32 results on '"Amer M. Zeidan"'
Search Results
2. Advances in myelodysplastic syndromes: promising novel agents and combination strategies
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Yazan F. Madanat, Zhuoer Xie, and Amer M. Zeidan
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Hematology - Abstract
Myelodysplastic syndromes (MDS) are heterogeneous group of clonal hematopoietic stem cell neoplasms that have limited approved treatment options. Multiple novel agents are currently being tested in a clinical trial setting. From a therapeutic perspective, MDS is generally divided into lower-risk and higher-risk disease. In this review, we summarize some of the most prominent novel agents currently in development.This review focuses on select clinical trials in both lower- and higher-risk MDS, elucidating the mechanisms of action and rationale for drug combinations and summarizing early safety and efficacy data using novel agents in MDS.Advances in understanding the innate immune system, telomere biology, as well as genomic drivers of the disease have led to the development of multiple novel agents that are currently in late stages of clinical development in MDS, imetelstat is being tested in lower-risk disease and the phase III clinical trial recently completed accrual. Whereas magrolimab, sabatolimab and venetoclax in addition to novel oral hypomethylating agents (HMA) are being investigated in higher-risk MDS. These advances will hopefully bring better treatment options to patients and lead to a shift in the treatment paradigm. Post HMA therapy remains an area of dire unmet need.Myelodysplastic syndromes are rare bone marrow cancers that lead to low blood counts and carry the risk of disease progression to acute myeloid leukemia. The disease risk (lower vs higher) determines the treatment approach. For lower-risk MDS, the focus has been to improve blood counts and patients’ quality of life, novel treatment strategies are moving earlier in the course of disease to perhaps delay progression. In higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia, multiple advanced phase clinical trial are ongoing to evaluate agents in combination with azacitidine that have shown encouraging results in earlier phase studies.
- Published
- 2023
3. Cost-effectiveness of azacitidine and ivosidenib in newly diagnosed older, intensive chemotherapy-ineligible patients with IDH1-mutant acute myeloid leukemia
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Jan Philipp Bewersdorf, Kishan K. Patel, George Goshua, Rory M. Shallis, Nikolai A. Podoltsev, Maximilian Stahl, Eytan M. Stein, Scott F. Huntington, and Amer M. Zeidan
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Cancer Research ,Oncology ,Hematology - Published
- 2022
4. TP53-altered higher-risk myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a distinct genetic entity with unique unmet needs
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Somedeb Ball, Sanam Loghavi, and Amer M. Zeidan
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Cancer Research ,Oncology ,Hematology - Published
- 2022
5. Venetoclax-based salvage therapy in patients with relapsed/refractory acute myeloid leukemia previously treated with FLT3 or IDH1/2 inhibitors
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Jan Philipp Bewersdorf, Rory M. Shallis, Andriy Derkach, Aaron D. Goldberg, Anthony Stein, Eytan M. Stein, Guido Marcucci, Amer M. Zeidan, Shai Shimony, Daniel J. DeAngelo, Richard M. Stone, Ibrahim Aldoss, Brian J. Ball, and Maximilian Stahl
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Cancer Research ,Oncology ,Hematology - Abstract
FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with
- Published
- 2022
6. Gilteritinib vs salvage chemotherapy in FLT3-mutated acute myeloid leukemia: number needed to treat for clinical outcomes per a secondary analysis of the ADMIRAL trial
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Cynthia Z. Qi, Andy Garnham, Hongbo Yang, Amer M. Zeidan, Manasee V. Shah, and Bhavik J. Pandya
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Salvage Therapy ,Oncology ,Cancer Research ,medicine.medical_specialty ,Aniline Compounds ,business.industry ,Salvage treatment ,Gilteritinib ,Myeloid leukemia ,Hematology ,Newly diagnosed ,Leukemia, Myeloid, Acute ,fms-Like Tyrosine Kinase 3 ,Pyrazines ,hemic and lymphatic diseases ,Secondary analysis ,Internal medicine ,Tyrosine Kinase 3 ,Mutation ,Number needed to treat ,Humans ,Medicine ,business - Abstract
Approximately 30% of patients newly diagnosed with acute myeloid leukemia (AML) have FMS-like tyrosine kinase 3 mutations (FLT3mut+), conferring a negative effect on prognosis with a high likelihoo...
- Published
- 2021
7. Early mortality and overall survival in acute promyelocytic leukemia: do real-world data match results of the clinical trials?
