138 results on '"Farag, Sherif S."'
Search Results
102. Pre-Treatment Cytogenetics Predict Complete Remission and Long-Term Outcome in Patients (Pts) ≥60 Years with Acute Myeloid Leukemia (AML): Results from Cancer and Leukemia Group B (CALGB) 8461.
- Author
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Farag, Sherif S., primary, Archer, Kellie J., additional, Mrózek, Krzysztof, additional, Vardiman, James W., additional, Carroll, Andrew J., additional, Pettenati, Mark J., additional, Powell, Bayard L., additional, Moore, Joseph O., additional, Kolitz, Jonathan E., additional, Baer, Maria R., additional, Bigner, Sandra H., additional, Koduru, Prasad R., additional, Stamberg, Judith, additional, Mayer, Robert J., additional, Stone, Richard M., additional, Schiffer, Charles A., additional, Larson, Richard A., additional, and Bloomfield, Clara D., additional
- Published
- 2004
- Full Text
- View/download PDF
103. Single Institution Experience with Two High-Dose Chemotherapy (HDC) Conditioning Regimens Prior to Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma (MM).
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Benson, Don M., primary, Elder, Patrick J., primary, Lin, Thomas, primary, Blum, William, primary, Penza, Sam, primary, Avalos, Belinda, primary, Byrd, John C., primary, Copelan, Edward, primary, and Farag, Sherif S., primary
- Published
- 2004
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- View/download PDF
104. New directions in natural killer cell-based immunotherapy of human cancer
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Farag, Sherif S, primary, Fehniger, Todd A, additional, Becknell, Brian, additional, Blaser, Bradley W, additional, and Caligiuri, Michael A, additional
- Published
- 2003
- Full Text
- View/download PDF
105. The Therapeutic Use of Natural-Killer Cells in Hematological Malignancies.
- Author
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Teicher, Beverly A., Disis, Mary L., Farag, Sherif S., and Caligiuri, Michael A.
- Abstract
The role of natural-killer (NK) cells in the treatment of hematological malignancies has been investigated intensively during the past three decades. Until recently, the majority of research has focused on the use of in vitro or in vivo cytokine-expanded and -activated NK cells against autologous cancer cells, with generally disappointing results. The lack of observed efficacy of past attempts to harness the antitumor effect of NK cells can now be explained largely by inhibitory interactions between major histocompatibility complex class I molecules expressed on tumor cells and inhibitory receptors on NK cells. Better appreciation of how NK cells selectively recognize and kill target cells while sparing normal cells is evolving. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulin-like receptors, C-type lectins, and natural cytotoxicity receptors. In addition, identification of NK cell receptor ligands and their expression on normal and transformed cells is becoming better elucidated. The improved understanding of NK cell receptor biology has paved the way for development of novel and rational clinical approaches to manipulating receptor-ligand interactions for immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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- View/download PDF
106. Lack of In Vitro Cross-Reactivity Predicts Safety of Low-Molecular Weight Heparins in Heparin-Induced Thrombocytopenia
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Farag, Sherif S., primary, Savoia, Heten, additional, O'Malley, Cindy J., additional, and McGrath, Katherine M., additional
- Published
- 1997
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- View/download PDF
107. The potential role of PD0332991(Palbociclib) in the treatment of multiple myeloma
- Author
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Altenburg, Jeffrey D and Farag, Sherif S
- Abstract
Introduction:Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991(Palbociclib) is an orally bioavailable, highly selective inhibitor of the CDK4/6-cyclin complex and downstream retinoblastoma protein (Rb) activation pathway that induces cell cycle arrest in the G1 phase.Areas covered:In this review, the authors summarize the role of the CDK4/6 signaling pathway in MM. They also summarize the development of PD0332991 as a specific inhibitor of CDK4/6, and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM.Expert opinion:While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM.
- Published
- 2015
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- View/download PDF
108. Treating relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: liposome-encapsulated vincristine.
- Author
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Davis, Tyler and Farag, Sherif S.
- Published
- 2013
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- View/download PDF
109. Differential stem- and progenitor-cell trafficking by prostaglandin E2 .
- Author
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Hoggatt, Jonathan, Mohammad, Khalid S., Singh, Pratibha, Hoggatt, Amber F., Chitteti, Brahmananda R., Speth, Jennifer M., Hu, Peirong, Poteat, Bradley A., Stilger, Kayla N., Ferraro, Francesca, Silberstein, Lev, Wong, Frankie K., Farag, Sherif S., Czader, Magdalena, Milne, Ginger L., Breyer, Richard M., Serezani, Carlos H., Scadden, David T., Guise, Theresa A., and Srour, Edward F.
