regimens. With Pom-LoDex, pooled ORR was found to be 35.7% and mean OS 14.37 months. With triplet regimens, pooled ORR was found to be 61.9%. In a separate stratified analysis of triplet regimens based on type of regimen, pooled ORRs with few selected regimens were as follows; Bort-Pom-LoDex (pooled ORR 83.5%, mean PFS 15.7 months [mos]), CFZ-Pom-LoDex (pooled ORR 77.1%, mean PFS 15.3 mos), Pom-LoDex-bendamustine (pooled ORR 74.2%), Pom-Dex-daratumumab (pooled ORR 64.5%), Pom-LoDex-cyclophosphamide (pooled ORR 59.4%, mean PFS 9.5 mos), Pom-LoDex-doxorubicin (pooled ORR 32%). Most frequently reported adverse event with Pom based regimens was myelosuppression. Mean incidences of grade ≥3 hematologic adverse events were neutropenia (47.6%), anemia (26.5%), and thrombocytopenia (20.8%). Mean incidences of grade ≥3 non-hematologic adverse events were infections (29.1%), pneumonia (13.8%) and fatigue (10%). Most of the studies used pomalidomide 4mg daily dosing. Lacy et al. suggested no advantage of 4mg pomalidomide over 2 mg daily dosing. Conclusion From results of pooled analysis, we can infer that triplet combinations of Pom yield almost double response rates (pooled ORR 61.9%) when compared to dual combination of Pom-LoDex (pooled ORR 35.7%). Among three drug combinations, Bort-Pom-LoDex (pooled ORR 83.5%) and CFZ-Pom-LoDex (pooled ORR 77.1%) seem to produce better outcomes. Our study provides useful insight into relative efficacy of various Pom regimens for treatment of RRMM patients. Several trials involving various MoAbs like nivolumab, daratumumab, elotuzumab, isatuximab and pembrolizumab in combination with Pom-LoDex are currently ongoing. Pomalidomide has an acceptable safety profile. Most common treatment emergent adverse events were myelotoxicity and infections that can be effectively managed with supportive care and dose modifications. Disclosures No relevant conflicts of interest to declare.
• Majeed, A., Beatty, N., Iftikhar, A., Mushtaq, A., Fisher, J., Gaynor, P., Kim, J. C., Marquez, J. L., Mora, F. E., Georgescu, A., & Zangeneh, T. (2018). A 20-year experience with nocardiosis in solid organ transplant (SOT) recipients in the Southwestern United States: A single-center study. Transplant infectious disease : an official journal of the Transplantation Society, 20(4), e12904.
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  Nocardiosis is a life-threatening opportunistic infection. Solid organ transplant (SOT) recipients are at higher risk (incidence 0.04%-3.5%) of developing nocardiosis. Rate of nocardiosis in the Southwestern US may be high due to environmental factors.
• Mushtaq, A., Kapoor, V., Latif, A., Iftikhar, A., Zahid, U., McBride, A., Abraham, I., Riaz, I. B., & Anwer, F. (2018). Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review. Critical reviews in oncology/hematology, 125, 1-11.
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  Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70 mg/m2 dose of CFZ vs standard 20-27 mg/m2 dose in NDMM and RRMM.
• Sohail, A., Mushtaq, A., Iftikhar, A., Warraich, Z., Kurtin, S. E., Tenneti, P., McBride, A., & Anwer, F. (2018). Emerging immune targets for the treatment of multiple myeloma. Immunotherapy, 10(4), 265-282.
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  We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy achieved overall response (OR) of 24%. Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab. We included seven clinical trials on chimeric antigen receptor (CAR) T cells. CAR T-cell targets include BCMA, CD19, KLC and CD138. A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising.
• Tenneti, P., Zahid, U., Iftikhar, A., Yun, S., Sohail, A., Warraich, Z., & Anwer, F. (2018). Role of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for Children and Young Adults with Relapsed Ewing's Sarcoma: A Systematic Review. Sarcoma, 2018, 2640674.
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  Relapsed Ewing's sarcoma (RES) is an aggressive malignancy with poor survival. Although high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given after conventional chemotherapy (CC) has shown survival benefits, it is not generally used in the United States for RES. We performed a systemic review to evaluate the benefits of HDCT for RES.