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Vijaya Raj Bhatt, Krishna Gundabolu, Venkat Rajasurya, Elizabeth Lyden, Amer M. Zeidan, Prajwal Dhakal, and Chakra P Chaulagain
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Adult ,Acute promyelocytic leukemia ,Oncology ,Clinical Trials as Topic ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Hematology ,medicine.disease ,Article ,Clinical trial ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,Leukemia, Promyelocytic, Acute ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Overall survival ,Humans ,business ,Real world data ,030215 immunology - Abstract
Acute promyelocytic leukemia (APL) boasts overall survival (OS) of >90% at 3 years and early mortality of 60 years. OS at 1- and 3-year were 81% and 75%, respectively. In a multivariate analysis, age ≤ 40 years, treatment at academic center, use of multi-agent therapy, and diagnosis after 2009 conferred better OS. In this largest database study in APL till date, we demonstrated an overall improvement in OS over time but challenges still exist in translating successes of clinical trials to real-world practices.
- Published
- 2021
8. Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options
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Jan Philipp Bewersdorf, Amer M. Zeidan, and Russell Lewis
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0301 basic medicine ,medicine.medical_specialty ,Anemia ,Review ,03 medical and health sciences ,0302 clinical medicine ,erythropoiesis-stimulating agents ,Quality of life ,hemic and lymphatic diseases ,Medicine ,In patient ,Intensive care medicine ,Lenalidomide ,clinical trials ,business.industry ,Myelodysplastic syndromes ,Roxadustat ,novel agents ,medicine.disease ,myelodysplastic syndrome ,Clinical trial ,030104 developmental biology ,Oncology ,Novel agents ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
For the majority of patients with lower-risk myelodysplastic syndrome (LR-MDS), one of the primary clinical goals is to alleviate the symptoms associated with the resultant cytopenias and to minimize the transfusion burden. While supportive red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs) may lead to clinical improvement, frequent transfusions are often complicated by iron overload and decreased quality of life; furthermore, most patients either do not respond to ESAs or will eventually develop resistance. As such, there is a great need for further therapeutic options in the management of anemia related to MDS. Several additional therapeutics are now available in select patients with LR-MDS and symptomatic anemia including luspatercept, lenalidomide, and immunosuppressive therapy. Furthermore, several novel agents are currently in development to address this area of clinical need such as imetelstat and roxadustat. In this article, we review the currently available therapeutic options for symptomatic anemia in LR-MDS as well as review the therapeutic agents in development.
- Published
- 2021
9. Following in the footsteps of acute myeloid leukemia: are we witnessing the start of a therapeutic revolution for higher-risk myelodysplastic syndromes?
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Jan Philipp Bewersdorf and Amer M. Zeidan
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Oncology ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Azacitidine ,Decitabine ,Hematopoietic stem cell transplantation ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Genetic testing ,medicine.diagnostic_test ,Venetoclax ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia, Myeloid, Acute ,Hypomethylating agent ,chemistry ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
For most patients with higher-risk myelodysplastic syndromes (HR-MDS) the hypomethylating agents (HMA) azacitidine and decitabine remain the mainstay of therapy. However, the prognosis mostly remains poor and aside from allogeneic hematopoietic stem cell transplantation no curative treatment options exist. Unlike acute myeloid leukemia, which has seen a dramatic expansion of available therapies recently, no new agents have been approved for MDS in the United States since 2006. However, various novel HMAs, HMA in combination with venetoclax, immune checkpoint inhibitors, and targeted therapies for genetically defined patient subgroups such as APR-246 or IDH inhibitors, have shown promising results in early stages of clinical testing. Furthermore, the wider availability of genetic testing is going to allow for a more individualized treatment of MDS patients. Herein, we review the current treatment approach for HR-MDS and discuss recent therapeutic advances and the implications of genetic testing on management of HR-MDS.
- Published
- 2020
10. Clinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience*
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Rory M. Shallis, Stuart Seropian, Amer M. Zeidan, Nikolai A. Podoltsev, Steven D. Gore, Lohith Gowda, Karl Hager, Tae Kon Kim, Jan Philipp Bewersdorf, Iris Isufi, Alexa J. Siddon, Manoj M. Pillai, and Wei Wei
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Cancer Research ,endocrine system diseases ,Tumor suppressor gene ,Single Center ,Tp53 mutation ,Article ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,hemic and lymphatic diseases ,medicine ,Humans ,neoplasms ,Retrospective Studies ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia, Myeloid, Acute ,Oncology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Tumor Suppressor Protein p53 ,business ,030215 immunology - Abstract
Mutations in the tumor suppressor gene TP53 are detected in 5–10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n=75; 90%) and therapy-related malignancies (n=32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT.
- Published
- 2020
11. Leukocytapheresis for patients with acute myeloid leukemia presenting with hyperleukocytosis and leukostasis: a contemporary appraisal of outcomes and benefits
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Jeanne E. Hendrickson, Jan Philipp Bewersdorf, Rory M. Shallis, Maximilian Stahl, and Amer M. Zeidan
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Oncology ,medicine.medical_specialty ,Leukocytosis ,business.industry ,Total white blood cell count ,Myeloid leukemia ,Leukostasis ,Hematology ,Leukapheresis ,Leukemia, Myeloid, Acute ,03 medical and health sciences ,0302 clinical medicine ,Feature (computer vision) ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Humans ,Tumor Lysis Syndrome ,business ,030215 immunology - Abstract
Hyperleukocytosis, defined as a total white blood cell count (WBC) >50 or more commonly >100 × 109 cells/L, is a presenting feature of acute myeloid leukemia (AML) in about 6–20% of cases and is as...