- Subjects
PROGENITOR cells ,STEM cells ,BLOOD cells ,HEMATOPOIETIC stem cells ,HOMEOSTASIS ,OSTEOPONTIN ,THERAPEUTICS - Abstract
To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E
2 (PGE2 ) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
110. Fatal disseminated Scedosporium inflatum infection in a neutropenic immunocompromised patient
- Author
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Farag, Sherif S., primary, Firkin, Frank C., additional, Andrew, John H., additional, Soon Lee, C., additional, and Ellis, David H., additional
- Published
- 1992
- Full Text
- View/download PDF
111. Increased mobilization and yield of stem cells using plerixafor in combination with granulocytecolony stimulating factor for the treatment of non-Hodgkin's lymphoma and multiple myeloma.
- Author
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Pelus, Louis M. and Farag, Sherif S.
- Published
- 2011
- Full Text
- View/download PDF
112. Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma.
- Author
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Xiaojing Wang, Sinn, Anthony L., Pollok, Karen, Sandusky, George, Shuhong Zhang, Li Chen, Jing Liang, Crean, Colin D., Suvannasankha, Attaya, Abonour, Rafat, Sidor, Carolyn, Bray, Mark R., and Farag, Sherif S.
- Subjects
MULTIPLE myeloma ,PROTEIN-tyrosine kinases ,CELL-mediated cytotoxicity ,LABORATORY mice ,TUMOR growth - Abstract
ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24–48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G
2 /M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM. [ABSTRACT FROM AUTHOR]- Published
- 2010
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- View/download PDF
113. Blood progenitor cell separation from clinical leukapheresis product by magnetic nanoparticle binding and magnetophoresis.
- Author
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Jing, Ying, Moore, Lee R., Williams, P. Stephen, Chalmers, Jeffrey J., Farag, Sherif S., Bolwell, Brian, and Zborowski, Maciej
- Published
- 2007
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- View/download PDF
114. THE AUTHOR REPLIES.
- Author
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Farag, Sherif S.
- Subjects
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MEDICAL societies , *INFLAMMATORY bowel diseases , *GLUCAGON-like peptide 1 , *GASTROINTESTINAL diseases , *CORD blood - Published
- 2021
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- View/download PDF
115. Effect of family cohesion on symptom distress during hematopoietic stem cell transplantation.
- Author
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Yang, Yesol, Pan, Wei, Farag, Sherif S., and Von Ah, Diane
- Subjects
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HEMATOPOIETIC stem cell transplantation , *COHESION , *SYMPTOMS , *FAMILY roles , *QUALITY of life , *RESEARCH funding , *FAMILY relations - Abstract
Purpose: Family may play an important role in hematopoietic stem cell transplantation (HSCT) recovery; however, little is known about the effect of family functioning on an individual's health. The purpose of this study was to examine the effect of family cohesion (family functioning) on the trajectory of HSCT recipients' symptom distress (symptom frequency and symptom bother) before, during, and after HSCT.Methods: Secondary analysis was conducted using data collected from178 individuals who underwent HSCT. Longitudinal parallel process (LPP) modeling was used to examine how family cohesion and HSCT-associated symptoms (symptom frequency and symptom bother) change over time, and how these longitudinal changes relate to each other.Results: The trajectory of family cohesion predicted the trajectories of HSCT-associated symptom frequency and bother. HSCT recipients who experienced higher family cohesion at baseline (T1) showed lower symptom frequency (p < .01) as well as symptom bother (p < .01) at T1. This trajectory analysis also showed that HSCT recipients who had improved family cohesion over time reported decrease in symptom frequency (p < .01) as well as bother (p < .01) over time.Conclusion: Findings indicate that higher family cohesion predicts decrease in symptom distress over the HSCT trajectory. Interventions aimed at enhancing family cohesion have the potential to lower HSCT recipients' symptom distress. Further research is needed to understand the critical role of family cohesion and family functioning and their relationship with HSCT symptom distress prevention, early detection, and risk stratification. [ABSTRACT FROM AUTHOR]- Published
- 2022
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116. FCGR3Aand FCGR2Apolymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia
- Author
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Lin, Thomas S., Flinn, Ian W., Modali, Rama, Lehman, Teresa A., Webb, Jennifer, Waymer, Sharon, Moran, Mollie E., Lucas, Margaret S., Farag, Sherif S., and Byrd, John C.