• Abraham, I., Anwer, F., Iftikhar, A., Kapoor, V., Latif, A., Mcbride, A., Mushtaq, A., Russ, A. D., Tenneti, P., Warraich, S. U., Warraich, F. H., & Zafar, R. N. (2017). Efficacy and Toxicity Profile of Carfilzomib Based Regimens for Treatment of Multiple Myeloma, a Systematic Review. Blood, 130, 5413-5413. doi:10.1182/blood.v130.suppl_1.5413.5413
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  Abstract Background: Standard induction therapy for Multiple Myeloma (MM) is triple combination therapy based on three classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has serious issues of peripheral neuropathy (PN) with incidence of grade ≥ 3 PN reported between 2% to 23%. A novel proteasome inhibitor, carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PN. CFZ has been approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. We conducted comprehensive literature search to summarize efficacy, dosing and toxicity profile of CFZ in newly diagnosed and relapsed MM. Methods: Database search using PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov was performed on 6/5/2017. Phase II/III clinical trials from last 10 years and focusing on CFZ as primary drug therapy were included. Results: Literature search identified a total of 1839 articles. Twenty-six articles met the inclusion criteria (15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group) with a total of 5980 patients (4205 in RRMM and 1775 in NDMM group). For heavily pre-treated RRMM patients with median 5 prior lines of therapy, 20/27 mg/m2 of single agent CFZ produced outcomes ranging from 3.5 to 5.1 months of progression free survival (PFS), 16.7% to 23.7% of overall response rate (ORR) and 16% to 18.3% of partial response (PR). Higher dose 20/56 mg/m2 of CFZ in Kd (carfilzomib + dexamethasone) regimen produced PFS of 4.1 months and ORR of 55% in patients with 5 prior lines of therapy. Even higher 20/70 mg/m2 dose of CFZ in Kd regimen produced ORR of 77% and PFS of 12.6 months in patients with 1 prior therapy. ENDEAVOR and ASPIRE trials reported PFS of 18.7 months with Kd vs 9.4 months with Vd (bortezomib and dexamethasone) and 26.3 months with KRd (carfilzomib, lenalidomide and dexamethasone) vs 17.6 months with Rd (lenalidomide and dexamethasone) respectively, in patients with median 2 prior lines of therapy. CFZ in front line setting achieved high response rates. In NDMM, most commonly studied regimen was CFZ in combination with lenalidomide and dexamethasone (KRd) with 4 phase II and 1 phase I/II trial (n= 268). Their outcomes range from 96% to 98% ORR, 83% to 97% overall survival (OS) and 92% to 97% of 2-year PFS. Likewise, outcomes of other CFZ based regimens, 6 phase II and 3 phase I/II trials (n= 552) range from 72% to 97% ORR. Data on overall survival (OS) and progression free survival (PFS) was either not reported or reported at 2 or 3-year interim analysis. Observed PFS in a recent phase III trial comparing CFZ, melphalan and prednisone (KMP) with bortezomib, melphalan and prednisone (VMP) was 22.3 months vs 22.1 months respectively. Most common grade ≥3 AE were hematologic. Incidences of non-hematologic grade ≥ 3 AE include heart failure (3.4% to 20%), acute renal failure (3.4% to 9%), HTN (4.3% to 25%) and PNP ( Conclusion: CFZ demonstrates comparable if not higher efficacy to bortezomib with much favourable adverse effect (AE) profile. Most common grade ≥ 3 AE were hematologic that usually don't require dose changes or discontinuation of therapy. High incidence of grade ≥3 HTN deserves attention and underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20/27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20/56 and 20/70mg/m2 dose of CFZ vs standard 20/27mg/m2 dose. All trials except one on CFZ for NDMM were phase II clinical trials with data available mostly as abstracts. So, there was insufficient data available to compare studies. Deep, rapid and sustainable response with KRd with lower incidence of crippling PN strongly supports extension of KRd therapy to frontline setting. More data from phase III trials is needed for head to head comparison of KRd vs other regimens like bortezomib, lenalidomide and dexamethasone (RVd) for treatment of NDMM. CFZ should be tested in combination with other available drugs like daratumumab and pomalidomide. Download : Download high-res image (229KB) Download : Download full-size image Table . Disclosures Abraham: Janssen Oncology (Johnson & Johnson, LLC): Consultancy.