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- 2020
12. Cui bono? Finding the value of allogeneic stem cell transplantation for lower-risk myelodysplastic syndromes
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Rory M. Shallis, Lohith Gowda, Steven D. Gore, Amer M. Zeidan, and Nikolai A. Podoltsev
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Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Disease progression ,Bone marrow failure ,Myeloid leukemia ,macromolecular substances ,Hematology ,medicine.disease ,Lower risk ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Stem cell ,business ,Value (mathematics) ,030215 immunology - Abstract
Introduction: The myelodysplastic syndromes (MDS) vary in their risk of disease progression; progression includes increasingly severe bone marrow failure, reclassification as acute myeloid leukemia...
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- 2020
13. Hypomethylating agent (HMA) therapy use and survival in older adults with Refractory Anemia with Excess Blasts (RAEB) in the United States (USA): a large propensity score-matched population-based study
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Xiaomei Ma, Jan Philipp Bewersdorf, Amy J. Davidoff, Steven D. Gore, Nikolai A. Podoltsev, Rong Wang, Scott F. Huntington, Xin Hu, and Amer M. Zeidan
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Cancer Research ,medicine.medical_specialty ,Azacitidine ,Refractory anemia ,Medicare ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Propensity Score ,Aged ,Retrospective Studies ,Anemia, Refractory, with Excess of Blasts ,business.industry ,Myelodysplastic syndromes ,Retrospective cohort study ,Hematology ,medicine.disease ,United States ,humanities ,Population based study ,Clinical trial ,Oncology ,Hypomethylating agent ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Propensity score matching ,business ,030215 immunology ,medicine.drug - Abstract
Hypomethylating agents (HMA) showed overall survival (OS) benefits in patients with higher-risk myelodysplastic syndromes (HR-MDS) in clinical trials. We conducted a retrospective cohort study of Surveillance, Epidemiology, and End Results (SEER)-Medicare data of patients ≥66 years diagnosed with refractory anemia with excess blasts (RAEB), a proxy for HR-MDS, in 01/2001–04/2004 (pre-period) or 01/2006–12/2011 (post-period). Association between post-period diagnosis and OS was examined using propensity scores (PS)-matched samples. Among 1,876 RAEB patients, median OS was 9 months and 30.8% received HMAs (3.6% in pre-period; 43.0% in post-period) with no association between post-period diagnosis and OS. In the top PS quartile, post-period diagnosis was associated with a 74% lower risk of death (Hazard ratio [HR]=0.26, 95%-CI: 0.10–0.69, P=0.007), while outcomes were worse in the lowest PS quartile (HR=2.80, 95%-CI: 1.06–7.36, P=0.037). HMA lead to a 3-month OS benefit for patients most likely to receive HMA but not for unselected RAEB cohort.
- Published
- 2019
14. Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis
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Sara Mohamed Jaszczur, Amer M. Zeidan, Jan Philipp Bewersdorf, Jennifer Zhao, and Salma Afifi
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Anemia ,medicine.disease ,3. Good health ,Extramedullary hematopoiesis ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Drug development ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Myelofibrosis ,business ,Adverse effect ,Myeloproliferative neoplasm ,medicine.drug - Abstract
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke's encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.
- Published
- 2019
15. Association of provider experience and clinical outcomes in patients with myelodysplastic syndromes receiving hypomethylating agents
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Maximilian Stahl, Amy J. Davidoff, Nikolai A. Podoltsev, Weiwei Zhu, Xiaomei Ma, Jan Philipp Bewersdorf, Steven D. Gore, Rong Wang, Scott F. Huntington, Xin Hu, Smith Giri, and Amer M. Zeidan
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Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Population level ,Medicare ,Article ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,In patient ,Aged ,Proportional Hazards Models ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,United States ,Clinical trial ,Oncology ,Hypomethylating agent ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
Population level survival of patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) is inferior to clinical trials. Using SEER-Medicare data, we identified 2,086 MDS patients diagnosed in 2004–13, aged ≥66 years at diagnosis, and receiving ≥1 HMA cycle. We used multivariate logistic regression and Cox proportional hazards models to assess the impact of provider experience on persistent HMA therapy and overall survival (OS), respectively. Median number of HMA cycles was 4 and median OS was 10 months. 32% of patients were treated by providers with ≥1 prior HMA initiation in the last 2 years and were more likely to receive ≥4 cycles of HMA therapy (OR=1.29, 95%-CI: 1.06–1.57; P=.01). No significant association was found between MDS or HMA initiation volume and survival. In conclusion, while HMA initiation volume was associated with persistent HMA treatment, neither MDS nor HMA initiation volumes were associated with OS in older MDS patients.