- Abstract
The in vivo mechanism of action of alemtuzumab (anti-CD52; Campath-1H) remains unclear. With rituximab, FCGR3Aand FCGR2Ahigh-affinity polymorphisms have been associated with clinical response in lymphoma but not in CLL, suggesting potential divergent mechanisms of action between these 2 diseases. Herein, we examined FCGR3A(V/V, n = 4; V/F, n = 10; F/F, n = 19) and FCGR2A(A/A, n = 5; H/A, n = 22; H/H, n = 6) polymorphisms in 36 patients with relapsed CLL who were treated with thrice-weekly alemtuzumab for 12 weeks to assess the potential influence these high-affinity FcγR receptor polymorphisms had on response to alemtuzumab. Response to alemtuzumab was similar regardless of FCGR3Apolymorphism (V/V, 25%; V/F, 40%; F/F, 32%) or FCGR2Apolymorphism (A/A, 40%; H/A, 32%; H/H, 33%). These findings indicate that FCGR3Aand FCGR2Apolymorphisms may not predict response to alemtuzumab in CLL. Future studies examining larger cohorts of alemtuzumab-treated patients with CLL will be required to definitively determine the predictive value of specific FCGRpolymorphisms to treatment response. (Blood. 2005;105:289-291)
- Published
- 2005
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- View/download PDF
117. Depletion of alloreactive T cells: which cell?
- Author
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Farag, Sherif S.
- Published
- 2004
- Full Text
- View/download PDF
118. The Novel Aurora Kinase Inhibitor ENMD-2076 Has Potent Single Agent Activity against Multiple Myeloma (MM) in Vitroand in Vivo, and Shows Synergistic Activity in Combination with Lenalidomide
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Wang, Xiaojing, Sinn, Anthony L., Suvannasankha, Attaya, Crean, Colin D., Chen, Li, Zhang, Shuhong, Liang, Jing, Zhang, Genglin, Pollok, Karen E., Abonour, Rafat, Sidor, Carolyn, Bray, Mark R., and Farag, Sherif S.
- Abstract
ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against Aurora A kinase as well as multiple receptor tyrosine kinases (RTK). We investigated the single agent activity of ENMD-2076 against MM cells in vitroand in vivo, and in combination with lenalidomide. ENMD-2076 free base showed significant cytotoxicity against MM cells with a mean LC50of 3.84±0.86 μM at 48 hours in vitro. Cytotoxicity was associated with cleavage of caspase 3, 8, 9 and PARP, and loss of mitochondrial membrane potential as early as 6 hours. ENMD-2076 free base inhibited c-kit, FGFR-1, 3 and VEGFR1 and subsequently inhibition of downstream targets phosphorylated (p)-BAD, p-Foxo1a and p-GSK-3β was observed at 6 hours. NOD/SCID mice implanted with H929 human plasmacytoma xenografts and treated for 30 days with 50, 100, 200mg/kg/d ENMD-2076 showed a dose-dependent inhibition of tumor growth (Figure 1), with minimal toxicity as assessed by the stable weight of treated animals. Immunohistochemical staining of tumors from sacrificed animals showed significant reduction in Ki67 at all dose levels of treatment compared to control tumors. An increase in cleaved caspase-3 was observed on Western blot from the lysates of H929 tumors obtained from treated animals. ENMD-2076 free base also showed synergistic cytotoxic activity when combined with lenalidomide against H929, MM1.R and MM1.S cells as assessed by MTT assay and Annexin-V/PI staining. Using the Chou-Talalay method, the combination indices (CI) were < 1 for all three cell lines across a range of concentrations of ENMD-2076 free base (0.25–1.0 μM) plus lenalidomide (2.5–10 μM) indicating synergistic activity (CI=0.362 H929; CI=0.315 MM1.R; CI=0.415 MM1.S). Our results provide rationale for the investigation of ENMD-2076 alone and in combination with lenalidomide in patients with multiple myeloma.
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- 2008
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119. OSU-HDAC42, a Novel Histone Deacetylase Inhibitor, Induces Apoptosis in a Caspase-Dependent Manner and Induces p21WAF1/CIP1and p16 Expression in Multiple Myeloma Cell Lines.
- Author
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White, Valerie L., Zhang, Shuhong, Lucas, David, Chen, Ching-Shih, and Farag, Sherif S.
- Abstract
Multiple myeloma (MM) is a neoplastic disorder characterized by accumulation of slowly-proliferating clonal plasma cells. OSU-HDAC42 [a.k.a. (S)-HDAC-42] is a novel histone deacetylase inhibitor that induces apoptosis in various types of cancer cells and is being developed as an anti-cancer therapy in the NCI Rapid Access to Intervention Therapy (RAID) program. In this study, we tested the in vitroactivity of OSU-HDAC42 against human MM cells.
- Published
- 2006
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120. Meloxicam with Filgrastim may Reduce Oxidative Stress in Hematopoietic Progenitor Cells during Mobilization of Autologous Peripheral Blood Stem Cells in Patients with Multiple Myeloma.
- Author
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Patterson, Andrea M., Zhang, Shuhong, Liu, Liqiong, Li, Hongge, Singh, Pratibha, Liu, Yunlong, Farag, Sherif S., and Pelus, Louis M.