• Anwer, F., Bilal, J., Iftikhar, A., Kapoor, V., Latif, A., Mushtaq, A., Warraich, S. U., & Warraich, F. H. (2017). Disease Milestones through Bibliometeric Analysis of Top 100 Cited Articles in Multiple Myeloma. Blood. doi:10.1182/blood.v130.suppl_1.5420.5420
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  Abstract Background: Multiple Myeloma (MM) accounts for 1.6% of all cancers and 5-10% of hematologic malignancies in the United States. Novel therapeutic agents have raised the overall survival from 1-2 years to 7-8 years with meaningful improvement in quality of life. Ongoing clinical trials have significantly contributed to the favorable disease outcomes, however many of these interventions still remain unknown to clinicians. The significance of citation analysis lies in the fact that clinicians often modify their management strategy based on research published in high impact journals. In this article, our main objective is to assist medical professionals working in the field to identify the most influential research published on MM. Materials and methods: We conducted a bibliographic analysis on the Web of Science (WOS). Included journals were those listed in the Science Citation Index Expanded, without specific restrictions on the journals. We retrieved the articles for analysis by typing “Multiple Myeloma” into WOS search box and conducted this data search in Title setting with application of English language filter on 07-25-2017. Results: We identified 27,718 articles published between 1901 and 2017, ranked the articles on the basis of citation frequency from highest to lowest and thereafter shortlisted the top 100 cited articles. The most cited article received 2404 citations. Top 100 cited articles were published between 1990 and 2007. In our analysis, we found that highest number of articles were published in the year 2007 (Table 1). 44 out of 100 articles were published in journals with impact factor (IF) greater than 20. The journal with highest number of publications (36%) was BLOOD (IF 13.16). The country with leading number of publication on MM was the United States of America (77%), followed by France (20%), Italy (15%), and the United Kingdom (15%) (Table 2). The production of these 100 articles originated from 50 centers, the most significant contributors out of which were VA Boston Healthcare system and Harvard University each with 36% of total articles, followed by Dana-Farber with 34% of the total articles. Anderson KC., was found to be most frequently cited common author with his contributions amounting up to 26% of the total (Table 3). Maximum studies were found to be categorized under the title of hematology (40%), followed by general internal medicine (29%) and oncology (27%). Discussion: MM research has gone through milestones in areas including disease staging, pathogenesis and management. Seven articles focused on staging, 29 on disease pathogenesis and 51 on treatment. Two of the top ten most cited articles were aimed at staging. Clinical staging was proposed by Durie BGM et al., although the most cited article in our list is no longer the primary staging system. Current classification of MM is based on revised international staging system and disease cytogenetics. Second most frequently encompassed category was disease pathogenesis. Over the years, understanding of pathogenesis has laid the foundation for development of novel therapeutic agents. Among the top 100 cited articles, only 7 studies were focused on bortezomib containing regimens, whereas none of them included carfilzomib or Ixazomib based novel therapeutic regimens. This shows that articles with high frequency of citations mostly consist of early-published articles. Among the top 100 list, only two articles were from 2012 (latest year on the list). To capture important and latest research, a second search was carried out with strategy to limit articles published during last five years. Conclusion: A bibliographic analysis of top cited articles published focused on disease staging, pathogenesis and management. Search limited to last five years (2012-2017) portrayed different results from our original search. None of the studies in the last 5 years list were included in the original list due to less number of total citations received. Recent studies focused on latest developments including therapeutic agents such as novel proteasome inhibitors (carfilzomib, Ixazomib) and monoclonal antibodies (daratumumab, eculizumab) among others. Hence we can infer that top cited article set the stage with deeper understating about MM and helped make solid foundations for the latest developments in the field. We continue to expect ground breaking discoveries be shared through medical scientific literature. Download : Download high-res image (144KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.
• Anwer, F., Deen, I. U., Hua, A., Iftikhar, A., Khalid, M., McBride, A., Mushtaq, A., Russ, A. D., & Safdar, A. (2017). A Decade of Drug Development through Phase-1 Trials; Systematic Review of Literature for Novel Drugs and Targets in Multiple Myeloma. Blood. doi:10.1182/blood.v130.suppl_1.5399.5399