- Published
- 2019
16. Healthcare expenses for treatment of acute myeloid leukemia
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Xiaomei Ma, Jan Philipp Bewersdorf, Rory M. Shallis, Amer M. Zeidan, Sarah Perreault, Rong Wang, and Scott F. Huntington
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medicine.medical_specialty ,Cost effectiveness ,Cost-Benefit Analysis ,Antineoplastic Agents ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Health care ,medicine ,Humans ,In patient ,Treatment costs ,Intensive care medicine ,health care economics and organizations ,Health policy ,Modalities ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Health Care Costs ,Hematology ,Hospitalization ,Leukemia, Myeloid, Acute ,Cost driver ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
Introduction: The cost of acute myeloid leukemia (AML) treatment is substantial and increasing. Inpatient treatment costs for allogeneic hematopoietic stem cell transplant (HSCT) and intensive chemotherapy are the main cost drivers in AML, however this pattern may change as new, expensive oral therapies enter the market. Areas covered: The authors provide an overview of the healthcare costs in patients with AML treated with various modalities (intensive chemotherapy, allogeneic HSCT, low-intensity treatment and supportive care only). The authors review both the impact of the recently approved novel AML agents and an increasingly personalized treatment approach on healthcare resources. Finally, the authors discuss whether these treatments are cost-effective from a societal perspective and how the increase in AML-associated costs can potentially be slowed. Expert opinion: The direct healthcare costs of AML are substantial and vary depending on the treatment approach, the country studied, and in the United States, a patient's insurance status. Treatment costs have increased out of proportion to general inflation and this trend is likely going to continue or even accelerate. Societal consensus on cost-effectiveness is essential. It remains to be seen how advances in diagnostic techniques and the incorporation of novel agents will impact medical outcomes, costs and influence health policy.
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- 2019
17. Are we witnessing the start of a therapeutic revolution in acute myeloid leukemia?
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Jan Philipp Bewersdorf, Amer M. Zeidan, and Maximilian Stahl
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Oncology ,Cancer Research ,medicine.medical_specialty ,Gemtuzumab ozogamicin ,Daunorubicin ,medicine.medical_treatment ,Antineoplastic Agents ,Enasidenib ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Drug Discovery ,Biomarkers, Tumor ,Humans ,Medicine ,Molecular Targeted Therapy ,Midostaurin ,Drug Approval ,Clinical Trials as Topic ,United States Food and Drug Administration ,business.industry ,Disease Management ,Myeloid leukemia ,Hematology ,United States ,Clinical trial ,Leukemia, Myeloid, Acute ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Cytarabine ,business ,030215 immunology ,medicine.drug - Abstract
The 5-year overall survival rate of AML patients remains 25-40%. The prognosis is even more dismal for older patients who are ineligible for intensive chemotherapy and patients with secondary or relapsed/refractory AML. In 2017, 4 new drugs were approved by the US Food and Drug Administration for AML treatment: The FLT3 inhibitor midostaurin, the isocitrate dehydrogenase (IDH)-2 inhibitor enasidenib, a liposomal formulation of cytarabine and daunorubicin (CPX-351), and the anti-CD33 antibody gemtuzumab ozogamicin. Additionally, the IDH1 inhibitor ivosidenib has received FDA approval in July 2018. However, all these drugs were approved in certain settings and/or for certain subsets of AML patients. Herein, we review the mechanisms of actions and preclinical data, highlight pivotal clinical trial data, and discuss future directions and challenges for further development of these 5 novel therapeutics. Finally, we briefly overview some of the highly promising agents that are currently in advanced stages of clinical development.
- Published
- 2019
18. Immunosuppressive therapy in myelodysplastic syndromes: a borrowed therapy in search of the right place
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Maximilian Stahl, Rory M. Shallis, Amer M. Zeidan, Nora Chokr, and Alexander B Pine
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medicine.medical_treatment ,Adaptive Immunity ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Inflammation ,business.industry ,Myelodysplastic syndromes ,Immunosuppression ,Hematology ,medicine.disease ,Immunity, Innate ,Haematopoiesis ,Clonal Hematopoietic Stem Cell ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Immunology ,Cytokines ,Immunotherapy ,Inflammation Mediators ,business ,Biomarkers ,Immunosuppressive Agents ,030215 immunology - Abstract
Myelodysplastic syndromes (MDS) encompass a heterogenous collection of clonal hematopoietic stem cell disorders defined by dysregulated hematopoiesis, peripheral cytopenias, and a risk of leukemic progression. Increasing data support the role of innate and adaptive immune pathways in the pathogenesis and disease course of MDS. The role of immunosuppressive therapy has an established role in the treatment of other hematologic diseases, such as aplastic anemia whose pathogenesis is postulated to reflect that of MDS with regards to many aspects of immune activation. Areas covered: This paper discusses the current understanding of immune dysregulation as it pertains to MDS, the clinical experience with immunosuppressive therapy in the management of MDS, as well as future prospects which will likely improve therapeutic options and outcomes for patients with MDS. Expert commentary: Though limited by paucity of high quality data, immunomodulatory and immunosuppressive therapies for the treatment of MDS have shown meaningful clinical activity in selected patients. Continued clarification of the immune pathways that are dysregulated in MDS and establishing predictors for clinical benefit of immunosuppressive therapy are vital to improve the use and outcomes with these therapies.