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- *
PROGENITOR cells , *STEM cells , *BLOOD cells , *MULTIPLE myeloma , *OXIDATIVE stress - Abstract
Autologous stem cell transplantation (ASCT) is a potentially curative therapy but requires collection of sufficient blood stem cells (PBSC). Up to 40 % of patients with multiple myeloma (MM) fail to collect an optimum number of PBSC using filgrastim only and often require costly plerixafor rescue. The nonsteroidal anti-inflammatory drug meloxicam mobilizes PBSC in mice, nonhuman primates and normal volunteers, and has the potential to attenuate mobilization-induced oxidative stress on stem cells. In a single-center study, we evaluated whether a meloxicam regimen prior to filgrastim increases collection and/or homeostasis of CD34+ cells in MM patients undergoing ASCT. Mobilization was not significantly different with meloxicam in this study; a median of 2.4 × 106 CD34+ cells/kg were collected in the first apheresis and 9.2 × 106 CD34+ cells/kg were collected overall for patients mobilized with meloxicam-filgrastim, versus 4.1 × 106 in first apheresis and 7.2 × 106/kg overall for patients mobilized with filgrastim alone. CXCR4 expression was reduced on CD34+ cells and a higher CD4+/CD8+ T-cell ratio was observed after mobilization with meloxicam-filgrastim. All patients treated with meloxicam-filgrastim underwent ASCT, with neutrophil and platelet engraftment similar to filgrastim alone. RNA sequencing of purified CD34+ cells from 22 MM patients mobilized with meloxicam-filgrastim and 10 patients mobilized with filgrastim only identified > 4,800 differentially expressed genes (FDR < 0.05). Enrichment analysis indicated significant attenuation of oxidative phosphorylation and translational activity, possibly mediated by SIRT1, suggesting meloxicam may counteract oxidative stress during PBSC collection. Our results indicate that meloxicam was a safe, low-cost supplement to filgrastim mobilization, which appeared to mitigate HSPC oxidative stress, and may represent a simple means to lessen stem cell exhaustion and enhance graft quality. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
121. The Brain: Is it a Next Frontier to Better Understand the Regulation and Control of Hematopoiesis for Future Modulation and Treatment?
- Author
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Broxmeyer, Hal E., Yoder, Karmen K., Wu, Yu-Chien, Hutchins, Gary D., Cooper, Scott H., and Farag, Sherif S.
- Subjects
- *
HEMATOPOIESIS , *BONE marrow , *HEMATOPOIETIC stem cells - Abstract
We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
122. Pretransplant HLA typing revealed loss of heterozygosity in the major histocompatibility complex in a patient with acute myeloid leukemia.
- Author
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Lobashevsky, Andrew L., Krueger-Sersen, Mary, Britton, Rebecca M., Littrell, Courtney A., Singh, Susmita, Cui, Connie P., Kashi, Zahra, Martin, Russ K., Breman, Amy M., Vance, Gail H., and Farag, Sherif S.
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- *
ACUTE myeloid leukemia , *MAJOR histocompatibility complex - Abstract
Abstract Introduction Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. Purpose of the study In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. Materials and methods HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. Results Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. Conclusions LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
123. Low CD34+ Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors.
- Author
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Albany, Costantine, Hyder, Mustafa A., Schwartz, Jennifer E., Robertson, Michael J., Farag, Sherif S., Ervin, Kirsten D., Goebel, W. Scott, and Thakrar, Teresa C.
- Subjects
- *
STEM cell transplantation , *CD34 antigen , *HEALTH outcome assessment , *MEDICAL care costs , *GERM cell tumors , *CANCER relapse - Abstract
Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34 + cell doses > 5.0 × 10 6 /kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 10 6 CD34 + cells/kg is challenging. We analyzed the effect of CD34 + cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34 + dose per transplant was 3.1 × 10 6 /kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 × 10 6 /kg; Q2, 2.0 to 2.9 × 10 6 /kg; Q3, 3.0 to 4.1 × 10 6 /kg; and Q4, 4.2 to 16.0 × 10 6 /kg. For all patients higher CD34 + cell doses were associated with significantly shorter times to neutrophil ( P < .001) and platelet recovery ( P < .001). For inpatient transplants higher CD34 + doses were significantly associated with shorter length of hospital stay ( P < .001), fewer days of filgrastim ( P < .001), i.v. antibiotic ( P = .012) and antifungal ( P = .03) usage; and fewer RBC ( P = .001) and platelet units transfused ( P < .001), resulting in overall lower cost of care ( P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34 + cell dose quartiles, a significant trend was observed for shorter hospitalization ( P = .01) and fewer RBC ( P = .002) and platelet ( P = .005) transfusions with higher CD34 + cell dose quartile. Patients receiving CD34 + cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34 + cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34 + cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
124. Differential stem- and progenitor-cell trafficking by prostaglandin E2 .
- Author
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Hoggatt, Jonathan, Mohammad, Khalid S., Singh, Pratibha, Hoggatt, Amber F., Chitteti, Brahmananda R., Speth, Jennifer M., Hu, Peirong, Poteat, Bradley A., Stilger, Kayla N., Ferraro, Francesca, Silberstein, Lev, Wong, Frankie K., Farag, Sherif S., Czader, Magdalena, Milne, Ginger L., Breyer, Richard M., Serezani, Carlos H., Scadden, David T., Guise, Theresa A., and Srour, Edward F.