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  Abstract Introduction: Multiple Myeloma (MM) remains an incurable malignancy but response rates are reaching 90% with induction chemotherapy. Despite improved therapy, majority of the patients still face relapse and drug resistance (Korteum KM et al, 2014). There has been significant advancement in drug development for MM with the introduction of many new classes of drugs such as proteasome inhibitors, Immunomodulatory agents, histone deacetylase (HDAC) inhibitors, surface molecule targeting antibodies, intracellular transduction inhibitors and chimeric antigen T cells (CAR-T). The purpose of our study is to systematically summarize the drugs and targets tested through phase I during the last 10 years and their potential mechanisms of actions (MOA). Methods: To identify the Phase 1 trials of novel drugs (2006-2016) in the treatment of MM; we performed literature search by using PubMed, Cochrane, Embase, meeting abstracts from ASH library, Clinicaltrials.gov, and online indexing engines. Phase 1 studies involving a novel drug with a MOA, irrespective of the geo-location, age, sex or specific eligibility criteria were included. We excluded Phase II and III trials, mixed phase I/II trials, duplicates, and trials including transplantation as a treatment option. We excluded drugs already approved for clinical use. Results: More than 500 studies were identified, out of which 45 studies containing a total of 1191 patients were included in the final analysis. 20 studies consisted of single agent therapy while 25 had multiple agents as therapy. Only 2 studies consisted of subjects who underwent only one prior therapy as opposed to 43 studies which included 2 or more prior therapies as a result or either failure of therapy or a relapse. The mean Overall Survival Rates (ORR) were calculated. Mean ORR for HDACI was calculated to be 55.5%. Among Surface Molecule targeting antibodies, the mean ORR was calculated at 56.6%. Novel drugs including Proteasome Inhibitors (Ixazomib), Immunomodulatory agents (Pomalidomide, Lenalidomide), PI3K/AKT inhibitors (Perifosine, Enzastaurin), mTOR inhibitors (Temsirolimus) and Pan-deacetylase inhibitors (Panobinostat) showed a positive mean ORR% of 41.4%, 45.7%, 21.2%, 37% and 51.6% respectively. Due to phase 1 nature of these trials and many trials which are still accruing, full potential of clinical benefit is not known. Discussion: The MOA of novel drugs studied in these studies included Immunomodulation, HDAC inhibition, Surface molecule targeting, Proteasome inhibition, PI3K/AKT inhibition, mTOR inhibition, Pan-deacetylase inhibition and Anti-angiogenic properties among others. For an example Vorinostat, achieved a partial response (PR) in 22% patients along with pretreatment effect of Vorinostat sensitized the myeloma cells to Bortezomib (Weber et al, 2012). Novel drug, i.e. Dacetuzumab, is a monoclonal antibody (mAb) against CD40 which is expressed in many B cell malignancies including MM. Patients who has refractory disease showed decreases in serum and urine M protein excretion (Hussein M et al, 2010). NK cell killer immunoglobulin like receptors (KIRs) act as a means of immune invasion. Similarly, Anti KIR Ab, IPH 2101 is a IgG4 mAb against inhibitory (KIR) (Benson Jr. et. Al, 2012). Patients upon treatment showed an ORR of 33%. In conclusion, we identified phase I studies with about 150 compounds that were clinically tested in MM. The real number of agents is likely to be much higher because of publication bias against negative trials and exclusion of Phase I / II studies in this analysis. Most of the novel agents were tested on patients that had either failed initial and secondary therapies, were resistant or had multiple relapses. Among novel drug classes, immunomodulatory agents, proteasome inhibitors and surface molecule targeting antibodies have shown response rates of more than 40%. Pan-deacetylase inhibitors (Panobinostat) shows response rates above 40% and is already approved for clinical use. Our study shows that alkylating agent such as bendamustin have high response rates. Novel drug classes including oncolytic viral therapies, CDK-9 Inhibitors (Flavopiridol) and HSP90 Inhibitors (Tanespimysin) showed promise as primary and adjunctive therapies in the treatment of MM. Use of newer agents, early in the disease course, coupled with standard therapy may prove to be highly beneficial. Download : Download high-res image (182KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.
• Anwer, F., Iftikhar, A., Kapoor, V., Latif, A., Mcbride, A., Mushtaq, A., Tenneti, P., Yun, S., Zafar, R. N., & Zahid, U. (2017). Role of High Dose Chemotherapy and Autologous Stem Cell Transplant in Relapsed Ewing's Sarcoma — a Systematic Review. Blood, 130, 2014-2014. doi:10.1182/blood.v130.suppl_1.2014.2014
• Batool, S. S., Iftikhar, A., Ahmad, A. N., & Anwer, F. (2017). Limitations of routine skeletal survey: detection of critical but asymptomatic cervical spine lesion in multiple myeloma. BMJ case reports, 2017.