- Published
- 2018
19. Performance of the Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) score in predicting survival benefit with hypomethylating agent use in patients with relapsed or refractory acute myeloid leukemia
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John Barnard, Aref Al-Kali, Norbert Vey, Ellen K. Ritchie, Mark R. Litzow, Pau Montesinos, Ulrich Germing, Amer M. Zeidan, Mikkael A. Sekeres, Thomas Cluzeau, Rami S. Komrokji, Juan Bergua, Nikolai A. Podoltsev, Raphael Itzykson, Thomas Prebet, Josefina Serrano, Vivek Verma, Tae Kon Kim, Pierre Fenaux, Amir T. Fathi, Sarah Perreault, Steven D. Gore, Maximilian Stahl, Valeria Santini, Michelle DeVeaux, Andrew M. Brunner, Gail J. Roboz, and Vijaya Raj Bhatt
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,endocrine system diseases ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Risk Assessment ,Young Adult ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,neoplasms ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,Tolerability ,Hypomethylating agent ,Drug Resistance, Neoplasm ,hypomethylating agent, acute myeloid leukemia ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Patients with primary refractory or relapsed-acute myeloid leukemia (RR-AML), particularly older adults, have dismal outcomes and limited therapy options [1]. Given the tolerability of hypomethylat...
- Published
- 2018
20. Beliefs and practice patterns in hyperleukocytosis management in acute myeloid leukemia: a large U.S. web-based survey
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Selina M. Luger, Jeanne E. Hendrickson, Mikkael A. Sekeres, Harry P. Erba, Mark R. Litzow, Richard Stone, Steven D. Gore, Maximilian Stahl, Rami S. Komrokji, Alexander Pine, David P. Steensma, Amer M. Zeidan, and Tae Kon Kim
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Oncology ,Cancer Research ,medicine.medical_specialty ,Attitude of Health Personnel ,Leukocytosis ,Culture ,Early death ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Surveys and Questionnaires ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Practice Patterns, Physicians' ,Web based survey ,Internet ,business.industry ,Practice patterns ,Disease Management ,Myeloid leukemia ,Leukostasis ,Hematology ,Prognosis ,medicine.disease ,United States ,Tumor lysis syndrome ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,business - Abstract
Hyperleukocytosis in acute myeloid leukemia (AML) is associated with high risks of leukostasis, tumor lysis syndrome (TLS), organ failure and early death [1]. One option for achieving rapid cytored...
- Published
- 2018
21. Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia
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Michelle Nadeau, Natalie Uy, Maximilian Stahl, and Amer M. Zeidan
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Antibody-drug conjugate ,medicine.medical_treatment ,Salvage therapy ,Review ,acute lymphoblastic leukemia ,inotuzumab ozogamicin ,antibody-drug conjugate ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Calicheamicin ,medicine ,CD22 ,Inotuzumab ozogamicin ,Chemotherapy ,business.industry ,Hematology ,Chimeric antigen receptor ,Transplantation ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Blinatumomab ,monoclonal antibodies ,business ,medicine.drug - Abstract
The improvement in outcomes of adult patients with acute lymphoblastic leukemia (ALL) has been modest, with the exception of Philadelphia chromosome-positive disease, despite advances in supportive care and stem cell transplantation. The recent approvals of novel agents, including the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell products are changing the management of B-ALL, which traditionally relied on chemotherapy-based approaches. Inotuzumab ozogamicin is a humanized CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. CD22 is expressed on leukemic blasts in >90% of ALL patients, and inotuzumab ozogamicin has shown excellent clinical activity even among heavily pretreated relapsed/refractory (R/R) B-ALL patients and elderly B-ALL patients. Clinical trials have shown superior survival with the drug over chemotherapy-based approaches in the first- or second-line salvage therapy for relapsed B-ALL as monotherapy. Currently, new trials are evaluating inotuzumab ozogamicin in the frontline setting in combination-based approaches. In this review, we summarize the preclinical and clinical data of inotuzumab ozogamicin in R/R B-ALL and foresee the future use of this drug in the clinic.