- Subjects
- *
PROGENITOR cells , *STEM cells , *BLOOD cells , *HEMATOPOIETIC stem cells , *HOMEOSTASIS , *OSTEOPONTIN , *THERAPEUTICS - Abstract
To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
125. A phase 2 trial of CD24Fc for prevention of graft-versus-host disease.
- Author
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Magenau J, Jaglowski S, Uberti J, Farag SS, Riwes MM, Pawarode A, Anand S, Ghosh M, Maciejewski J, Braun T, Devenport M, Lu S, Banerjee B, DaSilva C, Devine S, Zhang MJ, Burns LJ, Liu Y, Zheng P, and Reddy P
- Subjects
- Adult, Humans, Methotrexate therapeutic use, Transplantation, Homologous, Neoplasm Recurrence, Local drug therapy, Transplantation Conditioning adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematologic Neoplasms
- Abstract
Abstract: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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126. Efficacy, safety, and cost of mobilization strategies in multiple myeloma: a prospective, observational study.
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Dhakal B, Zhang MJ, Burns LJ, Tang X, Meyer C, Mau LW, Nooka AK, Stadtmauer E, Micallef IN, McGuirk J, Costa L, Juckett MB, Shah N, Champlin RE, Usmani SZ, Farag SS, Nishihori T, Roy V, Bodiford A, Barnes YJ, Drea EJ, Hari P, and Hamadani M
- Subjects
- Humans, Prospective Studies, Hematopoietic Stem Cell Mobilization, Granulocyte Colony-Stimulating Factor, Benzylamines, Transplantation, Autologous, Multiple Myeloma therapy, Hematopoietic Stem Cell Transplantation, Heterocyclic Compounds
- Published
- 2023
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127. Age is no barrier for adults undergoing HCT for AML in CR1: contemporary CIBMTR analysis.
- Author
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Maakaron JE, Zhang MJ, Chen K, Abhyankar S, Bhatt VR, Chhabra S, El Jurdi N, Farag SS, He F, Juckett M, de Lima M, Majhail N, van der Poel M, Saad A, Savani B, Ustun C, Waller EK, Litzow M, Kebriaei P, Hourigan CS, Saber W, and Weisdorf D
- Subjects
- Adult, Aged, Humans, Middle Aged, Neoplasm, Residual, Receptors, Complement 3b therapeutic use, Recurrence, Retrospective Studies, Transplantation Conditioning adverse effects, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute
- Abstract
Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007-2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60-64; 65-69; 70+). With median follow-up of nearly 3 years, patients aged 60-64 had modestly, though significantly better OS, DFS and lower TRM than those either 65-69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p = 0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥3. Conditioning intensity was not a significant predictor of OS in the 60-69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p = 0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
128. Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia.
- Author
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Perna F, Espinoza-Gutarra MR, Bombaci G, Farag SS, and Schwartz JE
- Subjects
- Humans, Immunotherapy methods, Immunotherapy, Adoptive, T-Lymphocytes, Hematopoietic Stem Cell Transplantation methods, Immunoconjugates therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology
- Abstract
Acute myeloid leukemia (AML) is an aggressive, clonally heterogeneous, myeloid malignancy, with a 5-year overall survival of approximately 27%. It constitutes the most common acute leukemia in adults, with an incidence of 3-5 cases per 100,000 in the United States. Despite great advances in understanding the molecular mechanisms underpinning leukemogenesis, the past several decades had seen little change to the backbone of therapy, comprised of an anthracycline-based induction regimen for those who are fit enough to receive it, followed by risk-stratified post-remission therapy with consolidation cytarabine or allogeneic stem cell transplantation (allo-SCT). Allo-SCT is the most fundamental form of immunotherapy in which donor cytotoxic T and NK cells recognize and eradicate residual AML in the graft-versus-leukemia (GvL) effect. Building on that, several alternative or synergistic approaches to exploit both self and foreign immunity against AML have been developed. Checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors block proteins found on T cells or cancer cells that stop the immune system from attacking the cancer cells. They have been used with limited success in both the AML relapsed/refractory (R/R) and post SCT settings. AML tumor mutational burden is low compared to solid tumors and thus, it is less likely to generate neoantigens and respond to antibody-mediated checkpoint blockade that has shown unprecedented results in solid tumors. Therefore, alternative therapeutic strategies that work independently of the T cell receptor (TCR) specificity have been developed. They include bispecific antibodies, which recruit T cells through CD3 engagement, and in AML have shown an overall response rate ranging between 14 and 30% in early phase trials. Chimeric Antigen Receptor (CAR) T cell therapy is a type of treatment in which T cells are genetically engineered to produce a recombinant receptor that redirects the specificity and function of T lymphocytes. However, lack of cell surface targets exclusively expressed on AML cells including Leukemic Stem Cells (LSCs) combined with clonal heterogeneity represents the biggest challenge in developing CAR therapy for AML. Antibody-Drug Conjugates (ADC) constitute the only FDA-approved immunotherapy to treat AML with Gemtuzumab Ozogamicin, a CD33-specific ADC used in CEBPα-mutated AML. The identification of additional cell surface targets is critical for the development of other ADC's potentially useful in the induction and maintenance regimens, given the ease at which these reagents can be generated and managed. Here, we will review those immune-based therapeutic interventions and highlight active areas of research investigations toward fulfillment of the great promise of immunotherapy to AML., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