• Iftikhar, A., Akbar, F., Anwer, F., Batool, S. S., Fazeel, H. M., Kapoor, V., Latif, A., Mcbride, A., Mushtaq, A., Tenneti, P., Warraich, Z., Warraich, S. U., Warraich, F. H., & Zafar, R. N. (2017). Emerging Clinical Concepts for Personalized Therapy in Multiple Myeloma; Systemtic Review. Blood, 130, 5411-5411. doi:10.1182/blood.v130.suppl_1.5411.5411
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  Introduction: Personalization of Multiple Myeloma (MM) therapy according to individual patient requirements is an emerging need. Most patients with newly diagnosed MM are age 65 years or above and may have unique challenges due to comorbidities and risks for toxicity. Diverse prognostic factors, cytogenetic aberrations, age associated comorbidities, disease stage and systemic complications of MM call for tailoring the therapeutic regimens for MM according to each patient9s unique presentation. Bone disease, renal impairment, venous thromboembolism, cytopenias, infections and neuropathy are the common complications of MM or its treatment. Novel agents and stem cell transplantation have improved the overall (OS) and progression free survival (PFS). However, it is important to consider the pharmacokinetics, pharmacodynamics, personal preferences, economical concerns and side effect profile of individual drugs while using as a single agent or in combination to avoid further compromising the affected organ system of a susceptible patient. Published literature and guidelines highlight the benefits or disadvantages of particular regimens in patients with specific risk factors such as National Comprehensive Cancer Network, International Myeloma Working group, European Myeloma Working group and Mayo Stratification for Myeloma and Risk-Adapted guidelines. The purpose of this review is to identify and summarize findings from original studies and guidelines for personalized therapy in themanagement of MM. Methods and Results: A comprehensive literature search was carried out using PubMed, EMBASE, Wiley Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov (updated 7-29-2017) for original articles, institutional, national and international guidelines addressing the adjustments of myeloma therapy with a focus on personalized therapy. 129 articles focusing on individualization of therapy for MM patients with renal impairment, risk of venous thromboembolism, high-risk cytogenetics, bone disease, advance age, relapse and plasma cell leukemia are selected and summarized. Articles and guidelines regarding personalization of stem cell transplantation and therapy options after relapse are also summarized in this review. Conclusion: First step towards personalizing the MM therapy is identification of comorbidities (DM, HTN), organ function status (heart, renal failure), disease risk stratification (standard, intermediate, high), transplant eligibility (yes/no), and other risk factors (advanced age, marrow suppression, neuropathy, fluid overload, hyperglycemia). For elderly frail patients, the dosage of all drugs needs to be adjusted considering the age-related compromise of organ systems. Transplant eligibility needs to be considered before using melphalan based induction regimens. Maintenance therapy with novel agents increases OS and PFS but their long term use is associated with drug specific adverse effects. Lenalidomide is associated with bone marrow suppression and second primary malignancies (Kotchetkov et al., 2017). Thalidomide is associated with neuropathy worsening (Mohty, et al., 2010) and emergence of treatment resistant clones. Bortezomib is associated with neuropathy, herpes viral reactivation but is considered superior approach especially for high relapse risk population. In advance renal impairment (RI) patients, thalidomide and lenalidomide can cause hyperkalemia and pancytopenia respectively therefore, may require dose adjustment. Bortezomib is preferred in advanced RI and shows rapid improvement in kidney function. Melphalan and cyclophosphamide dose should be reduced in patients with RI (Dimopoulos et al., 2010). High dose steroids and immune modulators are associated with venous thromboembolism (De Stefano V et al. 2014) therefore, these drugs should be used with risk appropriate (low risk prophylaxis with ASA, high risk with full anticoagulation) prophylaxis. MM patients with high-risk cytogenetics should receive risk adapted bortezomib or carfilzomib based three drug induction therapy and long-term maintenance therapy preferably with a proteasome inhibitor. Bisphosphonate dose in MM patients with RI should be reduced and alternative options should be explored (Denosumab) if necessary. Disclosures No relevant conflicts of interest to declare.
• Iftikhar, A., Anwer, F., Baig, M. Z., Kapoor, V., Latif, A., Mcbride, A., Mushtaq, A., Sohail, A., Warraich, S. U., & Warraich, F. H. (2017). Emerging Immune Targets for Treatment of Multiple Myeloma. Blood, 130, 5429-5429. doi:10.1182/blood.v130.suppl_1.5429.5429