- Published
- 2018
22. Management of lower-risk myelodysplastic syndromes without del5q: current approach and future trends
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Amer M. Zeidan and Maximilian Stahl
- Subjects
Risk ,Oncology ,medicine.medical_specialty ,Lower risk ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Anemia, Macrocytic ,Lenalidomide ,Clinical Trials as Topic ,Cytopenia ,business.industry ,Myelodysplastic syndromes ,Bone marrow failure ,Disease Management ,Myeloid leukemia ,Standard of Care ,Hematology ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Treatment Outcome ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Immunology ,Chromosomes, Human, Pair 5 ,Chromosome Deletion ,business ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
Myelodysplastic syndromes (MDS) are characterized by progressive bone marrow failure manifesting as blood cytopenia and a variable risk of progression into acute myeloid leukemia. MDS is heterogeneous in biology and clinical behavior. MDS are generally divided into lower-risk (LR) and higher-risk (HR) MDS. Goals of care in HR-MDS focus on changing the natural history of the disease, whereas in LR-MDS symptom control and quality of life are the main goals. Areas covered: We review the epidemiology, tools of risk assessment, and the available therapeutic modalities for LR-MDS. We discuss the use of erythropoiesis stimulating agents (ESAs), immunosuppressive therapy (IST), lenalidomide and the hypomethylating agents (HMAs). We also discuss the predictors of response, combination treatment modalities, and management of iron overload. Lastly, we overview the most promising investigational agents for LR-MDS. Expert commentary: It remains unclear how to best incorporate a wealth of new genetic and epigenetic prognostic markers into risk assessment tools especially for LR-MDS patients. Only a subset of patients respond to current treatment modalities and most responders eventually lose their response. Once standard therapeutic options fail, management becomes more challenging. Combination-based approaches have been largely unsuccessful. Among the most promising investigational are the TPO agonists, TGF- β pathway inhibitors, telomerase inhibitors, and the splicing modifiers.
- Published
- 2017
23. Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings
- Author
-
Amer M. Zeidan, Steven D. Gore, Thomas Prebet, and Brian Ball
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,Azacitidine ,Decitabine ,Pharmacology ,Article ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Molecular Targeted Therapy ,Lenalidomide ,Protein Kinase Inhibitors ,Clinical Trials as Topic ,business.industry ,Myelodysplastic syndromes ,Hematology ,DNA Methylation ,medicine.disease ,Thalidomide ,Histone Deacetylase Inhibitors ,Treatment Outcome ,030104 developmental biology ,Hypomethylating agent ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
The hypomethylating agents (HMA) azacitidine and decitabine are both approved by the FDA for the treatment of myelodysplastic syndromes (MDS). Although heralded as a significant advancement, HMA lead to responses in less than half of patients and for those that respond most will relapse. As such, there is a crucial need to improve frontline therapy approaches. One promising strategy involves combining azacitidine or decitabine with investigational or existing therapies with the goal of achieving synergistic activity and better patient outcomes. The purpose of this paper is to critically review the efficacy and safety of reported HMA-based combination regimens in patients with higher-risk MDS.
- Published
- 2016
24. Economic burden associated with acute myeloid leukemia treatment
- Author
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Dalia Mahmoud, Marja Hensen, Barry S. Skikne, B. Douglas Smith, Cathelijne Alleman, Izabela Kucmin-Bemelmans, and Amer M. Zeidan
- Subjects
Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Myeloid leukemia ,Induction chemotherapy ,Hematology ,Intensive chemotherapy ,Direct cost ,Transplantation ,Leukemia, Myeloid, Acute ,03 medical and health sciences ,Indirect costs ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Economic cost ,medicine ,Humans ,Intensive care medicine ,business ,health care economics and organizations ,030215 immunology - Abstract
The economic burden associated with acute myeloid leukemia (AML) is poorly defined and understudied. The goal of this study is estimate the direct cost of illness for AML in the United States (US) and the United Kingdom (UK), by conducting a comprehensive literature review and calculating the average direct cost-of-illness per patient for the first 6 months of therapy. Patients were grouped by therapy: intensive chemotherapy alone; induction chemotherapy followed by allogeneic stem cell transplantation (alloSCT); low intensity therapy; and best supportive care. Data suggest that the pathways alloSCT, followed by intensive chemotherapy, are associated with the highest direct costs. Calculated direct costs suggest that they are higher in the US ($14,014 for BSC-only to $352,682 for alloSCT) than in the UK (£3708 [$5837] for BSC-only to £112,545 [$177,187]). AML appears to be associated with significant direct economic costs, but more studies are needed to fully assess the economic impact especially in relation to total and indirect costs.