- Published
- 2022
- Full Text
- View/download PDF
129. Sitagliptin for Prophylaxis of Acute Graft-versus-Host Disease. Reply.
- Author
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Farag SS
- Subjects
- Humans, Sitagliptin Phosphate therapeutic use, Transplantation Conditioning, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects
- Published
- 2021
- Full Text
- View/download PDF
130. Effect of Sirolimus levels between days 11 and 20 after allogeneic stem cell transplantation on the risk of hepatic sinusoidal obstruction syndrome.
- Author
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Agrawal V, Ranganath P, Ervin KD, Schmidt CA, Cox EA, Nelson RP Jr, Schwartz JE, Zaid MA, Abonour R, Robertson MJ, Brinda BJ, Griffin SP, Thakrar TC, and Farag SS
- Subjects
- Humans, Sirolimus adverse effects, Transplantation Conditioning adverse effects, Transplantation, Homologous, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Hepatic Veno-Occlusive Disease etiology
- Abstract
Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12-58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21-30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57-8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.
- Published
- 2021
- Full Text
- View/download PDF
131. Low CD34 + Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors.
- Author
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Hyder MA, Goebel WS, Ervin KD, Schwartz JE, Robertson MJ, Thakrar TC, Albany C, and Farag SS
- Subjects
- Adolescent, Adult, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal genetics, Neoplasms, Germ Cell and Embryonal pathology, Recurrence, Transplantation, Autologous methods, Young Adult, Antigens, CD34 metabolism, Hematopoietic Stem Cell Transplantation economics, Neoplasms, Germ Cell and Embryonal economics, Neoplasms, Germ Cell and Embryonal therapy, Transplantation, Autologous economics
- Abstract
Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34
+ cell doses > 5.0 × 106 /kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 × 106 /kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 × 106 /kg; Q2, 2.0 to 2.9 × 106 /kg; Q3, 3.0 to 4.1 × 106 /kg; and Q4, 4.2 to 16.0 × 106 /kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P <.001) and platelet recovery (P <.001). For inpatient transplants higher CD34+ doses were significantly associated with shorter length of hospital stay (P <.001), fewer days of filgrastim (P <.001), i.v. antibiotic (P = .012) and antifungal (P = .03) usage; and fewer RBC (P = .001) and platelet units transfused (P <.001), resulting in overall lower cost of care (P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34+ cell dose quartiles, a significant trend was observed for shorter hospitalization (P = .01) and fewer RBC (P = .002) and platelet (P = .005) transfusions with higher CD34+ cell dose quartile. Patients receiving CD34+ cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34+ cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34+ cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
132. The potential role of PD0332991 (Palbociclib) in the treatment of multiple myeloma.
- Author
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Altenburg JD and Farag SS
- Subjects
- Animals, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclin-Dependent Kinases metabolism, Humans, Multiple Myeloma pathology, Piperazines adverse effects, Piperazines pharmacology, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyridines adverse effects, Pyridines pharmacology, Signal Transduction drug effects, Antineoplastic Agents therapeutic use, Multiple Myeloma drug therapy, Piperazines therapeutic use, Pyridines therapeutic use
- Abstract
Introduction: Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991 (Palbociclib) is an orally bioavailable, highly selective inhibitor of the CDK4/6-cyclin complex and downstream retinoblastoma protein (Rb) activation pathway that induces cell cycle arrest in the G1 phase., Areas Covered: In this review, the authors summarize the role of the CDK4/6 signaling pathway in MM. They also summarize the development of PD0332991 as a specific inhibitor of CDK4/6, and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM., Expert Opinion: While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM.
- Published
- 2015
- Full Text
- View/download PDF
133. Increased mobilization and yield of stem cells using plerixafor in combination with granulocyte-colony stimulating factor for the treatment of non-Hodgkin's lymphoma and multiple myeloma.