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  Introduction: Multiple myeloma (MM) is the 14th leading cause of cancer deaths in the USA. According to NIH cancer statistics, there will be estimated 30,280 new cases and 12,590 deaths due to MM in 2017. Immunotherapy appears to be an appealing treatment modality for MM. Various immunotherapeutic approaches are being used and our aim is to summarize current knowledge on efficacy of non-FDA approved monoclonal antibodies (mAbs), chimeric antigen receptor modified (CAR-T) cells and their targets. Methods: For CAR-T cells literature search was performed on 7/16/2017 in following databases: PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrilas.gov. Only English language studies were included and no publication date limit was applied. For mAbs, phase I/II trials that were complete or recruiting participants were retrieved from clinicaltrials.gov on 7/19/2017. Trials on elotuzumab and daratumumab that have already proven efficacy were not included. Results: Literature search identified a total of 287 articles on CAR-T cells. After detailed scrutiny, 6 studies were included. Citation analysis retrieved one additional study. 7 studies included 86 relapsed and refractory MM (RRMM) patients. Targeted antigens included B-cell maturation antigen (BCMA) (n=4 studies), CD138 (n=1), CD19(n=1) and kappa light chain (n=1). There was significant variation in CAR T cell dose ranging from 1 x 10⁷ to 5 x 10⁸ per patient. Most patients were heavily pretreated with ≥ 6 median prior lines of therapy. Only one study additionally incorporated ASCT. No objective response (OR) was achieved with CD138 and kappa light chain directed CAR T cell therapy. For BCMA and CD19 directed CAR T cell therapy, there was significant variation in efficacy outcomes reported with PR ranging from 2 weeks to 3.2 months (m), VGPR 2m to 5m and sCR 2m to 7+m. Highest incidence of cytokine release syndrome (CRS) of all grades was reported with BCMA directed CAR T cell therapy, ranging from 58-83%. One case of posterior reversible encephalopathy syndrome was reported with BCMA targeted CAR T cell therapy. mAb targets included ICAM-I (BI-505), IL-6 (siltuximab), VEGF (bevacizumab), GRP78 (PAT-SMX), CD40 (dacetuzumab, lucatumumab), CD138 (indatuximab), PD-1 (pembrolizumab, nivolumab, pidilizumab), CD20 (rituximab), CD38 (isatuximab), CD56 (lorvotuzumab), IGF-1R (AVE1642, figitumumab), VEGF (bevacizumab), BAFF (atacicept, tabalumumab) and CD74 (milatuzumab). No objective response (≥PR) was observed with monotherapy with BI-505, siltuximab, bevacizumab, PAT-SMX, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab and nivolumab. Isatuximab (anti-CD38) was the only mAb with promising results (OR 24%) as monotherapy in patients with 6 prior lines of therapy. Most trials employed RRMM patients. Siltuximab in combination with VMP (velcade, melphalan and prednisone) was evaluated in frontline setting without significant improvement reported (CR of 22% vs 27% with VMP alone and PFS of 17 months in both arms). Antibodies tested as conjugates include indatuximab, ravtansine (anti CD138) and lorvotuzumab mertansine (anti CD56). Their results were encouraging when used in combination with Rd (lenalidomide and dexamethasone), OR of 78% with indatuximab +Rd and 56.4% with lorvotuzumab +Rd. MAbs that9ve been tested in combination therapy include siltuximab (S+Vd, OR 66%), dacetuzumab (D+Rd, OR 39%), indatuximab (I+Rd, OR 78%), isatuximab (I+Rd, OR 64.5%), lorvotuzumab (L+Rd, OR 56.4%) and pembrolizumab (P+Pd, OR 50%). Conclusion: Immunotherapy with mAb and CAR-T therapy seems to offer very promising results. Short term and log term toxicity with mAb and cellular therapy demands thorough understanding of mechanism, biology behind the " on target" and "off target" effects, side effect profile and their prevention. Further trials are warranted to determine best CAR-T cell construct and design for treating MM. Outcomes with many single agent mAb therapy were not encouraging and provide a rationale that future trials with mAbs should be done as multi-agent therapies. Promising results with isatuximab warrants further trials. Antibody-drug conjugate treatment is worth further evaluation both as single agent and in combination with standard anti-MM agents. Individualized treatment approach based on surface CD marker expression need to be developed and may produce better outcomes. Disclosures No relevant conflicts of interest to declare.
• Iftikhar, A., Anwer, F., Baig, M. Z., Kapoor, V., Latif, A., Mcbride, A., Russ, A. D., Tenneti, P., Warraich, S. U., Warraich, F. H., & Zafar, R. N. (2017). Precision Therapy Targeting Signal Transduction Aberrant Pathways in Multiple Myeloma. Blood, 130, 5403-5403. doi:10.1182/blood.v130.suppl_1.5403.5403
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  Introduction: Multiple myeloma (MM) is a genetically complex B cell neoplasm. Neoplastic clonal population of plasma cells acquire increasing levels of molecular aberrations including copy number variations, point mutations, gene deletions, and translocations. Guidelines define different levels of risk stratification based on genomic mutational landscape of the plasma cell in MM patients. Using genetics based information, testing aberrant pathways in individualized patients and targeting those pathways have potential for precision and personalized treatment. We summarize current literature on cancer driving mutations and signal transduction aberrant pathways. Methods: We searched PubMed, EMBASE, Wiley Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov (updated July 29th, 2017) for original articles regarding MM using keywords like cytogenetics, molecular profiling, mutations, disrupted, transduction pathways, prognosis and precision medicine. We found 154 articles. After detailed scrutiny, 27 articles were included in the study. Results: We summarized literature search results under three categories. 