- Published
- 2015
25. The clinical use of DNA methyltransferase inhibitors in myelodysplastic syndromes
- Author
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Amer M. Zeidan, Abdallah Abou Zahr, Ehab Saad Aldin, Lisa Barbarotta, and Nikolai A. Podoltsev
- Subjects
Oncology ,medicine.medical_specialty ,Azacitidine ,DNA Methyltransferase Inhibitor ,Decitabine ,Epigenesis, Genetic ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,DNA (Cytosine-5-)-Methyltransferases ,Enzyme Inhibitors ,Survival rate ,business.industry ,Myelodysplastic syndromes ,Cancer ,Myeloid leukemia ,medicine.disease ,Survival Rate ,Transplantation ,Myelodysplastic Syndromes ,Immunology ,Disease Progression ,business ,medicine.drug - Abstract
Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. Patients with higher risk MDS have dismal outcomes and treatment options are very limited. Aside from allogeneic hematopoietic cell transplantation, the only potentially curative treatment, DNA methyltransferase inhibitors (DNMTIs) are the only intervention that prolongs overall survival in patients with higher risk MDS. The clinical use of DNMTIs in MDS was one of the earliest successful attempts at epigenetic reprogramming of cancer. In this review, we discuss the clinical use of DNMTIs in MDS highlighting the current challenges and controversies and future directions of research needed to explore the full therapeutic potential of these agents.
- Published
- 2015
26. Genome sequencing in myelodysplastic syndromes: can molecular mutations predict benefit from hypomethylating agent therapy?
- Author
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Eun-Ju Lee and Amer M. Zeidan
- Subjects
Male ,Myeloid Neoplasia ,business.industry ,Myelodysplastic syndromes ,Hematology ,DNA Methylation ,medicine.disease ,Bioinformatics ,DNA sequencing ,DNA-Binding Proteins ,Hypomethylating agent ,Myelodysplastic Syndromes ,Proto-Oncogene Proteins ,Mutation ,medicine ,Animals ,Humans ,Female ,In patient ,business - Abstract
Evaluation of: Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014 Oct 23;124(17):2705-12. Patients with myelodysplastic syndromes (MDS) have clinically variable courses even within the same prognostic subgroups. Although hypomethylating agents (HMAs) have been shown to improve outcomes in patients with high-risk MDS, many patients do not derive benefit. There is an urgent clinical need to identify patients with low probability of benefiting from HMAs but no reliable clinical predictors or biomarkers have been discovered to date. Although some recurrent molecular mutations in MDS carry independent prognostic value, their ability to predict benefit from HMAs is not clear. Here, we discuss an important article in which sequencing from samples of 213 patients identified recurrent mutations associated with response to HMAs. Although an important step in the right direction, the clinical implications of these findings are far from optimal and identification of biomarkers that can reliably predict benefit from HMAs and other therapies in patients with MDS remains a top clinical and a research priority.
- Published
- 2015
27. An update on type 2B von Willebrand disease
- Author
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Sameh Mikhail, Michael B. Streiff, Ehab Saad Aldin, and Amer M. Zeidan
- Subjects
Blood Platelets ,congenital, hereditary, and neonatal diseases and abnormalities ,Hemorrhage ,von Willebrand Disease, Type 2 ,Disease ,medicine.disease_cause ,Diagnosis, Differential ,Von Willebrand factor ,hemic and lymphatic diseases ,von Willebrand Factor ,Von Willebrand disease ,Humans ,Medicine ,Deamino Arginine Vasopressin ,Platelet ,Desmopressin ,Receptor ,Mutation ,Factor VIII ,biology ,business.industry ,Hematology ,medicine.disease ,Drug Combinations ,Platelet transfusion ,Platelet Glycoprotein GPIb-IX Complex ,Immunology ,biology.protein ,business ,circulatory and respiratory physiology ,medicine.drug - Abstract
Type 2B von Willebrand disease (VWD) accounts for fewer than 5% of all VWD patients. In this disease, mutations in the A1 domain result in increased von Willebrand factor (VWF) binding to platelet GPIbα receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers. Diagnosis is complicated because of significant clinical variations even among patients with identical mutations. Platelet transfusion often provides suboptimal results since transfused platelets may be aggregated by the patients' abnormal VWF. Desmopressin may cause a transient decrease in platelet count that could lead to an increased risk of bleeding. Replacement therapy with factor VIII/VWF concentrates is the most effective approach to prevention and treatment of bleeding in type 2B VWD.