- Author
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Pelus LM and Farag SS
- Abstract
Multiple myeloma and non-Hodgkin's lymphoma remain the most common indications for high-dose chemotherapy and autologous peripheral blood stem cell rescue. While a CD34+ cell dose of 1 × 10(6)/kg is considered the minimum required for engraftment, higher CD34+ doses correlate with improved outcome. Numerous studies, however, support targeting a minimum CD34+ cell dose of 2.0 × 10(6)/kg, and an "optimal" dose of 4 to 6 × 10(6)/kg for a single transplant. Unfortunately, up to 40% of patients fail to mobilize an optimal CD34+ cell dose using myeloid growth factors alone. Plerixafor is a novel reversible inhibitor of CXCR4 that significantly increases the mobilization and collection of higher numbers of hematopoietic progenitor cells. Two randomized multi-center clinical trials in patients with non-Hodgkin's lymphoma and multiple myeloma have demonstrated that the addition of plerixafor to granulocyte-colony stimulating factor increases the mobilization and yield of CD34+ cells in fewer apheresis days, which results in durable engraftment. This review summarizes the pharmacology and evidence for the clinical efficacy of plerixafor in mobilizing hematopoietic stem and progenitor cells, and discusses potential ways to utilize plerixafor in a cost-effective manner in patients with these diseases.
- Published
- 2011
- Full Text
- View/download PDF
134. Immunotherapeutic strategies of stem cell transplant in lymphoma.
- Author
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Farag SS
- Subjects
- Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Murine-Derived, Humans, Immunologic Factors pharmacology, Immunotherapy methods, Rituximab, Antibodies, Monoclonal therapeutic use, Immunologic Factors therapeutic use, Killer Cells, Natural drug effects, Lymphoma drug therapy, Stem Cell Transplantation methods
- Published
- 2004
135. Prognostic significance of additional cytogenetic abnormalities in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha: a Cancer and Leukemia Group B study.
- Author
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Farag SS, Ruppert AS, Mrózek K, Carroll AJ, Pettenati MJ, Le Beau MM, Peterson BL, Powell BL, Ozer H, Silver RT, Larson RA, and Bloomfield CD
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Karyotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Prognosis, Survival Analysis, Time Factors, Interferon-alpha therapeutic use, Interferon-gamma therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Secondary cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) have been associated with an inferior outcome in reported series of largely chemotherapy-treated patients. To date, no study has specifically focused on the prognostic significance of secondary karyotypic abnormalities, detected at the time of diagnosis, in interferon (IFN)-alpha treated patients. We compared the outcome of 29 newly diagnosed Ph+ CML patients with additional abnormalities to that of 234 sole Ph+ patients, treated on CALGB protocols with IFN-alpha alone or together with IFN-gamma or low-dose cytarabine. Complete and partial cytogenetic responses were achieved in 20 and 19% of sole Ph+ patients, compared to 23 and 18%, respectively, of patients with additional abnormalities (P=1.00). None of 4 patients with 'high-risk' secondary abnormalities [+8, +Ph and i(17)(q10)], for whom follow-up cytogenetic samples were available, achieved a cytogenetic response. With a median follow-up of 11.3 years, the median overall survival (OS) was 6.0 years for sole Ph+ patients compared to 7.5 years for patients with additional abnormalities (P=0.70), with corresponding 8-year OS of 36 and 38%, respectively. On multivariable analysis, only age (P<0.001) and white blood cell count (P=0.02) were associated with outcome. We conclude that, with the possible exception of +8, +Ph and i(17)(q10), additional chromosomal abnormalities at diagnosis are not associated with inferior outcome in Ph+ CML patients treated with IFN-alpha-based therapy.
- Published
- 2004
136. Cytokine modulation of the innate immune system in the treatment of leukemia and lymphoma.
- Author
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Farag SS and Caligiuri MA
- Subjects
- Cytokines administration & dosage, Cytokines immunology, Humans, Cytokines therapeutic use, Immunity, Innate immunology, Immunotherapy, Leukemia immunology, Leukemia therapy, Lymphoma immunology, Lymphoma therapy
- Published
- 2004
- Full Text
- View/download PDF
137. Isolated trisomy of chromosomes 8, 11, 13 and 21 is an adverse prognostic factor in adults with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B 8461.