1: Genetic mutations in Myeloma 2: Mutation based risk stratification 3: Aberrant intracellular transduction pathways and novel drugs targeting pathways. Conclusion: 1: Genetic mutations in Myeloma: Cytogenetic aberrations in MM can be divided into two main groups: translocations involving the Immunoglobulin heavy locus (IGH) at 14q32.33 and genomic imbalances, defined as hyperdiploid and nonhyperdiploid subtypes. Hyperdiploid tumors are characterized by odd number chromosomal trisomy: 3, 5, 7, 9, 11, 15, 19, and 21. Nonhyperdiploid tumors harbor IGH translocations, mainly t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). Secondary mutational events contribute to tumor progression and can include: MYC rearrangements, copy number variations (CNV): del(13q), dup(1q), del(1p) del(17p) and somatic mutations in KRAS, NRAS, BRAF, P53, and many others. Co-occurrence of two adverse genetic lesions, termed "double-hit", is specifically associated with adverse outcome. 2: Mutation based risk stratification: MM is divided into high, intermediate and standard risk (mainly based on interphase FISH). High risk MM has Del (17p), t(14;16), t(14;20) and gene expression profiling (GEP) shows high risk signature. Intermediate risk have t(4;14), 1q gain, Cytogenetic Del 13, Hypodiploidy and PCLI ≥ 3%. Standard risk patients have t(11;14) and t(6;14). R-ISS and mSMART risk stratification guidelines rely on interphase FISH and serum biomarkers but many characterized aberrations in MM are not adequately surveyed by these methods. The use of massively parallel sequencing and array technologies to identify specific genetic mutations such as whole-exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, gene expression profiling (GEP), Plasma cell labeling index (PCLI), array comparative genomic hybridization (aCGH), whole-genome sequencing (WGS)/whole exome sequecing (WES) (MALDI-TOF, NGS) in addition to historical methods can identify new subgroups and novel targetable pathways. 3: Aberrant transduction pathways: Genetic aberrations lead to neoplastic proliferation and following aberrant pathways are detected in MM. KRAS/NRAS/BRAF mutations are detectable in up to 50% of newly diagnosed MM patients, making it a major therapeutic target (Walker et al 2015). Dysregulation of a Cyclin D gene, appears to be an early and unifying event in MM pathogenesis (Bergsagel et al., 2005). Pathological levels of MMSET (a histone methyltransferase) are found in t(4;14) MM cells, inhibition of MMSET would be of benefit in t(4;14) translocations. (Martinez-Garcia at al. 2011). Loss of CYLD enhances MM aggressiveness through Wnt pathway activation. WGS revealed V600E activating mutation in BRAF kinase (Andrulis et al 2013). NF-kB pathway remains constitutively active in MM and Proteasome inhibitors (Richardson et al., 2003) act principally by inhibiting NF-kB (Rajkumar et al., 2005). T cell exhaustion in MM via PD-1, PDL-1, PDL-2 signaling (Bae, Jooeun, et al 2017) can be blocked with immunecheck point inhibitors. Over active JAK Pathway (Chen, H, et al 2017) can be targeted with JAK2 Inhibitor Ruxolitinib. Disclosures No relevant conflicts of interest to declare.
• Iftikhar, A., Anwer, F., Hamadani, A. A., Hassan, N., Khalid, N., Larriva, M., Lim, M., Majeed, A., Mushtaq, A., & Zangeneh, T. T. (2017). Clostridium Difficile Infection in Hematopoietic Stem Cell Transplant Patients: A Single-Center experience.. Open Forum Infectious Diseases, 4(suppl_1), S390-S390. doi:10.1093/ofid/ofx163.971
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  Abstract Background C. difficile infection (CDI) is the most common cause of nosocomial infections in U.S. and leading cause of gastroenteritis associated death. Incidence of CDI in hematopoietic stem cell transplant (HSCT) patients has been reported between 5.7% to 24.7% during first year after HSCT. Literature review reveals many risk factors i.e., allogenic-HSCT, extremes of age, myeloablative conditioning, prior vancomycin resistance (VRE) colonization, pre-transplant C. difficile colonization, severe mucositis, graft vs. host disease (GVHD), duration and type of antibiotics used, immunosuppression, proton pump inhibitor use and NAP1 C. difficile strain. Methods To study incidence and different variables for CDI, we performed a retrospective review of medical records of adult patients who underwent HSCT between 2013 and 2016 at our center. REDCap database was used to record key variables related to each patient’s HSCT and CDI, keeping in mind HIPPA guidelines. Categorical data were summed up as percentages and counts and numeric data as means, medians, standard deviations and ranges. Results A total of 181 HSCT recipients were included. Incidence of CDI was 10% (18 Patients). Cohort’s most common underlying malignancy was multiple myeloma (35.4%). 70% had autologous HSCT and 30% had allogenic HSCT. Among allogenic transplants, 53% had matched unrelated donor. Peripheral blood was the most common stem cell source (93%). Most common myeloablative conditioning regimen was melphalan (70%). 27% patients were on PPIs. 4% had PEG/NG tube placed and 12% were on TPN. 10% had diabetes mellitus. 5 patients had previous episodes of CDI. 69% developed mucositis. 5% patients developed acute GVHD. 6% had VRE colonization while 66% had no documentation for VRE. Out of positive CDI cases, 17% were NAP1 positive. No episode of ileus or mega colon was documented. Most common treatment regimen were metronidazole 500 mg per orally every 8 hourly (65%) and vancomycin 125 mg per orally four times a day (58.8%). Conclusion This single-center study demonstrates that CDI has 10% incidence in patients undergoing HSCT. Risk factors include neutropenia, high dose chemotherapy, mucosal damage and provision of broad spectrum antibiotic prophylaxis. Data on CDI prophylaxis in these patients is emerging and randomized prospective trials are needed. Disclosures All authors: No reported disclosures.