- Published
- 2014
28. The use of novel oral anticoagulants for thromboprophylaxis after elective major orthopedic surgery
- Author
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Ehab Saad Aldin, Saleh Rachidi, Charles S. Greenberg, Michael B. Streiff, Barton L. Sachs, and Amer M. Zeidan
- Subjects
medicine.medical_specialty ,Pyridones ,medicine.drug_class ,Arthroplasty, Replacement, Hip ,Morpholines ,medicine.medical_treatment ,Administration, Oral ,Low molecular weight heparin ,Thiophenes ,Fondaparinux ,Article ,Dabigatran ,Postoperative Complications ,Rivaroxaban ,medicine ,Humans ,Arthroplasty, Replacement, Knee ,Clinical Trials as Topic ,business.industry ,Warfarin ,Anticoagulants ,Venous Thromboembolism ,Hematology ,Perioperative ,Arthroplasty ,Surgery ,beta-Alanine ,Pyrazoles ,Benzimidazoles ,Apixaban ,business ,medicine.drug - Abstract
Venous thromboembolism is a common cause of morbidity and mortality among patients undergoing elective orthopedic surgery. Due to the high incidence of venous thromboembolism in this setting, perioperative anticoagulation is the recommended approach for thromboprophylaxis. Low molecular weight heparin (LMWH), fondaparinux and warfarin are the agents commonly used for thromboprophylaxis. The well-recognized limitations of warfarin and the inconvenience and discomfort associated with the subcutaneous administration of low molecular weight heparin and fondaparinux inspired intense investigation to develop novel oral anticoagulants (NOACs) with more predictable pharmacokinetics, fewer drug interactions and no need for regular laboratory monitoring. Three NOACs have been demonstrated to be effective for thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in large randomized controlled trials. Here we review the pharmacology of rivaroxaban, dabigatran, and apixaban, summarize the major clinical trials of these agents in thromboprophylaxis after THA and TKA, and discuss the clinical factors to be considered by providers when selecting a NOAC for their patients.
- Published
- 2013
29. Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?
- Author
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Steven D. Gore and Amer M. Zeidan
- Subjects
Ineffective Hematopoiesis ,Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,medicine.medical_treatment ,Azacitidine ,De novo Myelodysplastic Syndrome ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Transplantation ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,medicine ,Transplantation Conditioning ,Stem cell ,business ,medicine.drug - Abstract
Evaluation of: Koreth J, Pidala J, Perez WS et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J. Clin. Oncol. 31(21), 2662–2670 (2013).Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct...
- Published
- 2013
30. Higher-risk myelodysplastic syndromes with del(5q): is sequential azacitidine–lenalidomide combination the way to go?
- Author
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Amer M. Zeidan, Rami S. Komrokji, and Steven D. Gore
- Subjects
Oncology ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Myeloid ,Combination therapy ,Azacitidine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,In patient ,Intensive care medicine ,Letter to the Editor ,Lenalidomide ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Hematology ,medicine.disease ,Thalidomide ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Chromosomes, Human, Pair 5 ,Chromosome Deletion ,business ,medicine.drug - Abstract
High-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML) with deletions of long arm of chromosome 5 (del[5q]) are characterized by rapid progression and poor survival. The majority of these patients are elderly with comorbidities, therefore limiting the use of intensive therapies which, even if used, unfortunately yield low responses. While azacitidine prolongs survival in patients with HR-MDS by a median of 9.5 months, responses only occur in less than half of the patients, and azacitidine therapy is not curative, with most patients relapsing within 2 years. Therefore, strategies to improve outcomes in these patients are needed. Azacitidine and lenalidomide both have meaningful single-agent clinical activity in HR-MDS and AML with del(5q). Early-phase trials in HR-MDS without del(5q) suggest increased activity with a concurrent azacitidine-lenalidomide combination. In this article, we review the results of a Phase I trial of a sequential azacitidine-lenalidomide combination approach in patients with HR-MDS and AML with del(5q) abnormality.
- Published
- 2013
31. Sustained remission in a patient with myelodysplastic syndrome and a complex karyotype after erythropoiesis-stimulating therapy followed by colonic T-cell lymphoblastic lymphoma
- Author
-
William Fricke, Steven D. Gore, Bishoy Faltas, Ronald L. Sham, Rhett P. Ketterling, and Amer M. Zeidan
- Subjects
Cancer Research ,business.industry ,T cell ,Lymphoblastic lymphoma ,Hematology ,medicine.disease ,Text mining ,medicine.anatomical_structure ,Oncology ,Complex Karyotype ,medicine ,Cancer research ,Erythropoiesis ,Sustained remission ,business - Published
- 2012
32. Hepatosplenic T-cell lymphoma in a patient with Crohn's disease who received infliximab therapy
- Author
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Anthony Baratta, Peter A. Kouides, Joel Shapiro, Ronald L. Sham, and Amer M. Zeidan
- Subjects
Infliximab therapy ,Cancer Research ,medicine.medical_specialty ,Crohn's disease ,business.industry ,Hepatosplenic T-cell lymphoma ,Hematology ,medicine.disease ,Gastroenterology ,Lymphoma ,Oncology ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,business - Abstract
Hepatosplenic T-cell lymphoma (HSTL) is a rare form of aggressive non-Hodgkin's lymphoma. About one fourth of HSTL cases have been associated with immunosuppressive therapy for various reasons, mos...
- Published
- 2007
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