- Author
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Farag SS, Archer KJ, Mrózek K, Vardiman JW, Carroll AJ, Pettenati MJ, Moore JO, Kolitz JE, Mayer RJ, Stone RM, Larson RA, and Bloomfield CD
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cytarabine therapeutic use, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Prognosis, Survival Rate, Treatment Outcome, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Leukemia, Myeloid, Acute genetics, Trisomy
- Abstract
Isolated trisomy is a relatively common cytogenetic abnormality in acute myeloid leukemia (AML), but with uncertain prognostic significance. We studied a large cohort of newly diagnosed de novo AML patients karyotyped on CALGB 8461 from 1984-1999, where trisomy was the sole abnormality. The common isolated trisomies (IT(C)), +8, +11, +13 and +21, comprised 90% of all sole trisomies. The outcome of 101 IT(C) patients was compared to that of 976 with normal and "poor risk" cytogenetics. The overall survival (OS) for IT(C) patients was unsatisfactory with 10% [95% confidence interval (CI), 3-17%] alive at 5 years. Repeated cycles of I/HDAC intensification did not improve outcome. However, SCT significantly improved relapse-free survival (RFS). Among IT(C) patients <60 years in first remission, only 1 of 7 receiving SCT relapsed, compared to 16 of 19 patients treated with chemotherapy only. The prognosis of IT(C) was dependent on SCT. For non-transplanted patients, the 5-year OS for IT(C) was 5% (95% CI, 0-11%), compared to 20% (95% CI, 16-23%) for 640 normal cytogenetics patients. IT(C) was an independent adverse prognostic factor for OS in non-transplanted patients. In those receiving SCT, however, the 5-year OS for IT(C) patients (69%, 95% CI, 32-100%) was not different to that of transplanted normal cytogenetics patients (60%, 95% CI, 38-81%). We conclude that in de novo adult AML patients not receiving SCT, IT(C) appears to independently predict a poor outcome that may be improved with SCT in first remission. Prospective studies are required to confirm this hypothesis.
- Published
- 2002
138. Postremission therapy with low-dose interleukin 2 with or without intermediate pulse dose interleukin 2 therapy is well tolerated in elderly patients with acute myeloid leukemia: Cancer and Leukemia Group B study 9420.
- Author
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Farag SS, George SL, Lee EJ, Baer M, Dodge RK, Becknell B, Fehniger TA, Silverman LR, Crawford J, Bloomfield CD, Larson RA, Schiffer CA, and Caligiuri MA
- Subjects
- Acute Disease, Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Cyclosporins administration & dosage, Cytarabine administration & dosage, Daunorubicin administration & dosage, Disease-Free Survival, Drug Administration Schedule, Etoposide administration & dosage, Fatigue chemically induced, Gene Expression Regulation, Neoplastic drug effects, Hematologic Diseases chemically induced, Humans, Immunologic Factors administration & dosage, Immunologic Factors adverse effects, Interleukin-2 administration & dosage, Interleukin-2 adverse effects, Killer Cells, Natural drug effects, Leukemia, Myeloid metabolism, Leukemia, Myeloid mortality, Life Tables, Middle Aged, NK Cell Lectin-Like Receptor Subfamily K, Nausea chemically induced, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Receptors, Immunologic drug effects, Receptors, Natural Killer Cell, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins adverse effects, Recombinant Fusion Proteins therapeutic use, Remission Induction, Survival Analysis, Treatment Outcome, Immunologic Factors therapeutic use, Interleukin-2 therapeutic use, Leukemia, Myeloid drug therapy
- Abstract
Purpose: The purpose of the study is to investigate the tolerability of interleukin 2 (IL-2) after intensive chemotherapy in elderly acute myeloid leukemia (AML) patients in first complete remission (CR)., Experimental Design: AML patients > or =60 years in CR after induction and consolidation chemotherapy on Cancer and Leukemia Group B study 9420 were eligible if they had neutrophils > or =1 x 10(9)/liters and platelets > or =75 x 10(9)/liters. Patients received low-dose IL-2 (1 x 10(6) IU/m(2)/day s.c. for 90 days) or low-dose IL-2 with intermediate pulse doses (6-12 x 10(6) IU/m(2)/day s.c. for 3 days) every 14 days (maximum five pulses). In a subset of patients, we investigated the expression of NKG2D ligands by leukemic cells because they are likely important mediators of natural killer cytotoxicity., Results: Of 35 CR patients receiving IL-2, 34 were evaluable for toxicity. Median age was 67 (range, 60-76) years. Thirteen of 16 patients receiving low-dose IL-2 completed the planned therapy, and 11 of 18 who also received intermediate pulse dose IL-2 therapy completed all five pulses. The spectrum of toxicity in both groups was similar, with predominantly grade 1-2 fatigue, fever, injection site reactions, nausea, anemia, and thrombocytopenia. Grade 3-4 hematological and nonhematological toxicity were more frequent in patients also receiving intermediate pulse dose IL-2 therapy. Grade 3-4 fatigue and hematological toxicity, although uncommon, were the major causes for discontinuing or attenuating therapy. In 8 cases, mRNA for one or more NKG2D ligands was detected in leukemic cells obtained at diagnosis before treatment., Conclusions: Low-dose IL-2, with or without intermediate pulse dose therapy, given immediately after chemotherapy in first CR to elderly AML patients is well tolerated. Expression of NKG2D ligands by leukemic cells was detected in the majority of cases tested and should be assessed for correlation with response to IL-2 in future studies.
- Published
- 2002
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