• Iftikhar, A., Anwer, F., Jethava, Y., Mcbride, A., Rafiullah, R., Riaz, I. B., Tricot, G. J., & Zahid, U. (2017). Does Your Smoldering Myeloma Patient Need Treatment? Evidence Based Recommendations. Blood, 130, 5431-5431. doi:10.1182/blood.v130.suppl_1.5431.5431
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  Introduction: The IMWG defined smoldering multiple myeloma (SMM) as presence of 10-60% plasma cells in bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end organ damage (increased calcium level, renal failure, anemia, destructive bone lesions). Patients considered to have SMM should not have any myeloma defining events or amyloidosis. Risks factors classify SMM into low, intermediate, or high risk categories. Rate of progression from SMM to symptomatic myeloma is ~10% per year during the first 5 years of diagnosis. SMM requires frequent follow up, ~ every 3 months during the first 5 years compared to monoclonal gammopathy of undermined significance (MGUS) which requires follow-up every 6 to 12 months. This review presents literature and available data that support or do not support early treatment of high risk SMM and provides evidence-based recommendations for SMM management. Materials and Methods: A literature search was performed using electronic bibliographic databases: MEDLINE (Ovid SP and PubMed), EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews (CDSR), and Cochrane Central Register of Controlled Trials (CENTRAL), as well as annual meetings abstracts from inception till May 2017. The literature search focused mainly on randomized clinical trials, phase II/III, and retrospective studies. Different search terms like Smoldering Multiple Myeloma, Smoldering Myeloma, early treatment. and asymptomatic myeloma treatment were used to find the relevant material for this review article.We selected 51 articles from the literature search. Discussion: Experts in the field of myeloma have differing opinions about the management of SMM. There is growing number of data (summarized in attached table ) that provides some rationale for the early treatment of high risk SMM, supported by the logic that it has a very high rate of conversion to myeloma and, therefore, it is in the best interest of the patient to control the disease before it causes end organ damage. Early treatment of high risk SMM carries the risk of development of resistance to current therapies. There are other concerns like toxicities of currently available therapies, questionable long term effectiveness of current therapies, and cost of therapies for SMM.Patients with SMM are asymptomatic and have a good quality of life in general; therefore, subjecting an asymptomatic patient to medication related side effects and potentially impairing their quality of life should be taken into consideration before recommending treatment for high risk SMM. There is also considerable concern for patient compliance and clinical follow up, especially with parenteral therapy. Oral therapy potentially should solve this issue. Conclusion: Based on current literature review and current practices, SMM should be managed with close follow up at 3 to 6 months interval and outside a clinical trial, treatment should only be initiated if patient develops active MM or myeloma defining events(MDE), because of the risk of developing resistance to current myeloma therapies, cost, treatment related toxicities, and psychological implications for patients and their families. With more sensitive imaging such as MRI and 18F-FDG PET/CT, many patients who were previously considered high risk SMM were actual cases of myeloma meeting the IMGW 2014 criteria. SMM is a spectrum, bridging MGUS on one extreme and multiple myeloma on the other. We foresee that this entity (SMM) will disappear in the near future with the use of better diagnostic criteria, utilizing sensitive radiological testing and incorporating molecular profile based on genomics of plasma cell disorders. Patients will be either MGUS, not needing any treatment or multiple myeloma, requiring therapy. Disclosures No relevant conflicts of interest to declare.
• Iftikhar, A., Mora, F. E., Beatty, N., Gaynor, P., Georgescu, A., Kim, J. C., Majeed, A., Marquez, J. L., Mushtaq, A., & Zangeneh, T. T. (2017). A 20-Year Experience with Nocardiosis in Solid Organ Transplant (SOT) Recipients in the Southwestern United States: A Single-center Study. Open Forum Infectious Diseases, 4(suppl_1), S707-S707. doi:10.1093/ofid/ofx163.1899
• Zahid, U., Akbar, F., Amaraneni, A., Husnain, M., Chan, O., Riaz, I. B., McBride, A., Iftikhar, A., & Anwer, F. (2017). A Review of Autologous Stem Cell Transplantation in Lymphoma. Current hematologic malignancy reports, 12(3), 217-226.
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  Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients.